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Long COVID

2021-02-28T08:11:53Z

FatigueTrackerBot:.

[[File:Long-COVID.jpg|alt=Long COVID logo with Coronavirus icon |thumb]]
'''Long COVID''', '''long covid''', '''post-acute COVID-19''' and '''ongoing COVID''' are terms used to describe a group of long term health problems that are found in a significant minority of people who developed [[COVID-19]] and remain ill a number of weeks or months later.<ref name="Navabi2020">{{Cite journal|title=Long covid: How to define it and how to manage it|last=Nabavi|first=Nikki|url=https://www.bmj.com/content/370/bmj.m3489|date=Sep 7, 2020|journal=BMJ|volume=370|pages=bmj.m3489}}</ref><ref name="BMJ11Aug2020" /><ref name="long-haulers-redefining">{{Cite news|url=https://www.theatlantic.com/health/archive/2020/08/long-haulers-covid-19-recognition-support-groups-symptoms/615382/|title=Long-Haulers Are Redefining COVID-19|last=Yong|first=Ed|date=Aug 19, 2020|work=The Atlantic|access-date=2020-08-21|archive-url=|archive-date=|dead-url=|issn=1072-7825|quote=|author-link=}}</ref><ref name="NIHR.ac.uk15Oct2020">{{Cite web|url=https://www.nihr.ac.uk/news/living-with-covid-nihr-publishes-dynamic-themed-review-into-ongoing-covid/25891|title=Living with COVID: NIHR publishes dynamic themed review into ‘ongoing COVID’|last=National Institute for Health Research|first=|authorlink=|date=|website=www.nihr.ac.uk|archive-url=|archive-date=|dead-url=|access-date=2020-10-15}}</ref>

In February 2020, the World Health Organization stated that the expected recovery time from [[COVID-19]] was 2 weeks for mild cases, and between three and six weeks for severe cases;<ref name="WHOFeb2020">{{Cite web|url=https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---24-february-2020|title=WHO Director-General's opening remarks at the media briefing on COVID-19|last=World Health Organization|first=|authorlink=World Health Organization|date=Feb 24, 2020|website=www.who.int|language=en|archive-url=|archive-date=|dead-url=|access-date=2020-09-24}}</ref> follow-up studies then identified a significant number of COVID-19 patients had remained ill much longer than this: those with long COVID.<ref name="Navabi2020" /><ref name="BMJ11Aug2020" />

A similar phenomenon to long COVID occurred after the 2003 outbreak of the similar SARS coronavirus, which lead to a [[Severe acute respiratory syndrome#post-SARS|post-SARS syndrome]] being proposed that included chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep. Another study found a subgroup SARS survivors developed [[chronic fatigue syndrome]] immediately after SARS.<ref name="Moldofsky2011">{{Cite journal|last=Moldofsky|first=Harvey|last2=Patcai|first2=John|date=2011-03-24|title=Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study|url=https://doi.org/10.1186/1471-2377-11-37|journal=BMC Neurology|volume=11|issue=1|pages=37|doi=10.1186/1471-2377-11-37|issn=1471-2377|pmc=PMC3071317|pmid=21435231}}</ref>
<ref name="Lam2009">{{Cite journal|last=Lam|first=Marco Ho-Bun|last2=Wing|first2=Yun-Kwok|last3=Yu|first3=Mandy Wai-Man|last4=Leung|first4=Chi-Ming|last5=Ma|first5=Ronald C. W.|last6=Kong|first6=Alice P. S.|last7=So|first7=W. Y.|last8=Fong|first8=Samson Yat-Yuk|last9=Lam|first9=Siu-Ping|date=2009-12-14|title=Mental Morbidities and Chronic Fatigue in Severe Acute Respiratory Syndrome Survivors: Long-term Follow-up|url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/415378|journal=Archives of Internal Medicine|language=en|volume=169|issue=22|pages=2142–2147|doi=10.1001/archinternmed.2009.384|issn=0003-9926}}</ref>

==Long-haulers==
A "long-hauler" is someone with long COVID, meaning someone who became ill with confirmed or suspected [[COVID-19]], who has remained ill with long-term symptoms many weeks or months later after first becoming ill.<ref name="long-haulers-redefining" /><ref name="BMJ1Oct2020">{{Cite web|url=https://blogs.bmj.com/bmj/2020/10/01/why-we-need-to-keep-using-the-patient-made-term-long-covid/|title=Why we need to keep using the patient made term “Long Covid”|date=2020-10-01|website=The BMJ|language=en-US|access-date=2020-10-11}}</ref>

==What is long COVID==
[[File:Long-COVID-1in10.jpg|alt=Long COVID poster - 1 in 10 people with COVID-19 may develop long COVID|thumb]]
Long COVID appears to be a multisystem disease, and may occur after any severity of COVID-19, including after relatively mild cases.<ref name="BMJ11Aug2020" /><ref name="BMJ1Oct2020" />

=== Four different syndromes ===
A recent review suggested that long COVID may actually be four different syndromes:
* [[Post-COVID-19 illness#pics|Post-Intensive Care Syndrome]]
* [[Postviral fatigue syndrome|Postviral Fatigue Syndrome]] (ME/CFS)
* Long Term COVID Syndrome
* Permanent organ damage
Patients with long COVID may have several syndromes at once.<ref name="NIHR15Oct2020" />

=== Signs and symptoms ===
Patient surveys have reported that the following symptoms commonly occur in long COVID.
*[[Fatigue]], which may be extreme (profound)
*[[myalgia|Muscle pain]] or body aches
*[[dyspnea|Breathlessness]]
*[[Concentration problems]]
*Inability to [[exercise]]/[[exercise intolerance]]
*[[Headache]]
*[[Insomnia]] or [[sleep dysfunction|problems sleeping]]
*Heavy chest, a feeling of pressure on the chest, or chest pain
Other reported symptoms include:
*[[Anxiety]]
*[[Paresis|Muscle weakness]]
*[[Memory problems]]
*Skin rashes
*[[Sore throat]] and difficulty swallowing
*[[Heart palpitation]]s
*[[Fever]]
*[[Diarrhea]]
*[[Dizziness]]
*The sensation of [[pins and needles]]
*Cough
*[[Low-grade fever]]
*Loss of sense of taste and smell
*[[Joint pain]]
*New onset diabetes<ref name="Rubino2020">{{Cite journal|last=Rubino|first=Francesco|last2=Amiel|first2=Stephanie A.|last3=Zimmet|first3=Paul|last4=Alberti|first4=George|last5=Bornstein|first5=Stefan|last6=Eckel|first6=Robert H.|last7=Mingrone|first7=Geltrude|last8=Boehm|first8=Bernhard|last9=Cooper|first9=Mark E.|date=2020-08-20|title=New-Onset Diabetes in Covid-19|url=https://doi.org/10.1056/NEJMc2018688|journal=New England Journal of Medicine|volume=383|issue=8|pages=789–790|doi=10.1056/NEJMc2018688|issn=0028-4793|pmc=PMC7304415|pmid=32530585}}</ref>
*New onset [[Hypertension|high blood pressure]]<ref name="Lambert25Jul2020" /><ref name="Navabi2020" /><ref name="NHSlongSep2020">{{Cite web|url=https://www.gov.uk/government/publications/covid-19-long-term-health-effects/covid-19-long-term-health-effects|title=COVID-19 Long Term Health Effects|last=National Health Service|first=|authorlink=National Health Service|last2=|first2=|authorlink2=|date=Sep 7, 2020|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref name="Yellin2020" />

{{Quote box|“A very common feature is the relapsing, remitting nature of the illness, where you feel as though you’ve recovered, then it hits you back|source=Dr. Nisreen Alwan, BMJ, Sep 2020}}

== COVID-19 testing ==
While some people with long COVID did have a positive test result for COVID-19, others were denied tests due to the limited availability of tests at the time, or they tested negative but were found to have clear evidence of COVID-19 from blood count tests or chest X-rays.<ref name="NIHR15Oct2020">{{Cite web|url=https://evidence.nihr.ac.uk/themedreview/living-with-covid19|title=Living with covid-19. A dynamic review of the evidence around ongoing covid-19 symptoms (often called long covid).|last=NIHR|first=|authorlink=|last2=|first2=|authorlink2=|date=October 2020|website=evidence.nihr.ac.uk|language=en-GB|archive-url=|archive-date=|dead-url=|access-date=2020-10-15}}</ref><ref name="Kingstone2020" /> Some people with Long COVID have described never having a cough or fever at the start of their illness, but developed these symptoms later. Long COVID diagnosis does not depend on a previous positive test.<ref name="NIHR15Oct2020" /><ref name="Kingstone2020" />

==Evidence of symptoms ==

There is no blood test or diagnostic biomarker to identify patients with long COVID. A study in the UK found that just over 10% of long COVID patients had abnormal findings on the standard tests and did not find an association between standard test results and degree of organ damage or long COVID severity.<ref name="Dennis2020" /> The same study used MRI scans combined with patient questionnaires to assess organ damage, finding that multi-organ impairment was common in people with long COVID, despite the fact that 80% had not been hospitalized for [[COVID-19]], the average patient age was forty-four years old, and rates of pre-existing conditions were also low.<ref name="Dennis2020" />

==Research ==
Surveys of data collected and published by long haulers using social media were the first evidence of what symptoms and health problems were caused by long COVID.<ref name="bodypoliticMay2020" /> Later academic studies confirmed many of the initial long hauler survey findings, although many only involved patients discharged from hospital,<ref name="Puntmann2020" /> patients who had been able to access early testing and tested positive, or patients who had sought medical care in a particular location.<ref name="Arnold2020b" /> People with mild COVID-19 symptoms, leaving people denied testing and those who may have had false negative test results and people who tested positive but were asymptomatic underrepresented in long COVID research.<ref name="bodypoliticMay2020" />

==Treatment==

===Pacing===
Pacing is a method of activity management which aims to adapt everday activities in order to avoid relapses or increased symptoms.
{{See also|Pacing}}

===Exercise therapy ===
ME/CFS patient groups have raised concerns about the use of [[graded exercise therapy]] (GET) in long COVID patients and a similar warning has been issued by [[NICE]] in the [[United Kingdom|UK]].<ref name="GETcovidForwardME" /> Graded exercise therapy, which is sometimes incorrectly referred to as "activity management" involves patients initially reducing their activity levels to a level that prevents regular crashes, and then typically increasing activity by 10% each week regardless of any increased symptoms or worsening illness. In graded exercise patients are told to ignore deterioration or increased symptoms and "push through" them.

====Theory and evidence ====
In graded exercise therapy patients are told that their symptoms are caused only by [[deconditioning|inactivity]] and other "bad habits" rather than an underlying illness. These assumptions have very weak evidence, and significant evidence exists of underlying illness in ME/CFS; there is a lack of research about exercise therapy for long COVID illness<ref name="Navabi2020" /> but some symptoms are inconsistent with this "deconditioning" assumption and some research has found physical abnormalities in some patients weeks or month after infection. Surveys of ME/CFS patients have consistently shown that large numbers of patients deteriorate as a result of graded exercise therapy, and a significant number become severely ill and never return to the level of functioning they had before the treatment.

==ME/CFS==
[[Postviral fatigue syndrome]] is one of the previous names used for Myalgic Encephalomyelitis (ME), sometimes known as Chronic Fatigue Syndrome (CFS), and it commonly begins immediately after events such as a virus, bacterial or other infection.<ref name="ICC2011primer">{{citation
| last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers
| last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande
| last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick
| last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell
| last7 = Staines | first7 = D | authorlink7 = Donald Staines
| last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles
| last9 = Speight | first9 = N | authorlink9 = Nigel Speight
| last10 = Vallings | first10= R | authorlink10= Rosamund Vallings
| last11 = Bateman | first11= L | authorlink11= Lucinda Bateman
| last12 = Bell | first12= DS | authorlink12= David Bell
| last13 = Carlo-Stella | first13= N | authorlink13= Nicoletta Carlo-Stella
| last14 = Chia | first14= J | authorlink14= John Chia
| last15 = Darragh | first15= A | authorlink15= Austin Darragh
| last16 = Gerken | first16= A | authorlink16= Anne Gerken
| last17 = Jo | first17= D | authorlink17= Daehyun Jo
| last18 = Lewis | first18= DP | authorlink18= Donald Lewis
| last19 = Light | first19= AR | authorlink19= Alan Light
| last20 = Light | first20= KC | authorlink20= Kathleen Light
| last21 = Marshall-Gradisnik | first21= S | authorlink21= Sonya Marshall-Gradisnik
| last22 = McLaren-Howard | first22= J | authorlink22= John McLaren-Howard| last23 = Mena | first23= I | authorlink23= Ismael Mena
| last24 = Miwa | first24= K | authorlink24= Kunihisa Miwa
| last25 = Murovska | first25= M | authorlink25= Modra Murovska
| last26 = Stevens | first26= SR | authorlink26= Staci Stevens
| title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners
| date = 2012| isbn = 978-0-9739335-3-6| url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf
}}</ref> ME/CFS is not normally diagnosed until symptoms have persisted for six months or more, and tests must be run to exclude other possible causes of the symptoms.<ref name="SEID2015">{{Citation|last=Institute of Medicine|author-link=Institute of Medicine|title=Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness|location=Washington, DC|publisher=The National Academies Press|date=2015|url=https://www.ncbi.nlm.nih.gov/books/NBK284902/}}</ref> Some contagious diseases including [[Epstein-Barr virus]], certain [[enterovirus]]es,<ref name="ICC2011primer" /> and the [[Severe acute respiratory syndrome|SARS]] virus,<ref name="Moldofsky2011" /> have caused outbreaks of ME/CFS. It is not yet known how likely it is for ME/CFS to begin immediately after COVID-19 illness, although around 10% people with certain viruses are known to develop ME/CFS, and according to [[the BMJ]] around 10% of people with COVID-19 have developed prolonged illness.<ref name="BMJ11Aug2020" />

==Patient surveys ==
'''Not peer reviewed'''
* May 2020, [https://docs.google.com/document/u/0/d/1KmLkOArlJem-PArnBMbSp-S_E3OozD47UzvRG4qM5Yk/mobilebasic What Does COVID-19 Recovery Actually Look Like? An Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team]<ref name="bodypoliticMay2020">{{Cite web|url=https://docs.google.com/document/u/0/d/1KmLkOArlJem-PArnBMbSp-S_E3OozD47UzvRG4qM5Yk/mobilebasic|title=What Does COVID-19 Recovery Actually Look Like? An Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team|date=May 11, 2020|vauthors=Assaf G, Davis H, McCorkell L, Wei H, O'Neil B, Akrami A, Low R, Mercier J, A A, L T, C A, S M, N L, H N, D JD, S}}</ref> - by Body Politic
::Data collected: Apr 21 - May 2 2020. Respondents: 640

* Jul 2020, [https://static1.squarespace.com/static/5e8b5f63562c031c16e36a93/t/5f459ef7798e8b6037fa6c57/1598398215120/2020+Survivor+Corps+COVID-19+%27Long+Hauler%27+Symptoms+Survey+Report+%28revised+July+25.4%29.pdf COVID-19 “Long Hauler” Symptoms Survey Report]<ref name="Lambert25Jul2020">{{Cite web|url=https://static1.squarespace.com/static/5e8b5f63562c031c16e36a93/t/5f459ef7798e8b6037fa6c57/1598398215120/2020+Survivor+Corps+COVID-19+%27Long+Hauler%27+Symptoms+Survey+Report+%28revised+July+25.4%29.pdf|title=COVID-19 “Long Hauler” Symptoms Survey Report|last=Lambert|first=Natalie J|author-link=Natalie Lambert|last2=Survivor Corps|author-link2=Survivor Corps|publisher=Indiana University School of Medicine|date=Jul 2020}}</ref> - with Survivor Corps
::Data collected: Jul 25, 2020. Respondents: 1,567+

==Notable studies==
*Jul 24, 2020, Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)<ref name="Puntmann2020">{{Cite journal|last=Puntmann|first=Valentina O.|last2=Carerj|first2=M. Ludovica|last3=Wieters|first3=Imke|last4=Fahim|first4=Masia|last5=Arendt|first5=Christophe|last6=Hoffmann|first6=Jedrzej|last7=Shchendrygina|first7=Anastasia|last8=Escher|first8=Felicitas|last9=Vasa-Nicotera|first9=Mariuca|date=2020-07-27|title=Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)|url=https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916|journal=JAMA Cardiology|language=en|doi=10.1001/jamacardio.2020.3557|issn=2380-6583}}</ref> [https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916 (Full text)]
*Aug 11, 2020, Management of post-acute covid-19 in primary care<ref name="BMJ11Aug2020">{{cite journal|title=Management of post-acute covid-19 in primary care|last=Greenhalgh|first=Trisha|first2=Matthew|last2=Knight|first3 =Christine|last3=A'Court|first4=Maria|last4=Buxton|first5= Laiba|last5=Husain|journal=BMJ|date=Aug 11, 2020|volume=370|doi=10.1136/bmj.m3026|pages=m3026|url =https://doi.org/10.1136/bmj.m3026}}</ref> - [https://doi.org/10.1136/bmj.m3026 (Full text)]
* Aug 14, 2020 (pre-print), Patient outcomes after hospitalisation with COVID-19 and implications for follow-up; results from a prospective UK cohort<ref name="Arnold2020b">{{Cite journal|last=Arnold|first=David T.|author-link=David Arnold|last2=Hamilton|first2=Fergus W.|author-link2=|last3=Milne|first3=Alice|author-link3=|last4=Morley|first4=Anna|author-link4=|last5=Viner|first5=Jason|author-link5=|last6=Attwood|first6=Marie|author-link6=|last7=Noel|first7=Alan|last8=Gunning|first8=Samuel|last9=Hatrick|first9=Jessica|date=2020-08-14|title=Patient outcomes after hospitalisation with COVID-19 and implications for follow-up; results from a prospective UK cohort.|url=https://www.medrxiv.org/content/10.1101/2020.08.12.20173526v1|journal=medRxiv|language=en|volume=|issue=|pages=2020.08.12.20173526|doi=10.1101/2020.08.12.20173526|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.medrxiv.org/content/10.1101/2020.08.12.20173526v1 (Full text)] - from the DISCOVER project
* Aug 20, 2020, New-Onset Diabetes in Covid-19<ref name="Rubino2020" /> - [https://www.nejm.org/doi/full/10.1056/NEJMc2018688 (Full text)]
* Oct 1, 2020, Long-term consequences of COVID-19: research needs<ref name="Yellin2020">{{Cite journal|last=Yelin|first=Dana|last2=Wirtheim|first2=Eytan|last3=Vetter|first3=Pauline|last4=Kalil|first4=Andre C.|last5=Bruchfeld|first5=Judith|last6=Runold|first6=Michael|last7=Guaraldi|first7=Giovanni|last8=Mussini|first8=Cristina|last9=Gudiol|first9=Carlota|date=2020-10-01|title=Long-term consequences of COVID-19: research needs|url=https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30701-5/abstract|journal=The Lancet Infectious Diseases|language=English|volume=20|issue=10|pages=1115–1117|doi=10.1016/S1473-3099(20)30701-5|issn=1473-3099|pmid=32888409}}</ref> - [https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30701-5/fulltext (Full text)]
* Oct 14, 2020, Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID<ref name="Kingstone2020">{{Cite journal|last=Kingstone|first=Tom|author-link=|last2=Taylor|first2=Anna K.|author-link2=|last3=O'Donnell|first3=Catherine A.|author-link3=|last4=Atherton|first4=Helen|author-link4=|last5=Blane|first5=David N.|author-link5=|last6=Chew-Graham|first6=Carolyn A.|author-link6=Carolyn Chew-Graham|date=2020-10-14|title=Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID|url=https://bjgpopen.org/content/early/2020/10/12/bjgpopen20X101143|journal=BJGP Open|language=en|volume=|issue=|pages=|doi=10.3399/bjgpopen20X101143|issn=2398-3795|pmc=|pmid=33051223|access-date=|quote=|via=}}</ref> - [https://bjgpopen.org/content/bjgpoa/early/2020/10/12/bjgpopen20X101143.full.pdf (Full text)]
*Oct 16, 2020, Multi-organ impairment in low-risk individuals with long COVID<ref name="Dennis2020">{{Cite journal|last=Dennis|first=Andrea|author-link=|last2=Wamil|first2=Malgorzata|author-link2=|last3=Kapur|first3=Sandeep|author-link3=|last4=Alberts|first4=Johann|author-link4=|last5=Badley|first5=Andrew D.|author-link5=|last6=Decker|first6=Gustav Anton|author-link6=|last7=Rizza|first7=Stacey A.|last8=Banerjee|first8=Rajarshi|last9=Banerjee|first9=Amitava|author-link9=Amitava Banerjee|date=2020-10-16|title=Multi-organ impairment in low-risk individuals with long COVID|url=https://www.medrxiv.org/content/10.1101/2020.10.14.20212555v1|journal=medRxiv|language=en|volume=|issue=|pages=2020.10.14.20212555|doi=10.1101/2020.10.14.20212555|pmc=|pmid=|access-date=|quote=|via=}}</ref> -[https://doi.org/10.1101/2020.10.14.20212555 (Full text)]
*Oct 21, 2020, Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App<ref name="Sudre2020a">{{Cite journal|last=Sudre|first=Carole H.|author-link=|last2=Murray|first2=Benjamin|author-link2=|last3=Varsavsky|first3=Thomas|author-link3=|last4=Graham|first4=Mark S.|author-link4=|last5=Penfold|first5=Rose S.|author-link5=|last6=Bowyer|first6=Ruth C.|author-link6=|last7=Pujol|first7=Joan Capdevila|last8=Klaser|first8=Kerstin|last9=Antonelli|first9=Michela|date=2020-10-19|others=|title=Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App|url=https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1|journal=medRxiv|language=en|volume=|issue=|pages=2020.10.19.20214494|doi=10.1101/2020.10.19.20214494|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1.full-text (Full text)]

==Presentations, interviews and videos==
*Aug 2020, [https://solvecfs.org/wp-content/uploads/2020/08/Post-COVID%20ME-to%20Solve.pdf Will Covid-19 lead to ME/CFS in some people?] - presentation - Dr [[Anthony Komaroff]]
*Jul 2020, [https://www.youtube.com/watch?v=IIeOoS_A4c8 Message in a Bottle] video - LongCovidSOS
*Jun 2020, [https://www.biomax.com/lib/press-releases/Initial-Result-Announcment_English.pdf Health of Corona Patients at Home in Alarmingly Poor Health Even After Several Months - Dutch Lung Foundation] - Press release (English translation) - [https://www.ad.nl/binnenland/longfonds-gezondheid-thuiszittende-coronapatienten-schrikbarend-slecht~a45346fe/ Dutch]

==Letters and blogs==
*May 2020, [http://somatosphere.net/2020/mild-covid.html/ Very, very mild: Covid-19 symptoms and illness classification] - [[Fiona Callard]]
*Jul 2020, [https://meassociation.org.uk/wp-content/uploads/ForwardME-Letter-re-Covid-19-Management-and-Exercise-Caution-27.08.20.pdf Letter re Covid-19 Management and Exercise Caution]<ref name="GETcovidForwardME">{{Cite web|url=https://meassociation.org.uk/wp-content/uploads/ForwardME-Letter-re-Covid-19-Management-and-Exercise-Caution-27.08.20.pdf|date=2020-08-27|last=Forward-ME|author-link=Forward-ME|title =Letter re Covid-19 Management and Exercise Caution}}</ref> - [[Forward-ME]]
*Sep 2020, [https://mecfsresearchreview.me/2020/09/17/understanding-long-covid-a-shortcut-to-solving-me-cfs/?#symptoms Understanding Long Covid, A Shortcut to Solving ME/CFS?] - [[Simon McGrath]]
*Sep 2020, [https://wellcomeopenresearch.org/articles/5-224 Why the Patient-Made Term 'Long Covid' is needed] - Open Letter
*Oct 2020, [https://blogs.bmj.com/bmj/2020/10/01/why-we-need-to-keep-using-the-patient-made-term-long-covid/ Why we need to keep using the patient made term “Long Covid”] - [[The BMJ]]

==National and international health bodies==
*[https://doi.org/10.1136/bmj.m2912 NICE cautions against using graded exercise therapy for patients recovering from COVID-19]<ref name="NICEcautionBMJ">{{Cite journal|last=Torjesen|first=Ingrid|date=2020-07-21|title=NICE cautions against using graded exercise therapy for patients recovering from covid-19|url=https://www.bmj.com/content/370/bmj.m2912|journal=BMJ|language=en|volume=370|doi=10.1136/bmj.m2912|issn=1756-1833|pmid=32694164}}</ref>

==News articles ==
* Oct 2020, [https://www.theguardian.com/world/2020/oct/21/women-aged-50-60-at-greatest-risk-of-long-covid-experts-suggest Women aged 50-60 at greatest risk of ‘long Covid’, experts suggest] - The Guardian

* Oct 2020, [https://www.wsj.com/articles/these-doctors-have-long-term-covid-now-theyre-pushing-for-better-care-11603144474 These Doctors Have Long-Term Covid. Now They’re Pushing for Better Care.] - Wall Street Journal
* Oct 2020, [https://time.com/5897992/long-haul-coronavirus-me-cfs/ Have We Been Thinking About Long-Haul Coronavirus All Wrong?] - Time
* Oct 2020, [https://www.nihr.ac.uk/news/living-with-covid-nihr-publishes-dynamic-themed-review-into-ongoing-covid/25891 Living with COVID: NIHR publishes dynamic-themed review into 'ongoing COVID'] - National Institute of Health Research
* Oct 2020, [https://www.theguardian.com/world/2020/oct/04/long-covid-the-evidence-of-lingering-heart-damage Long Covid: the evidence of lingering heart damage] - The Observer
* Sep 2020, [https://www.bbc.co.uk/news/uk-england-leicestershire-54106073 Coronavirus patient unable to work six months on] - BBC News
* Aug 2020, [https://www.huffingtonpost.co.uk/entry/long-term-symptoms-of-covid-19-identified-in-study-of-hospital-patients_uk_5f2bc0f6c5b64d7a55eefcfa The Most Common Long-Term Symptoms Of Covid-19] - HuffPost UK
* Jul 2020, [https://www.sciencemag.org/news/2020/07/brain-fog-heart-damage-covid-19-s-lingering-problems-alarm-scientists From ‘brain fog’ to heart damage, COVID-19’s lingering problems alarm scientists] - Science Mag

==See also==
*[[List of famous people with long COVID]]
*[[List of open letters about long COVID]]
*[[Post-COVID-19 illness]]
*[[COVID-19]] coronavirus disease 19
*[[Myalgic encephalomyelitis|Myalgic encephalomyelitis and chronic fatigue syndrome]]
*[[Postviral fatigue syndrome]]
*[[Post-Ebola syndrome]]
*[[Encephalitis lethargica]]
*[[Paul Garner]]
*[[Nisreen Alwan]]

==Learn more==
*[https://www.gov.uk/government/publications/covid-19-long-term-health-effects/covid-19-long-term-health-effects COVID-19 Long Term Health Effects]
*[https://www.bmj.com/sites/default/files/infographics/1353078336/static-infographic/background.png Infographic: "Long covid" in primary care] - BMJ journal
* List of long COVID studies (draft) - [[MEAction|#MEAction]]

==References==
{{reflist}}

[[Category:Potential comorbidities]]
[[Category:Diagnoses]]

Long COVID

2021-02-28T08:09:29Z

FatigueTrackerBot:Added refs

[[File:Long-COVID.jpg|alt=Long COVID logo with Coronavirus icon |thumb]]
'''Long COVID''', '''long covid''', '''post-acute COVID-19''' and '''ongoing COVID''' are terms used to describe a group of long term health problems that are found in a significant minority of people who developed [[COVID-19]] and remain ill a number of weeks or months later.<ref name="Navabi2020">{{Cite journal|title=Long covid: How to define it and how to manage it|last=Nabavi|first=Nikki|url=https://www.bmj.com/content/370/bmj.m3489|date=Sep 7, 2020|journal=BMJ|volume=370|pages=bmj.m3489}}</ref><ref name="BMJ11Aug2020" /><ref name="long-haulers-redefining">{{Cite news|url=https://www.theatlantic.com/health/archive/2020/08/long-haulers-covid-19-recognition-support-groups-symptoms/615382/|title=Long-Haulers Are Redefining COVID-19|last=Yong|first=Ed|date=Aug 19, 2020|work=The Atlantic|access-date=2020-08-21|archive-url=|archive-date=|dead-url=|issn=1072-7825|quote=|author-link=}}</ref><ref name="NIHR.ac.uk15Oct2020">{{Cite web|url=https://www.nihr.ac.uk/news/living-with-covid-nihr-publishes-dynamic-themed-review-into-ongoing-covid/25891|title=Living with COVID: NIHR publishes dynamic themed review into ‘ongoing COVID’|last=National Institute for Health Research|first=|authorlink=|date=|website=www.nihr.ac.uk|archive-url=|archive-date=|dead-url=|access-date=2020-10-15}}</ref>

In February 2020, the World Health Organization stated that the expected recovery time from [[COVID-19]] was 2 weeks for mild cases, and between three and six weeks for severe cases;<ref name="WHOFeb2020">{{Cite web|url=https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---24-february-2020|title=WHO Director-General's opening remarks at the media briefing on COVID-19|last=World Health Organization|first=|authorlink=World Health Organization|date=Feb 24, 2020|website=www.who.int|language=en|archive-url=|archive-date=|dead-url=|access-date=2020-09-24}}</ref> follow-up studies then identified a significant number of COVID-19 patients had remained ill much longer than this: those with long COVID.<ref name="Navabi2020" /><ref name="BMJ11Aug2020" />

A similar phenomenon to long COVID occurred after the 2003 outbreak of the similar SARS coronavirus, which lead to a [[Severe acute respiratory syndrome#post-SARS|post-SARS syndrome]] being proposed that included chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep. Another study found a subgroup SARS survivors developed [[chronic fatigue syndrome]] immediately after SARS.<ref name="Moldofsky2011">{{Cite journal|last=Moldofsky|first=Harvey|last2=Patcai|first2=John|date=2011-03-24|title=Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study|url=https://doi.org/10.1186/1471-2377-11-37|journal=BMC Neurology|volume=11|issue=1|pages=37|doi=10.1186/1471-2377-11-37|issn=1471-2377|pmc=PMC3071317|pmid=21435231}}</ref>
<ref name="Lam2009">{{Cite journal|last=Lam|first=Marco Ho-Bun|last2=Wing|first2=Yun-Kwok|last3=Yu|first3=Mandy Wai-Man|last4=Leung|first4=Chi-Ming|last5=Ma|first5=Ronald C. W.|last6=Kong|first6=Alice P. S.|last7=So|first7=W. Y.|last8=Fong|first8=Samson Yat-Yuk|last9=Lam|first9=Siu-Ping|date=2009-12-14|title=Mental Morbidities and Chronic Fatigue in Severe Acute Respiratory Syndrome Survivors: Long-term Follow-up|url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/415378|journal=Archives of Internal Medicine|language=en|volume=169|issue=22|pages=2142–2147|doi=10.1001/archinternmed.2009.384|issn=0003-9926}}</ref>

==Long-haulers==
A "long-hauler" is someone with long COVID, meaning someone who became ill with confirmed or suspected [[COVID-19]], who has remained ill with long-term symptoms many weeks or months later after first becoming ill.<ref name="long-haulers-redefining" /><ref name="BMJ1Oct2020">{{Cite web|url=https://blogs.bmj.com/bmj/2020/10/01/why-we-need-to-keep-using-the-patient-made-term-long-covid/|title=Why we need to keep using the patient made term “Long Covid”|date=2020-10-01|website=The BMJ|language=en-US|access-date=2020-10-11}}</ref>

==What is long COVID==
[[File:Long-COVID-1in10.jpg|alt=Long COVID poster - 1 in 10 people with COVID-19 may develop long COVID|thumb]]
Long COVID appears to be a multisystem disease, and may occur after any severity of COVID-19, including after relatively mild cases.<ref name="BMJ11Aug2020" /><ref name="BMJ1Oct2020" />

=== Four different syndromes ===
A recent review suggested that long COVID may actually be four different syndromes:
* [[Post-COVID-19 illness#pics|Post-Intensive Care Syndrome]]
* [[Postviral fatigue syndrome|Postviral Fatigue Syndrome]] (ME/CFS)
* Long Term COVID Syndrome
* Permanent organ damage
Patients with long COVID may have several syndromes at once.<ref name="NIHR15Oct2020" />

=== Signs and symptoms ===
Patient surveys have reported that the following symptoms commonly occur in long COVID.
*[[Fatigue]], which may be extreme (profound)
*[[myalgia|Muscle pain]] or body aches
*[[dyspnea|Breathlessness]]
*[[Concentration problems]]
*Inability to [[exercise]]/[[exercise intolerance]]
*[[Headache]]
*[[Insomnia]] or [[sleep dysfunction|problems sleeping]]
*Heavy chest, a feeling of pressure on the chest, or chest pain
Other reported symptoms include:
*[[Anxiety]]
*[[Paresis|Muscle weakness]]
*[[Memory problems]]
*Skin rashes
*[[Sore throat]] and difficulty swallowing
*[[Heart palpitation]]s
*[[Fever]]
*[[Diarrhea]]
*[[Dizziness]]
*The sensation of [[pins and needles]]
*Cough
*[[Low-grade fever]]
*Loss of sense of taste and smell
*[[Joint pain]]
*New onset diabetes<ref name="Rubino2020">{{Cite journal|last=Rubino|first=Francesco|last2=Amiel|first2=Stephanie A.|last3=Zimmet|first3=Paul|last4=Alberti|first4=George|last5=Bornstein|first5=Stefan|last6=Eckel|first6=Robert H.|last7=Mingrone|first7=Geltrude|last8=Boehm|first8=Bernhard|last9=Cooper|first9=Mark E.|date=2020-08-20|title=New-Onset Diabetes in Covid-19|url=https://doi.org/10.1056/NEJMc2018688|journal=New England Journal of Medicine|volume=383|issue=8|pages=789–790|doi=10.1056/NEJMc2018688|issn=0028-4793|pmc=PMC7304415|pmid=32530585}}</ref>
*New onset [[Hypertension|high blood pressure]]<ref name="Lambert25Jul2020" /><ref name="Navabi2020" /><ref name="NHSlongSep2020">{{Cite web|url=https://www.gov.uk/government/publications/covid-19-long-term-health-effects/covid-19-long-term-health-effects|title=COVID-19 Long Term Health Effects|last=National Health Service|first=|authorlink=National Health Service|last2=|first2=|authorlink2=|date=Sep 7, 2020|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref name="Yellin2020" />

{{Quote box|“A very common feature is the relapsing, remitting nature of the illness, where you feel as though you’ve recovered, then it hits you back|source=Dr. Nisreen Alwan, BMJ, Sep 2020}}

== COVID-19 testing ==
While some people with long COVID did have a positive test result for COVID-19, others were denied tests due to the limited availability of tests at the time, or they tested negative but were found to have clear evidence of COVID-19 from blood count tests or chest X-rays.<ref name="NIHR15Oct2020">{{Cite web|url=https://evidence.nihr.ac.uk/themedreview/living-with-covid19|title=Living with covid-19. A dynamic review of the evidence around ongoing covid-19 symptoms (often called long covid).|last=NIHR|first=|authorlink=|last2=|first2=|authorlink2=|date=October 2020|website=evidence.nihr.ac.uk|language=en-GB|archive-url=|archive-date=|dead-url=|access-date=2020-10-15}}</ref><ref name="Kingstone2020" /> Some people with Long COVID have described never having a cough or fever at the start of their illness, but developed these symptoms later. Long COVID diagnosis does not depend on a previous positive test.<ref name="NIHR15Oct2020" /><ref name="Kingstone2020" />

==Evidence of symptoms ==

There is no blood test or diagnostic biomarker to identify patients with long COVID. A study in the UK found that just over 10% of long COVID patients had abnormal findings on the standard tests and did not find an association between standard test results and degree of organ damage or long COVID severity.<ref name="Dennis2020" /> The same study used MRI scans combined with patient questionnaires to assess organ damage, finding that multi-organ impairment was common in people with long COVID, despite the fact that 80% had not been hospitalized for [[COVID-19]], the average patient age was forty-four years old, and rates of pre-existing conditions were also low.<ref name="Dennis2020" />

==Research ==
Surveys of data collected and published by long haulers using social media were the first evidence of what symptoms and health problems were caused by long COVID.<ref name="bodypoliticMay2020" /> Later academic studies confirmed many of the initial long hauler survey findings, although many only involved patients discharged from hospital,<ref name="Puntmann2020" /> patients who had been able to access early testing and tested positive, or patients who had sought medical care in a particular location.<ref name="Arnold2020b" /> People with mild COVID-19 symptoms, leaving people denied testing and those who may have had false negative test results and people who tested positive but were asymptomatic underrepresented in long COVID research.<ref name="bodypoliticMay2020" />

==Treatment==

===Pacing===
Pacing is a method of activity management which aims to adapt everday activities in order to avoid relapses or increased symptoms.
{{See also|Pacing}}

===Exercise therapy ===
ME/CFS patient groups have raised concerns about the use of [[graded exercise therapy]] (GET) in long COVID patients and a similar warning has been issued by [[NICE]] in the [[United Kingdom|UK]].<ref name="GETcovidForwardME" /> Graded exercise therapy, which is sometimes incorrectly referred to as "activity management" involves patients initially reducing their activity levels to a level that prevents regular crashes, and then typically increasing activity by 10% each week regardless of any increased symptoms or worsening illness. In graded exercise patients are told to ignore deterioration or increased symptoms and "push through" them.

====Theory and evidence ====
In graded exercise therapy patients are told that their symptoms are caused only by [[deconditioning|inactivity]] and other "bad habits" rather than an underlying illness. These assumptions have very weak evidence, and significant evidence exists of underlying illness in ME/CFS; there is a lack of research about exercise therapy for long COVID illness<ref name="Navabi2020" /> but some symptoms are inconsistent with this "deconditioning" assumption and some research has found physical abnormalities in some patients weeks or month after infection. Surveys of ME/CFS patients have consistently shown that large numbers of patients deteriorate as a result of graded exercise therapy, and a significant number become severely ill and never return to the level of functioning they had before the treatment.

==ME/CFS==
[[Postviral fatigue syndrome]] is one of the previous names used for Myalgic Encephalomyelitis (ME), sometimes known as Chronic Fatigue Syndrome (CFS), and it commonly begins immediately after events such as a virus, bacterial or other infection.<ref name="ICC2011primer">{{citation
| last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers
| last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande
| last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick
| last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell
| last7 = Staines | first7 = D | authorlink7 = Donald Staines
| last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles
| last9 = Speight | first9 = N | authorlink9 = Nigel Speight
| last10 = Vallings | first10= R | authorlink10= Rosamund Vallings
| last11 = Bateman | first11= L | authorlink11= Lucinda Bateman
| last12 = Bell | first12= DS | authorlink12= David Bell
| last13 = Carlo-Stella | first13= N | authorlink13= Nicoletta Carlo-Stella
| last14 = Chia | first14= J | authorlink14= John Chia
| last15 = Darragh | first15= A | authorlink15= Austin Darragh
| last16 = Gerken | first16= A | authorlink16= Anne Gerken
| last17 = Jo | first17= D | authorlink17= Daehyun Jo
| last18 = Lewis | first18= DP | authorlink18= Donald Lewis
| last19 = Light | first19= AR | authorlink19= Alan Light
| last20 = Light | first20= KC | authorlink20= Kathleen Light
| last21 = Marshall-Gradisnik | first21= S | authorlink21= Sonya Marshall-Gradisnik
| last22 = McLaren-Howard | first22= J | authorlink22= John McLaren-Howard| last23 = Mena | first23= I | authorlink23= Ismael Mena
| last24 = Miwa | first24= K | authorlink24= Kunihisa Miwa
| last25 = Murovska | first25= M | authorlink25= Modra Murovska
| last26 = Stevens | first26= SR | authorlink26= Staci Stevens
| title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners
| date = 2012| isbn = 978-0-9739335-3-6| url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf
}}</ref> ME/CFS is not normally diagnosed until symptoms have persisted for six months or more, and tests must be run to exclude other possible causes of the symptoms.<ref name="SEID2015">{{Citation|last=Institute of Medicine|author-link=Institute of Medicine|title=Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness|location=Washington, DC|publisher=The National Academies Press|date=2015|url=https://www.ncbi.nlm.nih.gov/books/NBK284902/}}</ref> Some contagious diseases including [[Epstein-Barr virus]], certain [[enterovirus]]es,<ref name="ICC2011primer" /> and the [[Severe acute respiratory syndrome|SARS]] virus,<ref name="Moldofsky2011" /> have caused outbreaks of ME/CFS. It is not yet known how likely it is for ME/CFS to begin immediately after COVID-19 illness, although around 10% people with certain viruses are known to develop ME/CFS, and according to [[the BMJ]] around 10% of people with COVID-19 have developed prolonged illness.<ref name="BMJ11Aug2020" />

==Patient surveys ==
'''Not peer reviewed'''
* May 2020, [https://docs.google.com/document/u/0/d/1KmLkOArlJem-PArnBMbSp-S_E3OozD47UzvRG4qM5Yk/mobilebasic What Does COVID-19 Recovery Actually Look Like? An Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team]<ref name="bodypoliticMay2020">{{Cite web|url=https://docs.google.com/document/u/0/d/1KmLkOArlJem-PArnBMbSp-S_E3OozD47UzvRG4qM5Yk/mobilebasic|title=What Does COVID-19 Recovery Actually Look Like? An Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team|date=May 11, 2020|vauthors=Assaf G, Davis H, McCorkell L, Wei H, O'Neil B, Akrami A, Low R, Mercier J, A A, L T, C A, S M, N L, H N, D JD, S}}</ref> - by Body Politic
::Data collected: Apr 21 - May 2 2020. Respondents: 640

* Jul 2020, [https://static1.squarespace.com/static/5e8b5f63562c031c16e36a93/t/5f459ef7798e8b6037fa6c57/1598398215120/2020+Survivor+Corps+COVID-19+%27Long+Hauler%27+Symptoms+Survey+Report+%28revised+July+25.4%29.pdf COVID-19 “Long Hauler” Symptoms Survey Report]<ref name="Lambert25Jul2020">{{Cite web|url=https://static1.squarespace.com/static/5e8b5f63562c031c16e36a93/t/5f459ef7798e8b6037fa6c57/1598398215120/2020+Survivor+Corps+COVID-19+%27Long+Hauler%27+Symptoms+Survey+Report+%28revised+July+25.4%29.pdf|title=COVID-19 “Long Hauler” Symptoms Survey Report|last=Lambert|first=Natalie J|author-link=Natalie Lambert|last2=Survivor Corps|author-link2=Survivor Corps|publisher=Indiana University School of Medicine|date=Jul 2020}}</ref> - with Survivor Corps
::Data collected: Jul 25, 2020. Respondents: 1,567+

==Notable studies==
*Jul 24, 2020, Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)<ref name="Puntmann2020">{{Cite journal|last=Puntmann|first=Valentina O.|last2=Carerj|first2=M. Ludovica|last3=Wieters|first3=Imke|last4=Fahim|first4=Masia|last5=Arendt|first5=Christophe|last6=Hoffmann|first6=Jedrzej|last7=Shchendrygina|first7=Anastasia|last8=Escher|first8=Felicitas|last9=Vasa-Nicotera|first9=Mariuca|date=2020-07-27|title=Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)|url=https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916|journal=JAMA Cardiology|language=en|doi=10.1001/jamacardio.2020.3557|issn=2380-6583}}</ref> [https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916 (Full text)]
*Aug 11, 2020, Management of post-acute covid-19 in primary care<ref name="BMJ11Aug2020">{{cite journal|title=Management of post-acute covid-19 in primary care|last=Greenhalgh|first=Trisha|first2=Matthew|last2=Knight|first3 =Christine|last3=A'Court|first4=Maria|last4=Buxton|first5= Laiba|last5=Husain|journal=BMJ|date=Aug 11, 2020|volume=370|doi=10.1136/bmj.m3026|pages=m3026|url =https://doi.org/10.1136/bmj.m3026}}</ref> - [https://doi.org/10.1136/bmj.m3026 (Full text)]
* Aug 14, 2020 (pre-print), Patient outcomes after hospitalisation with COVID-19 and implications for follow-up; results from a prospective UK cohort<ref name="Arnold2020b">{{Cite journal|last=Arnold|first=David T.|author-link=David Arnold|last2=Hamilton|first2=Fergus W.|author-link2=|last3=Milne|first3=Alice|author-link3=|last4=Morley|first4=Anna|author-link4=|last5=Viner|first5=Jason|author-link5=|last6=Attwood|first6=Marie|author-link6=|last7=Noel|first7=Alan|last8=Gunning|first8=Samuel|last9=Hatrick|first9=Jessica|date=2020-08-14|title=Patient outcomes after hospitalisation with COVID-19 and implications for follow-up; results from a prospective UK cohort.|url=https://www.medrxiv.org/content/10.1101/2020.08.12.20173526v1|journal=medRxiv|language=en|volume=|issue=|pages=2020.08.12.20173526|doi=10.1101/2020.08.12.20173526|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.medrxiv.org/content/10.1101/2020.08.12.20173526v1 (Full text)] - from the DISCOVER project
* Aug 20, 2020, New-Onset Diabetes in Covid-19<ref name="Rubino2020" /> - [https://www.nejm.org/doi/full/10.1056/NEJMc2018688 (Full text)]
* Oct 1, 2020, Long-term consequences of COVID-19: research needs<ref name="Yellin2020">{{Cite journal|last=Yelin|first=Dana|last2=Wirtheim|first2=Eytan|last3=Vetter|first3=Pauline|last4=Kalil|first4=Andre C.|last5=Bruchfeld|first5=Judith|last6=Runold|first6=Michael|last7=Guaraldi|first7=Giovanni|last8=Mussini|first8=Cristina|last9=Gudiol|first9=Carlota|date=2020-10-01|title=Long-term consequences of COVID-19: research needs|url=https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30701-5/abstract|journal=The Lancet Infectious Diseases|language=English|volume=20|issue=10|pages=1115–1117|doi=10.1016/S1473-3099(20)30701-5|issn=1473-3099|pmid=32888409}}</ref> - [https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30701-5/fulltext (Full text)]
* Oct 14, 2020, Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID<ref name="Kingstone2020">{{Cite journal|last=Kingstone|first=Tom|author-link=|last2=Taylor|first2=Anna K.|author-link2=|last3=O'Donnell|first3=Catherine A.|author-link3=|last4=Atherton|first4=Helen|author-link4=|last5=Blane|first5=David N.|author-link5=|last6=Chew-Graham|first6=Carolyn A.|author-link6=Carolyn Chew-Graham|date=2020-10-14|title=Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID|url=https://bjgpopen.org/content/early/2020/10/12/bjgpopen20X101143|journal=BJGP Open|language=en|volume=|issue=|pages=|doi=10.3399/bjgpopen20X101143|issn=2398-3795|pmc=|pmid=33051223|access-date=|quote=|via=}}</ref> - [https://bjgpopen.org/content/bjgpoa/early/2020/10/12/bjgpopen20X101143.full.pdf (Full text)]
*Oct 16, 2020, Multi-organ impairment in low-risk individuals with long COVID<ref name="Dennis2020">{{Cite journal|last=Dennis|first=Andrea|author-link=|last2=Wamil|first2=Malgorzata|author-link2=|last3=Kapur|first3=Sandeep|author-link3=|last4=Alberts|first4=Johann|author-link4=|last5=Badley|first5=Andrew D.|author-link5=|last6=Decker|first6=Gustav Anton|author-link6=|last7=Rizza|first7=Stacey A.|last8=Banerjee|first8=Rajarshi|last9=Banerjee|first9=Amitava|author-link9=Amitava Banerjee|date=2020-10-16|title=Multi-organ impairment in low-risk individuals with long COVID|url=https://www.medrxiv.org/content/10.1101/2020.10.14.20212555v1|journal=medRxiv|language=en|volume=|issue=|pages=2020.10.14.20212555|doi=10.1101/2020.10.14.20212555|pmc=|pmid=|access-date=|quote=|via=}}</ref> -[https://doi.org/10.1101/2020.10.14.20212555 (Full text)]
*Oct 21, 2020, Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App<ref name="Sudre2020a">{{Cite journal|last=Sudre|first=Carole H.|author-link=|last2=Murray|first2=Benjamin|author-link2=|last3=Varsavsky|first3=Thomas|author-link3=|last4=Graham|first4=Mark S.|author-link4=|last5=Penfold|first5=Rose S.|author-link5=|last6=Bowyer|first6=Ruth C.|author-link6=|last7=Pujol|first7=Joan Capdevila|last8=Klaser|first8=Kerstin|last9=Antonelli|first9=Michela|date=2020-10-19|others=|title=Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App|url=https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1|journal=medRxiv|language=en|volume=|issue=|pages=2020.10.19.20214494|doi=10.1101/2020.10.19.20214494|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1.full-text (Full text)]

==Presentations, interviews and videos==
*Aug 2020, [https://solvecfs.org/wp-content/uploads/2020/08/Post-COVID%20ME-to%20Solve.pdf Will Covid-19 lead to ME/CFS in some people?] - presentation - Dr [[Anthony Komaroff]]
*Jul 2020, [https://www.youtube.com/watch?v=IIeOoS_A4c8 Message in a Bottle] video - LongCovidSOS
*Jun 2020, [https://www.biomax.com/lib/press-releases/Initial-Result-Announcment_English.pdf Health of Corona Patients at Home in Alarmingly Poor Health Even After Several Months - Dutch Lung Foundation] - Press release (English translation) - [https://www.ad.nl/binnenland/longfonds-gezondheid-thuiszittende-coronapatienten-schrikbarend-slecht~a45346fe/ Dutch]

==Letters and blogs==
*May 2020, [http://somatosphere.net/2020/mild-covid.html/ Very, very mild: Covid-19 symptoms and illness classification] - [[Fiona Callard]]
*Jul 2020, [https://meassociation.org.uk/wp-content/uploads/ForwardME-Letter-re-Covid-19-Management-and-Exercise-Caution-27.08.20.pdf Letter re Covid-19 Management and Exercise Caution]<ref name="GETcovidForwardME">{{Cite web|url=https://meassociation.org.uk/wp-content/uploads/ForwardME-Letter-re-Covid-19-Management-and-Exercise-Caution-27.08.20.pdf|date=2020-08-27|last=Forward-ME|author-link=Forward-ME|title =Letter re Covid-19 Management and Exercise Caution}}</ref> - [[Forward-ME]]
*Sep 2020, [https://mecfsresearchreview.me/2020/09/17/understanding-long-covid-a-shortcut-to-solving-me-cfs/?#symptoms Understanding Long Covid, A Shortcut to Solving ME/CFS?] - [[Simon McGrath]]
*Sep 2020, [https://wellcomeopenresearch.org/articles/5-224 Why the Patient-Made Term 'Long Covid' is needed] - Open Letter
*Oct 2020, [https://blogs.bmj.com/bmj/2020/10/01/why-we-need-to-keep-using-the-patient-made-term-long-covid/ Why we need to keep using the patient made term “Long Covid”] - [[The BMJ]]

==National and international health bodies==
*[https://doi.org/10.1136/bmj.m2912 NICE cautions against using graded exercise therapy for patients recovering from COVID-19]<ref name="NICEcautionBMJ">{{Cite journal|last=Torjesen|first=Ingrid|date=2020-07-21|title=NICE cautions against using graded exercise therapy for patients recovering from covid-19|url=https://www.bmj.com/content/370/bmj.m2912|journal=BMJ|language=en|volume=370|doi=10.1136/bmj.m2912|issn=1756-1833|pmid=32694164}}</ref>

==News articles ==
* Oct 2020, [https://www.theguardian.com/world/2020/oct/21/women-aged-50-60-at-greatest-risk-of-long-covid-experts-suggest Women aged 50-60 at greatest risk of ‘long Covid’, experts suggest] - The Guardian

* Oct 2020, [https://www.wsj.com/articles/these-doctors-have-long-term-covid-now-theyre-pushing-for-better-care-11603144474 These Doctors Have Long-Term Covid. Now They’re Pushing for Better Care.] - Wall Street Journal
* Oct 2020, [https://time.com/5897992/long-haul-coronavirus-me-cfs/ Have We Been Thinking About Long-Haul Coronavirus All Wrong?] - Time
* Oct 2020, [https://www.nihr.ac.uk/news/living-with-covid-nihr-publishes-dynamic-themed-review-into-ongoing-covid/25891 Living with COVID: NIHR publishes dynamic-themed review into 'ongoing COVID'] - National Institute of Health Research
* Oct 2020, [https://www.theguardian.com/world/2020/oct/04/long-covid-the-evidence-of-lingering-heart-damage Long Covid: the evidence of lingering heart damage] - The Observer
* Sep 2020, [https://www.bbc.co.uk/news/uk-england-leicestershire-54106073 Coronavirus patient unable to work six months on] - BBC News
* Aug 2020, [https://www.huffingtonpost.co.uk/entry/long-term-symptoms-of-covid-19-identified-in-study-of-hospital-patients_uk_5f2bc0f6c5b64d7a55eefcfa The Most Common Long-Term Symptoms Of Covid-19] - HuffPost UK
* Jul 2020, [https://www.sciencemag.org/news/2020/07/brain-fog-heart-damage-covid-19-s-lingering-problems-alarm-scientists From ‘brain fog’ to heart damage, COVID-19’s lingering problems alarm scientists] - Science Mag

==See also==
*[[List of famous people with long COVID]]
*[[List of open letters about long COVID]]
*[[Post-COVID-19 illness]]
*[[COVID-19]] coronavirus disease 19
*[[Myalgic encephalomyelitis|Myalgic encephalomyelitis and chronic fatigue syndrome]]
*[[Postviral fatigue syndrome]]
*[[Post-Ebola syndrome]]
*[[Long COVID]]
*[[Encephalitis lethargica]]
*[[Paul Garner]]
*[[Nisreen Alwan]]

==Learn more==
*[https://www.gov.uk/government/publications/covid-19-long-term-health-effects/covid-19-long-term-health-effects COVID-19 Long Term Health Effects]
*[https://www.bmj.com/sites/default/files/infographics/1353078336/static-infographic/background.png Infographic: "Long covid" in primary care] - BMJ journal
* List of long COVID studies (draft) - [[MEAction|#MEAction]]

==References==
{{reflist}}

[[Category:Potential comorbidities]]
[[Category:Diagnoses]]

Post-Ebola syndrome

2021-02-28T08:06:42Z

FatigueTrackerBot:.

'''Post-ebola syndrome''' is a chronic syndrome that can occur after an acute [[ebola virus]] infection in those who survive.

Julian Hiscox chair in infection and global health at the University of Liverpool in the United Kingdom said "We’ve seen a number of people [[Post-Ebola syndrome|post-Ebola]] who have something that is very similar to [[chronic fatigue syndrome]]."<ref>[http://www.theguardian.com/world/2015/oct/09/pauline-cafferkey-case-know-little-ebola-virus-long-term-effects Pauline Cafferkey case shows we still know little of Ebola's long-term effects]</ref>

A study of 82 [[Ebola]] survivors in Liberia found that nearly all had neurological problems six months or longer after they were infected.<ref>[http://www.scientificamerican.com/article/ebola-may-leave-survivors-with-lasting-problems-in-brain-nerves/ Ebola May Leave Survivors with Lasting Problems in Brain, Nerves], Scientific American, February 25, 2016
</ref>

Symptoms included tremors, sensory abnormalities, headaches, depressed mood, muscle pain and memory hallucinations, symptoms similar to that found in previous [[outbreaks]] of [[myalgic encephalomyelitis]].

Twenty people in the study experienced [[meningitis]] (inflammation of the tissue that surrounds the brain and spinal cord)

==Notable studies==
*2015, [https://www.ncbi.nlm.nih.gov/pubmed/26293407 Post-Ebolavirus disease syndrome: what do we know?]

==Learn more==
*2016, [http://www.wired.co.uk/news/archive/2016-02/25/post-ebola-syndrome Ebola's ghost: the mystery after the outbreak]
*2016, [http://www.scientificamerican.com/article/ebola-may-leave-survivors-with-lasting-problems-in-brain-nerves/?utm_source=twitterfeed&utm_medium=twitter Ebola May Leave Survivors with Lasting Problems in Brain, Nerves]
*2016, [http://www.bbc.co.uk/news/health-35652095 Ebola 'devastates long-term health']
*2015, [http://www.cortjohnson.org/blog/2015/09/07/post-ebolavirus-disease-syndrome-pevds-the-new-chronic-fatigue-syndrome-fibromyalgia-the-post-infectious-syndromes-pt-i/ Post Ebolavirus Disease Syndrome (PEVDS) – the new Chronic Fatigue Syndrome / Fibromyalgia? The Post-Infectious Syndromes Pt I]
*2015, [http://www.virology.ws/2015/06/18/long-term-effects-of-ebolavirus-infection/ Long-term effects of Ebolavirus infection]
*2015, [http://www.nytimes.com/2015/05/08/health/weeks-after-his-recovery-ebola-lurked-in-a-doctors-eye.html?hp&action=click&pgtype=Homepage&module=mini-moth&region=top-stories-below&WT.nav=top-stories-below&_r=0 After Nearly Claiming His Life, Ebola Lurked in a Doctor’s Eye]
*2015, [http://www.theguardian.com/world/2015/oct/09/pauline-cafferkey-case-know-little-ebola-virus-long-term-effects Pauline Cafferkey case shows we still know little of Ebola's long-term effects]
*[https://en.wikipedia.org/wiki/Post-Ebola_virus_syndrome Wikipedia - Post-Ebola virus syndrome]

==See also==
*[[Ebola virus]]
*[[Long COVID]]
*[[Encephalitis lethargica]]

==References==
<references>

</references>
[[Category:Diagnoses]]

Post-Ebola syndrome

2021-02-28T08:03:01Z

FatigueTrackerBot:Refs

'''Post-ebola syndrome''' is a chronic syndrome that can occur after an acute [[ebola virus]] infection in those who survive.

Julian Hiscox chair in infection and global health at the University of Liverpool in the United Kingdom said "We’ve seen a number of people [[Post-Ebola syndrome|post-Ebola]] who have something that is very similar to [[chronic fatigue syndrome]]."<ref>[http://www.theguardian.com/world/2015/oct/09/pauline-cafferkey-case-know-little-ebola-virus-long-term-effects Pauline Cafferkey case shows we still know little of Ebola's long-term effects]</ref>

A study of 82 [[Ebola]] survivors in Liberia found that nearly all had neurological problems six months or longer after they were infected.<ref>[http://www.scientificamerican.com/article/ebola-may-leave-survivors-with-lasting-problems-in-brain-nerves/ Ebola May Leave Survivors with Lasting Problems in Brain, Nerves], Scientific American, February 25, 2016
</ref>

Symptoms included tremors, sensory abnormalities, headaches, depressed mood, muscle pain and memory hallucinations, symptoms similar to that found in previous [[outbreaks]] of [[myalgic encephalomyelitis]].

Twenty people in the study experienced [[meningitis]] (inflammation of the tissue that surrounds the brain and spinal cord)

==Notable studies==
*2015, [https://www.ncbi.nlm.nih.gov/pubmed/26293407 Post-Ebolavirus disease syndrome: what do we know?]

==Learn more==
*2016, [http://www.wired.co.uk/news/archive/2016-02/25/post-ebola-syndrome Ebola's ghost: the mystery after the outbreak]
*2016, [http://www.scientificamerican.com/article/ebola-may-leave-survivors-with-lasting-problems-in-brain-nerves/?utm_source=twitterfeed&utm_medium=twitter Ebola May Leave Survivors with Lasting Problems in Brain, Nerves]
*2016, [http://www.bbc.co.uk/news/health-35652095 Ebola 'devastates long-term health']
*2015, [http://www.cortjohnson.org/blog/2015/09/07/post-ebolavirus-disease-syndrome-pevds-the-new-chronic-fatigue-syndrome-fibromyalgia-the-post-infectious-syndromes-pt-i/ Post Ebolavirus Disease Syndrome (PEVDS) – the new Chronic Fatigue Syndrome / Fibromyalgia? The Post-Infectious Syndromes Pt I]
*2015, [http://www.virology.ws/2015/06/18/long-term-effects-of-ebolavirus-infection/ Long-term effects of Ebolavirus infection]
*2015, [http://www.nytimes.com/2015/05/08/health/weeks-after-his-recovery-ebola-lurked-in-a-doctors-eye.html?hp&action=click&pgtype=Homepage&module=mini-moth&region=top-stories-below&WT.nav=top-stories-below&_r=0 After Nearly Claiming His Life, Ebola Lurked in a Doctor’s Eye]
*2015, [http://www.theguardian.com/world/2015/oct/09/pauline-cafferkey-case-know-little-ebola-virus-long-term-effects Pauline Cafferkey case shows we still know little of Ebola's long-term effects]
*[https://en.wikipedia.org/wiki/Post-Ebola_virus_syndrome Wikipedia - Post-Ebola virus syndrome]

==See also==
*[[Ebola virus]]
*[[Long COVID]]
*[[Encephalitis Lethargica]]

==References==
<references>

</references>
[[Category:Diagnoses]]

Encephalitis lethargica

2021-02-28T07:57:43Z

FatigueTrackerBot:Refs

'''Encephalitis Lethargica''' or EL is an infectious disease that was first described by Dr Constantin von Economo in April 1917, and is sometimes referred to as "von Economo's disease". He defined the following different forms of the disease: somnolent-ophthalmoplegic, hyperkinetic, and amyostatic-akinetic. He also described postencephalitic Parkinsonism. Symptoms can emerge years after the original infection. The disease was defined by the following neuropathologic findings: "inflammatory changes in the tegmentum of the midbrain accounting for the sleep disturbance and ocular signs". <ref name=":0">{{Cite journal|last=Dickman|first=M. S.|author-link=|author-link2=|author-link3=|author-link4=|author-link5=|date=Oct 2001|title=von Economo encephalitis|url=https://www.ncbi.nlm.nih.gov/pubmed/11594935|journal=[[Archives of Neurology]]|volume=58|issue=10|pages=1696–1698|issn=0003-9942|pmid=11594935|quote=|via=}}</ref>

The Encephalitis Lethargica disease occurred at the same time and following the aftermath of the infamous Spanish Flu. The film "Awakenings", from 1990, described some patients with this disease.

== Disease recognition ==
The [[International Classification of Diseases]] categorizes EL in the category A85.8 "Other specified viral encephalitis".<ref>{{Cite web|url=https://icd.who.int/browse10/2016/en#/A85.8|title=ICD-10 Version:2016 {{!}} A85.8|last=World Health Organization|first=|authorlink=World Health Organization|last2=|first2=|authorlink2=|date=|website=icd.who.int|archive-url=|archive-date=|dead-url=|access-date=2019-04-07}}</ref> Encephalitis Lethargica has become much rarer over time, with the last study being published in 2012.<ref name=":1">{{Cite journal|last=Vilensky|first=Joel A.|author-link=|last2=Hoffman|first2=Leslie A.|author-link2=|author-link3=|author-link4=|author-link5=|date=Aug 1, 2017|title=Encephalitis lethargica: 100 years after the epidemic|url=https://academic.oup.com/brain/article/140/8/2246/3970828|journal=Brain|language=en|volume=140|issue=8|pages=2246–2251|doi=10.1093/brain/awx177|issn=0006-8950|quote=|via=}}</ref>

==Notable studies==
*2001, ”von Economo encephalitis”<ref name=":0" />
*2017, Encephalitis lethargica: 100 years after the epidemic <ref name=":1" />

==See also==
*[[Immune system]]
*[[Post-Ebola syndrome]]
*[[Long COVID]]
*[[Influenza]]
*[[wikipedia:Spanish_flu|Spanish Flu]]
*[[Ebola virus]]

==Learn more==
*1925, [https://www.youtube.com/watch?v=5lNVtUlroZc YouTube: Acute Encephalitis Lethargica]
*1990, [https://www.imdb.com/title/tt0099077/ iMDB: Awakenings]
==References==
<references />
[[Category:Diagnoses]]
[[Category:Infectious diseases]]
[[Category:Viruses]]

Delayed onset muscle soreness

2020-10-11T22:40:36Z

FatigueTrackerBot:Added muscle repair process

'''Delayed onset muscle soreness (DOMS)''' refers to next day muscle soreness and is coming 24-48 hours after exercise. Peak soreness is at 48 - 72 h post-exercise. Athletes will experience DOMS after high intensity excercise work-outs. At low intensity exercise/work-outs the athlete will rarely experience soreness. Lay public believes [[lactate]] production is causing DOMS, but this is not correct. [[Lactate]] removal from muscles is rapid, typical 60-120 minutes after exercise. The cause of DOMS is microscopic injury to muscle fibres which leads to [[inflammation]].

The damage to muscle cells triggers an inflammatory response which involves neutrophils and macrophages. These cells removes the damaged muscle tissue and release enzymes. The muscle fibres are then repaired
== Notable studies ==

== Notable articles ==

* 2018, Advances in Delayed-Onset Muscle Soreness (DOMS): Part I: Pathogenesis and Diagnostics: Hotfiel, T., Freiwald, J., Hoppe, M. W., Lutter, C., Forst, R., Grim, C., Bloch, W., Hüttel, M., & Heiss, R. (2018). Advances in Delayed-Onset Muscle Soreness (DOMS): Part I: Pathogenesis and Diagnostics. Delayed Onset Muscle Soreness – Teil I: Pathogenese und Diagnostik. Sportverletzung Sportschaden : Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin, 32(4), 243–250. https://doi.org/10.1055/a-0753-1884 [https://pubmed.ncbi.nlm.nih.gov/30537791/]

* 2019, Advances in Delayed-Onset Muscle Soreness (DOMS) - Part II: Treatment and Prevention.: Heiss, R., Lutter, C., Freiwald, J., Hoppe, M. W., Grim, C., Poettgen, K., Forst, R., Bloch, W., Hüttel, M., & Hotfiel, T. (2019). Advances in Delayed-Onset Muscle Soreness (DOMS) - Part II: Treatment and Prevention. Delayed Onset Muscle Soreness – Teil II: Therapie und Prävention. Sportverletzung Sportschaden : Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin, 33(1), 21–29. https://doi.org/10.1055/a-0810-3516 [https://pubmed.ncbi.nlm.nih.gov/30865998/]

==Talks and interviews==

==See also==
*[[Exercise]]
*[[Lactate]]
*[[Inflammation]]
*[[Exertion]]
*[[Malaise]]
*[[Post-exertional malaise]]

==Learn more==

Delayed onset muscle soreness

2020-10-11T21:52:32Z

FatigueTrackerBot:.

'''Delayed onset muscle soreness (DOMS)''' refers to next day muscle soreness and is coming 24-48 hours after exercise. Peak soreness is at 48 - 72 h post-exercise. Athletes will experience DOMS after high intensity excercise work-outs. At low intensity exercise/work-outs the athlete will rarely experience soreness. Lay public believes [[lactate]] production is causing DOMS, but this is not correct. [[Lactate]] removal from muscles is rapid, typical 60-120 minutes after exercise. The cause of DOMS is microscopic injury to muscle fibres which leads to [[inflammation]].

== Notable studies ==

== Notable articles ==

* 2018, Advances in Delayed-Onset Muscle Soreness (DOMS): Part I: Pathogenesis and Diagnostics: Hotfiel, T., Freiwald, J., Hoppe, M. W., Lutter, C., Forst, R., Grim, C., Bloch, W., Hüttel, M., & Heiss, R. (2018). Advances in Delayed-Onset Muscle Soreness (DOMS): Part I: Pathogenesis and Diagnostics. Delayed Onset Muscle Soreness – Teil I: Pathogenese und Diagnostik. Sportverletzung Sportschaden : Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin, 32(4), 243–250. https://doi.org/10.1055/a-0753-1884 [https://pubmed.ncbi.nlm.nih.gov/30537791/]

* 2019, Advances in Delayed-Onset Muscle Soreness (DOMS) - Part II: Treatment and Prevention.: Heiss, R., Lutter, C., Freiwald, J., Hoppe, M. W., Grim, C., Poettgen, K., Forst, R., Bloch, W., Hüttel, M., & Hotfiel, T. (2019). Advances in Delayed-Onset Muscle Soreness (DOMS) - Part II: Treatment and Prevention. Delayed Onset Muscle Soreness – Teil II: Therapie und Prävention. Sportverletzung Sportschaden : Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin, 33(1), 21–29. https://doi.org/10.1055/a-0810-3516 [https://pubmed.ncbi.nlm.nih.gov/30865998/]

==Talks and interviews==

==See also==
*[[Exercise]]
*[[Lactate]]
*[[Inflammation]]
*[[Exertion]]
*[[Malaise]]
*[[Post-exertional malaise]]

==Learn more==

Delayed onset muscle soreness

2020-10-11T21:51:49Z

FatigueTrackerBot:Added notable work

'''Delayed onset muscle soreness (DOMS)''' refers to next day muscle soreness and is coming 24-48 hours after exercise. Peak soreness is at 48 - 72 h post-exercise. Athletes will experience DOMS after high intensity excercise work-outs. At low intensity exercise/work-outs the athlete will rarely experience soreness. Lay public believes [[lactate]] production is causing DOMS, but this is not correct. [[Lactate]] removal from muscles is rapid, typical 60-120 minutes after exercise. The cause of DOMS is microscopic injury to muscle fibres which leads to [[inflammation]].

==Notable studies==

== Notable articles ==

* 2018, Advances in Delayed-Onset Muscle Soreness (DOMS): Part I: Pathogenesis and Diagnostics: Hotfiel, T., Freiwald, J., Hoppe, M. W., Lutter, C., Forst, R., Grim, C., Bloch, W., Hüttel, M., & Heiss, R. (2018). Advances in Delayed-Onset Muscle Soreness (DOMS): Part I: Pathogenesis and Diagnostics. Delayed Onset Muscle Soreness – Teil I: Pathogenese und Diagnostik. Sportverletzung Sportschaden : Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin, 32(4), 243–250. https://doi.org/10.1055/a-0753-1884 [https://pubmed.ncbi.nlm.nih.gov/30537791/]

* 2019, Advances in Delayed-Onset Muscle Soreness (DOMS) - Part II: Treatment and Prevention.: Heiss, R., Lutter, C., Freiwald, J., Hoppe, M. W., Grim, C., Poettgen, K., Forst, R., Bloch, W., Hüttel, M., & Hotfiel, T. (2019). Advances in Delayed-Onset Muscle Soreness (DOMS) - Part II: Treatment and Prevention. Delayed Onset Muscle Soreness – Teil II: Therapie und Prävention. Sportverletzung Sportschaden : Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin, 33(1), 21–29. https://doi.org/10.1055/a-0810-3516 [https://pubmed.ncbi.nlm.nih.gov/30865998/]

== Notable articles ==

==Talks and interviews==

==See also==
*[[Exercise]]
*[[Lactate]]
*[[Inflammation]]
*[[Exertion]]
*[[Malaise]]
*[[Post-exertional malaise]]

==Learn more==

Delayed onset muscle soreness

2020-10-11T21:34:09Z

FatigueTrackerBot:.

Post-exertional malaise

2020-10-11T21:26:17Z

FatigueTrackerBot:Added link

'''Post-exertional malaise (PEM)''' refers to a ''worsening'' of [[List of symptoms in ME CFS|ME/CFS symptoms]] after minimal ''physical'' or ''mental'' [[exertion]],<ref name=":14" /><ref name=":32" /> which can be delayed 24-72 hours or more.<ref>{{Cite journal|last=Lindheimer|first=Jacob B.|last2=Meyer|first2=Jacob D.|last3=Stegner|first3=Aaron J.|last4=Dougherty|first4=Ryan J.|last5=Van Riper|first5=Stephanie M.|last6=Shields|first6=Morgan|last7=Reisner|first7=Amanda|last8=Shukla|first8=Sanjay K.|last9=Light|first9=Alan R.|date=2017-04-03|title=Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise|url=https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal=Fatigue: Biomedicine, Health & Behavior|language=en|volume=5|issue=2|pages=69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref><ref name=":15" /><ref name=":30">{{Cite journal|last=|first=|date=2018|title=SAGE Journals: Your gateway to world-class journal research|url=http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf|journal=Sage Pub|language=en|volume=|pages=4-5|doi=10.1177/1359105318805819/suppl_file/appendix.__the_development_of_a_comprehensive_measure_of_post-exertional_malaise.8.20.2018.pdf|via=}}</ref><ref name=":31">{{Cite journal|last=Jason|first=Leonard A|last2=Holtzman|first2=Carly S|last3=Sunnquist|first3=Madison|last4=Cotler|first4=Joseph|date=2018-10-24|title=The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome|url=https://doi.org/10.1177/1359105318805819|journal=Journal of Health Psychology|language=en|pages=1359105318805819|doi=10.1177/1359105318805819|issn=1359-1053}}</ref> PEM is considered to be the '''hallmark symptom''' of [[ME/CFS]].<ref name=":0">{{Cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK274235/|title=Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness|last=Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|last2=Board on the Health of Select Populations|last3=Institute of Medicine|date=2015|publisher=National Academies Press (US)|isbn=9780309316897|series=The National Academies Collection: Reports funded by National Institutes of Health|location=Washington (DC)|pmid=25695122}}</ref><ref name=":2" /> While in most diseases patients experience symptom relief after [[exercise|exercise,]]<ref>{{Cite journal|last=Loy|first=Bryan D.|last2=O'Connor|first2=Patrick J.|last3=Dishman|first3=Rodney K.|date=Oct 2013|title=The effect of a single bout of exercise on energy and fatigue states: a systematic review and meta-analysis|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2013.843266?journalCode=rftg20|journal=Fatigue: Biomedicine, Health & Behavior|language=en|volume=1|issue=4|pages=223–242|doi=10.1080/21641846.2013.843266|issn=2164-1846}}</ref><ref>{{Cite journal|last=Robb-Nicholson|first=L. C.|last2=Daltroy|first2=L.|last3=Eaton|first3=H.|last4=Gall|first4=V.|last5=Wright|first5=E.|last6=Hartley|first6=L. H.|last7=Schur|first7=P. H.|last8=Liang|first8=M. H.|date=Dec 1989|title=Effects of aerobic conditioning in lupus fatigue: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/2590802|journal=British Journal of Rheumatology|volume=28|issue=6|pages=500–505|issn=0263-7103|pmid=2590802}}</ref><ref>{{Cite journal|last=Mostert|first=S.|last2=Kesselring|first2=J.|date=Apr 2002|title=Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/11990874|journal=Multiple Sclerosis (Houndmills, Basingstoke, England)|volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref><ref>{{Cite news|url=https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/exercise-and-chronic-disease/art-20046049|title=What you need to know about exercise and chronic disease|work=Mayo Clinic|access-date=2018-10-10|language=en}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion can cause a symptom flare-up.<ref>{{Cite journal|last=Nijs|first=Jo|last2=Almond|first2=Freya|last3=De Becker|first3=Pascale|last4=Truijen|first4=Steven|last5=Paul|first5=Lorna|date=May 2008|title=Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/18441039|journal=Clinical Rehabilitation|volume=22|issue=5|pages=426–435|doi=10.1177/0269215507084410|issn=0269-2155|pmid=18441039}}</ref> Because recovery is often prolonged,<ref name=":13">{{Cite journal|last=VanNess|first=J. Mark|last2=Stevens|first2=Staci R.|last3=Bateman|first3=Lucinda|last4=Stiles|first4=Travis L.|last5=Snell|first5=Christopher R.|date=Feb 2010|title=Postexertional malaise in women with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> lasting days or sometimes weeks to months,<ref>[https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf The Voice of the Patient.] A series of reports from the U.S. Food and Drug Administration’s (FDA’s) Patient-Focused Drug Development Initiative. September 2013</ref> patients refer to these post-exertional setbacks as ‘crashes’.<ref>{{Cite news|url=https://www.healthrising.org/the-community-reports-best-practices-on-managing-thriving-with-or-just-surviving-chronic-fatigue-syndrome-mecfs/how-to-best-recover-from-a-crash-the-mecfs-community-reports/|title=How to Best Recover From a Crash: the ME/CFS Community Reports|work=Health Rising|access-date=2018-10-10|language=en-US}}</ref><ref name=":28">{{Cite web|url=https://youtu.be/RC9TjgE_PlU?t=137|title=Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|last=Kaufman|first=David|date=2018-10-16|website=YouTube|publisher=Unrest Film|archive-url=|archive-date=|dead-url=|access-date=|quote=Part of the Unrest Continuing Education module.}}</ref>

Depending on the criteria a patient meets ([[Systemic Exertion Intolerance Disease]] (SEID) for ME/CFS's [[Systemic Exertion Intolerance Disease#Diagnostic criteria| minimum core symptoms]], the [[Canadian Consensus Criteria]] (CCC) for [[Canadian Consensus Criteria#Definition| this criterion's ME/CFS symptoms]], or the [[International Consensus Criteria]] (ICC) for [[myalgic encephalomyelitis]] (ME) and [[International Consensus Criteria#Criteria|its ME symptoms]]) will correlate with the patient's symptoms that will worsen.

PEM can be caused by [[Exertion#Exertion in ME.2FCFS|physical as well as mental exertion]]<ref name=":14" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name=":3" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name=":1" /> with [[brain fog|brain fog,]]<ref name=":13" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name=":3" /> In contrast to most forms of exercise intolerance, the onset of PEM is frequently delayed<ref name=":15" /> with many patients reporting the height of their symptom flare-up, two<ref name=":13" /> or several days after the initial trigger.

It is important to understand that in [[pediatric]] cases of ME/CFS, children do not describe having PEM. They can experience a relapse from exertion, perhaps from just taking the school bus, having to spend prolonged periods in bed.<ref>[https://www.me-pedia.org/wiki/Pediatric_myalgic_encephalomyelitis_and_chronic_fatigue_syndrome ME/CFS in Children - by David S. Bell - David Bell - Open Medicine Foundation - June 25, 2016]</ref>

[[File:Cfs woman sketch.jpg|435x435px|thumb|Post-exertional malaise (PEM) is a [[List of symptoms in ME CFS|''worsening'' of ME/CFS symptoms]] after minimal [[Exertion#Exertion in ME.2FCFS|''physical'' or ''mental'' exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[brain fog|brain fog,]] [[cognitive dysfunction]], and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[Headache|headaches]] and [[Migraine|migraines]]; [[chronic pain]]; [[Myalgia|muscle pain]] and [[muscle fatigability]]; [[orthostatic intolerance]], [[neurally mediated hypotension|neurally mediated hypotension,]] or [[Postural orthostatic tachycardia syndrome|POTS]]; and more. The onset of PEM can be delayed 24-72 hours and depending on ME/CFS severity can last days, weeks, or even months]]
The distinctive characteristics of post-exertional malaise are confirmed by scientific research. Exertion induces abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref>{{Cite journal|last=Blackwood|first=S.|last2=MacHale|first2=S.|last3=Power|first3=M.|last4=Goodwin|first4=G.|last5=Lawrie|first5=S.|date=October 1998|title=Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170292/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=65|issue=4|pages=541–546|issn=0022-3050|pmc=2170292|pmid=9771781|via=}}</ref><ref name=":33" /> [[immune activation|immune activation,]]<ref>{{Cite journal|last=Nijs|first=Jo|last2=Nees|first2=Andrea|last3=Paul|first3=Lorna|last4=De Kooning|first4=Margot|last5=Ickmans|first5=Kelly|last6=Meeus|first6=Mira|last7=Van Oosterwijck|first7=Jessica|date=2014|title=Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review|url=https://www.ncbi.nlm.nih.gov/pubmed/24974723|journal=Exercise Immunology Review|volume=20|pages=94–116|issn=1077-5552|pmid=24974723|issue=|quote=|author-link=Jo Nijs|author-link2=Andrea Nees|author-link3=Lorna Paul|author-link4=Margot De Kooning|author-link5=Kelly Ickmans|via=|author-link6=Mira Meeus|author-link7=Jessica Van Oosterwijck}}</ref> [[gene expression]]<ref name=":20">{{Cite journal|last=Light|first=Alan R.|last2=White|first2=Andrea T.|last3=Hughen|first3=Ronald W.|last4=Light|first4=Kathleen C.|date=Oct 2009|title=Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects|url=http://dx.doi.org/10.1016/j.jpain.2009.06.003|journal=The Journal of Pain|volume=10|issue=10|pages=1099–1112|doi=10.1016/j.jpain.2009.06.003|issn=1526-5900}}</ref><ref name=":21">{{Cite journal|last=Light|first=A. R.|last2=Bateman|first2=L.|last3=Jo|first3=D.|last4=Hughen|first4=R. W.|last5=VanHaitsma|first5=T. A.|last6=White|first6=A. T.|last7=Light|first7=K. C.|date=2011-07-13|title=Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome|url=http://dx.doi.org/10.1111/j.1365-2796.2011.02405.x|journal=Journal of Internal Medicine|volume=271|issue=1|pages=64–81|doi=10.1111/j.1365-2796.2011.02405.x|issn=0954-6820}}</ref><ref>{{Cite journal|last=Meyer|first=Jacob D.|last2=Light|first2=Alan R.|last3=Shukla|first3=Sanjay K.|last4=Clevidence|first4=Derek|last5=Yale|first5=Steven|last6=Stegner|first6=Aaron J.|last7=Cook|first7=Dane B.|date=Oct 2013|title=Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression|url=http://dx.doi.org/10.1080/21641846.2013.838444|journal=Fatigue: Biomedicine, Health & Behavior|volume=1|issue=4|pages=190–209|doi=10.1080/21641846.2013.838444|issn=2164-1846}}</ref><ref>{{Cite journal|last=White|first=A. T.|last2=Light|first2=A. R.|last3=Hughen|first3=R. W.|last4=VanHaitsma|first4=T. A.|last5=Light|first5=K. C.|date=2011-12-30|title=Differences in Metabolite-Detecting, Adrenergic, and Immune Gene Expression After Moderate Exercise in Patients With Chronic Fatigue Syndrome, Patients With Multiple Sclerosis, and Healthy Controls|url=http://dx.doi.org/10.1097/psy.0b013e31824152ed|journal=Psychosomatic Medicine|volume=74|issue=1|pages=46–54|doi=10.1097/psy.0b013e31824152ed|issn=0033-3174}}</ref> and [[endogenous pain inhibition]]<ref name=":22">{{Cite journal|last=Whiteside|first=Alan|last2=Hansen|first2=Stig|last3=Chaudhuri|first3=Abhijit|date=Jun 2004|title=Exercise lowers pain threshold in chronic fatigue syndrome|url=http://dx.doi.org/10.1016/j.pain.2004.02.029|journal=Pain|volume=109|issue=3|pages=497–499|doi=10.1016/j.pain.2004.02.029|issn=0304-3959}}</ref><ref name=":23">{{Cite journal|last=Meeus|first=M|last2=Roussel|first2=NA|last3=Truijen|first3=S|date=2010|title=Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study|url=http://dx.doi.org/10.2340/16501977-0595|journal=Journal of Rehabilitation Medicine|volume=42|issue=9|pages=884–890|doi=10.2340/16501977-0595|issn=1650-1977}}</ref><ref name=":24">{{Cite journal|last=Van Oosterwijck|first=J.|last2=Nijs|first2=J.|last3=Meeus|first3=M.|last4=Lefever|first4=I.|last5=Huybrechts|first5=L.|last6=Lambrecht|first6=L.|last7=Paul|first7=L.|date=2010-03-03|title=Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study|url=http://dx.doi.org/10.1111/j.1365-2796.2010.02228.x|journal=Journal of Internal Medicine|volume=268|issue=3|pages=265–278|doi=10.1111/j.1365-2796.2010.02228.x|issn=0954-6820|quote=|author-link=Jessica Van Oosterwijck|author-link2=Jo Nijs|author-link3=Mira Meeus|author-link4=|author-link5=|via=|author-link7=Lorna Paul}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls. Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name=":16" /><ref name=":28" /> On the second day [[Two-day cardiopulmonary exercise test|CPET]], ME/CFS patients display a significant drop in [[VO2 max]] and [[maximal workload]], that is not seen in healthy controls or other diseases.<ref>{{Cite journal|last=Snell|first=C. R.|last2=Stevens|first2=S. R.|last3=Davenport|first3=T. E.|last4=Van Ness|first4=J. M.|date=2013-06-27|title=Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=http://dx.doi.org/10.2522/ptj.20110368|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref>{{Cite journal|last=Vermeulen|first=Ruud CW|last2=Kurk|first2=Ruud M|last3=Visser|first3=Frans C|last4=Sluiter|first4=Wim|last5=Scholte|first5=Hans R|date=2010|title=Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity|url=http://dx.doi.org/10.1186/1479-5876-8-93|journal=Journal of Translational Medicine|volume=8|issue=1|pages=93|doi=10.1186/1479-5876-8-93|issn=1479-5876}}</ref><ref name=":17" /><ref>{{Cite journal|last=Vanness|first=J. Mark|last2=Snell|first2=Christopher R.|last3=Stevens|first3=Staci R.|date=Jan 2007|title=Diminished Cardiopulmonary Capacity During Post-Exertional Malaise|url=http://dx.doi.org/10.1300/j092v14n02_07|journal=Journal of Chronic Fatigue Syndrome|volume=14|issue=2|pages=77–85|doi=10.1300/j092v14n02_07|issn=1057-3321}}</ref><ref name=":18" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name=":0" /> [[Brian Vastag]] won a groundbreaking long term disability (LTD) claim using CPET to prove his PEM was a severe disabling symptom.<ref>[US District Court of NJ: Brian Vastag v. Prudential Insurance Company of America, Civ.15-6197 (KSH), (CLW) https://t.co/Vq9GXo4VEI]</ref><ref>{{Cite web|url=https://www.meaction.net/2018/06/04/victory-for-me-disability-claim-court-upholds-plaintiffs-lawsuit-after-being-denied-disability/|title=Victory for ME Disability Claim - U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability|last=Tillman|first=Adriane|authorlink=|last2=|first2=|authorlink2=|date=2018-06-04|website=#MEAction|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2019-02-02}}</ref>

A 2015 review of the literature by the [[National Academy of Medicine]] concluded there to be “sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions.”<ref name=":0" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name=":19">{{Cite journal|last=Jason|first=Leonard A.|last2=Evans|first2=Meredyth|last3=So|first3=Suzanna|last4=Scott|first4=Jilian|last5=Brown|first5=Abigail|date=2015|title=Problems in Defining Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295644/|journal=Journal of prevention & intervention in the community|volume=43|issue=1|pages=20–31|doi=10.1080/10852352.2014.973239|issn=1085-2352|pmc=4295644|pmid=25584525}}</ref> with some diagnostic criteria emphasizing [[Paresis|muscle weakness]] and others a more a general form of [[fatigue]] and exhaustion.<ref name=":8">{{Cite journal|last=McManimen|first=Stephanie L.|last2=Sunnquist|first2=Madison L.|last3=Jason|first3=Leonard A.|date=2016-08-24|title=Deconstructing post-exertional malaise: An exploratory factor analysis|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/|journal=Journal of health psychology|doi=10.1177/1359105316664139|issn=1359-1053|pmc=5325824|pmid=27557649}}</ref>

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms<ref name="VanNess2010" />]]
The [[Centers for Disease Control and Prevention]] (CDC) outline different types of exertion that may trigger PEM and how it impacts patients noting some may be house-bound or completely bed-bound during a crash. "People with ME/CFS may not be able to predict what will cause a crash or how long it will last."<ref name=":32">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html|title=Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|date=2018-05-18|website=www.cdc.gov|language=en-us|access-date=2018-11-21}}</ref> Examples of PEM given by the CDC are: attending a child’s school event may leave a patient house-bound for a couple of days unable to do needed tasks, like laundry; grocery shopping may cause a crash that requires a nap in the car before driving home or a call for a ride home; a shower may leave a patient bed-bound and unable to do anything for days; keeping up with work may lead to spending evenings and weekends recovering.<ref name=":32" />

== PEM described by Dr. David Kaufman ==
{{#ev:youtube|https://www.youtube.com/watch?v=RC9TjgE_PlU|400|right|'''PEM described by Dr. David Kaufman''' (2018) Kaufman/''Unrest'' Video begins @2:16 and PEM is described until @3:35|frame|start=136&rel=0&autoplay=0}}

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

(Video begins @2:16 and PEM is described until @3:35. View entire 11:47 for a full description of ME/CFS)

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module'''. US medical providers can [https://www.unrest.film/cme register to watch] [[Unrest]] online for free and receive Continuing Education credit.<ref>{{Cite web|url=https://www.youtube.com/watch?v=RC9TjgE_PlU|title=Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|date=Oct 16, 2018|access-date=|website=YouTube|last=|first=|authorlink=David Kaufman|last2=|first2=|authorlink2=|archive-url=|archive-date=|dead-url=|publisher=Unrest Film}}</ref>

==Patients' description==
[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We’re only out and about at our best, and our (more frequent) worst often remains hidden. I’m convinced it’s why #[[ME/CFS|MEcfs]] research funding is so low - the problem isn’t visible enough. I’m seriously ill in both these photos.<ref>{{Cite web|url=https://twitter.com/JackCroxall/status/1085900441328803840|title=I think #TwoFacesofME is a really important hashtag. We’re only out and about at our best, and our (more frequent) worst often remains hidden. I’m convinced it’s why #MEcfs research funding is so low - the problem isn’t visible enough. I’m seriously ill in both these photos.pic.twitter.com/hNjK5140kv|last=Croxall|first=Jack|date=2019-01-17|website=@JackCroxall|language=en|access-date=2019-01-17}}</ref>]]
[[File:PEM.JPG|300px|thumb|right|#TwoFacesofME First picture: Happy to be outside and feeling ok. Second picture: A crash with [[Neurally mediated hypotension|high pulse and very low energy]]. Even though you sometimes can see the exhaustion in someone's face, most [[List of symptoms in ME CFS|ME symptoms]] are invisible. #pwME #MEcfs #millionsmissing #PostExertionalMalaise<ref>{{Cite web|url=https://twitter.com/ezchili/status/1085927134248488965|title=#TwoFacesofME First picture: Happy to be outside and feeling ok. Second picture: A crash with high pulse and very low energy. Even though you sometimes can see the exhaustion in someone's face, most ME symptoms are invisible. #pwME #MEcfs #millionsmissing #PostExertionalMalaisepic.twitter.com/FKSTo8W0hH|last=ez 📎|date=2019-01-17|website=@ezchili|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM2.JPG|300px|thumb|right|#twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.<ref>{{Cite web|url=https://twitter.com/kaisecam/status/1085886323276349440|title=#twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.pic.twitter.com/nTJVG63jRm|last=Kaise 🥄|first=Mx|date=2019-01-17|website=@kaisecam|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM3.JPG|300px|thumb|right|#TwoFacesofME Workday me v’s weekend me. I’m so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.<ref>{{Cite web|url=https://twitter.com/RachelFrancis/status/1085940724774912000|title=#TwoFacesofME Workday me vs weekend me. I’m so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.pic.twitter.com/qZNiQaVHyD|last=Francis|first=Rachel|date=2019-01-17|website=@RachelFrancis|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair on a rare trip out]]. Second photo, the inevitable crash. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak etc., etc. #TwoFacesofME<ref>{{Cite web|url=https://twitter.com/hopeforMEyet/status/1085909800766980096|title=First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak etc., etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF|last=Karen|date=2019-01-17|website=@hopeforMEyet|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web|title=#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p|url=https://twitter.com/Authorportrait/status/1085815918846832640|website=@Authorportrait|date=2019-01-17|access-date=2019-01-17|language=en|first=Henry|last=Köhler}}</ref>]]

[[File:PEM6.JPG|300px|thumb|right|What the [world] don’t [see] two faces of M.E.<ref>{{Cite web|url=https://twitter.com/SharonTiday/status/1085122891220430848|title=What the don’t two faces of M.E.pic.twitter.com/DYZVhtyrG5|last=Awareness|first=CFDA #|date=2019-01-15|website=@SharonTiday|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM7.JPG|300px|thumb|right|Joining #pwME sharing #TwoFacesofME for #MEAwareness 1: a fall day when I got outside (but ended up in bed a week) 2: what no one sees (constant [[Chronic pain|pain]], post exertional malaise & [[Sleep dysfunction|sleep deprivation]]) Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)<ref>{{Cite web|url=https://twitter.com/ceibakoru/status/1085894325832040448|title=Joining #pwME sharing #TwoFacesofME for #MEAwareness, 1: a fall day when I got outside (but ended up in bed a week), 2: what no one sees (constant pain, post exertional malaise & sleep deprivation). Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)pic.twitter.com/EpsMLT8E11|last=Ceiba 🌳Koru 🌀|date=2019-01-17|website=@ceibakoru|language=en|access-date=2019-01-17}}</ref>]]

=== An illness within an illness ===

PEM refers to a worsening of many ME/CFS symptoms as a result of physical or mental exertion. It consists of more than post-exertional fatigue and pain, and can cause severe debility.<ref name=":34">{{Cite journal|last=Stussman|first=Barbara|author-link=|last2=Williams|first2=Ashley|author-link2=|last3=Snow|first3=Joseph|author-link3=Joseph Snow|last4=Gavin|first4=Angelique|author-link4=|last5=Scott|first5=Remle|author-link5=|last6=Nath|first6=Avindra|author-link6=Avindra Nath|last7=Walitt|first7=Brian|author-link7=Brian Walitt|date=2020|title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.01025|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref> As one patient described it: <blockquote>“When I do any activity that goes beyond what I can do—I literally collapse—my body is in major pain, it hurts to lay in bed, it hurts to think, I can’t hardly talk—I can’t find the words, I feel my insides are at war.”<ref name=":0" /></blockquote> Another patient emphasized that the feeling of PEM is very different from what one experiences as a healthy person: <blockquote>"PEM is like nothing else you will experience in healthy life; a combination of a hangover, the flu, finishing a 10k run, all at the same time at varying levels of severity."<ref>{{Cite news|url=https://twitter.com/Fatigo_MECFS/status/1050305665565102080|title=Fatigo_MECFS on Twitter|work=Twitter|access-date=2018-10-11|language=en}}</ref></blockquote>Considering the serious but fluctuating debility PEM causes, ME/CFS expert Dr. [[Anthony Komaroff]] described it as “an illness within an illness”.<ref>{{Cite news|url=https://phoenixrising.me/archives/11884|title=Post-Exertional Malaise II: Perception and Reality By Jennifer M. Spotila, J.D.|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref>

=== Energy conservation and pacing ===
Patients often report the feeling of a red line, an energy level that if exceeded, will result in a relapse. As one [[Norway|Norwegian]] patient described: <blockquote>“....And suddenly it is just too much. The body turns itself off, as if it has gone on strike. You have pushed too much for too long, it repeats itself, and the body stops functioning.”<ref>{{Cite journal|last=Larun|first=Lillebeth|last2=Malterud|first2=Kirsti|date=May 2011|title=Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>Energy conservation strategies such as [[pacing]] and the [[Energy Envelope Theory|envelope theory]] have been developed to minimize PEM while allowing patients to stay as active as possible.<ref>{{Cite journal|last=Goudsmit|first=Ellen M.|last2=Nijs|first2=Jo|last3=Jason|first3=Leonard A.|last4=Wallman|first4=Karen E.|date=2012|title=Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document|url=https://www.ncbi.nlm.nih.gov/pubmed/22181560|journal=Disability and Rehabilitation|volume=34|issue=13|pages=1140–1147|doi=10.3109/09638288.2011.635746|issn=1464-5165|pmid=22181560}}</ref> These techniques advise patients to balance energy availability and expenditure and to recognize early signs of PEM so they can reduce activity levels before a relapse occurs.

== The distinctive characteristics of PEM ==
Four aspects differentiate the post-exertional malaise of ME/CFS patients from the exercise intolerance commonly reported in patients suffering from [[deconditioning]] or other conditions.

=== Timing ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertional Malaise: History, Characteristics, Evidence'' (2015) By Dr. Lily Chu/Solve CFS">https://www.youtube.com/watch?v=hxJPrkWHcBo</embedvideo>
First of all, there is the time lapse. While physical complaints are usually reported during or shortly after exercise, PEM often has a delayed onset, hours or sometimes even days after the original trigger. Yoshiuchi et al. for example wrote that: “after a briefer maximal exercise task, reports of worsening CFS symptoms were inconsistent or absent until 5 days after the challenge, a pattern not typically observed in real life.”<ref name=":15">{{Cite journal|last=Yoshiuchi|first=Kazuhiro|last2=Cook|first2=Dane B.|last3=Ohashi|first3=Kyoko|last4=Kumano|first4=Hiroaki|last5=Kuboki|first5=Tomifusa|last6=Yamamoto|first6=Yoshiharu|last7=Natelson|first7=Benjamin H.|date=2007-12-05|title=A real-time assessment of the effect of exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5|pages=963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> The authors noted that this delay could be used to distinguish ME/CFS from other fatiguing illness. Another study from Stanford University showed that in up to 37% of the 150 ME/CFS patients studied, PEM may not begin until a day or more after an [[Exertion|exertional]] trigger.<ref name=":3" />

[[File:Rosa SEID.JPG|400px|thumb|left|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about PEM and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her condition worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM "[[Canadian Consensus Criteria#Definition|option]]"]]

Patients may not be familiar with this characteristic of their relapses, since it is very counter-intuitive. As one patient noted:<blockquote>"It's really counter-intuitive to feel bad after a delay of 24 hours after exertion. It may take quite some time before people even make that connection, if ever. I only noticed it about three years in, and I hesitated to mention to others because I thought it might make me sound nuts."<ref name=":5">{{Cite news|url=https://www.s4me.info/threads/s4me-submission-to-the-public-review-on-common-data-elements-for-me-cfs-concerns-with-the-proposed-measure-of-post-exertional-malaise.2220/|title=S4ME: Submission to the public review on Common Data Elements for ME/CFS: Concerns with the proposed measure of post-exertional malaise|work=Science for ME|access-date=2018-10-10|language=en-US}}</ref></blockquote>Another time-related characteristic of PEM is a prolonged recovery period. In a 2010 study 25 M/CFS patients and 23 matched controls were followed up for seven days after performing a maximal cardiopulmonary exercise test. After two days, all controls subjects were recovered while only one ME/CFS patient was. Most (60%) of the ME/CFS participants reported that it took more than five days to fully recover from the test and many reported feeling at their worst 24 to 48 hours after the test.<ref name=":9">{{Cite journal|last=VanNess|first=J. Mark|last2=Stevens|first2=Staci R.|last3=Bateman|first3=Lucinda|last4=Stiles|first4=Travis L.|last5=Snell|first5=Christopher R.|date=Feb 2010|title=Postexertional malaise in women with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health |volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> Other studies have found the same prolonged recovery period in ME/CFS patients after exertion. A Dutch study for example noted: <blockquote>"For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h."<ref>{{Cite journal|last=Bazelmans|first=Ellen|last2=Bleijenberg|first2=Gijs|last3=Voeten|first3=Marinus J. M.|last4=van der Meer|first4=Jos W. M.|last5=Folgering|first5=Hans|date=Oct 2005|title=Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16223622|journal=Journal of Psychosomatic Research|volume=59|issue=4|pages=201–208|doi=10.1016/j.jpsychores.2005.04.003|issn=0022-3999|pmid=16223622|quote=|author-link=Ellen Bazelmans|author-link2=Gijs Bleijenberg|author-link3=Marinus Voeten|author-link4=Jos van der Meer|author-link5=Hans Folgering|via=}}</ref></blockquote>[[Charles Lapp|Lapp]] et al. followed 31 ME/CFS patients for 12 days after performing a maximal exercise test of 8-10 minutes. The average relapse lasted 8,82 days, although 22% of patients were still in relapse when the study ended at 12 days.<ref>{{Cite journal|last=Lapp|first=C. W.|date=Jul 1997|title=Exercise limits in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9236491|journal=The American Journal of Medicine|volume=103|issue=1|pages=83–84|issn=0002-9343|pmid=9236491}}</ref> In the Stanford study by [[Lily Chu|Chu]] et al. 87% of respondents indicated that they endure PEM for 24 hours or more. The authors concluded: <blockquote>"In many medical conditions, exertion-exacerbated symptoms usually start during exertion or immediately after and usually resolve immediately or shortly after exertion stops. In contrast, PEM may not start until hours or even days after the trigger starts or has been removed, may peak after the first day, and may not stop until hours to months later. This characteristic of PEM often leads patients and clinicians to believe that symptom exacerbations are random rather than associated with a trigger; most people will not intuit that symptoms are caused by a trigger that occurred hours to days prior unless specifically asked by their clinicians to pay attention."<ref name=":3" /> </blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the [[List of symptoms in ME CFS|type of symptoms reported]]. The [[Canadian Consensus Criteria]], a 2003 clinical guideline formed by experts in the field, underlines that many PEM symptoms are [[Immune system|immune-related]]: <blockquote>"The [[malaise]] that follows exertion is difficult to describe but is often reported to be similar to the generalized [[pain]], discomfort and fatigue associated with the acute phase of [[influenza]]. Delayed malaise and fatigue may be associated with signs of immune activation: [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or [[Brain fog|cognitive fog]]."<ref name=":1" /> </blockquote>[[Mark VanNess|Van Ness]] et al. noted how [[Cognitive dysfunction|cognitive difficulties]] after exertion differentiate ME/CFS patients from healthy controls: <blockquote>"Another interesting difference between groups was the reported symptom of [[cognitive dysfunction]], for example, ‘‘[[Brain fog|brain-fog]]’’ or ‘‘difficulty concentrating.’’ Problems of this nature were not reported by any of the control subjects, whereas 12 patients (48%) experienced these problems: “Carrying on conversations was hard.” “Can’t think straight.” “My mind was not clear.”<ref name=":9" /></blockquote>This was elaborated by [[Lily Chu|Chu]] et al., the research team who conducted the first in-depth investigation on how ME/CFS patients describe their PEM: <blockquote>"There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ [[Inflammation|inflammatory]]-related symptoms like sore throat, tender lymph nodes, or flu-like feelings, yet 60% and 36% of our subjects, respectively, reported these symptoms with either stimuli and about a quarter experienced all 3 with exertion. Conversely, symptoms typically associated with physical exertion in other conditions, like [[Dyspnea|shortness of breath]] or [[chest pain]] in [[chronic lung]] or [[heart disease]], are rarely reported in ME/CFS. Furthermore, it is well-established that physical activity improves [[Mood swings|mood]], [[Sleep dysfunction|sleep]], and pain in both healthy people as well those with chronic illnesses like depression or anxiety yet our subjects report worsened sleep, mood, and pain with physical activity."<ref name=":3" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple types of triggers. Research has shown that ME/CFS patients experience PEM after [[Exertion#Exertion in ME.2FCFS|cognitive effort, physical or emotions]].<ref name=":34" /> A 2014 study for example followed up on 32 ME/CFS patients after completing a battery of neurocognitive tests. As the authors concluded: “following a challenging cognitive demand, fatigue significantly increased two days after testing”, which was “suggestive of post-exertional symptom exacerbation following mental effort.”<ref name=":14">{{Cite journal|last=Arroll|first=Megan A.|last2=Attree|first2=Elizabeth A.|last3=O'Leary|first3=John M.|last4=Dancey|first4=Christine P.|date=2014-04-03|title=The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2014.892755|journal=Fatigue: Biomedicine, Health & Behavior|language=en|volume=2|issue=2|pages=57–63|doi=10.1080/21641846.2014.892755|issn=2164-1846}}</ref> Commenting on the [https://www.me-pedia.org/wiki/1980-81_Ayrshire_outbreak outbreak in West Kilbride, Ayrshire], Ramsay remarked: <blockquote>“Once the disease was established the most characteristic symptom was extreme exhaustion, particularly after exercise. The exhaustion also occurred after emotional or mental strain.”<ref name=":10" /> </blockquote>Some other precipitants of PEM that have been reported include positional changes and exposure to excessive light or sounds<ref>{{Cite web|url=http://anilvanderzee.com/dance-hermit-16-vs-sumo-baby-part-1/|title=Dance hermit ’16 vs. Sumo Baby (part 1) {{!}} Anil van der Zee|website=anilvanderzee.com|language=en-GB|access-date=2018-10-13}}</ref>. While PEM was often thought of as symptom exacerbation after exercise, it is clear that for some ME/CFS patients even basic activities of daily living such as toileting, bathing, dressing, communicating, and reading can trigger relapses.<ref name=":11" /> As long time ME/CFS expert [[Jennie Spotila|Jennifer Spotila]] explained in a four-piece exploration of the phenomenon post-exertional malaise:<blockquote>“The use of the word ‘exertion’ may create the impression that PEM is triggered by strenuous or intense activity, but this is not the case […] Some patients need only attempt to make a simple meal or get dressed before PEM descends.”<ref>{{Cite news|url=https://phoenixrising.me/archives/11883|title=Unraveling Post-exertional Malaise By Jennifer M. Spotila, J.D.|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref></blockquote>This was confirmed by Chu et al. <blockquote>"[…] our results provide formal evidence supporting patient narratives, clinician experiences, and current case definitions which assert that even tasks like walking, cooking, or reading can provoke PEM."<ref name=":3" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name=":11">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Loss of functional capacity ===
A fourth distinctive element of PEM is often described as a loss of stamina and/or functional capacity. This refers to the results of the 2-day cardiopulmonary exercise test (CPET) procedure. A CPET is usually reproducible and normally has a test-retest difference of 7-12%<ref name=":16">{{Cite journal|last=Stevens|first=Staci|last2=Snell|first2=Chris|last3=Stevens|first3=Jared|last4=Keller|first4=Betsy|last5=VanNess|first5=J. Mark|date=2018|title=Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full|journal=Frontiers in Pediatrics|language=English|volume=6|doi=10.3389/fped.2018.00242|issn=2296-2360}}</ref>. ME/CFS patients however show strikingly lower results on several measures at the second CPET compared to the first, despite meeting objective markers of maximal effort. These results have been replicated by several research teams, though there is inconsistency on which measure ([[VO2]] or maximal workload, at peak or ventilatory threshold), the decline in functional capacity is best represented.

{| class="wikitable"
! colspan="8" |Physiological changes between first and second exercise test during 2-day CPET procedure in patients with ME/CFS
|-
|
|Number of ME/CFS patients
|VO2 peak
|VO2 at VT
|Workload peak
|Workload at VT
|HR peak
|O2pulse at VT
|-
|[[Mark VanNess|VanNess]] et al. 2007.
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|[[Vemeulen]] et al. 2010.
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|[[Hodges]] et al. 2018.
|10
| +5.3%
| +6.1%
| -6.7%
| -11.4%
| -0.6%
|?
|}
The drop in functional capacity on the second CPET is usually not seen in other diseases. According to [[Betsy Keller|Keller]] et al. "ME/CFS patients currently represent a unique class of ill patients who do not reproduce maximal CPET measures, unlike individuals with cardiovascular disease, lung disease, end-stage renal disease pulmonary arterial hypertension and cystic fibrosis".<ref name=":17">{{Cite journal|last=Keller|first=Betsy A.|last2=Pryor|first2=John Luke|last3=Giloteaux|first3=Ludovic|date=2014-04-23|title=Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment|url=https://www.ncbi.nlm.nih.gov/pubmed/24755065|journal=Journal of Translational Medicine|volume=12|pages=104|doi=10.1186/1479-5876-12-104|issn=1479-5876|pmc=4004422|pmid=24755065}}</ref> A preliminary study from [[New Zealand]] suggests that patients with MS do not display the same decline on the second day of exercise testing, as do patients with ME/CFS.<ref name=":18">{{Cite journal|last=Hodges|first=L. D.|last2=Nielsen|first2=T.|last3=Baken|first3=D.|date=Jul 2018|title=Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/28782878|journal=Clinical Physiology and Functional Imaging|volume=38|issue=4|pages=639–644|doi=10.1111/cpf.12460|issn=1475-097X|pmid=28782878}}</ref>

Questions have however been raised about the clinical use of the 2-day CPET procedure. [[Christopher Snell|Snell]] et al. suggested it might be unethical to use this method since many ME/CFS patients might suffer a serious relapse as a result of exercise performance.<ref>{{Cite journal|last=Snell|first=Christopher R.|last2=Stevens|first2=Staci R.|last3=Davenport|first3=Todd E.|last4=Van Ness|first4=J. Mark|date=Nov 2013|title=Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23813081|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=1538-6724|pmid=23813081}}</ref> Others have noted that the CPET- procedure is not practical either. It cannot be used in patients with severe ME/CFS (thus excluding these patients from study) and because of cost and expertise, may not be available to most clinicians.<ref name=":11" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name=":7">{{Cite journal|last=Cotler|first=Joseph|last2=Holtzman|first2=Carly|last3=Dudun|first3=Catherine|last4=Jason|first4=Leonard A.|date=2018-09-11|title=A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref> For these reasons PEM is usually assessed using self-reporting questionnaires.

== Differentiation ==
Several studies have shown that PEM is the symptom of ME/CFS that best differentiates it from other diseases.

=== Healthy controls and idiopathic chronic fatigue ===
PEM was one of the symptoms in the CDC symptom inventory list that differentiated subjects with ME/CFS from those without the disease.<ref>{{Cite journal|last=Wagner|first=Dieter|last2=Nisenbaum|first2=Rosane|last3=Heim|first3=Christine|last4=Jones|first4=James F.|last5=Unger|first5=Elizabeth R.|last6=Reeves|first6=William C.|date=2005-07-22|title=Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16042777|journal=Population Health Metrics|volume=3|pages=8|doi=10.1186/1478-7954-3-8|issn=1478-7954|pmc=1183246|pmid=16042777}}</ref> It was also the highest loading factor among a data set of 38 measurements used for a principal component analysis of unexplained chronic fatigue.<ref>{{Cite journal|last=Vollmer-Conna|first=Uté|last2=Aslakson|first2=Eric|last3=White|first3=Peter D|date=Apr 2006|title=An empirical delineation of the heterogeneity of chronic unexplained fatigue in women|url=https://www.futuremedicine.com/doi/abs/10.2217/14622416.7.3.355|journal=Pharmacogenomics|language=en|volume=7|issue=3|pages=355–364|doi=10.2217/14622416.7.3.355|issn=1462-2416}}</ref> Data for this study came from the epidemiological study in Wichita, Kansas.

The other major epidemiological study, carried out in Chicago, also identified PEM as the hallmark symptom of ME/CFS. In a 10 year follow-up study on the 32 patients originally identified as having ME/CFS, all of the contacted patients reported post-exertional malaise at some point in time. This symptom was able to differentiate ME/CFS patients with those with [[idiopathic chronic fatigue]], those with exclusionary illnesses and healthy controls. According to the author: <blockquote>"Among all the variables in this study, only for post-exertional malaise did the CFS group significantly differ from the other three conditions. This reaffirms the importance of this being a cardinal and critical symptom for CFS."<ref>{{Cite journal|last=Jason|first=Leonard A.|date=Feb 2011|title=Natural History of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171164/|journal=Rehabilitation psychology|volume=56|issue=1|pages=32–42|doi=10.1037/a0022595|issn=0090-5550|pmc=3171164|pmid=21401284}}</ref> </blockquote>Using a large sample of ME/CFS patients from Newcastle, [[Norway]] and the [https://www.me-pedia.org/wiki/Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank], Jason et al. conducted an analysis of different case definitions and symptoms. The domain of post-exertional malaise was found to be most adequate at differentiating ME/CFS patients from controls. As the authors noted: <blockquote>Using the latent variables from the empiric criteria, only one factor (PEM) was needed to reach a sensitivity of 90.8%, specificity of 92.5% and accuracy of 91.6%, and this was the only data mining where all percentages were over 90%. […] the fact that PEM came out in all analyses supports the importance of this domain in the case definition.<ref>{{Cite journal|last=Jason|first=Leonard A.|last2=Kot|first2=Bobby|last3=Sunnquist|first3=Madison|last4=Brown|first4=Abigail|last5=Reed|first5=Jordan|last6=Furst|first6=Jacob|last7=Newton|first7=Julia L.|last8=Strand|first8=Elin Bolle|last9=Vernon|first9=Suzanne D.|date=2014-04-01|title=Comparing and Contrasting Consensus versus Empirical Domains|url=https://www.ncbi.nlm.nih.gov/pubmed/26977374|journal=Fatigue: Biomedicine, Health & Behavior|volume=3|issue=2|pages=63–74|doi=10.1080/21641846.2015.1017344|issn=2164-1846|pmc=4788637|pmid=26977374}}</ref> </blockquote>A 2014 examination, using 236 patients and 86 controls, showed that three symptoms accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise.<ref>{{Cite journal|last=Jason|first=Leonard A.|last2=Sunnquist|first2=Madison|last3=Brown|first3=Abigail|last4=Evans|first4=Meredyth|last5=Vernon|first5=Suzanne D.|last6=Furst|first6=Jacob|last7=Simonis|first7=Valerie|date=2014-01-01|title=Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis|url=https://www.ncbi.nlm.nih.gov/pubmed/24511456|journal=Fatigue: Biomedicine, Health & Behavior|volume=2|issue=1|pages=40–56|doi=10.1080/21641846.2013.862993|issn=2164-1846|pmc=3912876|pmid=24511456}}</ref> Another data mining study by the same research group, suggested the selection of four symptoms: next to extreme tiredness, unrefreshing sleep and [[Word-finding problems|difficulty finding the right word to say]] or [[Aphasia|expressing thoughts]], PEM was once again represented with the item “physically drained/sick after mild activity.”<ref>{{Cite journal|last=Jason|first=Leonard A.|last2=Kot|first2=Bobby|last3=Sunnquist|first3=Madison|last4=Brown|first4=Abigail|last5=Evans|first5=Meredyth|last6=Jantke|first6=Rachel|last7=Williams|first7=Yolonda|last8=Furst|first8=Jacob|last9=Vernon|first9=Suzanne D.|date=2015|title=Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition|url=https://www.ncbi.nlm.nih.gov/pubmed/26029488|journal=Health Psychology and Behavioral Medicine|volume=3|issue=1|pages=82–93|doi=10.1080/21642850.2015.1014489|issn=2164-2850|pmc=4443921|pmid=26029488}}</ref>

[[Michael Maes|Maes]] et al. divided ME/CFS patients into two groups: those with or without PEM lasting for more than 24 hours. Analysis showed this to be a meaningful division as the former group (45% of the sample) not only had higher symptom scores on concentration difficulties and a subjective experience of infection, but also higher markers of immune-activation such as [[Interleukin 1|IL-1]], [[TNFa]], [[lysozyme]] and [[neopterin]], than the CFS group without PEM. According to the authors their findings, "underscore the relevance of post-exertional malaise to identify a subgroup of CFS patients that should be diagnosed as ME".<ref>{{Cite journal|last=Maes|first=Michael|last2=Twisk|first2=Frank N. M.|last3=Johnson|first3=Cort|date=2012-12-30|title=Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data|url=https://www.ncbi.nlm.nih.gov/pubmed/22521895|journal=Psychiatry Research|volume=200|issue=2-3|pages=754–760|doi=10.1016/j.psychres.2012.03.031|issn=1872-7123|pmid=22521895}}</ref>

=== Multiple sclerosis ===
According to a 2015 report by the National Academy of Medicine, the prevalence of PEM among ME/CFS patients varies from 69 to 100%, which is much higher than in other disease groups.<ref name=":0" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name=":12">{{Cite journal|last=Komaroff|first=A. L.|last2=Fagioli|first2=L. R.|last3=Geiger|first3=A. M.|last4=Doolittle|first4=T. H.|last5=Lee|first5=J.|last6=Kornish|first6=R. J.|last7=Gleit|first7=M. A.|last8=Guerriero|first8=R. T.|date=Jan 1996|title=An examination of the working case definition of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8579088|journal=The American Journal of Medicine|volume=100|issue=1|pages=56–64|issn=0002-9343|pmid=8579088}}</ref>, a figure similar to what Jason et al. found with the DSQ PEM subscale in a cohort of 106 MS-patients.<ref>{{Cite journal|last=Jason|first=L. A.|last2=Ohanian|first2=D.|last3=Brown|first3=A.|last4=Sunnquist|first4=M.|last5=McManimen|first5=S.|last6=Klebek|first6=L.|last7=Fox|first7=P.|last8=Sorenson|first8=M.|date=2017|title=Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29430570|journal=Insights in Biomedicine|volume=2|issue=2|doi=10.21767/2572-5610.10027|issn=2572-5610|pmc=5800741|pmid=29430570}}</ref> Both studies used a broad definition of PEM which focused on fatigue after exercise. Preliminary research suggests that adding more specific questions, for example about the prolonged recovery and various type of triggers, PEM might be able to differentiate ME/CFS from [[multiple sclerosis]]. A 2018 study for example showed that ME/CFS patients reported to experience PEM more often through mental exertion and to recover more slowly from PEM compared to multiple sclerosis patients.<ref name=":7" />
=== Major Depressive disorder ===
In the 1996 study by Komaroff et al., only 19% of patients with major [[depression]] reported PEM.<ref name=":12" /> A similar figure was found by Hawk et al., who found PEM in 3 patients in their sample of 15 with major depressive disorder.<ref>{{Cite journal|last=Hawk|first=Caroline|last2=Jason|first2=Leonard A.|last3=Torres-Harding|first3=Susan|date=2006|title=Differential diagnosis of chronic fatigue syndrome and major depressive disorder|url=https://www.ncbi.nlm.nih.gov/pubmed/17078775|journal=International Journal of Behavioral Medicine|volume=13|issue=3|pages=244–251|doi=10.1207/s15327558ijbm1303_8|issn=1070-5503|pmid=17078775}}</ref> In contrast all of the 15 studied ME/CFS patients reported PEM, making it the largest discriminant function for all investigated symptoms. White et al. studied patients with persistent symptoms of fatigue and poor concentration after glandular fever. According to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/8588010|title=The validity and reliability of the fatigue syndrome that follows glandular fever. - PubMed - NCBI|last=White|first=PD|website=www.ncbi.nlm.nih.gov|language=en|access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at [[MicroRNA]]<nowiki/>s (miRNA) in the [[cerebrospinal fluid]] of ME/CFS patients, healthy controls and patients with [[Gulf War Illness]] before and after an exercise challenge (a submaximal bicycle exercise). While there were no differences in miRNA between the groups at baseline, a distinct signature appeared after exercise. According to the authors, "exercise caused distinct patterns of [[miRNA]] changes in CFS and […] [[Gulf War Illness|GWI]] indicating significant pathophysiological differences between conditions."<ref>{{Cite journal|last=Baraniuk|first=James N.|last2=Shivapurkar|first2=Narayan|date=2017-11-10|title=Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects|url=https://www.nature.com/articles/s41598-017-15383-9|journal=Scientific Reports|language=En|volume=7|issue=1|doi=10.1038/s41598-017-15383-9|issn=2045-2322}}</ref> A 2013 study under the guidance of [[Nancy Klimas]] compared the immune signature in 30 Gulf war patients, 22 ME/CFS patients and 30 controls, after an graded exercise test. Results indicated the importance of physical exercise for differentiating these different groups: <blockquote>"Common to both GWI and CFS illness signatures were the direct or indirect contributions of IL-10 and IL-23 expression though these occurred at very different times. While levels measured at rest supported an illness signature in GWI, their impact in CFS was only observable during and after exercise, again emphasizing the importance of a challenge and response timeline in distinguishing these illnesses."<ref>{{Cite journal|last=Smylie|first=Anne Liese|last2=Broderick|first2=Gordon|last3=Fernandes|first3=Henrique|last4=Razdan|first4=Shirin|last5=Barnes|first5=Zachary|last6=Collado|first6=Fanny|last7=Sol|first7=Connie|last8=Fletcher|first8=Mary Ann|last9=Klimas|first9=Nancy|date=2013-06-25|title=A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23800166|journal=BMC immunology|volume=14|pages=29|doi=10.1186/1471-2172-14-29|issn=1471-2172|pmc=3698072|pmid=23800166}}</ref></blockquote>
A study by Washington et al. (2020) found different brain activation patterns after exercise in patients with Gulf War Illness compared to ME/CFS, including the opposite response in some areas, despite both illnesses causing post-exertional malaise.<ref name="Washington2020">{{Cite journal|last=Washington|first=Stuart D.|author-link=|last2=Rayhan|first2=Rakib U.|author-link2=Rakib Rayhan|last3=Garner|first3=Richard|author-link3=|last4=Provenzano|first4=Destie|author-link4=|last5=Zajur|first5=Kristina|author-link5=|last6=Addiego|first6=Florencia Martinez|author-link6=|last7=VanMeter|first7=John W.|last8=Baraniuk|first8=James N.|author-link8=James Baraniuk|date=2020-07-01|title=Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074|journal=Brain Communications|language=en|volume=2|issue=2|pages=|doi=10.1093/braincomms/fcaa070|pmc=|pmid=|access-date=|quote=|via=}}</ref> The same study found that brain activation patterns did not change after exercise in healthy controls.<ref name="Washington2020" />

== Objective findings after exertion: ==
In the 1980s Melvin A. Ramsay stressed the use of assessing ME patients after exertion. Regarding muscle weakness – what he regarded as the hallmark symptom of the disease –he noted: <blockquote>"If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few ME case can manage more. […] It is most important to stress the fact that cases of ME of mild or even moderate severity may have normal muscle power in a remission. In such cases, test for muscle power should be repeated after exercise."<ref name=":10" /> </blockquote>Though the definition of PEM has been expended far beyond muscle weakness, modern day research has confirmed the utility of testing ME/CFS after exertion. Many markers that are normal in resting state in ME/CFS patients turn out to be abnormal after a physical or cognitive stressor.<ref name=":0" />
A fairly small study of ME/CFS patients who met the widely used [[Fukuda criteria]] found different brain activation patterns in particular areas of the brain in ME/CFS patients after exercise compared to before exercise; these changes in brain activation was not found in healthy controls after exercise.<ref name="Washington2020" />

=== Gene expression ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''72. Gene-expression and exercise / Gen-expressie en inspanning – dr. Lucinda Bateman'' (2015) By Dr. Lucinda Bateman/Wetenschap voor Patienten - ME/cvs Vereniging">https://https://www.youtube.com/watch?v=F1PP21TmUPs</embedvideo>

One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[Leucocyte|leukocytes]] of ME/CFS patients showed an increase in expression of [[Adrenergic receptor|adrenergic]], [[metabolite]] detecting and [[immune-related genes]] that was not seen in healthy controls. Before the exercise test there were no abnormalities in the expression of these genes of ME/CFS patients. The authors speculated this to be evidence for sensitization of fatigue pathways in ME/CFS.<ref name=":20" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name=":21" /> In a 2012 comparison MS patients also displayed an increase in post-exercise gene expression, but only ME/CFS patients showed increases in metabolite-detecting sensory receptors. According to the authors:<blockquote>"Because only the CFS patients showed increases in these metabolite-detecting receptors, the sensory receptor elements of this gene profile seem particularly specific to CFS and may reflect dysregulated pathways that directly contribute to increased effort sense during exercise and postexertional malaise."<ref>{{Cite journal|last=White|first=Andrea T.|last2=Light|first2=Alan R.|last3=Hughen|first3=Ronald W.|last4=VanHaitsma|first4=Timothy A.|last5=Light|first5=Kathleen C.|date=Jan 2012|title=Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256093/|journal=Psychosomatic Medicine|volume=74|issue=1|pages=46–54|doi=10.1097/PSY.0b013e31824152ed|issn=0033-3174|pmc=3256093|pmid=22210239}}</ref></blockquote>Attempts at replication by other research teams have produced contradictory results. Meyer et al. were unable to confirm most of the post-exertional increases in gene expression, except for some in the adrenergic and glucocorticoid pathway.<ref>{{Cite journal|last=Meyer|first=Jacob|last2=R. Light|first2=Alan|last3=Shukla|first3=Sanjay|last4=Clevidence|first4=Derek|last5=Yale|first5=Steven|last6=Stegner|first6=Aaron|last7=Cook|first7=Dane|date=2013-10-01|title=Post-exertion malaise in chronic fatigue syndrome: Symptoms and gene expression|url=https://www.researchgate.net/publication/258165434_Post-exertion_malaise_in_chronic_fatigue_syndrome_Symptoms_and_gene_expression|journal=Fatigue: Biomedicine, Health & Behavior|volume=1|pages=190–209|doi=10.1080/21641846.2013.838444}}</ref> An [[Australia|Australian]] team under the guidance of [[Andrew Lloyd]] failed to find any significant exercise-induced changes in leucocyte gene expression, though the patient sample used (n = 10) was rather small and did not include any patients with severe [[functional disability]].<ref>{{Cite journal|last=Keech|first=Andrew|last2=Vollmer-Conna|first2=Ute|last3=Barry|first3=Benjamin K.|last4=Lloyd|first4=Andrew R.|date=2016|title=Gene Expression in Response to Exercise in Patients with Chronic Fatigue Syndrome: A Pilot Study|url=https://www.ncbi.nlm.nih.gov/pubmed/27713703|journal=Frontiers in Physiology|volume=7|pages=421|doi=10.3389/fphys.2016.00421|issn=1664-042X|pmc=5031769|pmid=27713703}}</ref>

=== Immune activation ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence'' (2015) By Dr. Peter Rowe/Solve CFS">https://www.youtube.com/watch?v=ux93w7yGQ5g</embedvideo>
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref>{{Cite journal|last=Nijs|first=Jo|last2=Nees|first2=Andrea|last3=Paul|first3=Lorna|last4=De Kooning|first4=Margot|last5=Ickmans|first5=Kelly|last6=Meeus|first6=Mira|last7=Van Oosterwijck|first7=Jessica|date=2014|title=Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review|url=https://www.ncbi.nlm.nih.gov/pubmed/24974723|journal=Exercise Immunology Review|volume=20|pages=94–116|issn=1077-5552|pmid=24974723}}</ref> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertion Malaise: The Intersection of Biology and Behavior'' (2015) By Dr. Dane B. Cook/Solve CFS">https://www.youtube.com/watch?v=vfmrPd4-rIE</embedvideo>
In 2005 the French team Yammes et al. found a lengthened and accentuated oxidative stress response in ME/CFS patients after a cycling exercise until exhaustion. At baseline markers of [[oxidative stress]] (thiobarbituric acidreactiv substances and ascorbic acid) did not differ significantly from healthy controls. After the exercise challenge however, the oxidative stress response occurred sooner and lasted longer in the ME/CFS group. This was associated with alterations in muscle excitability (lengthened [[M-wave]] duration) in ME/CFS-patients, which were not seen in controls.<ref>{{Cite journal|last=Jammes|first=Y.|last2=Steinberg|first2=J. G.|last3=Mambrini|first3=O.|last4=Brégeon|first4=F.|last5=Delliaux|first5=S.|date=Mar 2005|title=Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/15715687|journal=Journal of Internal Medicine|volume=257|issue=3|pages=299–310|doi=10.1111/j.1365-2796.2005.01452.x|issn=0954-6820|pmid=15715687}}</ref> A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of [[Heat shock protein|heat shock proteins]] HSP 27 and HSP 70 after exercise.<ref name=":25">{{Cite journal|last=Jammes|first=Y.|last2=Steinberg|first2=J. G.|last3=Delliaux|first3=S.|last4=Brégeon|first4=F.|date=Aug 2009|title=Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses|url=https://www.ncbi.nlm.nih.gov/pubmed/19457057|journal=Journal of Internal Medicine|volume=266|issue=2|pages=196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796|pmid=19457057}}</ref> According to the authors, this is another indication of an impaired redox status in ME/CFS patients. A 2011 study confirmed most of these results in a larger cohort of 43 ME/CFS patients and 23 healthy controls. Again the data indicated an increased exercise-induced oxidative stress and a reduced Hsp response. Though it is know that deconditioning can increase oxidative stress, the authors argued this to be unlikely in their study population, for several reasons: <blockquote>“…deconditioning can be ruled out in our study because (i) it induces carbohydrate and lipid disorders that were not observed during routine biochemical check-up in these CFS patients, (ii) CFS patients did not have reduced maximal exercise performance or an accentuated lactic acid response and (iii) we found no correlation between the duration of CFS symptoms […] and the resting levels of oxidant–antioxidant status and HSPs.”<ref>{{Cite journal|last=Jammes|first=Y.|last2=Steinberg|first2=J. G.|last3=Delliaux|first3=S.|date=Jul 2012|title=Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins|url=https://www.ncbi.nlm.nih.gov/pubmed/22112145|journal=Journal of Internal Medicine|volume=272|issue=1|pages=74–84|doi=10.1111/j.1365-2796.2011.02488.x|issn=1365-2796|pmid=22112145}}</ref></blockquote>A [[Canada|Canadian]] research team had already reported a marked decline of HSP 27 during the post-exercise period of six ME/CFS patients in 2002.<ref>{{Cite journal|last=Thambirajah|first=Anita A.|last2=Sleigh|first2=Kenna|last3=Stiver|first3=H. Grant|last4=Chow|first4=Anthony W.|date=2008-12-01|title=Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/19032901|journal=Clinical and Investigative Medicine. Medecine Clinique Et Experimentale|volume=31|issue=6|pages=E319–327|issn=1488-2353|pmid=19032901}}</ref>

==== Complement C4a ====
In 2003 Sorensen et al. found that the [[Complement C4a|complement split product C4a]] was increased after exercise in the 20 ME/CFS patients, but not in controls. Furthermore a significant correlation was found between the increase in C4a and total symptom score.<ref>{{Cite journal|last=Sorensen|first=Bristol|last2=Streib|first2=Joanne E.|last3=Strand|first3=Matthew|last4=Make|first4=Barry|last5=Giclas|first5=Patricia C.|last6=Fleshner|first6=Monika|last7=Jones|first7=James F.|date=Aug 2003|title=Complement activation in a model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12897748|journal=The Journal of Allergy and Clinical Immunology|volume=112|issue=2|pages=397–403|issn=0091-6749|pmid=12897748}}</ref> C4a is generated from the cleavage of the native complement protein C4 via the classical and lectin pathways. A follow up study, published in 2009, found that other elements of the lectin pathway also responded differently to an exercise challenge in ME/CFS patients compared to controls. Both C4 and mannan-binding lectin serine protease 2 (MASP2) were observed at higher levels in ME/CFS subjects 1 hour post-exercise.<ref>{{Cite journal|last=Sorensen|first=Bristol|author-link=|last2=Jones|first2=James F|author-link2=|last3=Vernon|first3=Suzanne D|author-link3=Suzanne Vernon|last4=Rajeevan|first4=Mangalathu S|author-link4=Mangalathu Rajeevan|author-link5=|date=Jan 2009|title=Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/|journal=Molecular Medicine|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|pmc=2583111|pmid=19015737|quote=|via=}}</ref> The authors speculated this to contribute to the increased C4a split product 6 hours after the exercise challenge. In a 2010 study by Nijs et al. there was no increase in C4a after exercise in ME/CFS patients, though a significant correlation with post-exertional pain and fatigue was found.<ref>{{Cite journal|last=Nijs|first=J.|last2=Van Oosterwijck|first2=J.|last3=Meeus|first3=M.|last4=Lambrecht|first4=L.|last5=Metzger|first5=K.|last6=Frémont|first6=M.|last7=Paul|first7=L.|date=Apr 2010|title=Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02178.x|journal=Journal of Internal Medicine|volume=267|issue=4|pages=418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=0954-6820}}</ref>
==== Cytokines ====
The expression of cytokines after physical exercise has been researched in ME/CFS patients since the mid-1990s. Most of these studies have found negative results (see table below).

{| class="wikitable"
|Study
|Number of participants
|Exercise challenge
|Cytokines tested:
|Results:
|-
|[[Daniel Peterson|Peterson]] et al. (1994)<ref>{{Cite journal|last=Peterson|first=P. K.|last2=Sirr|first2=S. A.|last3=Grammith|first3=F. C.|last4=Schenck|first4=C. H.|last5=Pheley|first5=A. M.|last6=Hu|first6=S.|last7=Chao|first7=C. C.|date=Mar 1994|title=Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7496949|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>
|10 ([[Holmes criteria]], all cases were post-infectious)
|Walking 1 mile per hour for 30 min
|[[Interleukin 1 beta|IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF beta|TGF-β]]
|Negative results
|-
|[[Andrew Lloyd|Lloyd]] et al. (1994)<ref>{{Cite journal|last=Lloyd|first=A.|last2=Gandevia|first2=S.|last3=Brockman|first3=A.|last4=Hales|first4=J.|last5=Wakefield|first5=D.|date=Jan 1994|title=Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/8148442|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|12 ([[Australian criteria]])
|30 min hand grip exercises
|[[Interferon gamma|IFN-γ]], [[Interferon alpha |IFN-α]], [[Interleukin 1 beta|IL-1 β]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|[[La Manca]] et al. (1999)<ref>{{Cite journal|last=LaManca|first=J. J.|last2=Sisto|first2=S. A.|last3=Zhou|first3=X. D.|last4=Ottenweller|first4=J. E.|last5=Cook|first5=S.|last6=Peckerman|first6=A.|last7=Zhang|first7=Q.|last8=Denny|first8=T. N.|last9=Gause|first9=W. C.|date=Mar 1999|title=Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion|url=https://www.ncbi.nlm.nih.gov/pubmed/10226888|journal=Journal of Clinical Immunology|volume=19|issue=2|pages=135–142|issn=0271-9142|pmid=10226888}}</ref>
|20 ([[Fukuda criteria]]) "only patients with an illness duration of less than 6 years, who reported at least substantial intensity on symptom severity scales in the month prior to recruitment and who had no major psychiatric diagnosis in the 5 years prior to illness onset" were included
|An exhaustive treadmill exercise test
|[[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]]<nowiki>, [[Interferon gamma|IFN-γ, </nowiki>[[TNF-alpha|TNF-α]]
|Negative results
|-
|Cannon et al. (1997)<ref>{{Cite journal|last=Cannon|first=J. G.|last2=Angel|first2=J. B.|last3=Abad|first3=L. W.|last4=Vannier|first4=E.|last5=Mileno|first5=M. D.|last6=Fagioli|first6=L.|last7=Wolff|first7=S. M.|last8=Komaroff|first8=A. L.|date=May 1997|title=Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9168406|journal=Journal of Clinical Immunology|volume=17|issue=3|pages=253–261|issn=0271-9142|pmid=9168406}}</ref>
|8 (Holmes criteria) “their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin-1 receptor antagonist]] (IL-1Ra), and [[soluble interleukin-1 receptor type II]] (IL-lsRII).
|Negative results
|-
|Gupta et al. (1998)<ref>{{Cite journal|last=Gupta|first=S.|last2=Aggarwal|first2=S.|last3=Starr|first3=A.|date=Feb 1999|title=Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during 'natural fatigue' but not following 'experimental fatigue' in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9917531|journal=International Journal of Molecular Medicine|volume=3|issue=2|pages=209–213|issn=1107-3756|pmid=9917531}}</ref>
|5 (Holmes criteria)
|30 min hand grip exercises
|[[Interleukin 6|IL-6]]
|Negative results
|-
|Cannon et al. (1999)<ref>{{Cite journal|last=Cannon|first=J. G.|last2=Angel|first2=J. B.|last3=Ball|first3=R. W.|last4=Abad|first4=L. W.|last5=Fagioli|first5=L.|last6=Komaroff|first6=A. L.|date=Nov 1999|title=Acute phase responses and cytokine secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10634215|journal=Journal of Clinical Immunology|volume=19|issue=6|pages=414–421|issn=0271-9142|pmid=10634215}}</ref>
|10 (Holmes criteria) their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]],[[IL-6]]
|Negative results
|-
|Yammes et al. (2009)<ref name=":25" />
|9 ([[Fukuda criteria]]) 6/9 had practiced sport at high levelxxxxxxxx, for more than 4 years before the symptoms occurred.
|Cycling test until maximal work load
|[[IL-6]], [[TNF-a]]
|Negative results
|-
|Robinson et al (2010)<ref>{{Cite journal|last=Robinson|first=M.|last2=Gray|first2=S. R.|last3=Watson|first3=M. S.|last4=Kennedy|first4=G.|last5=Hill|first5=A.|last6=Belch|first6=J. J. F.|last7=Nimmo|first7=M. A.|date=Apr 2010|title=Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19422646|journal=Scandinavian Journal of Medicine & Science in Sports|volume=20|issue=2|pages=282–290|doi=10.1111/j.1600-0838.2009.00895.x|issn=1600-0838|pmid=19422646}}</ref>
|6 (Fukuda criteria)
|Incremental exercise test to exhaustion
|IL-6, [[sIL-6R]] and [[sgp130]]
|Negative results
|-
|[[Andrea White]] et al. (2010)<ref name=":26">{{Cite journal|last=White|first=Andrea T.|last2=Light|first2=Alan R.|last3=Hughen|first3=Ronald W.|last4=Bateman|first4=Lucinda|last5=Martins|first5=Thomas B.|last6=Hill|first6=Harry R.|last7=Light|first7=Kathleen C.|date=2010-07-01|title=Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20230500|journal=Psychophysiology|volume=47|issue=4|pages=615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1540-5958|pmc=4378647|pmid=20230500}}</ref>
|19 (Fukuda criteria)
|The authors used "a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients."
|[[Interleukin 1 beta |IL-1β]], [[Interleukin 2 |IL-2]], [[Interleukin 12|IL-12]], [[TNF-alpha |TNFα]], soluble [[CD40L]], [[Interferon gamma |IFN-γ]], [[Interleukin 4|IL-4]], [[Interleukin 10 |IL-10]], [[Interleukin 13|IL-13]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]

 
|Positive results for a subgroup (11/19) of patients with high PEM

 
|-
|Andrew Lloyd et al. (2018)<ref name=":27">{{Cite journal|last=Moneghetti|first=Kegan J.|last2=Skhiri|first2=Mehdi|last3=Contrepois|first3=Kévin|last4=Kobayashi|first4=Yukari|last5=Maecker|first5=Holden|last6=Davis|first6=Mark|last7=Snyder|first7=Michael|last8=Haddad|first8=Francois|last9=Montoya|first9=Jose G.|date=2018-02-09|title=Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.nature.com/articles/s41598-018-20941-w|journal=Scientific Reports|language=En|volume=8|issue=1|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref>
|24 ([[Fukuda criteria]]) “we used the 1994 Centers for Disease Control (CDC)/Fukuda international diagnostic criteria for ME/CFS, but required participants to have post exertional malaise. Terefore, in labeling our patients this refers to the revised [[International Consensus Criteria|international consensus criteria]] from 2011”
|Symptom limited exercise on an ergocycle.
|Growth factors: [[FGF beta|FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGF alpha|TGFα]], [[TGF-β1]], [[Vascular endothelial growth factor|VEGF]]

 

[[Colony stimulating factors]] and [[stem cell factors]]: [[G-CSF]], [[GM-CSF]], [[M-CSF]], [[SCF]]

 

Interleukins: [[Interleukin 1alpha|IL-1α]], [[Interleukin 1beta|IL-1β]], [[Interleukin 1RA|IL-1RA]], [[Interleukin 2|IL-2]], [[IL-4]], [[IL-5]], [[IL-6]], [[Interleukin 7|IL-7]], [[Interleukin |IL-8]], [[Interleukin 10|IL-10]], [[Interleukin 12p40|IL12p40]], [[Interleukin 12p70|IL12p70]], [[Interleukin 13|IL-13]], [[Interleukin 15|IL-15]], [[Interleukin 17|IL-17]], [[Interleukin 17f|IL-17F]], [[Interleukin 18|IL-18]] and [[LIF]]

 

[[Chemokine|Chemokines]]: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[CCL5]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro alpha|Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])

 

[[Interferon|Interferons]]: [[Interferon alpha |INF-α]], [[Interferon beta |INF-β]], [[Interferon gamma|INF-γ]]

 

[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]

 

Other factors: [[CD40L]], [[FASL]], [[Leptin]], [[PAI-1]], [[Resistin]], [[TNF-α]], [[TNF-β]], [[TRAIL]]
|Positive results: ME/CFS had a distinct [[cytokine profile]] post-exercise.
|}
Moneghetti et al. took a different approach and looked at the cytokine profiling after exercise, as this may differentiate patients with ME/CFS from sedentary controls. Of the 51 [[cytokine]]s and growth factors tested, 10 significantly changed after exercise in both groups, a further 7 only changed in controls and five only changed in ME/CFS (namely, [[CXCL10]], [[IL-8]], [[CCL4]], [[TNF-β]] and [[ICAM-1]]). This suggests a distinct [[cytokine inflammatory signature]] in ME/CFS.<ref name=":27" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare SF, in the study). While the cytokine expression after exercise of patients with low PEM was similar to those of healthy controls, patients with high PEM showed opposite results. As the authors noted:<blockquote>"In sum, low SF patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in IL-8), whereas the high SF patients showed a pattern of increases in both cytokine types at 8 h and no decreases at any time."<ref name=":26" /></blockquote>

=== Autonomic response ===
Several research teams have noted post-exertional abnormalities in the [[Autonomic nervous system|autonomic]] function of ME/CFS patients, though the exact meaning of these results is not yet clear.

A Canadian team under the guidance of [[Terrence Montague]] noted that during a maximal exercise test, ME/CFS patients have a lower maximal heart rate than controls. The authors noted that: <blockquote>“...patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved.”<ref>{{Cite journal|last=Montague|first=T.J.|last2=Marrie|first2=T.J.|last3=Klassen|first3=G.A.|last4=Bewick|first4=D.J.|last5=Horacek|first5=B.M.|date=Apr 1989|title=Cardiac function at rest and with exercise in the chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/2924607|journal=Chest|volume=95|issue=4|pages=779–784|issn=0012-3692|pmid=2924607}}</ref> </blockquote>A significantly lower peak heart rate has been repeatedly observed in CPET-studies with ME/CFS patients.<ref>{{Cite journal|last=Gibson|first=H|last2=Carroll|first2=N|last3=Clague|first3=J E|last4=Edwards|first4=R H|date=Sep 1993|title=Exercise performance and fatiguability in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC489735/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=56|issue=9|pages=993–998|issn=0022-3050|pmid=8410041}}</ref><ref>{{Cite journal|last=Sisto|first=Sue Ann|last2=LaManca|first2=John|last3=Cordero|first3=Douglas L.|last4=Bergen|first4=Michael T.|last5=Ellis|first5=Steven P.|last6=Drastal|first6=Susan|last7=Boda|first7=Wanda L.|last8=Tapp|first8=Walter N.|last9=Natelson|first9=Benjamin H.|date=Jun 1996|title=Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(96)00041-1/pdf|journal=The American Journal of Medicine|language=English|volume=100|issue=6|pages=634–640|doi=10.1016/S0002-9343(96)00041-1|issn=0002-9343}}</ref><ref>{{Cite journal|last=Rowbottom|first=David|last2=Keast|first2=David|last3=Pervan|first3=Zhukov|last4=Morton|first4=Alan|date=Jan 1998|title=The Physiological Response to Exercise in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n02_04|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=4|issue=2|pages=33–49|doi=10.1300/j092v04n02_04|issn=1057-3321}}</ref> In one of the largest of these into exercise performance, the authors noted the same phenomenon as Montague et al. <blockquote>“The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects.”<ref>{{Cite journal|last=De Becker|first=P.|last2=Roeykens|first2=J.|last3=Reynders|first3=M.|last4=McGregor|first4=N.|last5=De Meirleir|first5=K.|date=2000-11-27|title=Exercise capacity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/11088089|journal=Archives of Internal Medicine|volume=160|issue=21|pages=3270–3277|issn=0003-9926|pmid=11088089}}</ref></blockquote>The Belgium team Van Oosterwijck et al. reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref>{{Cite journal|last=Van Oosterwijck|first=J.|last2=Marusic|first2=U.|last3=De Wandele|first3=I.|last4=Meeus|first4=M.|last5=Paul|first5=L.|last6=Lambrecht|first6=L.|last7=Moorkens|first7=G.|last8=Nijs|first8=J.|date=May 2015|title=Reduced parasympathetic reactivation during recovery from exercise in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)|url=https://www.physiotherapyjournal.com/article/S0031-9406(15)02014-3/fulltext|journal=Physiotherapy|language=English|volume=101|pages=e1091–e1092|doi=10.1016/j.physio.2015.03.1984|issn=0031-9406|issue=|quote=|author-link=Jessica Van Oosterwijck|author-link2=|author-link3=|author-link4=|author-link5=|via=|author-link8=Jo Nijs}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. did not find a significant difference in mean heart rate between 11 ME/CFS patients and six healthy controls after walking on a treadmill, but they did find patients to have significantly less ‘vagal power’, a measure for respiratory-related parasympathetic contributions to heart rate.<ref>{{Cite journal|last=Cordero|first=D. L.|last2=Sisto|first2=S. A.|last3=Tapp|first3=W. N.|last4=LaManca|first4=J. J.|last5=Pareja|first5=J. G.|last6=Natelson|first6=B. H.|date=Dec 1996|title=Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8985621|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=6|issue=6|pages=329–333|issn=0959-9851|pmid=8985621}}</ref> Soetekouw et al. noted that during a handgrip exercise, the hemodynamics response was lower in the ME/CFS group than in the control group, although this could be attributed to the lower level of muscle exertion in the ME/CFS group.<ref>{{Cite journal|last=Soetekouw|first=P. M.|last2=Lenders|first2=J. W.|last3=Bleijenberg|first3=G.|last4=Thien|first4=T.|last5=van der Meer|first5=J. W.|date=Dec 1999|title=Autonomic function in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10638807|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=9|issue=6|pages=334–340|issn=0959-9851|pmid=10638807}}</ref> LaManca et al. studied 19 ME/CFS (Holmes criteria) and found that they had a diminished heart rate and blood pressure in response to a cognitive test compared to healthy controls, though exercise did not magnify this effect.<ref>{{Cite journal|last=LaManca|first=J. J.|last2=Peckerman|first2=A.|last3=Sisto|first3=S. A.|last4=DeLuca|first4=J.|last5=Cook|first5=S.|last6=Natelson|first6=B. H.|date=Sep 2001|title=Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/11573024|journal=Psychosomatic Medicine|volume=63|issue=5|pages=756–764|issn=0033-3174|pmid=11573024}}</ref> Similar results were found by a Norwegian research team. They studied 13 adolescents with ME/CFS and 53 age-matched controls after a mental stress test (arithmetic questions). Though heart rate was significantly higher in patients at baseline, there were no meaningful differences during the arithmetic challenge.<ref>{{Cite journal|last=Egge|first=Caroline|last2=Wyller|first2=Vegard Bruun|date=2010-12-14|title=No differences in cardiovascular autonomic responses to mental stress in chronic fatigue syndrome adolescents as compared to healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/21156045|journal=BioPsychoSocial Medicine|volume=4|pages=22|doi=10.1186/1751-0759-4-22|issn=1751-0759|pmc=3012010|pmid=21156045}}</ref> Finally, Ocon et al. (2012) studied 16 patients with both the diagnosis of ME/CFS and POTS after increased orthostatic stress and a cognitive challenge. An impairment of the neurocognitive abilities was noted, that was not seen in healthy controls.<ref>{{Cite journal|last=Ocon|first=Anthony J.|last2=Messer|first2=Zachary R.|last3=Medow|first3=Marvin S.|last4=Stewart|first4=Julian M.|date=Mar 2012|title=Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/21919887|journal=Clinical Science (London, England: 1979)|volume=122|issue=5|pages=227–238|doi=10.1042/CS20110241|issn=1470-8736|pmc=3368269|pmid=21919887}}</ref>

=== Sleep ===
A first study into the effects of exercise on sleep in ME/CFS found a beneficial effect: approximately half the patients slept better after exercise.<ref>{{Cite journal|last=Togo|first=Fumiharu|last2=Natelson|first2=Benjamin H.|last3=Cherniack|first3=Neil S.|last4=Klapholz|first4=Marc|last5=Rapoport|first5=David M.|last6=Cook|first6=Dane B.|date=Jan 2010|title=Sleep is not disrupted by exercise in patients with chronic fatigue syndromes|url=https://www.ncbi.nlm.nih.gov/pubmed/20010134|journal=Medicine and Science in Sports and Exercise|volume=42|issue=1|pages=16–22|doi=10.1249/MSS.0b013e3181b11bc7|issn=1530-0315|pmc=2796587|pmid=20010134}}</ref> A follow-up study by the same research team (under the guidance of Benjamin Natelson) found more post-exercise improvement (transitions to deeper [[sleep stages]]) of sleep in ME/CFS patients than in controls. The patients, however, reported more fatigue in the morning after exercise while healthy controls showed significant improvement in sleepiness and fatigue. The authors speculated this to be due to a disruption of the [[REM]] sleep: ME/CFS showed, both at baseline and post-exercise, an increased rate of transition from REM to wake compared to controls and this correlated with symptoms of fatigue, pain and sleepiness.<ref>{{Cite journal|last=Kishi|first=Akifumi|last2=Togo|first2=Fumiharu|last3=Cook|first3=Dane B|last4=Klapholz|first4=Marc|last5=Yamamoto|first5=Yoshiharu|last6=Rapoport|first6=David M|last7=Natelson|first7=Benjamin H|date=Nov 2013|title=The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871467/|journal=Physiological Reports|volume=1|issue=6|doi=10.1002/phy2.152|issn=2051-817X|pmc=3871467|pmid=24400154}}</ref> An Australian study followed up on 35 ME/CFS patients after performing a physical (stationary cycling) or cognitive (stimulated driving) challenge. While patients spent a greater proportion of wakeful hours lying down, they did not report significant changes in sleep quality or sleep duration. The authors did however note that the expected increase in [[heart rate variability]] (HRV) between wake and sleep, was significantly reduced in ME/CFS patients after completing the challenges. These changes in HRV have been associated with the falling asleep, and might be related to the unfreshed sleep of ME/CFS patients.<ref>{{Cite journal|last=Cvejic|first=Erin|last2=Sandler|first2=Carolina X.|last3=Keech|first3=Andrew|last4=Barry|first4=Benjamin K.|last5=Lloyd|first5=Andrew R.|last6=Vollmer-Conna|first6=Uté|date=Dec 2017|title=Autonomic nervous system function, activity patterns, and sleep after physical or cognitive challenge in people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29167053|journal=Journal of Psychosomatic Research|volume=103|pages=91–94|doi=10.1016/j.jpsychores.2017.10.010|issn=1879-1360|pmid=29167053}}</ref> Finally, Ohashi et al. recorded physical activity for 6-days in 10 patients with ME/CFS and 6 controls before and after performing a maximal treadmill test. Their results indicate an increase in [[circadian]] rest-activity in ME/CFS patients after exercise as the activity pattern of patients shifted toward later hours in the day.<ref>{{Cite journal|last=Ohashi|first=Kyoko|last2=Yamamoto|first2=Yoshiharu|last3=Natelson|first3=Benjamin H.|date=Sep 2002|title=Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12213500|journal=Physiology & Behavior|volume=77|issue=1|pages=39–44|issn=0031-9384|pmid=12213500}}</ref>
=== Cognitive performance ===
While some studies have found a decreased cognitive performance after exercise in ME/CFS, others have not (see table below).<ref name=":0" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|Study
|Number of ME/CFS subjects
|Neurocognitive tests
|Results
|-
|[[Marshall]] et al. (1997)<ref>{{Cite journal|last=Marshall|first=P. S.|last2=Forstot|first2=M.|last3=Callies|first3=A.|last4=Peterson|first4=P. K.|last5=Schenck|first5=C. H.|date=Jan 1997|title=Cognitive slowing and working memory difficulties in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9021867|journal=Psychosomatic Medicine|volume=59|issue=1|pages=58–66|issn=0033-3174|pmid=9021867}}</ref>
|8
|Buschke Selective Reminding Test, Continuous-Performance Test-Identical Pairs Version (CPTIP), Paced Auditory Serial Addition Task (PASAT), Stroop Color Word Test, Reaction-Time Tests, Salthouse Reading Span Task (SRST), Verbal Scholastic Aptitude Test (SAT).
|Negative
|-
|[[Blackwood]] et al. (1998)<ref>{{Cite journal|last=Blackwood|first=S.|last2=MacHale|first2=S.|last3=Power|first3=M.|last4=Goodwin|first4=G.|last5=Lawrie|first5=S.|date=Oct 1998|title=Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170292/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=65|issue=4|pages=541–546|issn=0022-3050|pmc=2170292|pmid=9771781}}</ref>
|10
|"The following aspects of cognitive function were examined (in order): working memory/auditory attention (digit span, from WAIS-R); psychomotor speed (digit symbol, also from WAIS-R); word fluency (FAS test, using the letters F and S only); and selective attention and sustained attention (telephone search and lottery tasks respectively, both from the test of everyday attention)”
|Positive
|-
|[[La Manca]] et al. (1998)<ref>{{Cite journal|last=LaManca|first=J. J.|last2=Sisto|first2=S. A.|last3=DeLuca|first3=J.|last4=Johnson|first4=S. K.|last5=Lange|first5=G.|last6=Pareja|first6=J.|last7=Cook|first7=S.|last8=Natelson|first8=B. H.|date=1998-09-28|title=Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9790484|journal=The American Journal of Medicine|volume=105|issue=3A|pages=59S–65S|issn=0002-9343|pmid=9790484}}</ref>
|19
|The Stroop Color and Word Test, the Symbol Digit Modalities Test (SDMT), an oral version of the Trail Making Test (TMT) and the Serial 13s Test (STT)
|Positive
|-
|[[Claypoole]] et al. (2001)<ref>{{Cite journal|last=Claypoole|first=Keith|last2=Mahurin|first2=Roderick|last3=Fischer|first3=Mary E.|last4=Goldberg|first4=Jack|last5=Schmaling|first5=Karen B.|last6=Schoene|first6=Robert B.|last7=Ashton|first7=Suzanne|last8=Buchwald|first8=Dedra|date=Mar 2001|title=Cognitive Compromise Following Exercise in Monozygotic Twins Discordant for Chronic Fatigue Syndrome: Fact or Artifact?|url=http://dx.doi.org/10.1207/s15324826an0801_5|journal=Applied Neuropsychology|volume=8|issue=1|pages=31–40|doi=10.1207/s15324826an0801_5|issn=0908-4282}}</ref>
|21
|The Wechsler Adult Intelligence Scale–Revised, Digit Span Forward and Backward subtests, The Hopkins Verbal Learning Test, . The Digit Vigilance Test, the Lafayette Clinic Repeatable Neuropsychological Test Battery, Controlled Oral Word Association Test (COWAT)
|Negative
|-
|[[Dane Cook|Cook]] et al. (2005)<ref>{{Cite journal|last=Cook|first=Dane B.|last2=Nagelkirk|first2=Paul R.|last3=Peckerman|first3=Arnold|last4=Poluri|first4=Ashok|last5=Mores|first5=John|last6=Natelson|first6=Benjamin H.|date=Sep 2005|title=Exercise and cognitive performance in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16177595|journal=Medicine and Science in Sports and Exercise|volume=37|issue=9|pages=1460–1467|issn=0195-9131|pmid=16177595}}</ref>
|20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia
|Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)
|Negative
|-
|[[Yoshiuchi]] et al. (2007)<ref>{{Cite journal|last=Yoshiuchi|first=Kazuhiro|last2=Cook|first2=Dane B.|last3=Ohashi|first3=Kyoko|last4=Kumano|first4=Hiroaki|last5=Kuboki|first5=Tomifusa|last6=Yamamoto|first6=Yoshiharu|last7=Natelson|first7=Benjamin H.|date=2007-12-05|title=A real-time assessment of the effect of exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5|pages=963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref>
|9
|A one-back memory task
|Negative
|-
|Cook et al. (2017)<ref name=":33">{{Cite journal|date=2017-05-01|title=Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.sciencedirect.com/science/article/pii/S088915911730051X|journal=Brain, Behavior, and Immunity|language=en|volume=62|pages=87–99|doi=10.1016/j.bbi.2017.02.009|issn=0889-1591}}</ref>
|15
|The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task
|Positive
|}

=== Pain modulation ===
Another post-exertional abnormality reported in ME/CFS is pain modulation. When healthy people exercise, their brain produces [[endorphins]] that increase pain thresholds. In some chronic pain patients like [[fibromyalgia]] and whiplash associated disorders, this endogenous pain inhibition response is defect and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004 Whiteside et al. first showed this defect in ME/CFS patients.<ref name=":22" /> These results were confirmed by two studies by the Belgium pain in motion team: while pain thresholds increased in normal controls they decreased in the ME/CFS patient group.<ref name=":23" /><ref name=":24" /> As a caveat, one must note that these studies only included ME/CFS patients that were suffering from chronic pain, while comorbid FM was not assessed. So it remains unclear if these results will also show up in ME/CFS patients that do not have comorbid FM.<ref>{{Cite journal|last=Yunus|first=Muhammad|date=2015-07-02|title=Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)|url=http://dx.doi.org/10.2174/157339711102150702112236|journal=Current Rheumatology Reviews|language=en|volume=11|issue=2|pages=70–85|doi=10.2174/157339711102150702112236|issn=1573-3971}}</ref>

=== Other ===

==== The gut microbiome ====
Shukla et al. (2015) found post-exertional changes in the gut microbiome in ME/CFS patients that were not seen in healthy controls. Increased clearance of bacteria in the blood was also noted, which made the authors speculate that exercise induced a bacterial translocation in ME/CFS patients.<ref>{{Cite journal|last=Shukla|first=Sanjay K.|last2=Cook|first2=Dane|last3=Meyer|first3=Jacob|last4=Vernon|first4=Suzanne D.|last5=Le|first5=Thao|last6=Clevidence|first6=Derek|last7=Robertson|first7=Charles E.|last8=Schrodi|first8=Steven J.|last9=Yale|first9=Steven|date=2015-12-18|title=Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)|url=http://dx.doi.org/10.1371/journal.pone.0145453|journal=PLOS ONE|volume=10|issue=12|pages=e0145453|doi=10.1371/journal.pone.0145453|issn=1932-6203}}</ref>

==== Catecholaminergic hyporeactivity ====
Strahler et al. found that ME/CFS patients showed an attenuated response (lower increases) of epinephrine to an exercise challenge, compared to heathy controls. This ‘catecholaminergic hyporeactivity’ was however subtle and short-lived.<ref>{{Cite journal|last=Strahler|first=Jana|last2=Fischer|first2=Susanne|last3=Nater|first3=Urs M.|last4=Ehlert|first4=Ulrike|last5=Gaab|first5=Jens|date=Sep 2013|title=Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23770415|journal=Biological Psychology|volume=94|issue=1|pages=160–166|doi=10.1016/j.biopsycho.2013.06.002|issn=1873-6246|pmid=23770415}}</ref>

==== Nitric oxide metabolites ====
A [[Spain|Spanish]] research team found much higher increases of nitric oxide metabolites (nitrates) after a maximal exercise test in 44 ME/CFS patients compared to 25 healthy controls while there were no differences between the groups at baseline.<ref>{{Cite journal|last=Suárez|first=Andrea|last2=Guillamó|first2=Elisabet|last3=Roig|first3=Teresa|last4=Blázquez|first4=Alicia|last5=Alegre|first5=José|last6=Bermúdez|first6=Jordi|last7=Ventura|first7=José Luis|last8=García-Quintana|first8=Ana María|last9=Comella|first9=Agustí|date=Jun 2010|title=Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study|url=http://dx.doi.org/10.1089/jwh.2008.1255|journal=Journal of Women's Health|volume=19|issue=6|pages=1073–1077|doi=10.1089/jwh.2008.1255|issn=1540-9996}}</ref>

== Problems in defining PEM ==

=== Asking the right questions ===
[[Leonard Jason|Jason]] et al. (1999) reported that in a group of ME/CFS patients, the percentage endorsing PEM ranged from 40,6 to 93,8% depending on how the question assessed this symptom.<ref>{{Cite web|url=https://www.meassociation.org.uk/2012/04/to-pem-or-not-to-pem-that-is-the-question-for-case-definition-research-1st-website-27-april-2012/|title=To PEM or not to PEM? That is the question for case definition {{!}} Research 1st website|date=27 April 2012|website=www.meassociation.org.uk|language=en-US|access-date=2018-10-10}}</ref> The report of the National Academy of Medicine noted that “the prevalence of PEM among ME/CFS patients as diagnosed by existing criteria varies from 69 to 100 percent.”<ref name=":0" />

Some patients try to reduce post-exertional relapses by pacing themselves and reducing exertion that exceeds their energy limits. Questionnaires assessing PEM by frequency instead of propensity, might erroneously label these patients as not having PEM. In a 2015 study, Jason et al. measured ME/CFS patients’ responses to the PEM-criterion in the [[Keiji Fukida|Fukuda]] et al. (1994) definition: ‘Do you feel generally worse than usual or fatigued for 24 hours or more after you have exercised?’ Although the majority (75%) endorsed this item, a notable percentage (25%) did not. Yet when the question was framed differently, leaving out the 24 hours’ time period and substituting exercise with normal daily activity, these participants also agreed they experienced high levels of fatigue after normal daily activity.<ref name=":19" /> This clearly shows that patients who have already modified their activities to avoid or reduce PEM may potentially show up as false negatives.

Another issue is the definition of PEM in the Fukuda-criteria. While the wording used here is vague, the time criterion is rather strict requiring PEM to last more than 24 hours. Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref>{{Cite journal|last=Jason|first=Leonard A.|last2=King|first2=Caroline P.|last3=Richman|first3=Judith A.|last4=Taylor|first4=Renee R.|last5=Torres|first5=Susan R.|last6=Song|first6=Sharon|date=Jan 1999|title=U.S. Case Definition of Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v05n03_02?journalCode=icfs20|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=5|issue=3-4|pages=3–33|doi=10.1300/j092v05n03_02|issn=1057-3321}}</ref> A 2018 study concluded that setting the criterion at 24 hours would exclude almost 30% of ME/CFS patients. It advises that this definition might be useful in research settings but that in a clinical context, a 14-23 hour time period might be more appropriate.<ref>{{Cite journal|last=Cotler|first=Joseph|last2=Holtzman|first2=Carly|last3=Dudun|first3=Catherine|last4=Jason|first4=Leonard A.|date=2018-09-11|title=A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref>

These observations point to the need of a more precise definition of PEM and several attempts to this end have been made.
=== More than just fatigue and pain ===
Few instruments have assessed PEM adequately. The [[CDC 2005 Symptom Inventory for CFS|CDC symptom inventory]] for example, only asks about fatigue after exertion, while PEM entails much more than that. An [[Australia|Australian]] group at the University of New South Wales tried to better define PEM, using 19 ME/CFS patients after exposure to different stressors.<ref>{{Cite journal|last=Keech|first=Andrew|last2=Sandler|first2=Carolina X.|last3=Vollmer-Conna|first3=Ute|last4=Cvejic|first4=Erin|last5=Lloyd|first5=Andrew R.|last6=Barry|first6=Benjamin K.|date=Dec 2015|title=Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26359713|journal=Journal of Psychosomatic Research|volume=79|issue=6|pages=537–549|doi=10.1016/j.jpsychores.2015.08.008|issn=1879-1360|pmid=26359713}}</ref> Participants indicated that the term fatigue did not adequately describe the sensation they experienced on a daily basis. A word frequency analysis of descriptors nominated by these patients indicated 5 themes:
# Exhausted or tired.
# Heaviness in the limbs or whole-body.
# Fogginess in the head.
# Weakness in the muscles.
# Drained of energy.
===The DePaul Symptom Questionnaire (DSQ) subscale ===
The instrument most commonly used to assess PEM is a subscale from the [[DePaul Symptom Questionnaire]] (DSQ). The DSQ is a 54-item questionnaire was developed in 2010 to operationalize the Canadian Consensus Criteria, providing concrete directives to assess ME/CFS-symptoms with their frequency and severity.<ref>{{Cite web|url=https://www.semanticscholar.org/paper/The-Development-of-a-Revised-Canadian-Myalgic-Case-Jason-Evans/b2a2564f55daa57721d24502df6bd6c161238ff0|title=The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition|last=Jason|first=Leonard A.authorlink1=Leonard Jason||last2=Evans|first2=Meredyth Anne|date=2010|language=en|access-date=2018-10-10|last3=Porter|first3=Nicole|authorlink3=Nicole Porter|last4=Brown|first4=Molly|authorlink4=Molly Brown|last5=Brown|first5=Abigail A.|authorlink5=Abigail Brown|last6=Hunnell|first6=Jessica|last7=Anderson|first7=Valerie C.|last8=Lerch|first8=Athena|last9=Meirleir|first9=Kenny de|authorlink9=Kenny De Meirleir}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref>{{Cite journal|last=Strand|first=Elin B.|last2=Lillestøl|first2=Kristine|last3=Jason|first3=Leonard A.|last4=Tveito|first4=Kari|last5=Diep|first5=Lien My|last6=Valla|first6=Simen Strand|last7=Sunnquist|first7=Madison|last8=Helland|first8=Ingrid B.|last9=Herder|first9=Ingrid|date=2016-01-02|title=Comparing the DePaul Symptom Questionnaire with physician assessments: a preliminary study|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1126026|journal=Fatigue: Biomedicine, Health & Behavior|language=en|volume=4|issue=1|pages=52–62|doi=10.1080/21641846.2015.1126026|issn=2164-1846}}</ref> This indicated that the DSQ is a useful tool in detecting and screening symptoms, but that a follow-up medical examination is necessarily to confirm the diagnosis and identify possible exclusionary medical and psychiatric disorders.

The post-exertional malaise subscale on the DSQ particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref>{{Cite journal|last=Murdock|first=Kyle W.|last2=Wang|first2=Xin Shelley|last3=Shi|first3=Qiuling|last4=Cleeland|first4=Charles S.|last5=Fagundes|first5=Christopher P.|last6=Vernon|first6=Suzanne D.|date=Apr 2017|title=The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/27600520|journal=Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation|volume=26|issue=4|pages=913–921|doi=10.1007/s11136-016-1406-3|issn=1573-2649|pmc=5336422|pmid=27600520}}</ref> In early 2018 the Common Data Elements working group on PEM formed by [[National Institute of Neurological Disorders and Stroke|NINDS]] and the CDC, recommended the use of 5 items from the DSQ to measure PEM.<ref name=":4">https://www.commondataelements.ninds.nih.gov/Doc/MECFS/PEM_Subgroup_Summary.pdf</ref>
# Dead, heavy feeling after starting to exercise.
# Next day soreness after non-strenuous, everyday activities.
# Mentally tired after the slightest effort.
# Minimum exercise makes physically tired.
# Physically drained or sick after mild activity.
To meet criteria for post-exertional malaise, one of these items need to be endorsed at sufficient frequency and severity (2 or greater on a scale of 0-4).

Although the DSQ has good test-retest reliability and is regarded as a useful tool in making the diagnosis of ME/CFS, its ability to capture PEM accurately has been questioned. Originally these five items formed one of the five subdomains of the ME/CFS Fatigue Types Questionnaire (MFTQ)<ref>{{Cite journal|last=Jason|first=Leonard| authorlink1=Leonard Jason|last2=Jessen|first2=Tricia|last3=Porter|first3=Nicole| authorlink3=Nicole Porter|last4=Boulton|first4=Aaron|last5=Gloria-Njoku|authorlink5=Mary Gloria Njoku|first5=Mary|date=2009-07-16|title=Examining Types of Fatigue Among Individuals with ME/CFS|url=http://dsq-sds.org/article/view/938|journal=Disability Studies Quarterly|language=en|volume=29|issue=3|doi=10.18061/dsq.v29i3.938|issn=2159-8371}}</ref><ref>{{Cite journal|last=Jason|first=L. A.|last2=McManimen|first2=S. L.|last3=Sunnquist|first3=M.|last4=Holtzman|first4=C. S.|date=2018-03-21|title=Patient perceptions of post exertional malaise|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1453265|journal=Fatigue: Biomedicine, Health & Behavior|language=en|volume=6|issue=2|pages=92–105|doi=10.1080/21641846.2018.1453265|issn=2164-1846}}</ref> and critics argue that these items are focused too much on fatigue/tiredness to be an adequate measure of PEM. A document formulated by the Science for ME PEM working group to address these issues, explained:<blockquote>"The DSQ PEM items focus largely on feeling fatigue or tiredness, and, apart from one item, do not mention that post-exertional symptoms may be delayed. There is no mention of prolonged recovery or the loss of functional capacity."<ref name=":5" /></blockquote>The NINDS/CDC common data elements PEM subgroup also noted about the DSQ: <blockquote>"...the instrument does not assess the full range of symptoms that could be exacerbated by PEM and only one item addresses the sometimes delayed onset/ prolonged duration of PEM.<ref>https://www.commondataelements.ninds.nih.gov/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf</ref> </blockquote>In an online poll to which 783 people responded, 68% answered that the DSQ PEM did not reflect their experience of post-exertional malaise<ref name=":5" />, though questions have been raised about the neutrality of the wording used.<ref name=":6">{{Cite journal|last=Jason|first=L. A.|last2=McManimen|first2=S. L.|last3=Sunnquist|first3=M.|last4=Holtzman|first4=C. S.|date=2018-03-21|title=Patient perceptions of post exertional malaise|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1453265|journal=Fatigue: Biomedicine, Health & Behavior|language=en|volume=6|issue=2|pages=92–105|doi=10.1080/21641846.2018.1453265|issn=2164-1846}}</ref> In response Jason et al. noted that the DSQ PEM items were developed and selected to screen for the presence of PEM, rather than to comprehensively measure all aspects and variations of PEM. A 2018 analysis, using a large patient sample (n = 704), showed that screening items from the DSQ PEM subscale, were able to identify 97% of patients, which was higher than any other item to describe PEM.<ref name=":6" />

Furthermore, the authors have recently revised the DSQ PEM subscale to include new items, some based on Ramsay’s writings.<ref name=":7" /> An extra 5 questions can be used after the initial screening with the DSQ PEM subscale, to better differentiate ME/CFS from other, comparable conditions:
# Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?
# Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?
# If you feel worse after activities, how long does this last?
# If you were to become exhausted after actively participating in extracurricular activities, sports, or outings with friends, would you recover within an hour or two after the activity ended?
# If you do not exercise, is it because exercise makes your symptoms worse?
An analysis showed that these questions (the duration of PEM in particular) helped to differentiate ME/CFS patients from controls with [[Multiple sclerosis|MS]] or [[post-polio syndrome]].<ref name=":7" />

=== The DePaul Post-Exertional Malaise Questionnaire (DPEMQ) ===
The DPEMQ is a [http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf questionnaire] based on input from hundreds of patients.<ref name=":29">{{Cite journal|last=Jason|first=Leonard A|last2=Holtzman|first2=Carly S|last3=Sunnquist|first3=Madison|last4=Cotler|first4=Joseph|date=2018-10-24|title=The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome|url=https://doi.org/10.1177/1359105318805819|journal=Journal of Health Psychology|language=en|pages=1359105318805819|doi=10.1177/1359105318805819|issn=1359-1053}}</ref><blockquote>Post-exertional malaise, or a variation of this term, is a key symptom of myalgic encephalomyelitis and chronic fatigue syndrome, as this symptom is mentioned in almost all myalgic encephalomyelitis and chronic fatigue syndrome case definitions. Until now there has not been a comprehensive questionnaire to assess post-exertional malaise. To rectify this situation, in this article we describe the development of a new questionnaire, called the DePaul Post-Exertional Malaise Questionnaire, which was based on input from hundreds of patients. Preliminary validation was provided by the findings of significant and predictable relationships between different domains of this post-exertional malaise questionnaire and physical functioning.<ref name=":29" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 International Consensus Criteria (ICC)<ref>{{Cite journal|last=Carruthers|first=Bruce M.|author-link=Bruce Carruthers|last2=van de Sande|first2=Marjorie I.|author-link2=Marjorie van de Sande|last3=De Meirleir|first3=Kenny L.|author-link3=Kenny De Meirleir|last4=Klimas|first4=Nancy G.|author-link4=Nancy Klimas|last5=Broderick|first5=Gordon|author-link5=Gordon Broderick|last6=Mitchell|first6=Terry|author-link6=Terry Mitchell|last7=Staines|first7=Donald|author-link7=Donald Staines|last8=Powles|first8=A. C. Peter|author-link8=A C Peter Powles|last9=Speight|first9=Nigel|author-link9=Nigel Speight|last10=Vallings|first10=Rosamund|author-link10=Rosamund Vallings|last11=Bateman|first11=Lucinda|author-link11=Lucinda Bateman|last12=Baumgarten-Austrheim|first12=Barbara|author-link12=Barbara Baumgarten-Austrheim|last13=Bell|first13=David|author-link13=David Bell|last14=Carlo-Stella|first14=Nicoletta|author-link14=Nicoletta Carlo-Stella|last15=Chia|first15=John|author-link15=John Chia|last16=Darragh|first16=Austin|author-link16=Austin Darragh|last17=Jo|first17=Daehyun|author-link17=Daehyun Jo|last18=Lewis|first18=Donald|author-link18=Donald Lewis|last19=Light|first19=Alan|author-link19=Alan Light|last20=Marshall-Gradisnik|first20=Sonya|author-link20=Sonya Marshall-Gradisnik|last21=Mena|first21=Ismael|author-link21=Ismael Mena|last22=Mikovits|first22=Judy|author-link22=Judy Mikovits|last23=Miwa|first23=Kunihisa|author-link23=Kunihisa Miwa|last24=Murovska|first24=Modra|author-link24=Modra Murovska|last25=Pall|first25=Martin|author-link25=Martin Pall|last26=Stevens|first26=Staci|author-link26=Staci Stevens|date=2011-08-22|title=Myalgic encephalomyelitis: International Consensus Criteria|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref> offered the most precise and elaborated definition of the post-exertional relapses that characterize ME. To differentiate it with post-exertional malaise, the term used in the Fukuda-criteria, the authors introduced a new name: Post-Exertional Neuroimmune Exhaustion (PENE). PENE is described as “a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions”<ref name=":2" /> and has the following characteristics:
# Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
# Postexertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.
# Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.
# Recovery period is prolonged, usually taking 24 hours or longer. A relapse can last days, weeks or longer.
# Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level.
The definition fails however to make clear how many of these characteristics are necessary to diagnose PENE.
=== Muscle weakness ===
A more prominent criticism of PENE came from a 2016 factor analysis of PEM, using a large sample of 704 participants. Results suggested that “PEM is composed of two empirically different experiences, one for generalized fatigue and one for muscle-specific fatigue.”<ref name=":8" /> The latter refers to the description of ME by Ramsay, where post-exertional muscle weakness was highlighted. This element of PEM was confirmed in a study by the [[Workwell Foundation]] where the symptoms of 25 ME/CFS patients and 23 age-matched controls were followed up. As the report noted: <blockquote>"The two groups also differed with respect to the experience of physical weakness or instability immediately after testing. This was reported by 16 patients (64%) as opposed to 5 controls (22%). Weakness persisted into the next day in 10 patients (40%) but in only 1 control (4%). However, distinct differences can be observed in the severity of the weakness between groups when analyzing their reports. The sole report of weakness from a control stated: '[I had] tired legs when going up stairs—fine overall.' In contrast, statements from CFS patients included: 'Unable to walk without assistance.' '[I experienced] falling from muscle weakness.'<ref name=":13" /></blockquote>A Norwegian in depth-report of ME/CFS-patients relationship to exercise also highlighted muscle weakness: <blockquote>"Some related how they would struggle to get home after exercise – one had to stop her car on her way from the fitness centre. Another was walking in the woods and suddenly felt it would be impossible to make his way back home. They described feeling that something completely wrong had happened to their bodies, without understanding what was going on. Thought processes did not work as usual, motor abilities were reduced, or the legs would not move them as they would usually expect. Some participants described a paralyzed feeling subsequent to activity, where a lot of energy would be needed to be able to move."<ref>{{Cite journal|last=Larun|first=Lillebeth|last2=Malterud|first2=Kirsti|date=May 2011|title=Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>While many descriptions of PEM like the DSQ subscale assess this element indirectly by asking patients about a dead heavy feeling after exercise or next day soreness, it is fully lacking in the ICC definition of PENE.<ref name=":8" />
=== Common data elements PEM working group ===
The NINDS/CDC Common Data Elements (CDE) PEM working group emphasized the need of a better definition of PEM. Its draft recommendations highlighted that <blockquote>"The definition of PEM is based primarily on clinician experience, patient reports and a few formal studies. There is a dearth of studies asking participants about their experiences of PEM in an openended manner, which is needed."<ref name=":4" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref>{{Cite journal|last=Jason|first=Leonard|last2=McManimen|first2=Stephanie|last3=Sunnquist|first3=Madison|date=2018-03-21|title=Patient perceptions of post exertional malaise|url=https://www.researchgate.net/publication/323916016_Patient_perceptions_of_post_exertional_malaise|journal=Fatigue: Biomedicine, Health & Behavior|doi=10.1080/21641846.2018.1453265}}</ref> Although the CDE working group acknowledged the need to device a better instrument to assess PEM, it currently promotes the use of the DSQ PEM subscale as a screening tool, after which a clinician’s assessment is advised to diagnose PEM. The CDE PEM working group also provided a description of PEM, based on the 2015 literature review by the National Academy of Medicine: <blockquote>"PEM is defined as an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:</blockquote>
# Exacerbation of some or all of an individual study participant's ME/CFS symptoms. Symptoms exacerbated can include physical fatigue, cognitive fatigue, problems thinking (e.g. slowed information processing speed, memory, concentration), [[unrefreshing sleep]], [[Myalgia|muscle pain]], [[Arthralgia|joint pain]], [[Headache|headaches]], weakness/instability, light-headedness, flu-like symptoms, sore throat, [[nausea]], and other symptoms. Study participants can experience new or non-typical symptoms as well as exacerbation of their more typical symptoms.
# Loss of stamina and/or functional capacity.
# An onset that can be immediate or delayed after the exertional stimulus by hours, days or even longer.
# A prolonged, unpredictable recovery period that may last days, weeks, or even months.
# Severity and duration of symptoms that is often out-of-proportion to the type, intensity, frequency, and/or duration of the exertion. For some study participants, even basic activities of daily living like toileting, bathing, dressing, communicating, and reading can trigger PEM."<ref name=":4" />

== History ==

=== Case definitions ===
Early descriptions of symptom exacerbation in [[Myalgic encephalomyelitis|ME]] focused on post-exertional muscle weakness. Renowned ME-expert [[Melvin Ramsay]] for example wrote: <blockquote>"[[Muscle fatigability]] whereby, even after a minor degree of physical effort, three, four or five days or longer elapse before full [[muscle]] power is restored is unique and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from ME."<ref name=":10">Ramsay M. (1988). Myalgic Encephalomyelitis and Postviral Fatigue States: The Saga of Royal Free Disease. Gower Medical Publishing. Second edition.</ref> </blockquote>In a 1985 study [[Peter Behan|Behan]] et al. noted that all of their patients “had the same primary symptom that of gross fatigue made worse by exercise".<ref>{{Cite journal|last=Behan|first=P. O.|last2=Behan|first2=W. M.|last3=Bell|first3=E. J.|date=May 1985|title=The postviral fatigue syndrome - an analysis of the findings in 50 cases|url=https://www.ncbi.nlm.nih.gov/pubmed/2993423|journal=The Journal of Infection|volume=10|issue=3|pages=211–222|issn=0163-4453|pmid=2993423}}</ref>

====Formerly used to define Chronic fatigue syndrome====

In the 1988 [[Holmes criteria|Holmes definition]] of [[Chronic fatigue syndrome|CFS]], unexplained generalized muscle weakness was one of the 11 minor symptoms, yet it was fatigue that set the tone. Another minor symptom referred to “prolonged (24 hours or greater) generalized fatigue after levels of [[exercise]] that would have been easily tolerated in the patient’s premorbid state”.<ref>{{Cite journal|last=Holmes|first=G. P.|last2=Kaplan|first2=J. E.|last3=Gantz|first3=N. M.|last4=Komaroff|first4=A. L.|last5=Schonberger|first5=L. B.|last6=Straus|first6=S. E.|last7=Jones|first7=J. F.|last8=Dubois|first8=R. E.|last9=Cunningham-Rundles|first9=C.|date=Mar 1988|title=Chronic fatigue syndrome: a working case definition|url=https://www.ncbi.nlm.nih.gov/pubmed/2829679|journal=Annals of Internal Medicine|volume=108|issue=3|pages=387–389|issn=0003-4819|pmid=2829679}}</ref> PEM is not a mandatory symptom under the Holmes definition.

The wording post-exertional malaise was first used in one of the 8 minor symptoms in the 1994 [[Fukuda criteria]], but without further clarification of the term, except that it lasts more than 24 hours. PEM is not a mandatory symptom under the Fukuda criterion.

====Currently disputed to define Chronic fatigue syndrome====

The [[Oxford criteria]] is flawed as it does not list PEM as a requirement or even a symptom. Patients with the symptom of [[fatigue]], which many illnesses and diseases have, are swept into the diagnosis and research studies. ''The Argus Report'' article ''US NIH Report Calls for UK Definition of ME/CFS to be Scrapped'' wrote the following:<blockquote> The [[United States]] [[National Institutes of Health]] (NIH) has issued a draft report that highlights the dire need for scientific research that will help find a cure for the millions of people suffering from [[ME/CFS|myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS) worldwide. The report also highlights the fact that the decades-old UK Royal Society of Medicine’s Oxford criteria for ME/CFS are severely “flawed,” and that continuing to use these criteria may “cause harm.” Further, the NIH report says that the Royal Society definition should “be retired” and replaced with a single case definition agreed to by the ME/CFS community.<ref>[http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ US NIH Report Calls for UK Definition of ME/CFS to be Scrapped - The Argus Report By: Penny Swift]</ref></blockquote>There are further criticisms [https://www.me-pedia.org/wiki/Oxford_criteria#Criticisms here].

====Currently used as the hallmark symptom defining ME/CFS====
In 2003, [[Canadian Consensus Criteria]] (CCC) PEM became a recognized symptom for the diagnosis of ME/CFS. The CCC were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a flu-like distress.<ref name=":1">{{Cite journal|last=Carruthers|first=Bruce M.|last2=Jain|first2=Anil Kumar|last3=De Meirleir|first3=Kenny L.|last4=Peterson|first4=Daniel L.|last5=Klimas|first5=Nancy G.|last6=Lerner|first6=A. Martin|last7=Bested|first7=Alison C.|last8=Flor-Henry|first8=Pierre|last9=Joshi|first9=Pradip|date=Jan 2003|title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v11n01_02|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=11|issue=1|pages=7–115|doi=10.1300/j092v11n01_02|issn=1057-3321}}</ref> [[Canadian Consensus Criteria#Definition|PEM and/or post-exertional fatigue]] is a mandatory symptom under the CCC criterion.<ref>{{Cite web|url=http://www.investinme.org/Documents/PDFdocuments/Canadian_ME_Overview_A4.pdf|title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical Practitioners - An Overview fo the Canadian Consensus Document|last=|first=|authorlink=Bruce Carruthers|last2=|first2=|authorlink2=Marjorie van de Sande|date=|website=investinme.org|page=4|type=|archive-url=|archive-date=|dead-url=|access-date=|quote=Physical or mental exertion often causes debilitating malaise and/or fatigue, generalized pain, deterioration of cognitive functions, and worsening of other symptoms that may occur immediately after activity or be delayed. Patients experience rapid muscle fatigue and lack endurance.}}</ref>

The 2015 report of the [[National Academy of Medicine]] describes PEM more generally as “an exacerbation of some or all of an individual’s ME/CFS symptoms that occurs after physical or cognitive exertion and leads to a reduction in functional ability.” The report confirmed PEM as the hallmark symptom of ME/CFS and advised to rename the disease accordingly to [[Systemic Exertion Intolerance Disease]] (SEID).<ref name=":0" /> PEM is a mandatory symptom under the SEID criterion.

====Currently used to define Myalgic encephalomyelitis====

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''Post-Exertional Neuro-immune Exhaustion (PENE)''' to refer to the characteristic exercise and exertion intolerance of [[myalgic encephalomyelitis]] (ME) patients. It notes a delayed onset and prolonged recovery, and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a substantial reduction in functioning, as even simple activities of daily living can cause a relapse.<ref name=":2">{{Cite journal|last=Carruthers|first=Bruce M.|author-link=Bruce Carruthers|last2=van de Sande|first2=Marjorie I.|author-link2=Marjorie van de Sande|last3=De Meirleir|first3=Kenny L.|author-link3=Kenny De Meirleir|last4=Klimas|first4=Nancy G.|author-link4=Nancy Klimas|last5=Broderick|first5=Gordon|author-link5=Gordon Broderick|last6=Mitchell|first6=Terry|author-link6=Terry Mitchell|last7=Staines|first7=Donald|author-link7=Donald Staines|last8=Powles|first8=A. C. Peter|author-link8=A C Peter Powles|last9=Speight|first9=Nigel|author-link9=Nigel Speight|last10=Vallings|first10=Rosamund|author-link10=Rosamund Vallings|last11=Bateman|first11=Lucinda|author-link11=Lucinda Bateman|last12=Baumgarten-Austrheim|first12=Barbara|author-link12=Barbara Baumgarten-Austrheim|last13=Bell|first13=David|author-link13=David Bell|last14=Carlo-Stella|first14=Nicoletta|author-link14=Nicoletta Carlo-Stella|last15=Chia|first15=John|author-link15=John Chia|last16=Darragh|first16=Austin|author-link16=Austin Darragh|last17=Jo|first17=Daehyun|author-link17=Daehyun Jo|last18=Lewis|first18=Donald|author-link18=Donald Lewis|last19=Light|first19=Alan|author-link19=Alan Light|last20=Marshall-Gradisnik|first20=Sonya|author-link20=Sonya Marshall-Gradisnik|last21=Mena|first21=Ismael|author-link21=Ismael Mena|last22=Mikovits|first22=Judy|author-link22=Judy Mikovits|last23=Miwa|first23=Kunihisa|author-link23=Kunihisa Miwa|last24=Murovska|first24=Modra|author-link24=Modra Murovska|last25=Pall|first25=Martin|author-link25=Martin Pall|last26=Stevens|first26=Staci|author-link26=Staci Stevens|date=2011-08-22|title=Myalgic encephalomyelitis: International Consensus Criteria|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref> PENE is a mandatory symptom under the ICC criterion.

===Dismissed as disturbed effort perceptions or kinesiophobia ===
[[File:Brian vastag.png|thumb|right|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]
The existence of PEM as a distinctive and complex symptom of ME/CFS has been dismissed in early research into the disease. Some interpreted it as just fatigue after exercise<ref>https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf</ref>, while others saw it as an artifact of disturbed effort perceptions<ref>{{Cite journal|last=Lawrie|first=S. M.|last2=Machale|first2=S. M.|last3=Power|first3=M. J.|last4=Goodwin|first4=G. M.|date=Sep 1997|title=Is the chronic fatigue syndrome best understood as a primary disturbance of the sense of effort?|url=https://www.cambridge.org/core/journals/psychological-medicine/article/editorial-is-the-chronic-fatigue-syndrome-best-understood-as-a-primary-disturbance-of-the-sense-of-effort/434A5EB2C5B4F971A4A36C1DC3400A7E|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=995–999|issn=1469-8978}}</ref><ref>{{Cite journal|last=Rosen|first=S D|last2=King|first2=J C|last3=Wilkinson|first3=J B|last4=Nixon|first4=P G|date=Dec 1990|title=Is chronic fatigue syndrome synonymous with effort syndrome?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292947/|journal=Journal of the Royal Society of Medicine|volume=83|issue=12|pages=761–764|issn=0141-0768|pmc=1292947|pmid=2125315}}</ref><ref>{{Cite journal|last=Wallman|first=Karen E.|last2=Sacco|first2=Paul|date=Jan 2007|title=Sense of effort during a fatiguing exercise protocol in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17365951|journal=Research in Sports Medicine|volume=15|issue=1|pages=47–59|doi=10.1080/15438620601184331|issn=1543-8627|pmid=17365951}}</ref> or an [[Illness beliefs|irrational fear of movement]]<ref>{{Cite journal|last=Silver|first=A.|last2=Haeney|first2=M.|last3=Vijayadurai|first3=P.|last4=Wilks|first4=D.|last5=Pattrick|first5=M.|last6=Main|first6=C. J.|date=Jun 2002|title=The role of fear of physical movement and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12069873|journal=Journal of Psychosomatic Research|volume=52|issue=6|pages=485–493|issn=0022-3999|pmid=12069873}}</ref><ref>{{Cite journal|last=Fischler|first=B.|last2=Dendale|first2=P.|last3=Michiels|first3=V.|last4=Cluydts|first4=R.|last5=Kaufman|first5=L.|last6=De Meirleir|first6=K.|date=Apr 1997|title=Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology|url=https://www.ncbi.nlm.nih.gov/pubmed/9160276|journal=Journal of Psychosomatic Research|volume=42|issue=4|pages=369–378|issn=0022-3999|pmid=9160276}}</ref>. One example of this is the [http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf Tampa scale kinesiophobia], adapted for [[chronic fatigue syndrome]]. Some of the questions in this scale ask about the experience of PEM such as: “If I were to try to overcome it, my symptoms would increase” or “my symptoms let me know when to stop exercising so that I do not harm myself”. Yet these symptoms are classified as an indicator of irrational fear of movement and exercise, instead of PEM.<ref>{{Cite web|url=http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf|title=Tampa Scale Kinesiophobia - Version Chronic Fatigue Syndrome|last=Nijs|first=J|last2=De Meirleir|first2=K|date=2004|website=painmotion.be|publisher=Archives of Physical Medicine and Rehabilitation|archive-url=|archive-date=|dead-url=|access-date=|last3=Duquet|first3=W}}</ref>

=== Critique of the term ===
The name post-exertional malaise was introduced by the 1994 Fukuda criteria and had no prior medical meaning attached to it.<ref name=":3">{{Cite journal|last=Chu|first=Lily|last2=Valencia|first2=Ian J.|last3=Garvert|first3=Donn W.|last4=Montoya|first4=Jose G.|date=2018|title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey|url=https://www.ncbi.nlm.nih.gov/pubmed/29856774|journal=PloS One|volume=13|issue=6|pages=e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|author-link=Lily Chu|author-link2=Ian Valencia|author-link3=Donn Gavert|author-link4=Jose Montoya|author-link5=|via=}}</ref> While in the scientific literature, the term has become the standard to describe the relapses ME/CFS patients suffer after exertion, patients argue that it trivializes their experience. The term malaise after all refers to “a general feeling of discomfort, illness, or unease whose exact cause is difficult to identify”<ref>{{Cite web|url=https://en.oxforddictionaries.com/definition/malaise|title=Definition of malaise in English by Oxford Dictionaries|website=Oxford Dictionaries {{!}} English|access-date=2018-10-13}}</ref>. Doctor of [http://sph.berkeley.edu/ Public Health at Berkely], [[David Tuller]], calls post-exertional malaise a “complete misnomer” arguing what ME/CFS patients experience "is much closer to a serious crash or relapse than a Victorian fainting spell.”<ref>{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/|title=Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=www.virology.ws|language=en-US|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term ‘crash’ to describe their relapses.

==Notable studies==
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref>{{Cite journal|last=Paul|first=L.|last2=Wood|first2=L.|last3=Behan|first3=W. M.|last4=Maclaren|first4=W. M.|date=1999|title=Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10209352|journal=European Journal of Neurology|volume=6|issue=1|pages=63–69|issn=1351-5101|pmid=10209352|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pubmed/10209352 (Abstract)]
* 2010, Postexertional Malaise in Women with Chronic Fatigue Syndrome<ref name="VanNess2010" /> [https://www.liebertpub.com/doi/10.1089/jwh.2009.1507 (Abstract)]
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="MeyerJ2013" /> [http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2015, Myalgic Encephalomyelitis: Symptoms and [[Biomarker]]s<ref name="JasonL2015bio" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799 (Full Text)]
*2015, Changes in Gut and Plasma [[Microbiome]] following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="ShuklaS2015" /> [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2015, Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains<ref>{{Cite journal|last=Jason|first=Leonard A.|author-link=Leonard Jason|last2=Sunnquist|first2=Madison|author-link2=Madison Sunnquist|last3=Brown|first3=Abigail|author-link3=Abigail Brown|last4=Furst|first4=Jacob|author-link4=|last5=Cid|first5=Marjoe|author-link5=|last6=Farietta|first6=Jillianna|author-link6=|last7=Kot|first7=Bobby|last8=Bloomer|first8=Craig|last9=Nicholson|first9=Laura|date=September 2015|title=Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/|journal=Journal of neurology and neurobiology|volume=1|issue=4|pages=|doi=|issn=2379-7150|pmc=4830389|pmid=27088131|access-date=|quote=|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/ (Full text)] - assessed different types of post-exertional malaise
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen, 2016" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]
*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref>{{Cite journal|last=Mateo|first=Lariel J.|date=2018|title=Comparing Post-Exertional Symptoms Following Serial Exercise Tests|url=https://scholarlycommons.pacific.edu/purcc/2018/events/87/|journal=PURCC|language=en|volume=|pages=|via=Scholarly Commons}}</ref> [https://scholarlycommons.pacific.edu/purcc/2018/events/87/ (Abstract)]
*2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name=":31" /><ref name=":30" /> [http://journals.sagepub.com/doi/abs/10.1177/1359105318805819?journalCode=hpqa& (Abstract)] [http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf (Questionnaire)]
*2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref>{{Cite journal|last=Stussman|first=Barbara|author-link=|last2=Williams|first2=Ashley|author-link2=|last3=Snow|first3=Joseph|author-link3=Joseph Snow|last4=Gavin|first4=Angelique|author-link4=|last5=Scott|first5=Remle|author-link5=|last6=Nath|first6=Avindra|author-link6=Avindra Nath|last7=Walitt|first7=Brian|author-link7=Brian Walitt|date=2020|title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.01025|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref> [https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full (Full text)]

== Notable articles ==
* Dec 30, 2015 [http://me-cfs.se/blogg/suggestion-to-replace-pem-by-par/ Suggestion to replace PEM (Post Exertional Malaise) with PAR (Post Activity Relapse)]<ref name="MEBlogg2015" />
*Nov 4, 2016 [http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome]<ref>{{Cite web|url=http://www.medscape.com/viewarticle/871482#vp_1|title=Postexertion 'Crash,' not Fatigue per se, Marks Syndrome|last=Tucker|first=Miriam|date=|website=www.medscape.com|type=Login Required|archive-url=|archive-date=|dead-url=|access-date=2018-09-06}}</ref>

==Talks and interviews==
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]<ref>{{Cite web|url=https://www.youtube.com/watch?v=zZ8aPYihkpQ|title=CFS gene expression after exercise (part 1)|last=|first=|date=May 26, 2013|website=YouTube|publisher=Jw N|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*2012, [https://www.youtube.com/watch?v=B20H1u1LjCE Top 10 Things You Should Know About Post-Exertional Relapse] - University of the Pacific/Solve CFS - 2010 study, PEM in Women w/ CFS is discussed

==See also==
*[[Delayed onset muscle soreness]]
*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==

*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health]<ref>{{Cite web|url=http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html|title=International CFS/ME Awareness Day - 12th May 2019|last=Hartley|first=Simon|website=www.whathealth.com|language=en|access-date=2018-08-17}}</ref> (PEM Definition Included)
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]<ref name="SpotilaJ2010" />
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]<ref name="SpotilaJ20120523" />
*[https://www.verywellhealth.com/what-is-post-exertional-malaise-716023 What is Post-Exertional Malaise]<ref name="AboutHealthPEM" />
*[http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/ The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?]<ref>{{Cite news|url=http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/|title=The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained? - Health Rising|last=Johnson|first=Cort|date=2016-07-04|work=Health Rising|access-date=2018-08-17|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

== References ==
<references>
<ref name="AboutHealthPEM">{{Cite news|url=https://www.verywellhealth.com/what-is-post-exertional-malaise-716023|title=What is Post-Exertional Malaise? Learn About a Key ME/CFS Symptom|last=Dellwo|first=Adrienne|authorlink=Adrienne Dellwo|date=|work=Verywell Health|access-date=2018-08-17|archive-url=|archive-date=|dead-url=}}</ref>
<ref name="JasonL2015bio">{{Citation
| last1 = Jason | first1 = LA | authorlink1 = Leonard Jason
| last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn
| last3 = Zinn | first3 = MA | authorlink3 = Mark Zinn
| display-authors =
| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers
| journal = Current Neuropharmacology | volume = 13(5) | page = 701-734
| date = September 2015
| doi = 10.2174/1570159X13666150928105725
| url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799
}}</ref>
<ref name="McManimen, 2016">{{Citation
| last1 = McManimen | first1 = SL | authorlink1 =
| last2 = Sunnquist | first2 = ML | authorlink2 = Madison Sunnquist
| last3 = Jason | first3 = LA | authorlink3 = Leonard Jason
| title = Deconstructing post-exertional malaise: An exploratory factor analysis
| journal = Journal of Health Psychology | volume = | issue = | page =
| date = 2016
| pmid = 27557649
| doi = 10.1177/1359105316664139
}}
</ref>
<ref name="MEBlogg2015">{{citation
| author = ME Blogg
| title = Suggestion to replace PEM by PAR
| date = 30 Dec 2015
| url = http://me-cfs.se/blogg/suggestion-to-replace-pem-by-par/
}}</ref>
<ref name="MeyerJ2013">{{citation
| last1 = Meyer | first1 = JD | authorlink1 = Jacob Meyer
| last2 = Light | first2 = AR | authorlink2 = Alan Light
| last3 = Shukla | first3 = SK | authorlink3 = Sanjay Shukla
| last4 = Clevidence | first4 = D | authorlink4 = Derek Clevidence
| last5 = Yale | first5 = S | authorlink5 = Steven Yale
| last6 = Stegner | first6 = AJ | authorlink6 = Aaron Stegner
| last7 = Cook | first7 = DB | authorlink7 = Dane Cook
| display-authors =
| title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression
| journal = Fatigue: Biomedicine, Health & Behavior | volume = 1 | issue = 4 | page = 190-209
| date = 2 Oct 2013
| doi = 10.1080/21641846.2013.838444
| url = http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444
}}</ref>
<ref name="ShuklaS2015">{{Citation
| last1 = Shukla | first1 = SK | authorlink1 = Sanjay Shukla
| last2 = Cook | first2 = D | authorlink2 = Dane Cook
| last3 = Meyer | first3 = JD | authorlink3 = Jacob Meyer
| last4 = Vernon | first4 = SD | authorlink4 = Suzanne Vernon
| last5 = Lee | first5 = T | authorlink5 = Thao Lee
| last6 = Clevidence | first6 = D | authorlink6 = Derek Clevidence
| last7 = Robertson | first7 = CE | authorlink7 = Charles Robertson
| last8 = Schrodi | first8 = SJ | authorlink8 = Steven Schrodi
| last9 = Yale | first9 = S | authorlink9 = Steven Yale
| last10 = Frank | first10= DN | authorlink10= Daniel Frank
| display-authors = 3
| title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
| journal = Plos One | volume = 10(12) | page =
| date = 18 December 2015
| pmid =
| doi = 10.1371/journal.pone.0145453
| url = http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453
}}</ref>
<ref name="SpotilaJ2010">{{citation
| last1 = Spotila | first1 = JM | authorlink1 = Jennie Spotila
| title = Post-Exertional Malaise in Chronic Fatigue Syndrome
| journal = Solve ME/CFS
| date = 2010
| url = http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf
}}</ref>
<ref name="SpotilaJ20120523">{{citation
| last1 = Spotila | first1 = JM | authorlink1 = Jennie Spotila
| title = Post-Exertional Malaise: Cause and Effect
| journal = Solve ME/CFS
| date = 23 May 2012
| url = http://solvecfs.org/post-exertional-malaise-cause-and-effect/
}}</ref>
<ref name="VanNess2010">{{Citation
| last1 = VanNess | first1 = M | authorlink1 = Mark VanNess
| last2 = Stevens | first2 = S | authorlink2 = Staci Stevens
| last3 = Bateman | first3 = L | authorlink3 = Lucinda Bateman
| last4 = Stiles | first4 = TL | authorlink4 = TL Stiles
| last5 = Snell | first5 = CR | authorlink5 = Christopher Snell
| display-authors =
| title = Postexertional malaise in women with chronic fatigue syndrome
| journal = Journal of Women's Health | volume = | issue = | page =
| date = February 2010
| pmid = 20095909
| doi = 10.1089/jwh.2009.1507
}}
</ref>
</references>

[[Category:Signs and symptoms]]

Delayed onset muscle soreness

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FatigueTrackerBot:.

Delayed onset muscle soreness

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FatigueTrackerBot:.

Delayed onset muscle soreness

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FatigueTrackerBot:Creating page

Vitamin C deficiency

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FatigueTrackerBot:.

{{Cleanup|reason=Grammar and image violating copyright. |talk=TALKPAGENAME }}

'''Hypovitaminosis C''', aka '''scurvy''', is a condition caused by a dietary lack of [[vitamin C]] (ascorbic acid) and is characterized by an increased bleeding tendency and impaired collagen synthesis.<ref>{{Cite web|url=https://radiopaedia.org/articles/hypovitaminosis-c-scurvy-1?lang=us|title=Scurvy|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=radiopaedia.org|archive-url=|archive-date=|dead-url=|access-date=}}</ref> It can, also, be caused by reduced absorption of [[Vitamin C]] in the gut.<ref>{{Cite web|url=https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/|title=Office of Dietary Supplements - Vitamin C|website=ods.od.nih.gov|language=en|access-date=2020-01-24}}</ref>
==Overview==
Despite being considered a rare condition, scurvy still exists nowadays, even in children with no apparent risk factors living in wealthy families. The increasing popularity of dietary restriction for children, especially those with allergies, may potentially enhance the occurrence of scurvy in apparently healthy children.<ref name=":1">{{Cite journal|last=Brambilla|first=Alice|last2=Pizza|first2=Cristina|last3=Lasagni|first3=Donatella|last4=Lachina|first4=Lucia|last5=Resti|first5=Massimo|last6=Trapani|first6=Sandra|date=1 May 2018|title=Pediatric Scurvy: When Contemporary Eating Habits Bring Back the Past.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946015/|journal=Frontiers in Pediatric|volume=6|doi=10.3389/fped.2018.00126}}</ref>

In hospital patients, it can be highly prevalent, but often unrecognized.<ref name="Robitaille2016" /> Medical awareness of this potentially important disorder is hindered by the inability of most hospital laboratories to determine plasma [[Vitamin C]] concentrations. The availability of a simple, reliable method for analyzing plasma vitamin C could increase opportunities for routine plasma vitamin C analysis in clinical medicine.<ref name="Robitaille2016" />

== Symptoms ==
* lassitude<ref name="Levine1996" />
* fatigue<ref name="Levine1996" />
* irritability<ref name="Levine1996" />
* poor wound healing<ref name=":2">{{Cite journal|last=Maxfield|first=Luke|last2=Crane|first2=Jonathan S.|date=2019|title=Vitamin C Deficiency (Scurvy)|url=http://www.ncbi.nlm.nih.gov/books/NBK493187/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29630239}}</ref>
* gingival (gum) swelling with loss of teeth<ref name=":2" />
* mucocutaneous petechiae<ref name=":2" /> (small red or purple spots caused by bleeding into the skin where the mucosa transitions to skin)
* ecchymosis<ref name=":2" /> (a discoloration of the skin resulting from bleeding underneath, typically caused by [[bruising]])
* hyperkeratosis<ref name=":2" /> (skin condition that occurs when a person's skin becomes thicker)

== Evidence ==
The disease of terminal vitamin C deficiency – [[Scurvy]] – is first suspected on clinical grounds. The diagnosis is confirmed by documenting a plasma vitamin C concentration < 11.4 μmol/L and observing prompt clinical improvement after appropriate vitamin C provision. [[Scurvy]] is rare in the modern world, but hypovitaminosis C (plasma vitamin C concentration < 28.4 μmol/L ) or marginal vitamin C deficiency (plasma vitamin C concentration < 28.4 μmol/L but > 11.4 μmol/L ) is not. Hypovitaminosis C occurs in ~ 10% of the general population , in ~ 30 % of cigarette smokers and ~ 60% of acutely hospitalized patients, in whom it could contribute to fatigue and mood disturbance, immune system dysfunction, impaired wound healing, the complex regional pain syndrome and the complications of cardiovascular disease.<ref name="Robitaille2016" />

Cited from <ref name="Levine1996" /> : Subclinical Vitamin C Deficiency: Clinical Application. Six of seven volunteers noted mild but distinct fatigue and/or irritability at depletion, without scurvy. Symptoms disappeared within several days of the 30- or 60-mg daily dose. Although fatigue and irritability have myriad causes, vitamin C deficiency without scurvy should be an additional consideration. Since fatigue and irritability are common symptoms and were so easily reversible, physicians should ask patients with these symptoms about vitamin C ingestion from foods or supplements.

== Historical perspective ==
From a 18th century medical book, ''Observations of the Scurvy,'' by Thomas Trotter: "Every person who has been a sea voyage, must have perceived that longing desire for fresh vegetables after being for some time deprived of them. This I have often marked the harbinger of scurvy. Dr Lind, in some part of his work, has mentioned the same circumstances; and he might very justly have put it down as a symptom; for it is more or less an attendant on the disease and not only amuses their waking hours with thoughts of green fields and rivers of pure water but in dreams they are tantalized with the same ideas, and on waking nothing is so mortifying as the disappointment.<ref name=":0">{{Cite book|title=Observations on the Scurvy with a review of the theories lately advanced on that disease and the opinions of Dr Milman refuted from practice|pages=14-16|isbn=|edition=|volume=|language=en|title-link=|url=https://collections.nlm.nih.gov/ext/mhl/2575040R/PDF/2575040R.pdf|date=1793|publisher=John Parker|last=Trotter|first=Thomas|author-link=|last2=|first2=|author-link2=|last3=|first3=|author-link3=|last4=|first4=|author-link4=|last5=|first5=|author-link5=|last6=|first6=|author-link6=|last7=|first7=|author-link7=|last8=|first8=|author-link8=|last9=|first9=|author-link9=|veditors=|others=|doi=|oclc=|quote=|access-date=2020-01-23|archive-url=|archive-date=|location=Philadelphia, PA}}</ref>

When I heard a sailor expressing these desires, and lolling about, I was not surpriced to find him complain of sore gums and a few days after. About this time the colour of the face looks fallow, the eye is dull and heavy, and the whole countenance as it were bloated; the patient feels himself wearied even after sleep, and complains of pains in different parts of the body; he grows inactive, and easily fatigues; often timid; has gloomy ideas about his safety, as if hypochondrical; he flies from duty and wishes to indulge in sloth. To these generally succeed the apperance of the gums which so especially characherizes scurvy; they swell, are spongy and bleed on the slightest cause. The breath is fetid, and often attended with some disagreeable taste of the mouth. ... It is not uncommon for sailors, afflicted with scurvy, to walk upon deck, and drop down irrecoverably; though to all appearance, when below, there seemed no danger; From this I must infer no just prognosis can be always formed.”<ref name=":0" />

[[File:60mgperday.jpg|300px|thumb|left|Steady state plateau ascorbic acid concentration in plasma. Data are an example of plateau determination from volonteer 6 at the 60mg dose.]]

== Evaluation methods ==
The blood test procedure for Vitamin C deficiency is highly advanced.<ref name="Levine1996" /> A simpler but less accurate is proposed in <ref name="Robitaille2016" />
Another coarse method which might be used to evaluate [[Hypovitaminosis C]] is by measuring [[capillary fragility]] using a skin surface vacuum suction method
(VSM) such as the Parrot’s angiosterrometer. A relation between [[Hypovitaminosis C]] and [[capillary fragility]] is indicated. <ref name="Cox1975" />

==Notable studies==
*1996, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance<ref name="Levine1996" /> [https://www.pnas.org/content/pnas/93/8/3704.full.pdf (Full Text)]

==See also==
*[[Collagen]]
*[[Capillary fragility]]
*[[Irritable bowel syndrome]]
*[[Osteoporosis]]
*[[Vitamin C]]
*[[Vitamin C Deficiency without Scurvy hypothesis]]

== Learn more ==

==References==
<references>
<ref name="Levine1996">{{Citation
| last1 = Levine | first1 = Mark
| last2 = Conry-Cantilena | first2 = Cathy
| last3 = Wang | first3 = Yaohui
| last4 = Welch | first4 = Richard W.
| last5 = Washko | first5 = Louis R.
| last6 = Dhariwal | last7 = Park | last8 = Lazarev | last9 = Graumlich | last10 = King | last11 = Cantilena | title = Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance
| journal = Proc Natl Acad Sci U S A | volume = 93 | issue = 8 | page = 3704-9
| date = 1996
| url = https://www.pnas.org/content/93/8/3704.long

}}
</ref>
<ref name="Robitaille2016">{{Citation
| last1 = Robitaille | first1 = Line
| last2 = Hoffer | first2 = L John
| title = A simple method for plasma total vitamin C analysis suitable for routine clinical laboratory use
| journal = Nutrition Journal | volume = 15 | issue = 40
| date = 21 April 2016
| url = https://nutritionj.biomedcentral.com/articles/10.1186/s12937-016-0158-9

}}
</ref>
<ref name="Cox1975">{{Citation
| last1 = Cox | first1 = Brian D
| last2 = Butterfield | first2 = W J
| title = Vitamin C Supplements and Diabetic Cutaneous Capillary Fragility
| journal = British Medical Journal | volume = 26 | issue = 3
| date = 26 July 1975
| doi = 10.1136/bmj.3.5977.205
| url = https://pubmed.ncbi.nlm.nih.gov/1148732/
}}
</ref>
</references>
[[Category:Diagnoses]]
[[Category:Vitamins]]

Vitamin C deficiency

2020-05-30T12:46:21Z

FatigueTrackerBot:.

{{Cleanup|reason=Grammar and image violating copyright. |talk=TALKPAGENAME }}

'''Hypovitaminosis C''', aka '''scurvy''', is a condition caused by a dietary lack of [[vitamin C]] (ascorbic acid) and is characterized by an increased bleeding tendency and impaired collagen synthesis.<ref>{{Cite web|url=https://radiopaedia.org/articles/hypovitaminosis-c-scurvy-1?lang=us|title=Scurvy|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=radiopaedia.org|archive-url=|archive-date=|dead-url=|access-date=}}</ref> It can, also, be caused by reduced absorption of [[Vitamin C]] in the gut.<ref>{{Cite web|url=https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/|title=Office of Dietary Supplements - Vitamin C|website=ods.od.nih.gov|language=en|access-date=2020-01-24}}</ref>
==Overview==
Despite being considered a rare condition, scurvy still exists nowadays, even in children with no apparent risk factors living in wealthy families. The increasing popularity of dietary restriction for children, especially those with allergies, may potentially enhance the occurrence of scurvy in apparently healthy children.<ref name=":1">{{Cite journal|last=Brambilla|first=Alice|last2=Pizza|first2=Cristina|last3=Lasagni|first3=Donatella|last4=Lachina|first4=Lucia|last5=Resti|first5=Massimo|last6=Trapani|first6=Sandra|date=1 May 2018|title=Pediatric Scurvy: When Contemporary Eating Habits Bring Back the Past.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946015/|journal=Frontiers in Pediatric|volume=6|doi=10.3389/fped.2018.00126}}</ref>

In hospital patients, it can be highly prevalent, but often unrecognized.<ref name="Robitaille2016" /> Medical awareness of this potentially important disorder is hindered by the inability of most hospital laboratories to determine plasma [[Vitamin C]] concentrations. The availability of a simple, reliable method for analyzing plasma vitamin C could increase opportunities for routine plasma vitamin C analysis in clinical medicine.<ref name="Robitaille2016" />

== Symptoms ==
* lassitude<ref name="Levine1996" />
* fatigue<ref name="Levine1996" />
* irritability<ref name="Levine1996" />
* poor wound healing<ref name=":2">{{Cite journal|last=Maxfield|first=Luke|last2=Crane|first2=Jonathan S.|date=2019|title=Vitamin C Deficiency (Scurvy)|url=http://www.ncbi.nlm.nih.gov/books/NBK493187/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29630239}}</ref>
* gingival (gum) swelling with loss of teeth<ref name=":2" />
* mucocutaneous petechiae<ref name=":2" /> (small red or purple spots caused by bleeding into the skin where the mucosa transitions to skin)
* ecchymosis<ref name=":2" /> (a discoloration of the skin resulting from bleeding underneath, typically caused by [[bruising]])
* hyperkeratosis<ref name=":2" /> (skin condition that occurs when a person's skin becomes thicker)

== Evidence ==
The disease of terminal vitamin C deficiency – [[Scurvy]] – is first suspected on clinical grounds. The diagnosis is confirmed by documenting a plasma vitamin C concentration < 11.4 μmol/L and observing prompt clinical improvement after appropriate vitamin C provision. [[Scurvy]] is rare in the modern world, but hypovitaminosis C (plasma vitamin C concentration < 28.4 μmol/L ) or marginal vitamin C deficiency (plasma vitamin C concentration < 28.4 μmol/L but > 11.4 μmol/L ) is not. Hypovitaminosis C occurs in ~ 10% of the general population , in ~ 30 % of cigarette smokers and ~ 60% of acutely hospitalized patients, in whom it could contribute to fatigue and mood disturbance, immune system dysfunction, impaired wound healing, the complex regional pain syndrome and the complications of cardiovascular disease.<ref name="Robitaille2016" />

Cited from <ref name="Levine1996" /> : Subclinical Vitamin C Deficiency: Clinical Application. Six of seven volunteers noted mild but distinct fatigue and/or irritability at depletion, without scurvy. Symptoms disappeared within several days of the 30- or 60-mg daily dose. Although fatigue and irritability have myriad causes, vitamin C deficiency without scurvy should be an additional consideration. Since fatigue and irritability are common symptoms and were so easily reversible, physicians should ask patients with these symptoms about vitamin C ingestion from foods or supplements.

== Historical perspective ==
From a 18th century medical book, ''Observations of the Scurvy,'' by Thomas Trotter: "Every person who has been a sea voyage, must have perceived that longing desire for fresh vegetables after being for some time deprived of them. This I have often marked the harbinger of scurvy. Dr Lind, in some part of his work, has mentioned the same circumstances; and he might very justly have put it down as a symptom; for it is more or less an attendant on the disease and not only amuses their waking hours with thoughts of green fields and rivers of pure water but in dreams they are tantalized with the same ideas, and on waking nothing is so mortifying as the disappointment.<ref name=":0">{{Cite book|title=Observations on the Scurvy with a review of the theories lately advanced on that disease and the opinions of Dr Milman refuted from practice|pages=14-16|isbn=|edition=|volume=|language=en|title-link=|url=https://collections.nlm.nih.gov/ext/mhl/2575040R/PDF/2575040R.pdf|date=1793|publisher=John Parker|last=Trotter|first=Thomas|author-link=|last2=|first2=|author-link2=|last3=|first3=|author-link3=|last4=|first4=|author-link4=|last5=|first5=|author-link5=|last6=|first6=|author-link6=|last7=|first7=|author-link7=|last8=|first8=|author-link8=|last9=|first9=|author-link9=|veditors=|others=|doi=|oclc=|quote=|access-date=2020-01-23|archive-url=|archive-date=|location=Philadelphia, PA}}</ref>

When I heard a sailor expressing these desires, and lolling about, I was not surpriced to find him complain of sore gums and a few days after. About this time the colour of the face looks fallow, the eye is dull and heavy, and the whole countenance as it were bloated; the patient feels himself wearied even after sleep, and complains of pains in different parts of the body; he grows inactive, and easily fatigues; often timid; has gloomy ideas about his safety, as if hypochondrical; he flies from duty and wishes to indulge in sloth. To these generally succeed the apperance of the gums which so especially characherizes scurvy; they swell, are spongy and bleed on the slightest cause. The breath is fetid, and often attended with some disagreeable taste of the mouth. ... It is not uncommon for sailors, afflicted with scurvy, to walk upon deck, and drop down irrecoverably; though to all appearance, when below, there seemed no danger; From this I must infer no just prognosis can be always formed.”<ref name=":0" />

[[File:60mgperday.jpg|300px|thumb|left|Steady state plateau ascorbic acid concentration in plasma. Data are an example of plateau determination from volonteer 6 at the 60mg dose.]]

== Evaluation methods ==
The blood test procedure for Vitamin C deficiency is highly advanced.<ref name="Levine1996" /> A simpler but less accurate is proposed in <ref name="Robitaille2016" />
Another coarse method which might give an indication of [[Hypovitaminosis C]] is by evaluation of [[capillary fragility]] using a vacuum apparatus to the skin. This plausible relation between [[Hypovitaminosis C]] and [[capillary fragility]] require to further evaluation. <ref name="Cox1975" />

==Notable studies==
*1996, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance<ref name="Levine1996" /> [https://www.pnas.org/content/pnas/93/8/3704.full.pdf (Full Text)]

==See also==
*[[Collagen]]
*[[Capillary fragility]]
*[[Irritable bowel syndrome]]
*[[Osteoporosis]]
*[[Vitamin C]]
*[[Vitamin C Deficiency without Scurvy hypothesis]]

== Learn more ==

==References==
<references>
<ref name="Levine1996">{{Citation
| last1 = Levine | first1 = Mark
| last2 = Conry-Cantilena | first2 = Cathy
| last3 = Wang | first3 = Yaohui
| last4 = Welch | first4 = Richard W.
| last5 = Washko | first5 = Louis R.
| last6 = Dhariwal | last7 = Park | last8 = Lazarev | last9 = Graumlich | last10 = King | last11 = Cantilena | title = Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance
| journal = Proc Natl Acad Sci U S A | volume = 93 | issue = 8 | page = 3704-9
| date = 1996
| url = https://www.pnas.org/content/93/8/3704.long

}}
</ref>
<ref name="Robitaille2016">{{Citation
| last1 = Robitaille | first1 = Line
| last2 = Hoffer | first2 = L John
| title = A simple method for plasma total vitamin C analysis suitable for routine clinical laboratory use
| journal = Nutrition Journal | volume = 15 | issue = 40
| date = 21 April 2016
| url = https://nutritionj.biomedcentral.com/articles/10.1186/s12937-016-0158-9

}}
</ref>
<ref name="Cox1975">{{Citation
| last1 = Cox | first1 = Brian D
| last2 = Butterfield | first2 = W J
| title = Vitamin C Supplements and Diabetic Cutaneous Capillary Fragility
| journal = British Medical Journal | volume = 26 | issue = 3
| date = 26 July 1975
| doi = 10.1136/bmj.3.5977.205
| url = https://pubmed.ncbi.nlm.nih.gov/1148732/
}}
</ref>
</references>
[[Category:Diagnoses]]
[[Category:Vitamins]]

Vitamin C deficiency

2020-05-30T12:45:21Z

FatigueTrackerBot:Adding ref

{{Cleanup|reason=Grammar and image violating copyright. |talk=TALKPAGENAME }}

'''Hypovitaminosis C''', aka '''scurvy''', is a condition caused by a dietary lack of [[vitamin C]] (ascorbic acid) and is characterized by an increased bleeding tendency and impaired collagen synthesis.<ref>{{Cite web|url=https://radiopaedia.org/articles/hypovitaminosis-c-scurvy-1?lang=us|title=Scurvy|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=radiopaedia.org|archive-url=|archive-date=|dead-url=|access-date=}}</ref> It can, also, be caused by reduced absorption of [[Vitamin C]] in the gut.<ref>{{Cite web|url=https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/|title=Office of Dietary Supplements - Vitamin C|website=ods.od.nih.gov|language=en|access-date=2020-01-24}}</ref>
==Overview==
Despite being considered a rare condition, scurvy still exists nowadays, even in children with no apparent risk factors living in wealthy families. The increasing popularity of dietary restriction for children, especially those with allergies, may potentially enhance the occurrence of scurvy in apparently healthy children.<ref name=":1">{{Cite journal|last=Brambilla|first=Alice|last2=Pizza|first2=Cristina|last3=Lasagni|first3=Donatella|last4=Lachina|first4=Lucia|last5=Resti|first5=Massimo|last6=Trapani|first6=Sandra|date=1 May 2018|title=Pediatric Scurvy: When Contemporary Eating Habits Bring Back the Past.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946015/|journal=Frontiers in Pediatric|volume=6|doi=10.3389/fped.2018.00126}}</ref>

In hospital patients, it can be highly prevalent, but often unrecognized.<ref name="Robitaille2016" /> Medical awareness of this potentially important disorder is hindered by the inability of most hospital laboratories to determine plasma [[Vitamin C]] concentrations. The availability of a simple, reliable method for analyzing plasma vitamin C could increase opportunities for routine plasma vitamin C analysis in clinical medicine.<ref name="Robitaille2016" />

== Symptoms ==
* lassitude<ref name="Levine1996" />
* fatigue<ref name="Levine1996" />
* irritability<ref name="Levine1996" />
* poor wound healing<ref name=":2">{{Cite journal|last=Maxfield|first=Luke|last2=Crane|first2=Jonathan S.|date=2019|title=Vitamin C Deficiency (Scurvy)|url=http://www.ncbi.nlm.nih.gov/books/NBK493187/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29630239}}</ref>
* gingival (gum) swelling with loss of teeth<ref name=":2" />
* mucocutaneous petechiae<ref name=":2" /> (small red or purple spots caused by bleeding into the skin where the mucosa transitions to skin)
* ecchymosis<ref name=":2" /> (a discoloration of the skin resulting from bleeding underneath, typically caused by [[bruising]])
* hyperkeratosis<ref name=":2" /> (skin condition that occurs when a person's skin becomes thicker)

== Evidence ==
The disease of terminal vitamin C deficiency – [[Scurvy]] – is first suspected on clinical grounds. The diagnosis is confirmed by documenting a plasma vitamin C concentration < 11.4 μmol/L and observing prompt clinical improvement after appropriate vitamin C provision. [[Scurvy]] is rare in the modern world, but hypovitaminosis C (plasma vitamin C concentration < 28.4 μmol/L ) or marginal vitamin C deficiency (plasma vitamin C concentration < 28.4 μmol/L but > 11.4 μmol/L ) is not. Hypovitaminosis C occurs in ~ 10% of the general population , in ~ 30 % of cigarette smokers and ~ 60% of acutely hospitalized patients, in whom it could contribute to fatigue and mood disturbance, immune system dysfunction, impaired wound healing, the complex regional pain syndrome and the complications of cardiovascular disease.<ref name="Robitaille2016" />

Cited from <ref name="Levine1996" /> : Subclinical Vitamin C Deficiency: Clinical Application. Six of seven volunteers noted mild but distinct fatigue and/or irritability at depletion, without scurvy. Symptoms disappeared within several days of the 30- or 60-mg daily dose. Although fatigue and irritability have myriad causes, vitamin C deficiency without scurvy should be an additional consideration. Since fatigue and irritability are common symptoms and were so easily reversible, physicians should ask patients with these symptoms about vitamin C ingestion from foods or supplements.

== Historical perspective ==
From a 18th century medical book, ''Observations of the Scurvy,'' by Thomas Trotter: "Every person who has been a sea voyage, must have perceived that longing desire for fresh vegetables after being for some time deprived of them. This I have often marked the harbinger of scurvy. Dr Lind, in some part of his work, has mentioned the same circumstances; and he might very justly have put it down as a symptom; for it is more or less an attendant on the disease and not only amuses their waking hours with thoughts of green fields and rivers of pure water but in dreams they are tantalized with the same ideas, and on waking nothing is so mortifying as the disappointment.<ref name=":0">{{Cite book|title=Observations on the Scurvy with a review of the theories lately advanced on that disease and the opinions of Dr Milman refuted from practice|pages=14-16|isbn=|edition=|volume=|language=en|title-link=|url=https://collections.nlm.nih.gov/ext/mhl/2575040R/PDF/2575040R.pdf|date=1793|publisher=John Parker|last=Trotter|first=Thomas|author-link=|last2=|first2=|author-link2=|last3=|first3=|author-link3=|last4=|first4=|author-link4=|last5=|first5=|author-link5=|last6=|first6=|author-link6=|last7=|first7=|author-link7=|last8=|first8=|author-link8=|last9=|first9=|author-link9=|veditors=|others=|doi=|oclc=|quote=|access-date=2020-01-23|archive-url=|archive-date=|location=Philadelphia, PA}}</ref>

When I heard a sailor expressing these desires, and lolling about, I was not surpriced to find him complain of sore gums and a few days after. About this time the colour of the face looks fallow, the eye is dull and heavy, and the whole countenance as it were bloated; the patient feels himself wearied even after sleep, and complains of pains in different parts of the body; he grows inactive, and easily fatigues; often timid; has gloomy ideas about his safety, as if hypochondrical; he flies from duty and wishes to indulge in sloth. To these generally succeed the apperance of the gums which so especially characherizes scurvy; they swell, are spongy and bleed on the slightest cause. The breath is fetid, and often attended with some disagreeable taste of the mouth. ... It is not uncommon for sailors, afflicted with scurvy, to walk upon deck, and drop down irrecoverably; though to all appearance, when below, there seemed no danger; From this I must infer no just prognosis can be always formed.”<ref name=":0" />

[[File:60mgperday.jpg|300px|thumb|left|Steady state plateau ascorbic acid concentration in plasma. Data are an example of plateau determination from volonteer 6 at the 60mg dose.]]

== Evaluation methods ==
The blood test procedure for Vitamin C deficiency is highly advanced.<ref name="Levine1996" /> A simpler but less accurate is proposed in <ref name="Robitaille2016" />
Another coarse method which might give an indication of [[Hypervitaminosis C]] is by evaluation of [[capillary fragility]] using a vacuum apparatus to the skin. This plausible relation between [[Hypervitaminosis C]] and [[capillary fragility]] require to further evaluation. <ref name="Cox1975" />

==Notable studies==
*1996, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance<ref name="Levine1996" /> [https://www.pnas.org/content/pnas/93/8/3704.full.pdf (Full Text)]

==See also==
*[[Collagen]]
*[[Capillary fragility]]
*[[Irritable bowel syndrome]]
*[[Osteoporosis]]
*[[Vitamin C]]
*[[Vitamin C Deficiency without Scurvy hypothesis]]

== Learn more ==

==References==
<references>
<ref name="Levine1996">{{Citation
| last1 = Levine | first1 = Mark
| last2 = Conry-Cantilena | first2 = Cathy
| last3 = Wang | first3 = Yaohui
| last4 = Welch | first4 = Richard W.
| last5 = Washko | first5 = Louis R.
| last6 = Dhariwal | last7 = Park | last8 = Lazarev | last9 = Graumlich | last10 = King | last11 = Cantilena | title = Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance
| journal = Proc Natl Acad Sci U S A | volume = 93 | issue = 8 | page = 3704-9
| date = 1996
| url = https://www.pnas.org/content/93/8/3704.long

}}
</ref>
<ref name="Robitaille2016">{{Citation
| last1 = Robitaille | first1 = Line
| last2 = Hoffer | first2 = L John
| title = A simple method for plasma total vitamin C analysis suitable for routine clinical laboratory use
| journal = Nutrition Journal | volume = 15 | issue = 40
| date = 21 April 2016
| url = https://nutritionj.biomedcentral.com/articles/10.1186/s12937-016-0158-9

}}
</ref>
<ref name="Cox1975">{{Citation
| last1 = Cox | first1 = Brian D
| last2 = Butterfield | first2 = W J
| title = Vitamin C Supplements and Diabetic Cutaneous Capillary Fragility
| journal = British Medical Journal | volume = 26 | issue = 3
| date = 26 July 1975
| doi = 10.1136/bmj.3.5977.205
| url = https://pubmed.ncbi.nlm.nih.gov/1148732/
}}
</ref>
</references>
[[Category:Diagnoses]]
[[Category:Vitamins]]

Collagen

2020-05-30T12:28:20Z

FatigueTrackerBot:/* See also */ Added refs

'''Collagen''' is the main component of [[connective tissue]] and the most abundant protein in the human body. It is mostly found in fibrous tissues such as tendons, ligaments and skin.

== Types ==
There are over 28 types of collagen found in the human body.<ref name=":3">{{Cite journal|last=Wu|first=Marlyn|last2=Crane|first2=Jonathan S.|date=2019|title=Biochemistry, Collagen Synthesis|url=http://www.ncbi.nlm.nih.gov/books/NBK507709/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29939531}}</ref> Over 90% is made of of these fives types<ref name=":3" />:
* Type I: skin, tendon, vasculature, organs, bone (main component of the organic part of bone)
* Type II: cartilage (main collagenous component of cartilage)
* Type III: reticulate (main component of reticular fibers), commonly found alongside type I.
* Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.
* Type V: cell surfaces, hair, and placenta
The main collagen in ligaments is collagen type I, which comprises 70% of the dry weight of a ligament.<ref>{{Cite web|url=https://www.orthobullets.com/basic-science/9016/ligaments|title=Ligaments|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=www.orthobullets.com|archive-url=|archive-date=|dead-url=|access-date=2019-09-16}}</ref> Elastin is also found at 4–9% of the dry weight in ligaments.<ref>{{Cite journal|last=Zitnay|first=Jared L.|last2=Weiss|first2=Jeffrey A.|date=Dec 2018|title=Load Transfer, Damage and Failure in Ligaments and Tendons|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454883/|journal=Journal of orthopaedic research : official publication of the Orthopaedic Research Society|volume=36|issue=12|pages=3093–3104|doi=10.1002/jor.24134|issn=0736-0266|pmc=6454883|pmid=30175857}}</ref>

== Biology ==

=== Components ===
Collagen is made up primarily of the amino acids [[glycine]] and [[proline]]. The primary amino acid sequence of collagen is glycine-proline-X or glycine-X-hydroxyproline.<ref>{{Cite journal|last=Szulc|first=Pawel|date=Oct 2018|title=Bone turnover: Biology and assessment tools|url=https://www.ncbi.nlm.nih.gov/pubmed/30449551|journal=Best Practice & Research. Clinical Endocrinology & Metabolism|volume=32|issue=5|pages=725–738|doi=10.1016/j.beem.2018.05.003|issn=1878-1594|pmid=30449551|last2=|first2=|pmc=|quote=|last3=|first3=|last4=|first4=|last5=|first5=|last6=|first6=|last7=|first7=|last8=|first8=|author-link=|author-link2=|access-date=|author-link3=|author-link4=|author-link5=|author-link6=|via=}}</ref> X can be any of the other 17 amino acids. Every third amino acid is glycine.<ref name=":3" />

=== Co-factors ===
[[Vitamin C]] is a co-factor of many of the chemical reactions involved in collagen production. Vitamin C is also a [[mast cell]] stabilizer. Vitamin C deficiency can result in impaired collagen synthesis and [[scurvy]].{{Citation needed|reason=}}

=== Structure ===
Collagen is composed of three chains that wind together to form a triple helix.<ref name=":3" />

=== Biosynthesis ===
Collagen synthesis occurs mainly in [[Fibroblast|fibroblasts]], cells whose many function is the synthesis of collagen and [[stroma]].<ref name=":3" /> Synthesis occurs in both intracellular and extracellular spaces.<ref name=":3" />

== Collagen-degrading factors ==

=== Pathogens ===
Infection can degrade collagen via direct secretion<ref name=":1">{{Cite journal|last=Harrington|first=D J|date=Jun 1996|title=Bacterial collagenases and collagen-degrading enzymes and their potential role in human disease.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC174012/|journal=Infection and Immunity|volume=64|issue=6|pages=1885–1891|issn=0019-9567|pmid=8675283}}</ref> of collagenases and other [[Enzyme|enzymes]] (in the case of [[bacteria]]) or increased host production of [[Matrix metalloproteinase|matrix metalloproteinases]] (MMPs) as part of the normal [[immune response]] (in the case of bacteria and [[Virus|viruses]]). Numerous bacteria secrete their own [[collagenase|collagenases]].<ref name=":1" /><ref>{{Cite journal|last=Duarte|first=Ana Sofia|last2=Correia|first2=Antonio|last3=Esteves|first3=Ana Cristina|date=2016|title=Bacterial collagenases - A review|url=https://www.ncbi.nlm.nih.gov/pubmed/24754251|journal=Critical Reviews in Microbiology|volume=42|issue=1|pages=106–126|doi=10.3109/1040841X.2014.904270|issn=1549-7828|pmid=24754251}}</ref> [[Borrelia]] spirochetes upregulate production of human collagenase (MMP-1) and [[gelatinase B]] (MMP-9)<ref>{{Cite journal|last=Gebbia|first=Joseph A.|last2=Coleman|first2=James L.|last3=Benach|first3=Jorge L.|date=2001-01-01|title=Borrelia Spirochetes Upregulate Release and Activation of Matrix Metalloproteinase Gelatinase B (MMP-9) and Collagenase 1 (MMP-1) in Human Cells|url=https://iai.asm.org/content/69/1/456|journal=Infection and Immunity|language=en|volume=69|issue=1|pages=456–462|doi=10.1128/IAI.69.1.456-462.2001|issn=0019-9567|pmid=11119537}}</ref>, an enzyme that can degrade both [[elastin]] and collagen.<ref>{{Cite web|url=https://www.sciencedirect.com/topics/neuroscience/gelatinase-b|title=ScienceDirect|website=www.sciencedirect.com|access-date=2018-11-09}}</ref> Borrelia infection has been associated with damage to collagen and elastin fibres, causing "spontaneous ruptures of tendons after slight strain, dislocation of vertebrae and an accumulation of prolapsed intervertebral discs as well as ossification of tendon insertions."<ref>{{Cite journal|last=Müller|first=Kurt E|date=2012-12-31|title=Damage of Collagen and Elastic Fibres by Borrelia Burgdorferi – Known and New Clinical and Histopathological Aspects|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751012/|journal=The Open Neurology Journal|volume=6|pages=179–186|doi=10.2174/1874205X01206010179|issn=1874-205X|pmc=3751012|pmid=23986790}}</ref> MMP-8 and MMP-9 are upregulated in bacterial [[meningitis]] and the latter is associated with an increased risk of [[blood-brain barrier]] breakdown and neurological sequale such as [[epilepsy]] and [[Cognitive dysfunction|cognitive impairment]].<ref>{{Cite journal|last=Tiveron|first=Marcos Gradim|last2=Pomerantzeff|first2=Pablo Maria Alberto|last3=de Lourdes Higuchi|first3=Maria|last4=Reis|first4=Marcia Martins|last5=de Jesus Pereira|first5=Jaqueline|last6=Kawakami|first6=Joyce Tieko|last7=Ikegami|first7=Renata Nishiyama|last8=de Almeida Brandao|first8=Carlos Manuel|last9=Jatene|first9=Fabio Biscegli|date=2017-04-21|title=Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study|url=https://www.ncbi.nlm.nih.gov/pubmed/28431520|journal=BMC infectious diseases|volume=17|issue=1|pages=297|doi=10.1186/s12879-017-2387-8|issn=1471-2334|pmc=5399830|pmid=28431520}}</ref> [[Herpes simplex virus]]<ref name=":2">{{Cite journal|date=2006-12-13|title=Herpes-simplex virus encephalitis is characterized by an early MMP-9 increase and collagen type IV degradation|url=https://www.sciencedirect.com/science/article/pii/S0006899306029246|journal=Brain Research|language=en|volume=1125|issue=1|pages=155–162|doi=10.1016/j.brainres.2006.09.093|issn=0006-8993}}</ref>, [[Human herpesvirus 6|HHV-6]]<ref>{{Cite journal|date=2014-11-01|title=Serum levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in human herpesvirus-6–infected infants with or without febrile seizures|url=https://www.sciencedirect.com/science/article/pii/S1341321X14002682|journal=Journal of Infection and Chemotherapy|language=en|volume=20|issue=11|pages=716–721|doi=10.1016/j.jiac.2014.07.017|issn=1341-321X}}</ref> and [[Coxsackie B]]<ref>{{Cite journal|last=De Palma|first=Armando M.|last2=Verbeken|first2=Erik|last3=Van Aelst|first3=Ilse|last4=Van den Steen|first4=Philippe E.|last5=Opdenakker|first5=Ghislain|last6=Neyts|first6=Johan|date=2008-12-05|title=Increased gelatinase B/matrix metalloproteinase 9 (MMP-9) activity in a murine model of acute coxsackievirus B4-induced pancreatitis|url=https://www.ncbi.nlm.nih.gov/pubmed/18929380|journal=Virology|volume=382|issue=1|pages=20–27|doi=10.1016/j.virol.2008.08.046|issn=1096-0341|pmid=18929380}}</ref><ref>{{Cite journal|date=2006-03-01|title=Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis|url=https://www.sciencedirect.com/science/article/pii/S1054880705001729|journal=Cardiovascular Pathology|language=en|volume=15|issue=2|pages=63–74|doi=10.1016/j.carpath.2005.11.008|issn=1054-8807}}</ref> infection result in increased production of MMP-9, which is associated with Type IV and Type V collagen degradation.<ref name=":2" /><ref>{{Cite journal|last=Zeng|first=Z. S.|last2=Cohen|first2=A. M.|last3=Guillem|first3=J. G.|date=May 1999|title=Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis|url=https://www.ncbi.nlm.nih.gov/pubmed/10334190|journal=Carcinogenesis|volume=20|issue=5|pages=749–755|issn=0143-3334|pmid=10334190}}</ref><ref>{{Cite journal|last=Van den Steen|first=Philippe E.|last2=Dubois|first2=Bénédicte|last3=Nelissen|first3=Inge|last4=Rudd|first4=Pauline M.|last5=Dwek|first5=Raymond A.|last6=Opdenakker|first6=Ghislain|date=Jan 2002|title=Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9)|url=https://www.tandfonline.com/doi/abs/10.1080/10409230290771546|journal=Critical Reviews in Biochemistry and Molecular Biology|language=en|volume=37|issue=6|pages=375–536|doi=10.1080/10409230290771546|issn=1040-9238}}</ref> Coxsackie B infection induces immune cells to secrete MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12.<ref>{{Cite journal|last=Cheung|first=Caroline|last2=Luo|first2=Honglin|last3=Yanagawa|first3=Bobby|last4=Leong|first4=Hon Sing|last5=Samarasekera|first5=Dinesh|last6=Lai|first6=John C. K.|last7=Suarez|first7=Agripina|last8=Zhang|first8=Jingchun|last9=McManus|first9=Bruce M.|date=Mar 2006|title=Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis|url=https://www.ncbi.nlm.nih.gov/pubmed/16533694|journal=Cardiovascular Pathology: The Official Journal of the Society for Cardiovascular Pathology|volume=15|issue=2|pages=63–74|doi=10.1016/j.carpath.2005.11.008|issn=1054-8807|pmid=16533694}}</ref><ref>{{Cite journal|last=Meng|first=Xiao-hui|last2=Wang|first2=Yi|last3=Zhuang|first3=Jian-xin|last4=Han|first4=Xiu-zhen|last5=Chen|first5=Yao|last6=Jin|first6=You-peng|last7=Wang|first7=Yu-lin|last8=Yu|first8=Yong-hui|last9=Spires|first9=James P.|date=Aug 2004|title=Dynamic changes in myocardial matrix metalloproteinase activity in mice with viral myocarditis|url=https://www.ncbi.nlm.nih.gov/pubmed/15361294|journal=Chinese Medical Journal|volume=117|issue=8|pages=1195–1199|issn=0366-6999|pmid=15361294}}</ref><ref>{{Cite journal|last=Rutschow|first=Susanne|last2=Leschka|first2=Sebastian|last3=Westermann|first3=Dirk|last4=Puhl|first4=Kerstin|last5=Weitz|first5=Anneke|last6=Ladyszenskij|first6=Leonid|last7=Jaeger|first7=Sebastian|last8=Zeichhardt|first8=Heinz|last9=Noutsias|first9=Michel|date=2010-03-25|title=Left ventricular enlargement in coxsackievirus-B3 induced chronic myocarditis--ongoing inflammation and an imbalance of the matrix degrading system|url=https://www.ncbi.nlm.nih.gov/pubmed/20035743|journal=European Journal of Pharmacology|volume=630|issue=1-3|pages=145–151|doi=10.1016/j.ejphar.2009.12.019|issn=1879-0712|pmid=20035743}}</ref>
==== Infection and Ehlers-Danlos Syndrome ====
[[Ehlers-Danlos syndrome|Ehlers-Danlos Syndrome]] is a group connective tissue disorders caused by genetic defects in the production of collagen. Type III, [[hypermobile EDS]] (hEDS), is also thought to be genetic but as a genetic marker has not yet been identified; it is diagnosed via signs and symptoms. A 2018 case study of a patient who met the diagnostic criteria for hEDS and had a chronic Bartonella infection found their hEDS symptoms resolved with antibiotic treatment for Bartonella.<ref name=":0">{{Cite journal|last=Mozayeni|first=Bobak Robert|last2=Maggi|first2=Ricardo Guillermo|last3=Bradley|first3=Julie Meredith|last4=Breitschwerdt|first4=Edward Bealmear|date=Apr 2018|title=Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias|url=https://journals.lww.com/md-journal/Pages/articleviewer.aspx?year=2018&issue=04270&article=00032&type=Fulltext|journal=Medicine|language=en-US|volume=97|issue=17|pages=e0465|doi=10.1097/MD.0000000000010465|issn=0025-7974}}</ref> [[Mycoplasma pneumoniae]] has been associated with [[mitral valve]] degeneration, a complication of EDS.<ref>{{Cite journal|last=Tiveron|first=Marcos Gradim|last2=Pomerantzeff|first2=Pablo Maria Alberto|last3=de Lourdes Higuchi|first3=Maria|last4=Reis|first4=Marcia Martins|last5=de Jesus Pereira|first5=Jaqueline|last6=Kawakami|first6=Joyce Tieko|last7=Ikegami|first7=Renata Nishiyama|last8=de Almeida Brandao|first8=Carlos Manuel|last9=Jatene|first9=Fabio Biscegli|date=2017-04-21|title=Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study|url=https://www.ncbi.nlm.nih.gov/pubmed/28431520|journal=BMC infectious diseases|volume=17|issue=1|pages=297|doi=10.1186/s12879-017-2387-8|issn=1471-2334|pmc=5399830|pmid=28431520}}</ref>

=== Fluoroquinolone antibiotics ===
“Fluoroquinolones upregulate cell matrix metalloproteinases, resulting in a reduction of collagen fibrils of types I and III collagen.”<ref>{{Cite web|url=https://www.jwatch.org/na48248/2019/02/13/adverse-effects-fluoroquinolones-where-do-we-stand|title=NEJM Journal Watch: Summaries of and commentary on original medical and scientific articles from key medical journals|website=www.jwatch.org|access-date=2019-06-18}}</ref> A longitudinal study found Fluoroquinolones increased the risk of collagen-related adverse events like tendon ruptured and detached retinas.<ref>{{Cite journal|last=Redelmeier|first=Donald A.|last2=Lu|first2=Hong|last3=Daneman|first3=Nick|date=2015-11-01|title=Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study|url=https://bmjopen.bmj.com/content/5/11/e010077|journal=BMJ Open|language=en|volume=5|issue=11|pages=e010077|doi=10.1136/bmjopen-2015-010077|issn=2044-6055|pmid=26582407}}</ref> In December 2018, the FDA recommended against its use in patients with connective tissue disorders like Ehlers-Danlos Syndrome and Marfan Syndrome.<ref>{{Cite journal|last=Research|first=Center for Drug Evaluation and|date=2019-04-15|title=FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients|url=http://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics|journal=FDA|language=en}}</ref>

[[Doxycycline]], by contrast, inhibits MMP production.<ref name=":02">{{Cite journal|last=De Paiva|first=Cintia S.|last2=Corrales|first2=Rosa M.|last3=Villarreal|first3=Arturo L.|last4=Farley|first4=William J.|last5=Li|first5=De-Quan|last6=Stern|first6=Michael E.|last7=Pflugfelder|first7=Stephen C.|date=2006-09-01|title=Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye|url=http://www.sciencedirect.com/science/article/pii/S0014483506001709|journal=Experimental Eye Research|volume=83|issue=3|pages=526–535|doi=10.1016/j.exer.2006.02.004|issn=0014-4835}}</ref><ref>{{Cite journal|last=Roach|first=D. M|last2=Fitridge|first2=R. A|last3=Laws|first3=P. E|last4=Millard|first4=S. H|last5=Varelias|first5=A|last6=Cowled|first6=P. A|date=2002-03-01|title=Up-regulation of MMP-2 and MMP-9 Leads to Degradation of Type IV Collagen During Skeletal Muscle Reperfusion Injury; Protection by the MMP Inhibitor, Doxycycline|url=http://www.sciencedirect.com/science/article/pii/S1078588402915984|journal=European Journal of Vascular and Endovascular Surgery|volume=23|issue=3|pages=260–269|doi=10.1053/ejvs.2002.1598|issn=1078-5884}}</ref><ref>{{Cite journal|last=Niedzwiecki|first=A.|last2=Rath|first2=M.|last3=Kalinovsky|first3=T.|last4=Monterrey|first4=J. C.|last5=Roomi|first5=M. W.|date=2010-03-01|title=In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors|url=http://www.spandidos-publications.com/or/23/3/605/abstract|journal=Oncology Reports|volume=23|issue=3|pages=605–614|doi=10.3892/or_00000675|issn=1021-335X}}</ref><ref>{{Cite journal|last=Choi|first=Dong-Hoon|last2=Moon|first2=Ik-Sang|last3=Choi|first3=Bong-Kyu|last4=Paik|first4=Jeong-Won|last5=Kim|first5=Yoon-Sik|last6=Choi|first6=Seong-Ho|last7=Kim|first7=Chong-Kwan|date=2004|title=Effects of sub-antimicrobial dose doxycycline therapy on crevicular fluid MMP-8, and gingival tissue MMP-9, TIMP-1 and IL-6 levels in chronic periodontitis|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0765.2004.00696.x|journal=Journal of Periodontal Research|language=en|volume=39|issue=1|pages=20–26|doi=10.1111/j.1600-0765.2004.00696.x|issn=1600-0765}}</ref><ref>{{Cite journal|last=Li|first=De-Quan|last2=Lokeshwar|first2=Balakrishna L|last3=Solomon|first3=Abraham|last4=Monroy|first4=Dagoberto|last5=Ji|first5=Zhonghua|last6=Pflugfelder|first6=Stephen C|date=2001-10-01|title=Regulation of MMP-9 Production by Human Corneal Epithelial Cells|url=http://www.sciencedirect.com/science/article/pii/S0014483501910541|journal=Experimental Eye Research|volume=73|issue=4|pages=449–459|doi=10.1006/exer.2001.1054|issn=0014-4835}}</ref><ref>{{Cite journal|last=Brown David L.|last2=Desai Kavita K.|last3=Vakili Babak A.|last4=Nouneh Chadi|last5=Lee Hsi-Ming|last6=Golub Lorne M.|date=2004-04-01|title=Clinical and Biochemical Results of the Metalloproteinase Inhibition with Subantimicrobial Doses of Doxycycline to Prevent Acute Coronary Syndromes (MIDAS) Pilot Trial|url=https://www.ahajournals.org/doi/full/10.1161/01.ATV.0000121571.78696.dc|journal=Arteriosclerosis, Thrombosis, and Vascular Biology|volume=24|issue=4|pages=733–738|doi=10.1161/01.ATV.0000121571.78696.dc}}</ref>

=== Mold ===
''[[Stachybotrys chartarum]]'' (black [[mold]]) release proteinases that can hydrolyze [[gelatin]] and collagen I and IV.<ref>{{Cite journal|last=Yike|first=Iwona|last2=Rand|first2=Thomas|last3=Dearborn|first3=Dorr G.|date=2007-07-03|title=The role of fungal proteinases in pathophysiology of Stachybotrys chartarum|url=https://doi.org/10.1007/s11046-007-9037-4|journal=Mycopathologia|language=en|volume=164|issue=4|pages=171|doi=10.1007/s11046-007-9037-4|issn=1573-0832}}</ref> Three [[Mycotoxin|mycotoxins]], deoxynivalenol (DON), nivalenol (NIV) and T-2 toxin, were study in an the context of an experimental cartilage model. They were found to increase the expression of MMPs and result in the loss of [[aggrecan]] and type II collagen. Selenium partially inhibited the effects of these mycotoxins.<ref>{{Cite journal|last=Caterson|first=Bruce|last2=Li|first2=Jin|last3=Wang|first3=Jiali|last4=Luo|first4=Mingxiu|last5=Liu|first5=Jiayuan|last6=Zhang|first6=Zengtie|last7=Fu|first7=Qiang|last8=Chen|first8=Jinghong|last9=Li|first9=Siyuan|date=2012|title=The Effects of Mycotoxins and Selenium Deficiency on Tissue-Engineered Cartilage|url=https://www.karger.com/Article/FullText/335046|journal=Cells Tissues Organs|language=english|volume=196|issue=3|pages=241–250|doi=10.1159/000335046|issn=1422-6405|pmid=22538829}}</ref>

=== Sex hormones ===
Several animal studies of collagen in muscle and the aorta have found that [[estrogen]] decreases and [[testosterone]] collagen and elastin.<ref>{{Cite journal|last=Fischer|first=G. M.|last2=Swain|first2=M. L.|date=1977-06-01|title=Effect of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats|url=https://www.physiology.org/doi/abs/10.1152/ajpheart.1977.232.6.H617|journal=American Journal of Physiology-Heart and Circulatory Physiology|volume=232|issue=6|pages=H617–H621|doi=10.1152/ajpheart.1977.232.6.H617|issn=0363-6135}}</ref><ref>{{Cite journal|last=Cembrano|first=JosÉ|last2=Lillo|first2=Manuel|last3=Val|first3=JosÉ|last4=Mardones|first4=Jorge|date=1960-05-01|title=Influence of Sex Difference and Hormones on Elastine and Collagen in the Aorta of Chickens|url=http://insights.ovid.com/|journal=Circulation Research|language=ENGLISH|volume=8|issue=3|pages=527–529|issn=0009-7330|pmid=13808759}}</ref><ref>{{Cite journal|last=Fischer|first=Grace M.|last2=Swain|first2=Margaret L.|date=1980-08-01|title=Influence of contraceptive and other sex steroids on aortic collagen and elastin|url=http://www.sciencedirect.com/science/article/pii/0014480080900039|journal=Experimental and Molecular Pathology|volume=33|issue=1|pages=15–24|doi=10.1016/0014-4800(80)90003-9|issn=0014-4800}}</ref><ref>{{Cite journal|last=Fischer|first=G. M.|last2=Swain|first2=M. L.|date=1985-02-01|title=Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas|url=http://www.sciencedirect.com/science/article/pii/0021915085901777|journal=Atherosclerosis|volume=54|issue=2|pages=177–185|doi=10.1016/0021-9150(85)90177-7|issn=0021-9150}}</ref><ref>{{Cite journal|last=Fischer|first=Grace M.|date=1972-11-01|title=In Vivo EflEects of Estradiol on Collagen and Elastin Dynamics in Rat Aorta|url=https://academic.oup.com/endo/article/91/5/1227/2621144|journal=Endocrinology|language=en|volume=91|issue=5|pages=1227–1232|doi=10.1210/endo-91-5-1227|issn=0013-7227}}</ref> A study of collagen in male cattle found that collagen synthesis increased with puberty, possibly as a result of testosterone.<ref>{{Cite journal|last=Cross|first=H. R.|last2=Schanbacher|first2=B. D.|last3=Crouse|first3=J. D.|date=1984-01-01|title=Sex, age and breed related changes in bovine testosterone and intramuscular collagen|url=http://www.sciencedirect.com/science/article/pii/0309174084900214|journal=Meat Science|volume=10|issue=3|pages=187–195|doi=10.1016/0309-1740(84)90021-4|issn=0309-1740}}</ref> Another, that intramuscular collagen was higher in bulls than in steers (castrated cattle).<ref>{{Cite journal|last=Judge|first=M. D.|last2=Diekman|first2=M. A.|last3=Lemenager|first3=R. P.|last4=Aberle|first4=E. D.|last5=Jones|first5=S. J.|last6=Gerrard|first6=D. E.|date=1987-11-01|title=Collagen Stability, Testosterone Secretion and Meat Tenderness in Growing Bulls and Steers|url=https://academic.oup.com/jas/article/65/5/1236/4662470|journal=Journal of Animal Science|language=en|volume=65|issue=5|pages=1236–1242|doi=10.2527/jas1987.6551236x|issn=0021-8812}}</ref> An ''in vitro'' study of rat cartilage cells found that testosterone stimulated collagen synthesis, but only in male cells.<ref>{{Cite journal|last=Boyan|first=B. D.|last2=Soskolne|first2=W. A.|last3=Brooks|first3=B. P.|last4=Ornoy|first4=A.|last5=Nasatzky|first5=E.|last6=Schwartz|first6=Z.|date=1994-04-01|title=Gender-specific, maturation-dependent effects of testosterone on chondrocytes in culture|url=https://academic.oup.com/endo/article/134/4/1640/3035468|journal=Endocrinology|language=en|volume=134|issue=4|pages=1640–1647|doi=10.1210/endo.134.4.8137726|issn=0013-7227}}</ref>

== In human disease ==
=== Ehlers-Danlos Syndrome ===
{{Main article|page_name=Ehlers-Danlos Syndrome}}

=== Mast cell activation syndrome ===
{{Main article|page_name=Mast cell activation syndrome}}

=== ME/CFS ===
{{Main article|page_name=Myalgic encephalomyelitis}}

Preliminary data from the [[UK ME/CFS biobank]] show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of [[prolyl 4-hydroxylase]] subunit alpha 1 (P4HA1), which encodes for [[procollagen-proline dioxygenase]], an enzyme involved in the production of collagen that also plays a role in the regulation of [[energy metabolism]] via downregulation of [[pyruvate dehydrogenase]] during [[hypoxia]].<ref>{{Cite journal|last=Schneider|first=Martin|last2=Harnoss|first2=Jonathan Michael|last3=Strowitzki|first3=Moritz J.|last4=Radhakrishnan|first4=Praveen|last5=Platzer|first5=Lisa|last6=Harnoss|first6=Julian Camill|last7=Hank|first7=Thomas|last8=Cai|first8=Jun|last9=Ulrich|first9=Alexis|date=Jan 2015|title=Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges|url=https://www.dovepress.com/therapeutic-inhibition-of-prolyl-hydroxylase-domain-containing-enzymes-peer-reviewed-fulltext-article-HP|journal=Hypoxia|language=English|volume=3|pages=1|doi=10.2147/HP.S60872|issn=2324-1128}}</ref> The data are based on self-reported diagnosis of [[chronic fatigue syndrome]] and involve a sample size that is very small for genome-wide association studies (n=1829), making confidence intervals difficult to estimate.<ref>{{Cite news|url=https://mecfsresearchreview.me/2018/06/11/analysis-of-data-from-500000-individuals-in-uk-biobank-demonstrates-an-inherited-component-to-me-cfs/amp/?__twitter_impression=true|title=Analysis of data from 500,000 individuals in UK Biobank demonstrates an inherited component to ME/CFS|date=2018-06-11|work=ME/CFS Research Review|access-date=2018-11-11|language=en-US}}</ref>

Elevated levels of [[hydroxyproline]], a marker of collagen breakdown, was found by [[Wenzhong Xiao]] in the [[Severely Ill Patient Study]].<ref>{{Citation|last=Open Medicine Foundation - OMF|title=Wenzhong Xiao, PhD {{!}} Results from the Severely Ill Patient Study (SIPS)|date=2018-11-07|url=https://www.youtube.com/watch?v=_N1o2gbaCl4&feature=youtu.be&t=853|access-date=2019-07-16}}</ref> [[Robert Naviaux]]’s work has suggested it as a possible [[Diagnostic biomarker|biomarker]] for female [[ME/CFS]] patients.<ref>{{Cite journal|last=Gordon|first=Eric|last2=Anderson|first2=Wayne|last3=Nathan|first3=Neil|last4=Baxter|first4=Asha|last5=Wang|first5=Lin|last6=Alaynick|first6=William A.|last7=Bright|first7=A. Taylor|last8=Li|first8=Kefeng|last9=Naviaux|first9=Jane C.|date=2016-09-13|title=Metabolic features of chronic fatigue syndrome|url=https://www.pnas.org/content/113/37/E5472|journal=Proceedings of the National Academy of Sciences|language=en|volume=113|issue=37|pages=E5472–E5480|doi=10.1073/pnas.1607571113|issn=0027-8424|pmid=27573827}}</ref> [[Maureen Hanson]] failed to find elevated hydroxyproline in her metabolomics study.{{Citation needed|reason=}}

==As a supplement==
When hydrolyzed, collagen is reduced to small [[peptide]]s, which can be ingested in the form of [[dietary supplement]] or [[functional food]]s and beverages with the intent to aid joint and bone health and enhance skin health.<ref>{{Cite journal|last=Guillerminet|first=Fanny|last2=Beaupied|first2=Hélène|last3=Fabien-Soulé|first3=Véronique|last4=Tomé|first4=Daniel|last5=Benhamou|first5=Claude-Laurent|last6=Roux|first6=Christian|last7=Blais|first7=Anne|date=2010-03-01|title=Hydrolyzed collagen improves bone metabolism and biomechanical parameters in ovariectomized mice: An in vitro and in vivo study|url=http://www.thebonejournal.com/article/S8756-3282(09)02003-1/abstract|journal=Bone|language=English|volume=46|issue=3|pages=827–834|doi=10.1016/j.bone.2009.10.035|issn=8756-3282}}</ref><ref>{{Cite journal|last=Guillerminet|first=F.|last2=Fabien-Soulé|first2=V.|last3=Even|first3=P. C.|last4=Tomé|first4=D.|last5=Benhamou|first5=C.-L.|last6=Roux|first6=C.|last7=Blais|first7=A.|date=2012-07-01|title=Hydrolyzed collagen improves bone status and prevents bone loss in ovariectomized C3H/HeN mice|url=https://link.springer.com/article/10.1007/s00198-011-1788-6|journal=Osteoporosis International|language=en|volume=23|issue=7|pages=1909–1919|doi=10.1007/s00198-011-1788-6|issn=0937-941X}}</ref><ref>{{Cite journal|last=Daneault|first=A.|date=2014-04-01|title=Hydrolyzed collagen contributes to osteoblast differentiation in vitro and subsequent bone health in vivo|url=http://www.oarsijournal.com/article/S1063-4584(14)00280-5/fulltext|journal=Osteoarthritis and Cartilage|language=English|volume=22|pages=S131|doi=10.1016/j.joca.2014.02.240|issn=1063-4584}}</ref><ref>{{Cite journal|last=Daneault|first=Audrey|last2=Prawitt|first2=Janne|last3=Fabien Soulé|first3=Véronique|last4=Coxam|first4=Véronique|last5=Wittrant|first5=Yohann|date=2017-06-13|title=Biological effect of hydrolyzed collagen on bone metabolism|journal=Critical Reviews in Food Science and Nutrition|volume=57|issue=9|pages=1922–1937|doi=10.1080/10408398.2015.1038377|issn=1549-7852|pmid=25976422|url=https://zenodo.org/record/889529|deadurl=no|archiveurl=https://web.archive.org/web/20170913183348/https://zenodo.org/record/889529|archivedate=2017-09-13|df=}}</ref><ref>{{Cite journal|last=Jiang|first=J.X.|date=2014|title=Collagen peptides improve knee osteoarthritis in elderly women: A 6-month randomized, double-blind, placebo-controlled study|url=http://old.teknoscienze.com//articles/agro-food-industry-hi-tech-collagen-peptides-improve-knee-osteoarthritis-in-elderly-women-a.aspx#.WXCW-oSGNtR|journal=Agro FOOD Indusrty Hi Tech|volume=25|pages=19–23|via=|deadurl=no|archiveurl=https://web.archive.org/web/20170913183401/http://old.teknoscienze.com//articles/agro-food-industry-hi-tech-collagen-peptides-improve-knee-osteoarthritis-in-elderly-women-a.aspx#.WXCW-oSGNtR|archivedate=2017-09-13|df=}}</ref><ref>{{Cite journal|last=Dar|first=Qurratul-Ain|last2=Schott|first2=Eric M.|last3=Catheline|first3=Sarah E.|last4=Maynard|first4=Robert D.|last5=Liu|first5=Zhaoyang|last6=Kamal|first6=Fadia|last7=Farnsworth|first7=Christopher W.|last8=Ketz|first8=John P.|last9=Mooney|first9=Robert A.|date=2017-04-06|title=Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174705|journal=PLOS ONE|volume=12|issue=4|pages=e0174705|doi=10.1371/journal.pone.0174705|issn=1932-6203|pmc=5383229|pmid=28384173|deadurl=no|archiveurl=https://web.archive.org/web/20170913184032/http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0174705|archivedate=2017-09-13|df=|bibcode=2017PLoSO..1274705D}}</ref><ref>{{Cite journal|last=Asserin|first=Jérome|last2=Lati|first2=Elian|last3=Shioya|first3=Toshiaki|last4=Prawitt|first4=Janne|date=2015-12-01|title=The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo‐controlled clinical trials|url=http://onlinelibrary.wiley.com/doi/10.1111/jocd.12174/full|journal=Journal of Cosmetic Dermatology|language=en|volume=14|issue=4|pages=291–301|doi=10.1111/jocd.12174|issn=1473-2165|deadurl=no|archiveurl=https://web.archive.org/web/20170910193750/http://onlinelibrary.wiley.com/doi/10.1111/jocd.12174/full|archivedate=2017-09-10|df=}}</ref> These [[hydroxyproline]]-containing peptides are transported into the target tissues (e.g., skin, bones, and cartilage), where they act as building blocks for local cells and help boost the production of new collagen fibers.<ref>{{Cite journal|last=Ichikawa|first=Satomi|last2=Morifuji|first2=Masashi|last3=Ohara|first3=Hiroki|last4=Matsumoto|first4=Hitoshi|last5=Takeuchi|first5=Yasuo|last6=Sato|first6=Kenji|date=2010-02-01|title=Hydroxyproline-containing dipeptides and tripeptides quantified at high concentration in human blood after oral administration of gelatin hydrolysate|url=https://dx.doi.org/10.3109/09637480903257711|journal=International Journal of Food Sciences and Nutrition|volume=61|issue=1|pages=52–60|doi=10.3109/09637480903257711|issn=0963-7486|pmid=19961355}}</ref><ref>{{Cite journal|last=Shigemura|first=Yasutaka|last2=Kubomura|first2=Daiki|last3=Sato|first3=Yoshio|last4=Sato|first4=Kenji|date=2014-09-15|title=Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion|url=http://www.sciencedirect.com/science/article/pii/S0308814614002763|journal=Food Chemistry|volume=159|pages=328–332|doi=10.1016/j.foodchem.2014.02.091}}</ref><ref>{{Cite journal|last=Watanabe-Kamiyama|first=Mari|last2=Shimizu|first2=Muneshige|last3=Kamiyama|first3=Shin|last4=Taguchi|first4=Yasuki|last5=Sone|first5=Hideyuki|last6=Morimatsu|first6=Fumiki|last7=Shirakawa|first7=Hitoshi|last8=Furukawa|first8=Yuji|last9=Komai|first9=Michio|date=2010-01-27|title=Absorption and Effectiveness of Orally Administered Low Molecular Weight Collagen Hydrolysate in Rats|url=https://dx.doi.org/10.1021/jf9031487|journal=Journal of Agricultural and Food Chemistry|volume=58|issue=2|pages=835–841|doi=10.1021/jf9031487|issn=0021-8561}}</ref>

== Potential modulators ==
The following are compounds that can or might increase collagen synthesis, inhibit collagen destruction, or improve collagen strength. Compounds proven to promote connective tissue repair in vivo, or proven to reduce connective tissue-degrading [[matrix metalloproteinase]] (MMP) enzymes in vivo, are indicated by the "shown effective in vivo" column.

{| class="wikitable"
!Compound
!Type
!Shown effective in vivo
!
!Mechanism of action
|-
|[[Aloe vera]]
|[[Polysaccharide]]
|
|Promotes synthesis, and inhibits destruction
|Stimulates fibroblast proliferation and collagen synthesis. Inhibits MMP-2 and MMP-9 in vitro.<ref name=":4">{{Cite journal|last=Kudalkar|first=Mithun D.|last2=Nayak|first2=Aarati|last3=Bhat|first3=Kishore S.|last4=Nayak|first4=Ranganath N.|date=Jan 2014|title=Effect of Azadirachta indica (Neem) and Aloe vera as compared to subantimicrobial dose doxycycline on matrix metalloproteinases (MMP)-2 and MMP-9: An in-vitro study|url=https://www.ncbi.nlm.nih.gov/pubmed/25364206|journal=Ayu|volume=35|issue=1|pages=85–89|doi=10.4103/0974-8520.141947|issn=0974-8520|pmc=4213975|pmid=25364206}}</ref>
|-
|[[Pentadecapeptide BPC 157]]
|[[Peptide]]
|Yes
|Promotes synthesis
|Stimulates growth factor receptors on fibroblasts.<ref>{{Cite journal|last=Gwyer|first=Daniel|last2=Wragg|first2=Nicholas M.|last3=Wilson|first3=Samantha L.|date=Aug 2019|title=Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing|url=https://www.ncbi.nlm.nih.gov/pubmed/30915550|journal=Cell and Tissue Research|volume=377|issue=2|pages=153–159|doi=10.1007/s00441-019-03016-8|issn=1432-0878|pmid=30915550}}</ref><ref>{{Cite journal|last=Staresinic|first=M.|last2=Sebecic|first2=B.|last3=Patrlj|first3=L.|last4=Jadrijevic|first4=S.|last5=Suknaic|first5=S.|last6=Perovic|first6=D.|last7=Aralica|first7=G.|last8=Zarkovic|first8=N.|last9=Borovic|first9=S.|date=Nov 2003|title=Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth|url=https://www.ncbi.nlm.nih.gov/pubmed/14554208|journal=Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society|volume=21|issue=6|pages=976–983|doi=10.1016/S0736-0266(03)00110-4|issn=0736-0266|pmid=14554208}}</ref>
|-
|[[GABA]]
|Supplement
|Yes
|Promotes synthesis
|GABA dramatically increases the formation of elastic fibers and up-regulates the expression of type I collagen in human dermal fibroblasts.<ref>{{Cite journal|last=Uehara|first=Eriko|last2=Hokazono|first2=Hideki|last3=Hida|first3=Mariko|last4=Sasaki|first4=Takako|last5=Yoshioka|first5=Hidekatsu|last6=Matsuo|first6=Noritaka|date=Jun 2017|title=GABA promotes elastin synthesis and elastin fiber formation in normal human dermal fibroblasts (HDFs)|url=https://www.ncbi.nlm.nih.gov/pubmed/28485217|journal=Bioscience, Biotechnology, and Biochemistry|volume=81|issue=6|pages=1198–1205|doi=10.1080/09168451.2017.1290518|issn=1347-6947|pmid=28485217}}</ref> GABA 100 mg daily is shown to increase skin skin elasticity in women.<ref>{{Cite journal|last=絵理子|first=上原|last2=英樹|first2=外薗|date=2016-07-15|title=γ-アミノ酪酸の経口摂取による皮膚状態改善効果|url=https://www.jstage.jst.go.jp/article/nskkk/63/7/63_306/_article/-char/en|journal=日本食品科学工学会誌|language=ja|volume=63|issue=7|pages=306–311|doi=10.3136/nskkk.63.306|issn=1341-027X}}</ref>
|-
|Thymosin beta 4 (TB-500)
|Peptide
|Yes
|Promotes synthesis
|Helps repair ligaments.<ref>{{Cite journal|last=Xu|first=Bo|last2=Yang|first2=Mowen|last3=Li|first3=Zhaozhu|last4=Zhang|first4=Yubo|last5=Jiang|first5=Zhitao|last6=Guan|first6=Shengyang|last7=Jiang|first7=Dapeng|date=2013-06-10|title=Thymosin β4 enhances the healing of medial collateral ligament injury in rat|url=https://www.ncbi.nlm.nih.gov/pubmed/23523891|journal=Regulatory Peptides|volume=184|pages=1–5|doi=10.1016/j.regpep.2013.03.026|issn=1873-1686|pmid=23523891}}</ref>
|-
|Collagen peptides
|[[Amino acid]]
|
|Co-factor essential for synthesis
|Contains proline, lysine and other amino acids necessary for collagen synthesis.
|-
|[[Vitamin C]]
|[[Vitamin]]
|
|Co-factor essential for synthesis
|Catalyzes the enzymes [[procollagen-proline dioxygenase]] and lysl hydroxylase.
|-
|[[Copper]]
|[[Mineral]]
|
|Co-factor essential for synthesis
|Catalyzes the enzyme [[lysyl dioxidase]].
|-
|EGCG
|Supplement
|Yes
|Inhibits destruction
|In a human study, breast cancer patients undergoing radiotherapy ingested 400 mg oral EGCG x3 / day for several weeks. The levels of serum active MMP-9 decreased by an average of 31% at week 2 and 55% at week 8. The levels of serum MMP-2 zymogens decreased by an average of 22% at week 2 and 51% at week 8.<ref>{{Cite web|url=http://www.eurekaselect.com/76103/article|title=Anti-Cancer Activities of Tea Epigallocatechin-3-Gallate in Breast Cancer Patients under Radiotherapy|last=Zhang|first=G.|last2=Wang|first2=Y.|date=2012-01-31|website=Current Molecular Medicine|language=en|doi=10.2174/156652412798889063|access-date=2020-04-25|last3=Zhang|first3=Y.|last4=Wan|first4=X.|last5=Li|first5=J.|last6=Liu|first6=K.|last7=Wang|first7=F.|last8=Liu|first8=Q.|last9=Yang|first9=C.}}</ref> However, only EGCG doses <800mg/day have been shown to have no risk of hepatotoxicity effects according to the European Food Safety Authority.<ref>{{Cite journal|last=Younes|first=Maged|last2=Aggett|first2=Peter|last3=Aguilar|first3=Fernando|last4=Crebelli|first4=Riccardo|last5=Dusemund|first5=Birgit|last6=Filipič|first6=Metka|last7=Frutos|first7=Maria Jose|last8=Galtier|first8=Pierre|last9=Gott|first9=David|date=2018|title=Scientific opinion on the safety of green tea catechins|url=https://efsa.onlinelibrary.wiley.com/doi/abs/10.2903/j.efsa.2018.5239|journal=EFSA Journal|language=en|volume=16|issue=4|pages=e05239|doi=10.2903/j.efsa.2018.5239|issn=1831-4732}}</ref>
|-
|[[Doxycycline]]
|[[Antibiotic]]
|Yes
|Inhibits destruction
|Inhibits matrix metalloproteinases MMP-1, 2, 7, 8, 9, 12 and 13, and is effective at MMP inhibition at a low dose of 20 mg twice daily.<ref>{{Cite journal|last=Del Buono|first=Angelo|last2=Oliva|first2=Francesco|last3=Osti|first3=Leonardo|last4=Maffulli|first4=Nicola|date=2013-05-21|title=Metalloproteases and tendinopathy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676164/|journal=Muscles, Ligaments and Tendons Journal|volume=3|issue=1|pages=51–57|doi=10.11138/mltj/2013.3.1.051|issn=2240-4554|pmc=3676164|pmid=23885345}}</ref> Sold as the drug Periostat, which is the only FDA approved MMP inhibitor.
|-
|[[Fish oil]]
|Supplement
|Yes
|Inhibits destruction
|Fish oil 9.6 grams per day reduced MMP-9 secretion from immune cells by 58% after 3 months in multiple sclerosis patients.<ref>{{Cite journal|last=Shinto|first=L.|last2=Marracci|first2=G.|last3=Baldauf-Wagner|first3=S.|last4=Strehlow|first4=A.|last5=Yadav|first5=V.|last6=Stuber|first6=L.|last7=Bourdette|first7=D.|date=Feb 2009|title=Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/19171471|journal=Prostaglandins, Leukotrienes, and Essential Fatty Acids|volume=80|issue=2-3|pages=131–136|doi=10.1016/j.plefa.2008.12.001|issn=0952-3278|pmc=2692605|pmid=19171471}}</ref>
|-
|Q10
|Supplement
|Yes
|Inhibits destruction
|Q10 at 500 mg daily reduced MMP-9 in multiple sclerosis patients.<ref>{{Cite journal|last=Sanoobar|first=Meisam|last2=Eghtesadi|first2=Shahryar|last3=Azimi|first3=Amirreza|last4=Khalili|first4=Mohammad|last5=Khodadadi|first5=Behnam|last6=Jazayeri|first6=Shima|last7=Gohari|first7=Mahmood Reza|last8=Aryaeian|first8=Nahid|date=May 2015|title=Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/24621064|journal=Nutritional Neuroscience|volume=18|issue=4|pages=169–176|doi=10.1179/1476830513Y.0000000106|issn=1476-8305|pmid=24621064}}</ref>
|-
|Ecklonia cava
|Supplement
|Yes
|Inhibits destruction
|Ecklonia cava, an edible marine brown alga sold as a supplement, inhibits MMP-2 and MMP-9 and in a rat study reduced periodontitis.<ref>{{Cite journal|last=Kim|first=Seonyoung|last2=Choi|first2=Soo-Im|last3=Kim|first3=Gun-Hee|last4=Imm|first4=Jee-Young|date=2019-05-22|title=Anti-Inflammatory Effect of Ecklonia cava Extract on Porphyromonas gingivalis Lipopolysaccharide-Stimulated Macrophages and a Periodontitis Rat Model|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566535/|journal=Nutrients|volume=11|issue=5|doi=10.3390/nu11051143|issn=2072-6643|pmc=6566535|pmid=31121899}}</ref>
|-
|Captopril
|Drug
|Yes
|Inhibits destruction
|Angiotensin-converting enzyme (ACE) inhibitor captopril inhibits serum MMP-9 in patients with Kawasaki disease (this disease is likely caused by infection).<ref>{{Cite journal|last=Inoue|first=Nao|last2=Takai|first2=Shinji|last3=Jin|first3=Denan|last4=Okumura|first4=Kenichi|last5=Okamura|first5=Naoyuki|last6=Kajiura|first6=Mitsugu|last7=Yoshikawa|first7=Sosuke|last8=Kawamura|first8=Naohisa|last9=Tamai|first9=Hiroshi|date=Feb 2010|title=Effect of angiotensin-converting enzyme inhibitor on matrix metalloproteinase-9 activity in patients with Kawasaki disease|url=https://www.ncbi.nlm.nih.gov/pubmed/19945447/|journal=Clinica Chimica Acta; International Journal of Clinical Chemistry|volume=411|issue=3-4|pages=267–269|doi=10.1016/j.cca.2009.11.020|issn=1873-3492|pmid=19945447}}</ref>
|-
|Losartan
|Drug
|Yes
|Inhibits destruction
|Angiotensin II receptor blocker drug losartan decreases MMP-2 and MMP-9.<ref>{{Cite journal|last=Derosa|first=Giuseppe|last2=Maffioli|first2=Pamela|last3=Ferrari|first3=Ilaria|last4=Palumbo|first4=Ilaria|last5=Randazzo|first5=Sabrina|last6=Fogari|first6=Elena|last7=D'Angelo|first7=Angela|last8=Cicero|first8=Arrigo F. G.|date=Jan 2011|title=Different actions of losartan and ramipril on adipose tissue activity and vascular remodeling biomarkers in hypertensive patients|url=https://www.ncbi.nlm.nih.gov/pubmed/21107327|journal=Hypertension Research: Official Journal of the Japanese Society of Hypertension|volume=34|issue=1|pages=145–151|doi=10.1038/hr.2010.205|issn=1348-4214|pmid=21107327}}</ref>
|-
|Neem
|Herb
|
|Inhibits destruction
|Inhibits MMP-2 and MMP-9 in vitro.<ref name=":4" />
|-
|Magnesium
|[[Mineral]]
|
|Inhibits destruction
|An in vitro study found magnesium reduces MMP-2.
|-
|Glucosamine sulfate
|Supplement
|
|Inhibits destruction
|Glucosamine sulfate inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells in vitro.<ref>{{Cite journal|last=Rajapakse|first=Niranjan|last2=Mendis|first2=Eresha|last3=Kim|first3=Moon-Moo|last4=Kim|first4=Se-Kwon|date=2007-07-15|title=Sulfated glucosamine inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells|url=https://www.ncbi.nlm.nih.gov/pubmed/17498959|journal=Bioorganic & Medicinal Chemistry|volume=15|issue=14|pages=4891–4896|doi=10.1016/j.bmc.2007.04.048|issn=0968-0896|pmid=17498959}}</ref>
|-
|Triphala
|Herbal formula
|
|Inhibits destruction
|Inhibits MMP-9 in vitro.<ref>{{Cite journal|last=Abraham|first=Sajith|last2=Kumar|first2=M. Senthil|last3=Sehgal|first3=P. K.|last4=Nitish|first4=S.|last5=Jayakumar|first5=N. D.|date=Apr 2005|title=Evaluation of the inhibitory effect of triphala on PMN-type matrix metalloproteinase (MMP-9)|url=https://www.ncbi.nlm.nih.gov/pubmed/15857087/|journal=Journal of Periodontology|volume=76|issue=4|pages=497–502|doi=10.1902/jop.2005.76.4.497|issn=0022-3492|pmid=15857087}}</ref>
|-
|Vitamin K2
|Supplement
|
|
|Inhibits MMP-1 in vitro
|-
|Glucuronolactone
|Supplement
|
|Structural component
|Glucuronolactone is an important structural component of connective tissues in tendons, ligaments and cartilage. A 250 ml can of Red Bull contains 600 mg of glucuronolactone.
|-
|[[Hyaluronic acid]]
|
|
|
|
|}

== See also ==

* [[Capillary fragility]]
* [[Ehlers-Danlos syndrome]]
* [[Mast cell activation syndrome]]
* [[Extracellular matrix]]
* [[Mast cell]]
* [[Osteoporosis]]
* [[Hypovitaminosis C]]
* [[Vitamin C]]

== References ==
<references />
[[Category:Proteins]]
[[Category:Biochemistry and cell biology]]

Capillary fragility

2020-05-30T12:26:25Z

FatigueTrackerBot:.

[[Capillary fragility]] is manifested by the appearance of extensive point hemorrhagic spots (petechiae, bruises and hematomas).
This may occur especially on the face and legs. The condition is determined by the tendency of the capillaries to spontaneously break, releasing the blood content in the surrounding area.

Alterations in capillary fragility (ACF) can be determined by different causes and be associated with many diseases; these can be congenital, alterations caused by drugs, microtraumas or other diseases such as collagen diseases. <ref name="Romano2018" /><ref name="Brown1947" />

==Evaluation methods==
[[Capillary fragility]] can typically be evaluated with the vacuum suction method (VSM) using Parrot's angiosterrometer. <ref name="Szolnoky2008" /> <ref name="Szolnoky2017" />

==See also==
*[[Collagen]]

==References==
<references>
<ref name="Romano2018">{{Citation
| last1 = Romano | first1 = C
| last2 = Costa | first2 = M
| last3 = Rapisarda | first3 = M
| last4 = Messina | first4 = M
| last5 = Bertini | first5 = M
| title = Treatment of Capillary Fragility in Subjects with Spontaneous Hematomas
| journal = Journal of Clinical Case Reports | volume = 8 | issue = 7
| date = 2018
| doi = 10.4172/2165-7920.10001152
}}
</ref>

<ref name="Brown1947">{{Citation
| last1 = Brown | first1 = Edward E.
| title = Diseases associated with low capillary resistance
| journal = American Heart Journal | volume = 34 | issue = 2 | page = 241-248
| date = August 1947
| doi = 10.1016/0002-8703(47)90293-7
}}
</ref>

<ref name="Szolnoky2008">{{Citation
| last1 = Szolnoky | first1 = G
| last2 = Nagy | first2 = N
| last3 = Kovács | first3 = R K
| last4 = Dósa-Rácz | first4 = E
| last5 = Szabó | first5 = A
| last6 = Bársony | first6 = K
| last7 = Balogh | first7 = M
| last8 = Kemény | first8 = L
| title = Complex Decongestive Physiotherapy Decreases Capillary Fragility in Lipedema
| journal = Lymphology | volume = 41 | issue = 4 | page = 161-6
| date = 2008
| url = https://pubmed.ncbi.nlm.nih.gov/19306662/
}}
</ref>

<ref name="Szolnoky2017">{{Citation
| last1 = Szolnoky | first1 = G
| last2 = Ifeoluwa | first2 = A
| last3 = Tuczai | first3 = M
| last4 = Varga | first4 = E
| last5 = Varga | first5 = M
| last6 = Dosa-Racz | first6 = E
| last7 = Kemeny | first7 = L
| title = Measurement of Capillary Fragility: A Useful Tool to Differentiate Lipedema From Obesity?
| journal = Lymphology | volume = 50 | issue = 4 | page = 203-209
| date = 2017
| url = https://pubmed.ncbi.nlm.nih.gov/30248725/
}}
</ref>

</references>
[[Category:Signs and symptoms]]

Capillary fragility

2020-05-30T12:24:34Z

FatigueTrackerBot:.

[[Capillary fragility]] is manifested by the appearance of extensive point hemorrhagic spots (petechiae, bruises and hematomas).
This may occur especially on the face and legs. The condition is determined by the tendency of the capillaries to spontaneously break, releasing the blood content in the surrounding area. Alterations in capillary fragility (ACF) can be determined by different causes and be associated with many diseases; these can be congenital, alterations caused by drugs, microtraumas or other diseases such as collagen diseases. <ref name="Romano2018" /><ref name="Brown1947" />

==Evaluation methods==
[[Capillary fragility]] can typically be evaluated with the vacuum suction method (VSM) using Parrot's angiosterrometer. <ref name="Szolnoky2008" /> <ref name="Szolnoky2017" />

==See also==
*[[Collagen]]

==References==
<references>
<ref name="Romano2018">{{Citation
| last1 = Romano | first1 = C
| last2 = Costa | first2 = M
| last3 = Rapisarda | first3 = M
| last4 = Messina | first4 = M
| last5 = Bertini | first5 = M
| title = Treatment of Capillary Fragility in Subjects with Spontaneous Hematomas
| journal = Journal of Clinical Case Reports | volume = 8 | issue = 7
| date = 2018
| doi = 10.4172/2165-7920.10001152
}}
</ref>

<ref name="Brown1947">{{Citation
| last1 = Brown | first1 = Edward E.
| title = Diseases associated with low capillary resistance
| journal = American Heart Journal | volume = 34 | issue = 2 | page = 241-248
| date = August 1947
| doi = 10.1016/0002-8703(47)90293-7
}}
</ref>

<ref name="Szolnoky2008">{{Citation
| last1 = Szolnoky | first1 = G
| last2 = Nagy | first2 = N
| last3 = Kovács | first3 = R K
| last4 = Dósa-Rácz | first4 = E
| last5 = Szabó | first5 = A
| last6 = Bársony | first6 = K
| last7 = Balogh | first7 = M
| last8 = Kemény | first8 = L
| title = Complex Decongestive Physiotherapy Decreases Capillary Fragility in Lipedema
| journal = Lymphology | volume = 41 | issue = 4 | page = 161-6
| date = 2008
| url = https://pubmed.ncbi.nlm.nih.gov/19306662/
}}
</ref>

<ref name="Szolnoky2017">{{Citation
| last1 = Szolnoky | first1 = G
| last2 = Ifeoluwa | first2 = A
| last3 = Tuczai | first3 = M
| last4 = Varga | first4 = E
| last5 = Varga | first5 = M
| last6 = Dosa-Racz | first6 = E
| last7 = Kemeny | first7 = L
| title = Measurement of Capillary Fragility: A Useful Tool to Differentiate Lipedema From Obesity?
| journal = Lymphology | volume = 50 | issue = 4 | page = 203-209
| date = 2017
| url = https://pubmed.ncbi.nlm.nih.gov/30248725/
}}
</ref>

</references>
[[Category:Signs and symptoms]]

Capillary fragility

2020-05-30T12:20:15Z

FatigueTrackerBot:Added refs

[[Capillary fragility]] is manifested by the appearance of extensive point hemorrhagic spots (petechiae, bruises and hematomas).
This may occur especially on the face and legs. The condition is determined by the tendency of the capillaries to spontaneously break, releasing the blood content in the surrounding area. <ref name="Romano2018" />

Alterations in capillary fragility (ACF) can be determined by different causes and be associated with many diseases; these can be congenital, alterations caused by drugs, microtraumas or other diseases such as collagen diseases. <ref name="Brown1947" />

==Evaluation methods==
[[Capillary fragility]] can typically be evaluated with the vacuum suction method (VSM) using Parrot's angiosterrometer. <ref name="Szolnoky2008" /> <ref name="Szolnoky2017" />

==See also==
*[[Collagen]]

==References==
<references>
<ref name="Romano2018">{{Citation
| last1 = Romano | first1 = C
| last2 = Costa | first2 = M
| last3 = Rapisarda | first3 = M
| last4 = Messina | first4 = M
| last5 = Bertini | first5 = M
| title = Treatment of Capillary Fragility in Subjects with Spontaneous Hematomas
| journal = Journal of Clinical Case Reports | volume = 8 | issue = 7
| date = 2018
| doi = 10.4172/2165-7920.10001152
}}
</ref>

<ref name="Brown1947">{{Citation
| last1 = Brown | first1 = Edward E.
| title = Diseases associated with low capillary resistance
| journal = American Heart Journal | volume = 34 | issue = 2 | page = 241-248
| date = August 1947
| doi = 10.1016/0002-8703(47)90293-7
}}
</ref>

<ref name="Szolnoky2008">{{Citation
| last1 = Szolnoky | first1 = G
| last2 = Nagy | first2 = N
| last3 = Kovács | first3 = R K
| last4 = Dósa-Rácz | first4 = E
| last5 = Szabó | first5 = A
| last6 = Bársony | first6 = K
| last7 = Balogh | first7 = M
| last8 = Kemény | first8 = L
| title = Complex Decongestive Physiotherapy Decreases Capillary Fragility in Lipedema
| journal = Lymphology | volume = 41 | issue = 4 | page = 161-6
| date = 2008
| url = https://pubmed.ncbi.nlm.nih.gov/19306662/
}}
</ref>

<ref name="Szolnoky2017">{{Citation
| last1 = Szolnoky | first1 = G
| last2 = Ifeoluwa | first2 = A
| last3 = Tuczai | first3 = M
| last4 = Varga | first4 = E
| last5 = Varga | first5 = M
| last6 = Dosa-Racz | first6 = E
| last7 = Kemeny | first7 = L
| title = Measurement of Capillary Fragility: A Useful Tool to Differentiate Lipedema From Obesity?
| journal = Lymphology | volume = 50 | issue = 4 | page = 203-209
| date = 2017
| url = https://pubmed.ncbi.nlm.nih.gov/30248725/
}}
</ref>

</references>
[[Category:Signs and symptoms]]

Capillary fragility

2020-05-30T12:02:34Z

FatigueTrackerBot:Brushing up and adding references

[[Capillary fragility]] is manifested by the appearance of extensive point hemorrhagic spots (petechiae, bruises and hematomas).
This may occur especially on the face and legs. The condition is determined by the tendency of the capillaries to spontaneously break, releasing the blood content in the surrounding area. <ref name="Romano2018" />

Alterations in capillary fragility (ACF) can be determined by different causes and be associated with many diseases; these can be congenital, alterations caused by drugs, microtraumas or other diseases such as collagen diseases. <ref name="Brown1947" />

==Evaluation methods==
[[Capillary fragility]] can typically be evaluated with the vacuum suction method (VSM) using Parrot's angiosterrometer. <ref name="Szolnoky2008" /> <ref name="Szolnoky2017" />

==See also==
*[[Collagen]]

==References==
<references>
<ref name="Romano2018">{{Citation
| last1 = Romano | first1 = C
| last2 = Costa | first2 = M
| last3 = Rapisarda | first3 = M
| last4 = Messina | first4 = M
| last5 = Bertini | first5 = M
| title = Treatment of Capillary Fragility in Subjects with Spontaneous Hematomas
| journal = Journal of Clinical Case Reports | volume = 8 | issue = 7
| date = 2018
| doi = 10.4172/2165-7920.10001152
}}
</ref>

<ref name="Brown1947">{{Citation
| last1 = Brown | first1 = Edward E.
| title = Diseases associated with low capillary resistance
| journal = American Heart Journal | volume = 34 | issue = 2 | page = 241-248
| date = August 1947
}}
</ref>

<ref name="Szolnoky2008">{{Citation
| last1 = Szolnoky | first1 = G
| last2 = Nagy | first2 = N
| last3 = Kovács | first3 = R K
| last4 = Dósa-Rácz | first4 = E
| last5 = Szabó | first5 = A
| last6 = Bársony | first6 = K
| last7 = Balogh | first7 = M
| last8 = Kemény | first8 = L
| title = Complex Decongestive Physiotherapy Decreases Capillary Fragility in Lipedema
| journal = Lymphology | volume = 41 | issue = 4 | page = 161-6
| date = 2008
| url = https://pubmed.ncbi.nlm.nih.gov/19306662/
}}
</ref>

<ref name="Szolnoky2017">{{Citation
| last1 = Szolnoky | first1 = G
| last2 = Ifeoluwa | first2 = A
| last3 = Tuczai | first3 = M
| last4 = Varga | first4 = E
| last5 = Varga | first5 = M
| last6 = Dosa-Racz | first6 = E
| last7 = Kemeny | first7 = L
| title = Measurement of Capillary Fragility: A Useful Tool to Differentiate Lipedema From Obesity?
| journal = Lymphology | volume = 50 | issue = 4 | page = 203-209
| date = 2017
| url = https://pubmed.ncbi.nlm.nih.gov/30248725/
}}
</ref>

</references>
[[Category:Signs and symptoms]]

Gabapentin

2020-05-30T11:02:52Z

FatigueTrackerBot:.

Gabapentin is an anticonvulsant drug primarily used to treat epilepsy. It is being used off-label for [[ME/CFS]] and [[fibromyalgia]] patients mostly to augment pain relief.<ref>[http://www.mayoclinic.org/diseases-conditions/fibromyalgia/expert-answers/fibromyalgia-treatment/FAQ-20058273 Is gabapentin (Neurontin, others) an effective fibromyalgia treatment? - Mayo Clinic - Fibromyalgia]</ref><ref>[https://www.nih.gov/news-events/news-releases/gabapentin-shown-effective-fibromyalgia-pain Gabapentin Shown Effective for Fibromyalgia Pain Gabapentin Shown Effective for Fibromyalgia Pain - NIH]</ref><ref>[https://livingwithchronicfatiguesyndrome.wordpress.com/2016/04/13/gabapentin-neurontin-for-me/ Gabapentin (Neurontin) for ME - Living with Chronic Fatigue Syndrome]</ref> Common brand names are Neurontin, Horizant, and Gralise.<ref>[https://www.drugs.com/ingredient/gabapentin.html Gabapentin (Includes Brand Names - Drugs.com]</ref> A newer, slightly different, version of gabapentin has been developed, named [[pregabalin]].

==Side Effects==
Many side effects have been reported. This list is compiled by the Mayo Clinic.<ref>http://www.mayoclinic.org/drugs-supplements/gabapentin-oral-route/side-effects/drg-20064011</ref>

More commonly ones reported are:
*clumsiness
*unsteadiness, and continuous, uncontrolled, back-and-forth, or rolling eye movements

More commonly one reported in children are:
*aggressive behavior or other behavior problems
*anxiety
*concentration problems and change in school performance
*crying
*depression
*false sense of well-being
*hyperactivity or increase in body movements
*rapidly changing moods
*reacting too quickly, too emotional, or overreacting
*restlessness
*suspiciousness or distrust

Less commonly ones reported are:
*black, tarry stools
*chest pain
*chills
*cough
*depression, irritability, or other mood or mental changes
*fever
*loss of memory
*pain or swelling in the arms or legs
*painful or difficult urination
*shortness of breath
*sore throat
*sores, ulcers, or white spots on the lips or in the mouth
*swollen glands
*unusual bleeding or [[bruising]]
*unusual tiredness or weakness

==Learn more==
*Nov 9, 2016, [http://www.medicaldaily.com/gabapentin-side-effects-dangers-label-prescriptions-surprising-side-effects-403998 Gabapentin Side Effects: The Dangers Of Off-Label Prescriptions’ Surprising Side Effects], by Samantha Olson
*2016, [https://livingwithchronicfatiguesyndrome.wordpress.com/2016/04/13/gabapentin-neurontin-for-me/ Gabapentin (Neurontin) for ME]
*June 07, 2004, [http://articles.latimes.com/2004/jun/07/health/he-offlabel7 When drugs are used off-label], by Daniel Costello

== See also ==
*[[Fibromyalgia]]
*[[Pregabalin]]
*[[Baclofen]]

== References ==

[[Category:Potential treatments]]
[[Category:Analgesics]]
[[Category:Anticonvulsants]]
<references />

RCCX Genetic Module Theory

2020-05-30T11:01:01Z

FatigueTrackerBot:.

''NOTE: This page is modified from a summary of findings available at the [http://rccxandillness.com/downloads.html RCCX and Illness] website.''

The RCCX Gene Module is postulated to be the origin of a wide range of over-lapping chronic medical and psychiatric conditions and illnesses, including [[myalgic encephalomyelitis]] (ME).

==Theory Background==
[[Sharon Meglathery]] MD, a board certified psychiatrist and previously also board certified in internal medicine, with 20 years of practice experience, developed chronic illness in 2009. Her illness included, but was not limited to: [[Mast cell activation disorder|mast cell activation syndrome]] (MCAS), [[Postural orthostatic tachycardia syndrome]] (POTS), [[Chronic fatigue syndrome]] (CFS) and raised intracranial pressure (ICP) in the setting of [[Ehlers-Danlos syndrome]], Hypermobility Type (EDS-HT).

Meglathery was motivated to figure out the basis for all these co-occurring conditions. She carefully examined her patients, herself, the literature and people on the various chronic illness forums to see what characteristics people with these illnesses have in common. First, she found a psychological profile, now dubbed CAPS ([[CYP21A2 Mutation Associated Neuropsychiatric Spectrum]]) which could predict the development of chronic illness. From there, she was able to assess many of the characteristics of this population and their families. Then, she learned of the unique properties of the RCCX Module and how its genes could explain all of her observations, as well as results of the research since then.

Meglathery says the RCCX Theory explains the co-inheritance of a wide range of overlapping chronic medical conditions in individuals and families ([[EDS]]/hypermobility, [[autoimmune disease]], chronic fatiguing illness, psychiatric conditions, autism, etc.). It explains the underlying pathophysiology of [[Chronic fatigue|chronic fatiguing illnesses]] with so many overlapping features ([[Ehlers-Danlos syndrome|EDS]]-HT, [[Chronic fatigue syndrome|CFS]], [[chronic Lyme disease]], [[Fibromyalgia]] (FM), toxic [[mold]], [[Epstein-Barr virus]] infection, [[mast cell activation syndrome]] (MCAS, [[POTS]], etc.) and why many are associated with varying degrees of hypermobility, with the degree of hypermobility unrelated to the degree of physical or psychiatric illness. Meglathery further postulates that CYP21A2 mutations are the genetic diathesis (predisposition to abnormal/diseased medical conditions) which predisposes to all of the psychiatric conditions in the vast majority of affected people.

==RCCX Theory==
Co-inheritance of the highly mutable genes of the RCCX module (CYP21A2, TNXB, C4) may confer vulnerability to familial clusters of overlapping syndromes of chronic illness (hypermobility, [[autoimmune disease]], [[CFS/ME]], [[Mast cell activation syndrome|MCAS]], POTS, psychiatric illness, etc.). CYP21A2 mutations may be the genetic diathesis of the stress-diathesis model of disease for both psychiatric and medical illness. This pathway predisposes to chronic psychiatric illness via: Low basal and spiking [[cortisol]] in utero and in infancy leading to CAPS ([[CYP21A2 Mutation Associated Neuropsychiatric Spectrum]]), putting the person at risk for developing severe [[PTSD]] brain circuitry (dissociative circuits) and all forms of [[Mental health|psychiatric illness]] due to exaggerated stress response, low basal arousal and resultant harm-avoidance and threat circuits (except schizophrenia which can be co-inherited via C4 mutation). CYP21A2 mutations also predispose to medical illnesses, such as ME/CFS, [[Postural orthostatic tachycardia syndrome|POTS]], [[Mast cell activation syndrome|MCAS]], [[Fibromyalgia|FM]], [[chronic Lyme disease]] and are the final common pathway of stress-induced mitochondrial shutdown in ME/CFS due to overwhelmed 21-hydroxylase triggering inflammatory cascades. Additionally, the genes of the RCCX Module have been found to co-segregate, creating overlapping "rare" genetic syndromes within families and individuals.

The RCCX module genes include:
*[[CYP21A2]] which codes for a crucial [[enzyme]] involved in the acute stress response (21-hydroxylase), mutations are associated with an exaggerated stress response in the setting of low [[basal cortisol]] and [[congenital adrenal hyperplasia]]

*[[TNXB]] which codes for [[tenascin X]], an important matrix protein implicated in hypermobility, and

*[[C4]], a gene involved in the complement system and implicated in [[schizophrenia]], CVID ([[common variable immune deficiency]]), [[MS]], [[lupus]] and other autoimmune diseases.

==Conditions associated with RCCX gene mutations==
*[[Ehlers-Danlos syndrome|Ehlers-Danlos Syndrome]], Hypermobility Type (EDS-HT)
*[[Chronic fatigue syndrome]] (CFS) / [[Myalgic Encephalomyelitis]] (ME)
*[[Fibromyalgia]] (FM)
*[[Chronic Lyme disease|Chronic Lyme Disease]], [[Gulf War Illness|Gulf War Syndrome]], Toxic [[Mold illness|Mold]]/[[Biologic Illness]]
*[[Mast cell activation syndrome|Mast Cell Activation Syndrome]] (MCAS): [[histamine intolerance]], [[Migraine|migraines]], [[diarrhea]], [[Sinusitis|sinus pain]], [[burning eyes]], [[Fainting|syncope]], [[distractibility]], [[brain fog]], [[Excessive irritability|irritability]], [[interstitial cystitis]], [[hyper-adrenergic POTS]], etc., depending on location of the mast cells
*[[Postural orthostatic tachycardia syndrome|Postural Orthostatic Tachycardia]] (POTS)
*[[Dysautonomia]]
*[[Orthostatic intolerance|Orthostatic Intolerance]], [[low blood volume]]
*Pain Syndromes: Neuropathic Pain Syndromes; Chronic Regional Pain Syndrome; Myofascial Pain Disorder; Frequent Dislocations; Dysmenorrhea; Chronic Headache; Migraines; Interstitial Cystitis; Vulvodynia; Temporomandibular Joint Disorder (TMJ)
*GI Syndromes: [[Irritable Bowel Syndrome]]; Cyclical Vomiting; [[Gastroparesis]]; Food Intolerance; Gut dysbiosis; Candida overgrowth; Leaky Gut Syndrome; Malabsorption Syndromes
*Raised Intracranial Pressure Conditions: Pseudotumor Cerebri; Benign Intracranial Hypertension; Posterior Reversible Encephalopathy; Acquired Chiari Malformation
*Neurological Issues: Neuropathies; Pain Syndromes; Uncoordinated Swallow; Vertigo; Central Apnea; Sleep Paralysis; Dysautonomia; Seizure-Like Episodes; Dystonia; Narcolepsy; [[White Matter Lesions]]; [[Small Fiber Polyneuropathy]] (Erythromelalgia); [[Restless Leg Syndrome]]; Brain Anatomic Abnormalities, e.g., enlarged amygdalae, small anterior cingulate, Chiari malformation, hydrocephalus
*Mitochondrial Disorders
*Immune Dysregulation: Combined Variable Immunodeficiency Disease (CVID); IgA deficiency; chronic fungal infections; recurrent herpes simplex virus (HSV) infections; no colds for years; severe bacterial infections; inability to clear chronic bacterial and viral infections (strep/Epstein Barr/mycoplasma/chlamydia/candida), dysbiosis; small intestine bacterial overgrowth (SIBO); classic and non classic autoimmune disorders, e.g., multiple sclerosis (MS); mixed connective tissue disorders; eosinophilic disorders; high TGF beta; inflammatory conditions (endometriosis); Chronic Inflammatory Response Syndrome (CIRS)
*Psychiatric Issues: Dysautonomia (Generalized Anxiety Disorder, ADD, Hyperfocus); Autistic spectrum; Sensory Processing Disorders; Psychosis; Schizophrenia; Chronic Stress; [[Post-traumatic stress disorder|PTSD]]; Mood Disorders; Chronic Insomnia; Obsessive Compulsive Disorder; Phobias; Paranoid Disorders; Emotional Dysregulation;
*Hormonal Disorders: Sex Hormone Disorders (Cystic Ovaries, Acne, Water/Fat-Associated Weight Gain, Breast and Tissue Swelling, Fertility issues, Hot Flashes/Night Sweats; Adrenal Gland Issues (Adrenal Fatigue, Addison's Disease, Cortisol dysregulation, Low Aldosterone); Pituitary Hormone Abnormalities (ACTH, TRH-Mediated Thyroid Disorders); Autoimmune Hormonal Issues (Hashimotos's Thyroiditis)
*GU/Renal Issues: Fibromuscular Dysplasia; Diabetes Insipidus; Interstitial Cystitis; Vesicoureteral Reflux (urine backing up into kidneys)
*Miscellaneous Issues: Extreme Temperature Dysregulation (with/without Dysautonomia), [[Multiple Chemical Sensitivity]], High Adrenaline/Noradrenaline (norepinephrine) States; Erythromelalgia; Raynaud's Phenomena; Livedo Reticularis; Poor Connective Tissue integrity (dislocations, [[bruising]], bleeding, petechaie, calcific aortic valves, Mitral Valve Prolapse); Dry eyes; Tinnitis; Subcutaneous Adipose Disorders (Lipidema, Dercum's Disease), Left Handedness, Gender Fluidity (LGTBQ); lack of traditional gender roles
*Possible other inclusions: Medullary Sponge Kidney; Pyroluria; disorders of copper and zinc regulation; early onset [[Parkinson's disease]]; Ion-Associated Illnesses

==Stress vulnerability==
Meglathery believes these genes, particularly C4 and CYP21A2, sit in the most highly mutagenic part of the genome because mutations of these genes provide novel ways of responding to ever-changing environments in terms of response to pathogens/brain wiring for C4 and stress response/brain wiring for CYP21A2. She posits that only one copy of a CYP21A2 mutation is necessary to create a stress vulnerability in its recipient. This vulnerability can have catastrophic consequences in settings of severe acute or chronic/prolonged stress, resulting in medical and/or psychiatric illness. she believes this is an evolutionarily programmed response to very high stress, resulting in decreased procreation and ultimately, the removal of the mutation from the gene pool.

There are two reasons for this stress vulnerability, according to Meglathery. There is CYP21A2-induced low basal and spiking cortisol in utero and infancy, leading to a brain "wired for danger" which then develops full [[PTSD]]-like wiring as stress continues. Under prolonged stress, the body can no longer make adequate 21-hydroxylase which then initiates inflammatory cascades/mast cell activation with or without the addition of the C4 mutation (which adds autoimmune disease and increases the severity of the inflammatory response).

Therefore, a child carrying a CYP21A2 mutation has the same brain as a child raised in adverse circumstances, with enlarged [[limbic]] structures ([[amygdala]]), wired-in [[dysautonomia]] and primed connections in the limbic and neuroendocrine systems. However, there are some benefits with a constant state of increased threat detection and enhanced stress response, such as: enhanced empathy, sensory sensitivity, superior pattern recognition/information processing, times of intense hyperfocus/obsession/flow and unusual abilities (in music, arts or abstract thinking).

With any stress (even minimal trauma), the threat response circuits are reinforced and [[epigenetic]] changes can further strengthen these connections, creating PTSD-like wiring and reactions. These stress-induced/primed circuits in the [[brainstem]] and limbic system can be associated with the emergence of bursts of emotional dysregulation, dysautonomia, motor and sensory syndromes (hallucinations, dystonia, catatonia, cataplexy, non-dermatomal sensory symptoms, non-epileptic seizures, etc.) and inappropriate states of consciousness (fight/flight, freeze, shutdown), all of which Meglathery observed clinically. This corresponds with findings of the landmark Adverse Childhood Experiences study<ref name="Anda-ACE" />, linking childhood [[Trauma|adverse events]] with adult chronic illness, medical and psychiatric.

==CAPS as a marker of illness==
In Meglathery's experience, people with classic psychiatric illnesses almost always have CAPS as a backdrop, with or without the PTSD wiring. She found that CAPS is invariably present in hypermobile psychiatric patients who develop chronic illness and is present in the vast majority of other people who develop chronic illness, leading her to believe that it is a reliable marker for vulnerability to chronic illness. She believes that CYP21A2 mutations are the genetic basis for the development of four of the five major psychiatric illnesses (anxiety disorders, mood disorders, ADD, autism). Schizophrenia, with its basis in C4 (situated next to CYP21A2), is responsible for the fifth. These psychiatric illnesses share similar genetic underpinnings, which Meglathery says supports the RCCX Theory.<ref name="APS-2013-FMPDSGL" />

Her theory also shows congruence with that of [[Robert Naviaux|Naviaux]]<ref name="Naviaux2016" /> in which he postulates a hibernation-like state in long-standing CFS. Meglathery believes the effect of 21-hydroxylase overwhelm, PTSD brain wiring, downstream effects from TNXB mutations, and C4 mutations trigger and maintain an adaptive shutdown response of the mitochondria. This stress-induced mitochondrial dysregulation has recently been discovered in patients with severe CFS/ME by [[Ron Davis]] PhD and [[Robert Naviaux]] MD PhD (initially described by Naviaux). The symptoms which occur after 21-hydroxylase is overwhelmed are the same, independent of the trigger.

While some mutations affecting these genes have been characterized (some TNXB and CYP21A2 mutations), evidence suggests there are many more uncharacterized genes. Many involve lengthy insertions and are therefore very difficult to study. These genes would have highly variable clinical effects, depending on the nature of the mutation. CYP21A2 mutations are in upwards of 20% of the population and C4 mutations are also extremely common, according to Meglathery.

==Silent epidemic==
Over time, it became clear to Meglathery that there is an epidemic involving a large number of syndromes/symptoms/diseases with overlapping symptoms affecting mainly young, vibrant, talented people (predominantly women). She found that many of these people manifesting different signs and symptoms, but not all, have joint hypermobility (double jointedness, ligament laxity). Clusters of the above chronic illness conditions are found in many families and individuals. For example, a family member, often female, who is hypermobile, very fatigued and suffers from severe [[allergy]] symptoms and [[orthostatic intolerance]] ([[Ehlers-Danlos syndrome|EDS]]-HT, [[MCAS]], [[POTS]], [[CFS]]) has children who may be diagnosed with attention deficit disorder (ADD), sensory processing issues and/or autistic features. In the extended family there often is at least one of the following: [[autoimmune disease]]; cutting (self-injury) and eating disorders (anorexia, bulemia); mood disorders; gender fluidity; a highly successful and innovative genius; someone with CFS or FM; someone with severe PTSD and/or someone else with bouts of psychosis. Many family members will react strongly to stress. The degree of hypermobility correlates with the degree of musculoskeletal involvement (joint pain/dislocations/surgeries required to stabilize joints) and orthostasis/dysautonomia, but not with the other "sick" symptoms which tend to develop later in life in some, mostly women.

To date, no gene has been found to explain the prevalence of EDS-hypermobility type, in the general population. Nor why these individuals become so ill with such a wide range of not easily explainable symptoms, including: psychiatric issues; white matter lesions; hormone disruptions; autoimmune diseases; and MCAS, and why some individuals with hypermobile relatives develop these same conditions without hypermobility. As discussed above, TNXB mutations are common with CYP21A2 (hormones, inflammation, psychiatric issues) and C4 (autoimmune) gene clusters. TNXB mutations are associated with most cases of calcified aortic valves and vesicoureteral reflux (urine backing up into kidneys) but not always associated with enough hypermobility to meet criteria for EDS.

==Criticism==
There are many people who believe that these chronic illness conditions are completely separate in pathophysiology, i.e., all symptoms associated with EDS are solely caused by a genetic defect of collagen, all of the symptoms of Lyme disease are caused by ''[[Borrelia burgdorferi]]'', all symptoms of CIRS are caused by the inciting agent, etc. However, it is becoming more clear that these conditions all go down a common pathway.{{Citation needed}} Further, it is also becoming increasingly clear that the above RCCX co-morbidities run with these conditions in individuals and within families.

==RCCX Theory unites all of these findings==
*White matter lesions
*Erythromelalgia / small fiber polyneuropathy
*Autonomic nervous system dysfunction / Postural orthostatic tachycardia syndrome (POTS) / Orthostatic intolerance (OI)
*Mast cell activation syndrome (MCAS)
*Neuropathic pain syndromes
*Autism
*Enlarged Amygdala
*Raised intracranial pressure / Chiari malformations
*Dysbiosis
*Salt and water loss
*Low baseline cortisol
*Association with autoimmune diseases
*High adrenaline / exaggerated acute stress response

==Common mechanism==
According to Meglathery, the most compelling piece of evidence that all of these conditions have a common mechanism is the psychological profile 'CAPS' which is universally present and allows prediction of who is at risk for developing chronic illness. CAPS is very often associated with hypermobility, but not always. It is very clear that CYP21A2 mutations are responsible for both CAPS and chronic illness (medical and psychiatric), whether or not they have the often accompanying TNXB mutation (which brings with it complications of musculoskeletal/structural issues and TGF beta).

Interestingly, a very large study<ref name="Cederlof2016" /> involving the Swedish registry (1,780 with EDS, 1,722 siblings of EDS patients, 10,019 with hypermobility syndrome and 11,082 hypermobility siblings) showed a substantially higher risk for autism spectrum, bipolar disorder, ADHD and depression in EDS patients, hypermobility syndrome patients and their non-affected siblings. This study confirms Meglathery's observation that psychological issues in hypermobile people are rampant, and not dependent on the presence or degree of individual hypermobility, but rather the presence of hypermobility within the family. A seven year study demonstrated that therapy was very helpful in decreasing issues with schizophrenia. Meglathery believes therapy decreased the patients' acute stress response, which decreased the stress burden and subsequently decreased the aberrations which happen when 21-hydroxylase is overwhelmed in someone carrying a CYP21A2 mutation. Characterizing RCCX variances may be the direct way to provide genetic tests for who is at risk for chronic illness. Effective prevention and treatments would follow naturally from this.

These conditions can occur due to other genes, but they occur without these clusters. For example, MCAS has many triggers and POTS often is associated with the vasodilating effects of excessive liberation of histamine. Also, it is important to remember that there are quite a few downstream issues which affect all of these conditions and muddy the waters. For example, most people with the RCCX gene module have raised intracranial pressure which affects pituitary hormones, making hormonal issues appear to be secondary rather than primary. Also, because of C4, and possibly other causes of autoimmune issues, there are also autoimmune hormone disorders.

==Treatment==
Treating MCAS, correcting [[MTHFR]] enzyme deficiencies, using [[Low dose naltrexone|Low-Dose Naltrexone]] (LDN), maintaining adequate hydration/salt repletion, correcting dysbiosis, incorporating anti-inflammatories, supporting mitochondria, using immune system enhancers, practicing mindfulness/grounding/brain retraining and stress reduction are overlapping treatments which seem to help.{{Citation needed}}

==Research help is needed==
There are many variances in this RCCX region which have not been characterized or even identified. This part of the genome needs to be explored and variances linked with the clinical picture (CAPS or chronic illness-medical or psychiatric).
After developing and refining her hypothesis Meglathery set up a [www.rccxandillness.com|website] in February 2016 to expose her theory and generate interest in research. Within eight hours of release an endocrinologist, [Karen Herbst] MD PhD, an international expert in subcutaneous fat disorders, contacted Meglathery. Herbst is also convinced that the RCCX module is involved in these conditions, given the high rate of hypermobility, chronic fatigue and psychiatric illness in this population.

The team is moving forward. Herbst is devising ways to demonstrate the clinical correlates of CYP21A2 mutations and Meglathery is creating a uniform way to detect and diagnose CAPS. "We need a very sophisticated genetics team to correlate our findings with RCCX mutations. If you are interested, please do not hesitate to contact us" - Meglathery.

==Online presence==
*[http://rccxandillness.com Website]
*[https://www.facebook.com/rccxandchronicillness/ Facebook]
*Email: info@rccxandillness.com

==Learn more==
* [http://rccxandillness.com/pathophysiology-diagrams.html RCCX Theory - Pathophysiology Diagrams]

==References==
<references>
<ref name="Anda-ACE">{{citation
| author = Robert Anda | authorlink1 = Robert Anda
| title = The Adverse Childhood Experiences Study: Child Abuse and Public Health
| journal = Prevent Child Abuse America
| date =
| url = http://www.preventchildabuse.org/images/docs/anda_wht_ppr.pdf
}}</ref>
<ref name="APS-2013-FMPDSGL">{{citation
| title = Five major psychiatric disorders share genetic links
| journal = American Psychological Association (website)
| date = May 2013
| url = http://www.apa.org/monitor/2013/05/disorders.aspx
}}</ref>
<ref name="Naviaux2016">{{citation
| author1 = Robert K Naviaux | authorlink1 = Robert Naviaux
| author2 = Jane C Naviaux | authorlink2 = Jane Naviaux
| author3 = Kefeng Lia
| author4 = A Taylor Bright
| author5 = William A Alaynicka
| author6 = Lin Wanga
| author7 = Asha Baxter
| author8 = Neil Nathan
| author9 = Wayne Anderson
| author10 = Eric Gordon
| title = Metabolic Features of Chronic Fatigue Syndrome
| journal = PNAS | volume = 13 | issue = 37
| date = 2016
| doi = 10.1073/pnas.1607571113
| url = http://www.pnas.org/content/113/37/E5472
}}</ref>
<ref name="Cederlof2016">{{citation
| last1 = Cederlöf | first1 = Martin | authorlink1 = Martin Cederlöf
| last2 = Larsson | first2 = Henrik | authorlink2 = Henrik Larsson
| last3 = Lichtenstein | first3 = Paul | authorlink3 = Paul Lichtenstein
| last4 = Almqvist | first4 = Catarina | authorlink4 = Catarina Almqvist
| last5 = Serlachius | first5 = Eva | authorlink5 = Eva Serlachius
| last6 = Ludvigsson | first6 = Jonas F | authorlink6 = Jonas F Ludvigsson
| title = Nationwide population-based cohort study of psychiatric disorders in individuals with Ehlers–Danlos syndrome or hypermobility syndrome and their siblings
| journal = BMC Psychiatry | volume = 2016; 16:207
| date = 4 Jul 2016
| doi = 10.1186/s12888-016-0922-6
| url = https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-016-0922-6
}}</ref>
</references>

[[Category:Medical hypotheses]]

Vitamin C deficiency

2020-05-30T10:58:43Z

FatigueTrackerBot:.

{{Cleanup|reason=Grammar and image violating copyright. |talk=TALKPAGENAME }}

'''Hypovitaminosis C''', aka '''scurvy''', is a condition caused by a dietary lack of [[vitamin C]] (ascorbic acid) and is characterized by an increased bleeding tendency and impaired collagen synthesis.<ref>{{Cite web|url=https://radiopaedia.org/articles/hypovitaminosis-c-scurvy-1?lang=us|title=Scurvy|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=radiopaedia.org|archive-url=|archive-date=|dead-url=|access-date=}}</ref> It can, also, be caused by reduced absorption of [[Vitamin C]] in the gut.<ref>{{Cite web|url=https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/|title=Office of Dietary Supplements - Vitamin C|website=ods.od.nih.gov|language=en|access-date=2020-01-24}}</ref>
==Overview==
Despite being considered a rare condition, scurvy still exists nowadays, even in children with no apparent risk factors living in wealthy families. The increasing popularity of dietary restriction for children, especially those with allergies, may potentially enhance the occurrence of scurvy in apparently healthy children.<ref name=":1">{{Cite journal|last=Brambilla|first=Alice|last2=Pizza|first2=Cristina|last3=Lasagni|first3=Donatella|last4=Lachina|first4=Lucia|last5=Resti|first5=Massimo|last6=Trapani|first6=Sandra|date=1 May 2018|title=Pediatric Scurvy: When Contemporary Eating Habits Bring Back the Past.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946015/|journal=Frontiers in Pediatric|volume=6|doi=10.3389/fped.2018.00126}}</ref>

In hospital patients, it can be highly prevalent, but often unrecognized.<ref name="Robitaille2016" /> Medical awareness of this potentially important disorder is hindered by the inability of most hospital laboratories to determine plasma [[Vitamin C]] concentrations. The availability of a simple, reliable method for analyzing plasma vitamin C could increase opportunities for routine plasma vitamin C analysis in clinical medicine.<ref name="Robitaille2016" />

== Symptoms ==
* lassitude<ref name="Levine1996" />
* fatigue<ref name="Levine1996" />
* irritability<ref name="Levine1996" />
* poor wound healing<ref name=":2">{{Cite journal|last=Maxfield|first=Luke|last2=Crane|first2=Jonathan S.|date=2019|title=Vitamin C Deficiency (Scurvy)|url=http://www.ncbi.nlm.nih.gov/books/NBK493187/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29630239}}</ref>
* gingival (gum) swelling with loss of teeth<ref name=":2" />
* mucocutaneous petechiae<ref name=":2" /> (small red or purple spots caused by bleeding into the skin where the mucosa transitions to skin)
* ecchymosis<ref name=":2" /> (a discoloration of the skin resulting from bleeding underneath, typically caused by [[bruising]])
* hyperkeratosis<ref name=":2" /> (skin condition that occurs when a person's skin becomes thicker)

== Evidence ==
The disease of terminal vitamin C deficiency – [[Scurvy]] – is first suspected on clinical grounds. The diagnosis is confirmed by documenting a plasma vitamin C concentration < 11.4 μmol/L and observing prompt clinical improvement after appropriate vitamin C provision. [[Scurvy]] is rare in the modern world, but hypovitaminosis C (plasma vitamin C concentration < 28.4 μmol/L ) or marginal vitamin C deficiency (plasma vitamin C concentration < 28.4 μmol/L but > 11.4 μmol/L ) is not. Hypovitaminosis C occurs in ~ 10% of the general population , in ~ 30 % of cigarette smokers and ~ 60% of acutely hospitalized patients, in whom it could contribute to fatigue and mood disturbance, immune system dysfunction, impaired wound healing, the complex regional pain syndrome and the complications of cardiovascular disease.<ref name="Robitaille2016" />

Cited from <ref name="Levine1996" /> : Subclinical Vitamin C Deficiency: Clinical Application. Six of seven volunteers noted mild but distinct fatigue and/or irritability at depletion, without scurvy. Symptoms disappeared within several days of the 30- or 60-mg daily dose. Although fatigue and irritability have myriad causes, vitamin C deficiency without scurvy should be an additional consideration. Since fatigue and irritability are common symptoms and were so easily reversible, physicians should ask patients with these symptoms about vitamin C ingestion from foods or supplements.

== Historical perspective ==
From a 18th century medical book, ''Observations of the Scurvy,'' by Thomas Trotter: "Every person who has been a sea voyage, must have perceived that longing desire for fresh vegetables after being for some time deprived of them. This I have often marked the harbinger of scurvy. Dr Lind, in some part of his work, has mentioned the same circumstances; and he might very justly have put it down as a symptom; for it is more or less an attendant on the disease and not only amuses their waking hours with thoughts of green fields and rivers of pure water but in dreams they are tantalized with the same ideas, and on waking nothing is so mortifying as the disappointment.<ref name=":0">{{Cite book|title=Observations on the Scurvy with a review of the theories lately advanced on that disease and the opinions of Dr Milman refuted from practice|pages=14-16|isbn=|edition=|volume=|language=en|title-link=|url=https://collections.nlm.nih.gov/ext/mhl/2575040R/PDF/2575040R.pdf|date=1793|publisher=John Parker|last=Trotter|first=Thomas|author-link=|last2=|first2=|author-link2=|last3=|first3=|author-link3=|last4=|first4=|author-link4=|last5=|first5=|author-link5=|last6=|first6=|author-link6=|last7=|first7=|author-link7=|last8=|first8=|author-link8=|last9=|first9=|author-link9=|veditors=|others=|doi=|oclc=|quote=|access-date=2020-01-23|archive-url=|archive-date=|location=Philadelphia, PA}}</ref>

When I heard a sailor expressing these desires, and lolling about, I was not surpriced to find him complain of sore gums and a few days after. About this time the colour of the face looks fallow, the eye is dull and heavy, and the whole countenance as it were bloated; the patient feels himself wearied even after sleep, and complains of pains in different parts of the body; he grows inactive, and easily fatigues; often timid; has gloomy ideas about his safety, as if hypochondrical; he flies from duty and wishes to indulge in sloth. To these generally succeed the apperance of the gums which so especially characherizes scurvy; they swell, are spongy and bleed on the slightest cause. The breath is fetid, and often attended with some disagreeable taste of the mouth. ... It is not uncommon for sailors, afflicted with scurvy, to walk upon deck, and drop down irrecoverably; though to all appearance, when below, there seemed no danger; From this I must infer no just prognosis can be always formed.”<ref name=":0" />

[[File:60mgperday.jpg|300px|thumb|left|Steady state plateau ascorbic acid concentration in plasma. Data are an example of plateau determination from volonteer 6 at the 60mg dose.]]

== Blood test ==
The blood test procedure for Vitamin C deficiency is highly advanced.<ref name="Levine1996" /> A simpler but less accurate is proposed in <ref name="Robitaille2016" />

==Notable studies==
*1996, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance<ref name="Levine1996" /> [https://www.pnas.org/content/pnas/93/8/3704.full.pdf (Full Text)]

==See also==
*[[Collagen]]
*[[Irritable bowel syndrome]]
*[[Osteoporosis]]
*[[Vitamin C]]
*[[Vitamin C Deficiency without Scurvy hypothesis]]

== Learn more ==

==References==
<references>
<ref name="Levine1996">{{Citation
| last1 = Levine | first1 = Mark
| last2 = Conry-Cantilena | first2 = Cathy
| last3 = Wang | first3 = Yaohui
| last4 = Welch | first4 = Richard W.
| last5 = Washko | first5 = Louis R.
| last6 = Dhariwal | last7 = Park | last8 = Lazarev | last9 = Graumlich | last10 = King | last11 = Cantilena | title = Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance
| journal = Proc Natl Acad Sci U S A | volume = 93 | issue = 8 | page = 3704-9
| date = 1996
| url = https://www.pnas.org/content/93/8/3704.long

}}
</ref>
<ref name="Robitaille2016">{{Citation
| last1 = Robitaille | first1 = Line
| last2 = Hoffer | first2 = L John
| title = A simple method for plasma total vitamin C analysis suitable for routine clinical laboratory use
| journal = Nutrition Journal | volume = 15 | issue = 40
| date = 21 April 2016
| url = https://nutritionj.biomedcentral.com/articles/10.1186/s12937-016-0158-9

}}
</ref>
</references>
[[Category:Diagnoses]]
[[Category:Vitamins]]

Fibromyalgia

2020-05-30T10:56:27Z

FatigueTrackerBot:.

{{Cleanup|date=May 2019|reason=It is fine to use verywellhealth for citations regarding general health information. Image captions should state author and copyright license (eg CC-BY-SA-4.0), which can be copied from the image's "File:" page, by clicking on the image. See [[help:Images%23Displaying_an_image_on_a_page]] for more information. [[MEpedia:External links|External Links]] in text should be moved to the "Learn more" section or replaced with citations. See [[MEpedia:External links]] for more information. External links in lists of notable studies should conform to [[mepedia:Manual_of_style%23Notable_studies]] style.}}

[[Fibromyalgia]] '''(FM/FMS)''' is a chronic disorder characterized by widespread [[Musculoskeletal system|musculoskeletal]] pain, [[fatigue]], and tenderness in localized areas. [[Myalgia|Muscle pain]] is widespread, on both sides of the body, and above and below the waist.<ref name=":50" /><ref name=":51" /><ref name=":48" /><ref name=":49" />

Sufferers are fatigued and tired even when sleeping for long periods of time, and sleep is often disrupted by pain. Many FM sufferers have [[Sleep dysfunction|sleep disorders]] like [[sleep apnea]] and [[restless legs syndrome]] (RLS).<ref name=":26" /><ref name=":27" /><ref name=":35" /> [[Cognitive impairment]], when one cannot focus or pay attention and the patient has difficulty concentrating on mental tasks, is known by FM sufferers as "[[fibro fog]]".<ref name=":17">{{Cite news|url=https://www.verywellhealth.com/brain-fibro-fog-causes-symptoms-possible-treatment-716014|title=What Is Fibro Fog and ME/CFS Brain Fog?|last=Dellwo|first=Adrienne|authorlink=Adrienne Dellwo|date=|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref><ref name=":26" /><ref name=":27" /><ref name=":35" /> Some experience [[depression]], [[headache]]s, and lower [[abdominal pain]] or [[muscle cramp|cramping]]. Other symptoms include [[Paresthesia|tingling]] or [[numbness]] in hands and feet, pain in jaw and disorders of the jaw such as [[temporomandibular joint disorder|temporomandibular joint disorder]] (TMJ/TMD), [[Menstrual cycle#Health effects in other conditions|menstrual cycle]] cramps, and [[digestive problems]] like i[[Irritable bowel syndrome|rritable bowel syndrome]] (IBS).<ref name=":26">{{Cite news|url=https://www.webmd.com/fibromyalgia/guide/fibromyalgia-symptoms#1|title=Fibromyalgia Symptoms|work=WebMD|access-date=2018-08-09|language=en-US}}</ref><ref name=":27">{{Cite news|url=https://www.mayoclinic.org/diseases-conditions/fibromyalgia/symptoms-causes/syc-20354780|title=Fibromyalgia - Symptoms and causes|work=Mayo Clinic|access-date=2018-08-09|language=en}}</ref><ref name=":35" />

[[Pain#Pain in Fibromyalgia|Other pain conditions are associated with FM]], such as [[rheumatoid arthritis]] (RA), [[Systemic lupus erythematosus|Lupus]], [[Ankylosing_spondylitis|ankylosing spondylitis]], [[Interstitial_cystitis|interstitial cystitis]], and more.<ref name=":05">{{Cite web|url=https://www.mayoclinic.org/diseases-conditions/fibromyalgia/symptoms-causes/syc-20354780|title=Fibromyalgia - Symptoms and causes|website=Mayo Clinic|language=en|access-date=2019-05-03}}</ref><ref name=":46">{{Cite web|url=https://www.health.com/health/gallery/0,,20520705,00.html|title=7 Conditions Linked to Fibromyalgia|last=Mann|first=Denise|authorlink=|last2=|first2=|authorlink2=|date=Sep 7, 2011|website=Health.com|language=en|archive-url=|archive-date=|dead-url=|access-date=2019-05-03}}</ref><ref name=":47">{{Cite web|url=https://www.verywellhealth.com/chronic-fatigue-syndrome-interstitial-cystitis-716168|title=Fibromyalgia, Chronic Fatigue Syndrome & Interstitial Cystitis|last=Dellwo|first=Adrienne|authorlink=Adrienne Dellwo|last2=|first2=|authorlink2=|date=Aug 21, 2018|website=Verywell Health|language=en|archive-url=|archive-date=|dead-url=|access-date=2019-05-03}}</ref>

The [[United Kingdom|United Kingdom]] (UK) [[National Health Service]] (NHS) lists FM as one of 20 most painful conditions.<ref>{{Cite web|url=https://www.newsweek.com/20-most-painful-conditions-nhs-1191081|title=Here are 20 of the most painful health conditions you can get|last=EDT|first=Hannah Osborne On 10/29/18 at 7:14 AM|date=2018-10-29|website=Newsweek|language=en|access-date=2019-03-26}}</ref><ref name=":39">{{Cite web|url=https://www.cambridge-news.co.uk/news/uk-world-news/nhs-gout-ulcer-endometriosis-arthritis-15339123|title=The NHS says these are the 20 most painful health conditions you can suffer from|last=Campbell|first=James|last2=Pengelly|first2=Ella|date=2019-03-26|website=cambridgenews|access-date=2019-03-26}}</ref> The NHS describes the pain as diffuse aching or burning, head to toe, and can be worse at some times than at others. The pain can change location. "The fatigue ranges from feeling tired, to the exhaustion of a [[flu-like illness]]."<ref name=":39" /> The [[United States|United States]] (US) [[Centers for Disease Control and Prevention]] (CDC) states FM "can cause pain, [[Fibromyalgia disability process|disability, and lower quality of life]]."<ref>{{Cite web|url=https://www.cdc.gov/arthritis/basics/fibromyalgia.htm|title=Fibromyalgia {{!}} Arthritis {{!}} CDC|date=2018-10-04|website=www.cdc.gov|language=en-us|access-date=2019-04-12}}</ref> The medical guide book [[Mayo Clinic Guide to Fibromyalgia: Strategies to Take Back Your Life|''Mayo Clinic Guide to'' ''Fibromyalgia: Strategies to Take Back Your Life'']] describes fibromyalgia as "a [[Central sensitization|sensory disorder]] caused by a miscommunication between the [[Nervous system|nerves through your body and your brain]]."<ref>{{Cite web|url=https://www.amazon.com/Mayo-Clinic-Guide-Fibromyalgia-Strategies/dp/1893005496/ref=sr_1_1?keywords=Mayo+Clinic+Guide+to+Fibromyalgia%3A+Strategies+to+Take+Back+Your+Life&qid=1573669190&s=books&sr=1-1|title=Mayo Clinic Guide to Fibromyalgia: Strategies to Take Back Your Life|last=Abril, M.D.|first=Andy|authorlink=|last2=Bruce Ph.D. L.P.|first2=Barbara K.|authorlink2=|date=|year=2019|website=www.amazon.com|publisher=Mayo Clinic Press; Paperback Original edition|page=15|archive-url=|archive-date=|dead-url=|access-date=2019-11-13}}</ref>

The [[American_College_of_Rheumatology|American College of Rheumatology]] (ACR) created and updates the diagnostic criteria for FM.<ref name=":12" /><ref name=":13">{{Cite web|url=https://www.rheumatology.org/Portals/0/Files/2010_Preliminary_Diagnostic_Criteria.pdf|title=American College of Rheumatology (ACR) Preliminary Diagnostic Criteria for Fibromyalgia|last=Wolfe|first=Frederick|date=2010|website=fibroknowledge.com|type=PDF|archive-url=|archive-date=|dead-url=|access-date=|authorlink=|last2=Clauw|first2=Daniel|authorlink2=|publisher=Arthritis Care & Research|last3=Fitzcharles|first3=Mary-Ann|first4=Don|last5=Katz|last4=Goldenberg|first5=Robert|last6=Mease|first6=Philip|last7=Russel|first7=Anthony|last8=Russel|first8=I. Jon|first9=John|last9=Winfield|others=Muhammad Yunus}}</ref><ref name=":50" /><ref name=":51" /><ref name=":48" /><ref name=":49">{{Cite web|url=https://www.rheumatology.org/Portals/0/Files/2010%20Fibromyalgia%20Diagnostic%20Criteria_Excerpt.pdf|title=2010 Fibromyalgia Diagnostic Criteria - Excerpt|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=2010|website=rheumatology.org|page=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> ''See:'' [[Fibromyalgia#Diagnosis|Fibromyalgia (''Diagnosis'' section)]].

[[File:Fibro_Tender_Points.png|400px|thumb|right|1990 ACR Diagnostic Criteria: 18 Tender Points<ref name=":50">{{Cite journal|last=|first=|author-link=Frederick Wolfe|author-link2=Hugh Smythe|author-link3=Muhammad Yunnus|author-link4=Robert Bennett|author-link5=Claire Bombardier|author-link6=Don Goldenberg|author-link7=Peter Tugwell|author-link8=Stephen Campbell|author-link9=Micha Abeles|date=|others=Patricia Clark, Adel Fam,Stephen Farber, Justus Fiechtner, C.Michael Franklin, Rober Gatter, Daniel Hamaty, James Lessard, Alan Lichtbroun, Alfonse Masi, Glenn McCain, W. John Reynolds, Thomas Romano, I. Jon Russell, and Robert Sheon|title=The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia|url=https://www.rheumatology.org/Portals/0/Files/1990_Criteria_for_Classification_Fibro.pdf|journal=Arthritis and Rheumatism|publisher=The American College of Rheumatology|volume=33|issue=2|pages=160-172|quote=|via=Arthritis and Rheumatism}}</ref><ref name=":51">{{Cite web|url=https://www.rheumatology.org/Portals/0/Files/1990%20Fibromyalgia_Excerpt.pdf|title=1990 Fibromyalgia Excerpt|last=Wolfe|first=Frederick|authorlink=|last2=|first2=|authorlink2=|date=1990|website=rheumatology.org|archive-url=|archive-date=|dead-url=|access-date=}}</ref>]]
[[File:Fibro_Widespread_Pain.png|400px|thumb|right|2010 ACR Preliminatry Diagnostic Criteria: '''Wisedpread Pain Index (WPI'''), 19 Tender Point Areas<ref name=":48">{{Cite journal|last=|first=|author-link=Frederick Wolfe|author-link2=Daniel Clauw|author-link3=Mary Ann Fitzcharles|author-link4=Don Goldenberg|author-link5=Robert Katz|author-link6=Philip Mease|author-link7=Anthony Russell|author-link8=I. Jon Russell|author-link9=John Winfield|date=2010|others=Muhammad Yunus|title=The American College of RheumatologyPreliminary Diagnostic Criteria for Fibromyalgiaand Measurement of Symptom Severity|url=https://www.rheumatology.org/Portals/0/Files/2010_Preliminary_Diagnostic_Criteria.pdf|journal=Arthritis Care & Research|publisher=American College of Rheumatology|volume=62|issue=5|pages=600-610|quote=|via=}}</ref><ref name=":49" />]]

==Prevalence==
FM is the second most common rheumatic disorder behind [[osteoarthritis]] and is "now considered to be a lifelong [[central nervous system]] disorder."<ref>{{Cite web|url=https://www.sciencedaily.com/releases/2015/05/150517071813.htm|title=Fibromyalgia has central nervous system origins|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=May 17, 2015|website=ScienceDaily|at=Summary:|language=en|archive-url=|archive-date=|dead-url=|access-date=2019-11-13|quote=now considered to be a lifelong central nervous system disorder}}</ref><ref>{{Cite news|url=https://naidw.org/blog/members-myblogs/fibromyalgia-now-considered-as-a-lifelong-central-nervous-system-disorder|title=Fibromyalgia now considered as a lifelong central nervous system disorder|work=NAIDW.org®|access-date=2018-08-09|language=en-gb}}</ref> An estimated 10 million people in the US and 3-6% of the world population have FM. It is seen in women, men, children, and all ethnic groups. It is often seen in families and diagnosed between the ages of 20 to 50 years; incidence increases with age.<ref>{{Cite news|url=http://www.fmaware.org/about-fibromyalgia/prevalence/|title=Prevalence - National Fibromyalgia Association (NFA)|work=National Fibromyalgia Association (NFA)|access-date=2018-08-09|language=en-US}}</ref>

FM has a female:male 7:1 ratio under the ''American College of Rheumatology (ACR) 1990 Diagnostic Criteria''<ref name=":50" /><ref name=":51" /> and 2:1 when the ''ACR 2010 Preliminary Diagnostic Criteria''<ref name=":48" /><ref name=":49" /> is used.<ref>{{Cite journal|last=Boomershine|first=Chad|date=Nov 4, 2017|title=Fibromyalgia: Practice Essentials, Background, Pathophysiology|url=http://emedicine.medscape.com/article/329838-overview#a5|journal=Medscape|volume=|pages=|via=|publisher=|editor-last=Diamond|editor-first=Herbert|at=Sex-related differences in incidence}}</ref> ''See'': [[Fibromyalgia#American College of Rheumatology (ACR) Criteria|Fibromyalgia (''American College of Rheumatology (ACR) Criteria'' section)]]. A September 2018, Wolfe et al study ''Fibromyalgia diagnosis and biased assessment: Sex, prevalence and bias''<ref name=":28" /> found fewer women and more men are diagnosed under the 2010/11 criteria (this criterion further updated in 2016<ref>{{Cite journal|date=2016-12-01|title=2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria|url=https://www.sciencedirect.com/science/article/pii/S0049017216302086|journal=Seminars in Arthritis and Rheumatism|language=en|volume=46|issue=3|pages=319–329|doi=10.1016/j.semarthrit.2016.08.012|issn=0049-0172}}</ref>). They found the ratio is F/M 1.5:1.<ref name=":28">{{Cite journal|last=Wolfe|first=Frederick|last2=Walitt|first2=Brian|last3=Perrot|first3=Serge|last4=Rasker|first4=Johannes J.|last5=Häuser|first5=Winfried|date=2018-09-13|title=Fibromyalgia diagnosis and biased assessment: Sex, prevalence and bias|url=https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203755|journal=PLOS ONE|language=en|volume=13|issue=9|pages=e0203755|doi=10.1371/journal.pone.0203755|issn=1932-6203|pmc=|pmid=30212526|via=}}</ref><blockquote>What we did not find in our unbiased CritFM samples was 9:1 female to male fibromyalgia ratios that are widely described by expert sources [11–13]. We believe that such findings only occur in the presence of selection bias or biased ascertainment.<ref name=":28" /></blockquote><blockquote>As unbiased epidemiological studies show only a small increase in the female to male sex ratio (~1.5:1) as opposed to the observed ratio in clinical studies of 9:1, we believe that the over-identification of fibromyalgia in women and the consequent under-identification of men is the result of bias.<ref name=":28" /></blockquote>

==Fibromyalgia in ME/CFS==
"The most common overlapping condition with [[ME/CFS]] is fibromyalgia."<ref name=":30">{{Cite web|url=https://ammes.org/overlapping-conditions/|title=Overlapping Conditions - American Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Society|last=|first=|date=|website=ammes.org|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2018-08-12}}</ref><ref name=":31">{{Cite journal|last=Jason|first=Leonard|last2=Taylor|first2=R.R.|last3=Kennedy|first3=C.L.|last4=Song|first4=S|last5=Johnson|first5=D|last6=Torres|first6=S.R.|date=2001-01-01|title=Chronic fatigue syndrome: Comorbidity with fibromyalgia and psychiatric illness|url=https://www.researchgate.net/publication/285787383_Chronic_fatigue_syndrome_Comorbidity_with_fibromyalgia_and_psychiatric_illness|journal=Medicine and Psychiatry|volume=4|pages=29–34}}</ref> While some have posited ME/CFS and FM are variants of the same illness, [[Benjamin Natelson]], MD summoned considerable amounts of data that suggest the two illnesses differ with different pathophysiologic processes leading to different treatments.<ref name=":36">{{Cite journal|last=Natelson|first=Benjamin H.|date=2019-02-19|title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: Definitions, Similarities, and Differences|url=https://www.clinicaltherapeutics.com/article/S0149-2918(19)30003-7/abstract|journal=Clinical Therapeutics|language=English|volume=0|issue=0|doi=10.1016/j.clinthera.2018.12.016|issn=0149-2918|pmid=30795933}}</ref>

Dr. [[Jarred Younger]] has said that many patients that meet the criteria for FM also meet criteria for [[chronic fatigue syndrome]] (CFS) but the reverse is not necessarily true as a lot of people with [[CFS]] do not have [[chronic pain]].<ref>{{Cite web|url=https://www.youtube.com/watch?v=wJB95m4FLa0#t=57m27s|title=Webinar with Jarred Younger, Ph.D.|last=Younger|first=Jared|date=May 20, 2016|website=YouTube|at=57:27|via=|archive-url=|archive-date=|dead-url=|access-date=|publisher=SolveCFS|type=Video}}</ref> However, the [[Canadian Consensus Criteria]] (CCC) requires the symptom of pain to diagnose ME/CFS.<ref name="Carruthers, 2003">{{Citation
| last1 = Carruthers | first1 = Bruce M. | authorlink1 = Bruce Carruthers
| last2 = Jain | first2 = Anil Kumar | authorlink2 = Anil Kumar Jain
| last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir
| last4 = Peterson | first4 = Daniel L. | authorlink4 = Daniel Peterson
| last5 = Klimas | first5 = Nancy G. | authorlink5 = Nancy Klimas
| last6 = Lerner | first6 = A. Martin | authorlink6 = Martin Lerner
| last7 = Bested | first7 = Alison C. | authorlink7 = Alison Bested
| last8 = Flor-Henry | first8 = Pierre | authorlink8 = Pierre Flor-Henry
| last9 = Joshi | first9 = Pradip | authorlink9 = Pradip Joshi
| last10 = Powles | first10 = A C Peter | authorlink10 = A C Peter Powles
| last11 = Sherkey | first11 = Jeffrey A. | authorlink11 = Jeffrey Sherkey
| last12 = van de Sande | first12 = Marjorie I. | authorlink12 = Marjorie van de Sande
| title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols
| journal = Journal of Chronic Fatigue Syndrome | volume = 11 | issue = 2 | page = 7-115
| date = 2003
| pmid =
| doi = 10.1300/J092v11n01_02
| url = http://phoenixrising.me/wp-content/uploads/Canadian-definition.pdf
}}</ref> It is the pattern (on both sides of the body, and above and below the waist) of chronic widespread [[Musculoskeletal system|musculoskeletal]] pain (involving muscle, cartilage, ligaments, and connective tissue) in FM that sets it apart from other diseases that have pain; it also causes [[cognitive symptoms]] and [[unrefreshing sleep]].<ref name=":17" /><ref name=":26" /><ref name=":27" />

A Swedish study of 234 ME/CFS patients meeting the [[Canadian Consensus Criteria]] found that 96% had trigger point pain consistent with fibromyalgia and 67% met the diagnostic criteria for fibromyalgia.<ref>{{Cite web|url=https://osf.io/qwn5h/|website=Center for Open Science|access-date=2019-12-03|title=Bragee Bertilson et al. - ME CFS and Intracranial Hypertension|date=Nov 27, 2019|last=|first=|authorlink=|last2=|first2=|authorlink2=|archive-url=|archive-date=|dead-url=}}</ref>

==Health complications==
FM is not a [[progressive disease]] but according to Dr. [[Daniel Clauw|Dan Clauw]] the "slow gradual worsening of chronic pain patients over time is due to downstream consequences of poorly controlled pain and other symptoms, wherein individuals then progressively get less active, sleep worse, are under more stress and unknowingly develop bad habits which worsen pain and other symptoms."<ref>{{Cite news|url=http://nationalpainreport.com/ask-the-dctors-is-fibromyalgia-progressive-8831105.html|title=Ask the Doctors: Is Fibromyalgia Progressive?|date=2016-08-09|work=National Pain Report|access-date=2018-08-09|language=en-US}}</ref>

*[https://www.sharecare.com/health/fibromyalgia-effects Fibromyalgia Complications]<ref name=":19" />

:<blockquote>People who have fibromyalgia frequently complain of a variety of symptoms that affect other parts of the body. Many people complain of [[gastrointestinal]] issues and restless legs syndrome (RLS). Additionally, the [[chronic pain]] and discomfort of fibromyalgia may lead to [[depression]].<ref name=":19">{{Cite news|url=https://www.sharecare.com/health/fibromyalgia-effects|title=Fibromyalgia Complications - Fibromyalgia - Joint Health|work=Sharecare|access-date=2018-08-09|language=en}}</ref></blockquote>

*[https://www.sharecare.com/health/fibromyalgia-effects/can-fibromyalgia-cause-medical-conditions Can fibromyalgia cause other medical conditions?]<ref name=":20" />

:<blockquote>Fibromyalgia is not known to cause other medical conditions. However, people who have fibromyalgia seem to be at high risk for developing other painful conditions, including [[osteoarthritis]] (the common type of arthritis caused by wear and tear on the joints) as well as other related conditions, such as [[rheumatoid arthritis]], [[lupus]], and [[ankylosing spondylitis]]. Also, people with fibromyalgia are frequently diagnosed with chronic fatigue syndrome, [[irritable bowel syndrome]] (IBS), and temporomandibular joint (TMJ) disorder.<ref name=":20">{{Cite web|url=https://www.sharecare.com/health/fibromyalgia-effects/can-fibromyalgia-cause-medical-conditions|title=Can fibromyalgia cause other medical conditions? {{!}} Fibromyalgia Complications|last=Honor Society of Nursing|first=|date=|website=Sharecare|language=en|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref></blockquote>

==Risk factors==
[[Lupus]] and [[rheumatoid arthritis]] (RA) are risk factors in developing FM. Car accidents, [[post-traumatic stress disorder]] (PTSD), [[Carpal tunnel syndrome|repetitive injuries]], illness such as a [[virus|viral infection]], [[family history]], and [[obesity]] have all been linked to FM.<ref name=":35">{{Cite web|url=https://www.cdc.gov/arthritis/basics/fibromyalgia.htm|title=Fibromyalgia {{!}} Arthritis {{!}} CDC|date=2018-04-03|website=www.cdc.gov|language=en-us|access-date=2018-08-09}}</ref><ref>{{Cite news|url=https://www.niams.nih.gov/health_info/Fibromyalgia/|title=Fibromyalgia What Causes it?|last=Director|first=Nancy Garrick, Deputy|date=2017-04-05|work=National Institute of Arthritis and Musculoskeletal and Skin Diseases|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en}}</ref><ref>{{Cite news|url=http://www.prohealth.com/library/showarticle.cfm?libid=22315|title=When Fibromyalgia Is More than Pain - Prohealth|date=2016-01-08|work=Prohealth|access-date=2018-08-09|language=en-US}}</ref>

==Diagnosis==
[https://www.verywellhealth.com/what-are-fibromyalgia-tender-points-189768 Tender points], not [https://en.wikipedia.org/wiki/Myofascial_trigger_point trigger points], are used to diagnose FM.<ref>{{Cite web|url=http://www.healthcentral.com/chronic-pain/c/662034/176031/fibromyalgia-trigger/|title=The Difference Between Fibromyalgia Tender Points and Myofascial Trigger Points - Chronic Pain {{!}} HealthCentral|last=Cooper|first=Celeste|date=May 8, 2015|website=www.healthcentral.com|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref> Tender points will be above and below the waist and on both sides of the body. (See: Illustrations of the 1990 and 2010 American College of Rheumatology (ACR) Criteria depicting tender points near the top of this page.) It is important to check for other conditions that could be causing pain such as [[hypothyroidism]], RA or lupus, osteoarthritis, ankylosing spondylitis, and [[wikipedia:Polymyalgia_rheumatica|polymyalgia rheumatica]].<ref>{{Cite news|url=https://www.webmd.com/fibromyalgia/guide/fibromyalgia-diagnosis-and-misdiagnosis#1|title=How Is Fibromyalgia Diagnosed?|work=WebMD|access-date=2018-08-12|language=en-US}}</ref>

===United States===
===== Blood test =====
EpicGenetics has a [[blood test]] that is identifying the presence of specific [[Leucocyte|white blood cell]] abnormalities of patients diagnosed with FM and has partnered with two universities to offer [[whole exome sequencing]] free of charge to those who test positive with their [http://fmtest.com/ FM/a® test].<ref>{{Cite news|url=http://www.businesswire.com/news/home/20170419005324/en/EpicGenetics-Assistance-Leading-Medical-Centers-Expands-Clinical|title=EpicGenetics, with the Assistance of Leading Medical Centers, Expands Clinical Study of FM/a® Test to Diagnose Fibromyalgia, Identify Genetic Markers Unique to the Disorder and Explore Direct Treatment Approaches|last=|first=|date=Apr 19, 2017|work=|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en}}</ref><ref name=":38">{{Cite web|url=http://fmtest.com/|title=Home|last=perceptivadmin|website=EpicGenetics' FM/a® Test is FDA-compliant and has successfully diagnosed patients with fibromyalgia since 2012.|language=en-US|access-date=2019-03-25}}</ref> Most insurance companies will cover the test.<ref>{{Cite web|url=https://www.painnewsnetwork.org/stories/2015/5/27/fibromyalgia-blood-test-gets-insurance-coverage|title=Fibromyalgia Blood Test Gets Insurance Coverage|last=Anson|first=Pat|authorlink=|last2=|first2=|authorlink2=|date=May 27, 2015|website=Pain News Network|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2019-03-25}}</ref><ref>{{Cite web|url=http://nationalpainreport.com/more-insurance-companies-now-paying-for-fibromyalgia-blood-test-8829994.html|title=More Insurance Companies Now Paying for Fibromyalgia Blood Test|last=Gregory-Burch|first=Donna|authorlink=|last2=|first2=|authorlink2=|date=2016-04-04|website=National Pain Report|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2019-03-25}}</ref> EpicGenetics offers help to determine if your insurance will [http://fmtest.com/ cover their test].<ref name=":38" />

==== American College of Rheumatology (ACR) Criteria ====

=====1990 ACR criteria=====

*1990, [http://www.rheumatology.org/Portals/0/Files/1990_Criteria_for_Classification_Fibro.pdf The American College Of Rheumatology 1990 Criteria For The Classification Of Fibromyalgia]<ref name=":12">{{Cite web|url=https://www.rheumatology.org/Portals/0/Files/1990_Criteria_for_Classification_Fibro.pdf|title=The American College of Rheumatology Criteria for the Classification of Fibromyalgia|last=Wolfe|first=Frederick|last2=Smythe|first2=Hugh|date=1990|website=rheumatology.org|publisher=|others=Abeles, Micha; Clark, Patricia; Fam, Adel; Farber, Stephen; Fiechtner, Justus; Franklin, Michael; Gatter, Robert; Hamaty, Daniel; Lessard, James; Lightbroun, Alan; Masi, Alfonse; McCain, Glenn; Reynolds, W. John; Romano, Thomas; Russell, Jon; Sheon, Robert|archive-url=|archive-date=|dead-url=|access-date=|last3=Yunus|first3=Muhammad|last4=Bennett|first4=Robert|last5=Bombardier|first5=Claire|last6=Goldenberg|first6=Don|last7=Tugwell|first7=Peter|last8=Campbell|first8=Stephen}}</ref><ref name=":50" /><ref name=":51" /> "American College of Rheumatology guidelines suggest that people with fibromyalgia have pain in at least 11 of these tender points when a doctor applies a certain amount of pressure."<ref>{{Cite news|url=http://www.health.com/health/gallery/0,,20345635,00.html|title=18 Points Used to Diagnose Fibromyalgia|last=|first=|date=Feb 4, 2011|work=Health.com|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en}}</ref><ref>{{Cite web|url=https://www.masscfids.org/8-resource-library/diagnosis/266-tender-points-might-no-longer-be-used-for-diagnosis-of-fibromyalgia|title=Tender Points might no longer be used for diagnosis of Fibromyalgia|last=Proskauer|first=Charmian|date=Feb 2011|website=www.masscfids.org|language=en-GB|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref>

=====2010 ACR criteria=====

*2010, The [https://www.rheumatology.org/Portals/0/Files/2010_Preliminary_Diagnostic_Criteria.pdf 2010 American College of Rheumatology (ACR) Preliminary Diagnostic Criteria for Fibromyalgia: Overview]<ref name=":48" /><ref name=":49" /> was proposed and modified in 2011<ref>{{Cite news|url=http://www.rheumatologynetwork.com/fibromyalgia/new-and-modified-fibromyalgia-diagnostic-criteria|title=New and Modified Fibromyalgia Diagnostic Criteria|last=Garg|first=Neha|date=Feb 9, 2012|work=Rheumatology Network|access-date=Aug 9, 2017|archive-url=|archive-date=|dead-url=|last2=Deodhar|first2=Atul}}</ref> with the modification being validated in 2013 and published in 2014.<ref>{{Cite journal|last=Bennett|first=Robert M.|last2=Friend|first2=Ronald|last3=Marcus|first3=Dawn|last4=Bernstein|first4=Cheryl|last5=Han|first5=Bobby Kwanghoon|last6=Yachoui|first6=Ralph|last7=Deodhar|first7=Atul|last8=Kaell|first8=Alan|last9=Bonafede|first9=Peter|date=2014|title=Criteria for the diagnosis of fibromyalgia: validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria|url=https://www.ncbi.nlm.nih.gov/pubmed/24497443|journal=Arthritis Care & Research|volume=66|issue=9|pages=1364–1373|doi=10.1002/acr.22301|issn=2151-4658|pmid=24497443|via=}}</ref> September of 2016, another revision has been made.<ref name=":14">{{Cite news|url=http://acrabstracts.org/abstract/2016-revisions-to-the-20102011-fibromyalgia-diagnostic-criteria/|title=2016 Revisions to the 2010/2011 Fibromyalgia Diagnostic Criteria - ACR Meeting Abstracts|last=|first=|date=Sep 28, 2016|work=ACR Meeting Abstracts|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

:Men do not seem to form the tender points needed for diagnosis under the 1990 criteria,<ref>{{Cite news|url=http://www.webmd.com/fibromyalgia/features/how-fibromyalgia-affects-men#2|title=How Fibromyalgia Affects Men: Symptoms and Diagnosis|work=WebMD|access-date=2018-08-09|language=en-US}}</ref> the 2010 proposed criteria diagnoses more men with a F/M ratio of 2:1.<ref>{{Cite journal|last=Boomershine|first=Chad|date=Nov 4, 2017|title=Fibromyalgia: Practice Essentials, Background, Pathophysiology|url=http://emedicine.medscape.com/article/329838-overview#a5|journal=Medscape|volume=|pages=|via=}}</ref>
:Tender points were used to diagnose with the 1990 criteria, however "considerable skill is needed to correctly check for a patient’s tender points (i.e., digital palpation that is done with certain amount of applied pressure), yet this technique is not typically taught at most medical schools."<ref name=":0">{{Cite web|url=https://www.masscfids.org/8-resource-library/diagnosis/266-tender-points-might-no-longer-be-used-for-diagnosis-of-fibromyalgia#2|title=Tender Points might no longer be used for diagnosis of Fibromyalgia|last=Proskauer|first=Charmian|date=Feb 5, 2011|website=www.masscfids.org|language=en-GB|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref>
:The new standards were designed to:
:*eliminate the use of a tender point examination
:*include a severity scale by which to identify and measure characteristic FM symptoms
:*utilize an index by which to rate pain<ref name=":0" />

There are 19 tender point areas in the widespread pain index '''''(WPI)''''', whereas the 1990 criteria had 18 tender points.<ref name=":0" /><ref>{{Cite news|url=https://www.verywellhealth.com/what-are-fibromyalgia-tender-points-189768|title=Why Tender Points Are No Longer Used to Diagnose Fibromyalgia|last=Eustice|first=Carol|date=Oct 3, 2018|work=Verywell Health|access-date=2018-10-04|archive-url=|archive-date=|dead-url=}}</ref>

====== Widespread pain index and Symptom severity ======

The '''''Widespread Pain Index (WPI)''''' and '''''Symptom Severity''' '''(SS)''''' is explained in the study ''Fibromyalgia Syndrome: An Overview of Pathophysiology, Diagnosis and Management''.<ref name=":21" />
[[File:Widespread Pain Index Areas with numbers.svg|200px|thumb|right|'''''WPI''''' 19 areas of pain. Count 1 point for each area of pain<ref name=":21" /><ref name=":48" /><ref name=":49" />]]
<blockquote>In place of the tender point count, patients (or their physician) may endorse 19 body regions in which pain has been experienced during the past week. One point is given for each area, so the score is between 0-19. This number is referred to as the '''''Widespread Pain Index (WPI)''''' and it is one of the two required scores needed for a doctor to make a diagnosis of fibromyalgia.</blockquote><blockquote>The second part of the score required to assess the diagnosis of fibromyalgia involves the evaluation of a person's symptoms. The patient ranks specific symptoms on a scale of 0-3. These symptoms include: [[Fatigue]], [[Unrefreshing sleep|Waking unrefreshed]], [[Cognitive dysfunction|Cognitive symptoms]], Somatic (physical) symptoms in general (such as [[headache]], [[Weakness|weakness]], [[Gastrointestinal system|bowel problems]], [[nausea]], [[dizziness]], [[numbness]] / [[Paresthesia|tingling]], [[hair loss]], [[Dry eye syndrome|dry eyes]], [[Raynaud's syndrome|Raynaud's]] phenomenon, painful urination, and more).<ref name=":21" /><ref name=":53">{{Cite journal|last=Wolfe|first=Frederick|author-link=|last2=Clauw|first2=Daniel J.|author-link2=Daniel Clauw|last3=Fitzcharles|first3=Mary-Ann|author-link3=|last4=Goldenberg|first4=Don L.|author-link4=|last5=Katz|first5=Robert S.|author-link5=|last6=Mease|first6=Philip|author-link6=|last7=Russell|first7=Anthony S.|last8=Russell|first8=I. Jon|last9=Winfield|first9=John B.|date=2010-02-23|title=The American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Measurement of Symptom Severity|url=http://doi.wiley.com/10.1002/acr.20140|journal=Arthritis Care & Research|language=en|volume=62|issue=5|pages=600–610|doi=10.1002/acr.20140|pmc=|pmid=|access-date=|quote=The reference list consisted of: muscle pain, irritable bowel syndrome, fatigue/tiredness, thinking or remembering problem, muscle weakness, headache, pain/cramps in the abdomen, numbness/tingling, dizziness, insomnia, depression, constipation, pain in the upper abdomen, nausea, nervousness, chest pain, blurred vision, fever, diarrhea, dry mouth, itching, wheezing, Raynaud’s phenomenon, hives/welts, ringing in ears, vomiting, heartburn, oral ulcers, loss of/change in taste, seizures, dry eyes, shortness of breath, loss of appetite, rash, sun sensitivity, hearing difficulties, easy [[bruising]], hair loss, frequent urination, painful urination, and bladder spasms.|via=}}</ref> The numbers assigned to each are added up, for a total of 0-12.</blockquote><blockquote>The diagnosis is based on both the '''''WPI''''' score and the '''''SS''''' score either:</blockquote>
:::<blockquote>'''''WPI''''' of at least 7 and '''''SS''''' scale score of at least 5, '''OR'''</blockquote>
:::<blockquote>'''''WPI''''' of 4-6<ref name=":14" /> and '''''SS''''' scale score of at least 9.<ref name=":21" /></blockquote>

[[File:WPI SS Fibro.JPG|600px|thumb|center|Table 2: '''''SS''''' scale score. Add a 4th column for Somatic (physical) symptoms in general (such as Headache, weakness, bowel problems, nausea, dizziness, numbness/tingling, hair loss, dry eyes, Raynaud's phenomenon, painful urination, and more).<ref name=":21" /><ref name=":53" /> The patient ranks specific symptoms on a scale of 0-3. The numbers assigned to each column are added up, for a total of 0-12.<ref name=":21" /> ]]

The [[Social Security Administration]] (SSA) accepts a diagnosis of FM with the 1990<ref name=":50" /><ref name=":51" /> or 2010<ref name=":48" /><ref name=":49" /> ACR criteria.<ref>{{Cite web|url=https://www.ssa.gov/OP_Home/rulings/di/01/SSR2012-02-di-01.html|title=Social Security Ruling: SSR 12-2p|last=ORDP,OPPS|first=|date=Jul 25, 2012|website=www.ssa.gov|language=en|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref> See the [[Fibromyalgia disability process]] page.

=== Sleep study ===
[[Sleep dysfunction]] is often involved in FM. Treating a sleep disorder can help with FM symptoms. A diagnosed sleep disorder is also helpful if one needs to [[Fibromyalgia disability process|file for disability]].

*[https://www.verywellhealth.com/sleep-study-fibromyalgia-cfs-716054 Getting a Sleep Study with Fibromyalgia or Chronic Fatigue Syndrome]<ref>{{Cite news|url=https://www.verywellhealth.com/sleep-study-fibromyalgia-cfs-716054|title=Getting a Sleep Study with Fibromyalgia or Chronic Fatigue Syndrome|last=Dellwo|first=Adrienne|date=Feb 15, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref>

*[http://www.sciencedaily.com/releases/2008/09/080903134311.htm What A Sleep Study Can Reveal About Fibromyalgia]<ref>{{Cite news|url=https://www.sciencedaily.com/releases/2008/09/080903134311.htm|title=What A Sleep Study Can Reveal About Fibromyalgia|work=ScienceDaily|access-date=2018-08-09|language=en}}</ref>

*[http://linkis.com/nationalpainreport.com/lzYea Fibromyalgia Sufferers Have Difficulty Maintaining Continuous Sleep, Study Says]<ref>{{Cite news|url=http://linkis.com/nationalpainreport.com/lzYea|title=Fibromyalgia Sufferers Have Difficulty Maintaining Continuous Sleep, Study Says|last=|first=|date=Mar 25, 2016|work=National Pain Report|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

=== ICD Diagnostic code===
'''ICD-10'''

The [[World Health Organization]] (WHO) International Classification of Diseases (ICD) lists FM as a "disease of the [[musculoskeletal system]] and connective tissue", under the code M79.7 (WHO ICD-10 Version: 2016).<ref name=":24">{{Cite web|url=http://apps.who.int/classifications/icd10/browse/2016/en#/M79.7|title=ICD-10 Version:2016|last=World Health Organization|first=|date=2016|website=apps.who.int|at=M79.7 Fibromyalgia|language=en|archive-url=|archive-date=|dead-url=|access-date=2018-09-15|authorlink=World Health Organization|last2=|first2=|authorlink2=}}</ref> The WHO's ICD-10 does not refer to FM as a syndrome and it is not classified in the category for [[Medically unexplained physical symptoms|medically unexplained symptoms]].<ref name=":37" /><ref name=":24" />

*'''M79.7 Fibromyalgia'''
::Fibromyositis
::Fibrositis
::Myofibrositis<ref name=":24" />

In 2015, the [[United States|US]] finally adopted ICD-10 and FM as a diagnosis.<ref name=":37">{{Cite web|url=http://www.icd10data.com/ICD10CM/Codes/M00-M99/M70-M79/M79-/M79.7|title=2018 ICD-10-CM Diagnosis Code M79.7: Fibromyalgia|website=www.icd10data.com|language=en|access-date=2018-08-09|date=2018|last=World Health Organization|first=|archive-url=|archive-date=|dead-url=|authorlink=World Health Organization|last2=|first2=|authorlink2=}}</ref> <ref>{{Cite news|url=http://nationalpainreport.com/the-health-care-industry-finally-recognizes-fibromyalgia-8827637.html|title=The Health Care Industry Finally Recognizes Fibromyalgia|last=Liptan|first=Ginevra|date=2015-09-30|work=National Pain Report|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

'''ICD-11 (2019)'''

[https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/849253504 ICD-11] (2019) has diagnostic code ''MG30.1 Chronic widespread pain,'' and changed the category from a [[:Category:Musculoskeletal diseases and disorders|Musculoskeletal disease]], to the ''General signs and symptoms category'', sometimes referred to as [[Medically unexplained physical symptoms]].<ref name=":18">{{Cite web|url=https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/849253504|title=ICD-11 - Mortality and Morbidity Statistics|website=icd.who.int|language=en|access-date=2018-08-09}}</ref>

*'''MG30.01 Chronic widespread pain'''

'''Parent'''
::MG30.0 Chronic primary pain

'''Description'''
<blockquote>Chronic widespread pain (CWP) is diffuse pain in at least 4 of 5 body regions and is associated with significant emotional distress (anxiety, anger/frustration or depressed mood) or functional disability (interference in daily life activities and reduced participation in social roles). CWP is multifactorial: biological, psychological and social factors contribute to the pain syndrome. The diagnosis is appropriate when the pain is not directly attributable to a nociceptive process in these regions and there are features consistent with nociplastic pain and identified psychological and social contributors.<ref name=":18" /></blockquote>

'''Inclusions'''
:*Fibromyalgia
'''Exclusions'''
:*Acute pain (MG31)<ref name=":18" />

==Pathophysiology==
"Fibromyalgia (FM) is a [[chronic pain]] disorder with unknown etiology and unclear pathophysiology. There is no evidence that a single event “causes” FM. Rather, many physical and/or emotional [[Stress|stressors]] may trigger or aggravate symptoms. These have included certain [[Infection|infections]], such as a [[Viral infection|viral illness]] or [[Lyme disease]], as well as emotional or physical [[trauma]]."<ref>{{Cite web|url=https://www.uptodate.com/contents/pathogenesis-of-fibromyalgia#!|title=Pathogenesis of fibromyalgia|last=Goldenberg|first=Don L|date=|website=www.uptodate.com|archive-url=|archive-date=|dead-url=|access-date=2018-08-09|authorlink=|last2=Schur|first2=Paul H|authorlink2=|last3=Romain|first3=Paul L}}</ref> The widespread pain is severe, debilitating, and abnormal in processing its pain. There is also [[Sleep dysfunction|sleep disturbance]] and fatigue. Cause or causes are unproven.<ref>{{Cite news|url=https://www.omf.ngo/what-is-mecfs-old/fibromyalgia/|title=What is Fibromyalgia? {{!}} Open Medicine Foundation|work=Open Medicine Foundation|access-date=2018-08-09|language=en-US}}</ref>

*May 2012, [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394355/ Fibromyalgia Syndrome: An Overview of Pathophysiology, Diagnosis and Management]<ref name=":21">{{Cite journal|last=Jahan|first=Firdous|last2=Nanji|first2=Kashmira|last3=Qidwai|first3=Waris|last4=Qasim|first4=Rizwan|date=2012|title=Fibromyalgia Syndrome: An Overview of Pathophysiology, Diagnosis and Management|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394355/|journal=Oman Medical Journal|volume=27|issue=3|pages=192–195|doi=10.5001/omj.2012.44|issn=1999-768X|pmc=|pmid=22811766|via=}}</ref> ''See'' Table 1: "Conditions associated with fibromyalgia." Musculoskeletal, [[genitourianry]], [[Gastrointestinal system|gastro intestinal]], and miscellaneous conditions often exist among fibromyalgia patients.

<blockquote>Pathophysiology: Although the etiology remains unclear, characteristic alterations in the [[Sleep dysfunction|pattern of sleep]] and changes in neuroendocrine transmitters such as [[serotonin]], substance P, growth hormone and [[cortisol]] suggest that regulation of the [[Autonomic nervous system|autonomic]] and neuro-endocrine system appears to be the basis of the syndrome. Fibromyalgia is not a life-threatening, deforming, or [https://en.wikipedia.org/wiki/Progressive_disease progressive disease]. [[Anxiety]] and [[depression]] are the most common association. Aberrant pain processing, which can result in [[chronic pain]], may be the result of several interplaying mechanisms. [[Central sensitization]], blunting of inhibitory pain pathways and alterations in [[neurotransmitters]] lead to aberrant neuro-chemical processing of sensory signals in the CNS, thus lowering the threshold of pain and amplification of normal sensory signals causing constant pain.<ref name=":21" /></blockquote>

<blockquote>The frequent co-morbidity of fibromyalgia with [[Mood swings|mood disorders]] suggests a major role for the stress response and for [[neuroendocrine]] abnormalities. The [[hypothalamic pituitary axis]] (HPA) is a critical component of the stress-adaptation response. In FMS, stress adaptation response is disturbed leading to stress induce symptoms. Psychiatric co-morbidity has been associated with FMS and needs to be identified during the consultation process, as this requires special consideration during treatment.<ref name=":21" /></blockquote>

*May 2018, [https://www.chiropractic.ca/wp-content/uploads/2018/05/107243-2_Chiro_62_1d_Bourgaize.pdf A comparison of the clinical manifestation and pathophysiology of myofascial pain syndrome and fibromyalgia: implications for differential diagnosis and management]<ref>{{Cite journal|last=Bourgaize|first=Sheryl|last2=Newton|first2=Genevieve|last3=Kumbhare|first3=Dinesh|last4=Srbely|first4=John|date=2018|title=A comparison of the clinical manifestation and pathophysiology of myofascial pain syndrome and fibromyalgia: implications for differential diagnosis and management (Table 1).|url=https://www.chiropractic.ca/wp-content/uploads/2018/05/107243-2_Chiro_62_1d_Bourgaize.pdf|format=PDF|journal=Journal of the Canadian Chiropractic Assoc.|volume=|pages=26-41|at=|via=|page=}}</ref> ''See'' Table 1 "Summary of the pathophysiology of fibromyalgia and myofascial pain syndrome." pg. 29 (pg. 4 of PDF)

*Jun 2018, [https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198625 SNPs in inflammatory genes ''CCL11'', ''CCL4'' and ''MEFV'' in a fibromyalgia family study]<ref>{{Cite journal|last=Zhang|first=Zhifang|last2=Feng|first2=Jinong|last3=Mao|first3=Allen|last4=Le|first4=Keith|last5=Placa|first5=Deirdre La|last6=Wu|first6=Xiwei|last7=Longmate|first7=Jeffrey|last8=Marek|first8=Claudia|last9=Amand|first9=R. Paul St|date=2018-06-21|title=SNPs in inflammatory genes CCL11, CCL4 and MEFV in a fibromyalgia family study|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198625|journal=PLOS ONE|language=en|volume=13|issue=6|pages=e0198625|doi=10.1371/journal.pone.0198625|issn=1932-6203|pmid=29927949|via=}}</ref><ref>{{Cite news|url=https://fibromyalgianewstoday.com/2018/07/03/immune-system-may-play-role-fibromyalgia-study/|title=Fibromyalgia May Be Linked to Immune System, Study Suggests|last=Inacio|first=Patricia|date=2018-07-03|work=Fibromyalgia News Today|access-date=2018-08-22|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

<blockquote>SNPs with significant TDTs were found in 36% of the cohort for CCL11 and 12% for MEFV, along with a protein variant in CCL4 (41%) that affects CCR5 down-regulation, supporting an immune involvement for FM.</blockquote>

*Jul 2018, [https://fibromyalgianewstoday.com/2018/07/31/primary-secondary-fibromyalgia-share-similar-symptom-burden-study/ Primary and Secondary Fibromyalgia Share Same Symptom Burden, Study Suggests]<ref name=":22">{{Cite news|url=https://fibromyalgianewstoday.com/2018/07/31/primary-secondary-fibromyalgia-share-similar-symptom-burden-study/|title=Primary, Secondary Fibromyalgia Share Same Symptom Burden, Study Says|last=Carvalho|first=John|date=2018-07-31|work=Fibromyalgia News Today|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

<blockquote>Fibromyalgia can be considered either primary, or dominant, also known as idiopathic fibromyalgia, or secondary. In the primary form, the causes of the disorder are unknown, but in secondary fibromyalgia, the disorder usually occurs alongside other debilitating medical conditions, such as rheumatoid arthritis (RA), lupus, and multiple sclerosis.<ref name=":22" /></blockquote>

===Immune system research===

Dr. [[Jarred Younger]] believes an overactive [[immune system]] is the cause and will be conducting a study to test this hypothesis.<ref>{{Cite news|url=http://nationalpainreport.com/new-uab-study-could-radically-change-fibromyalgia-treatment-as-we-know-it-8833437.html|title=New UAB Study Could Radically Change Fibromyalgia Treatment As We Know It|last=Gregory Burch|first=Donna|date=2017-04-24|work=National Pain Report|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref><ref>{{Cite web|url=https://www.youtube.com/watch?v=8e5xKX036bE|title=Testing the fibromyalgia immune system with lipopolysaccharide (LPS)|last=Younger|first=Jarred|date=May 24, 2017|website=YouTube|archive-url=|archive-date=|dead-url=|access-date=|via=Younger Lab}}</ref> An overactive immune system can cause [[inflammation]] and [[chronic pain]].<ref>{{Cite news|url=https://www.epainassist.com/autoimmune/what-is-overactive-immune-system|title=What is Overactive Immune System{{!}}Causes{{!}}Symptoms{{!}}Treatment|last=Kerkar|first=Pramod|date=2016-09-29|work=ePainAssist|access-date=2018-10-04|archive-url=|archive-date=|dead-url=|language=en-gb}}</ref><ref>{{Cite news|url=https://www.webmd.com/a-to-z-guides/autoimmune-diseases|title=Autoimmune Diseases|work=WebMD|access-date=2018-10-04|language=en-US}}</ref>

Dr. William Pridgen's research of [[HSV-1]] (cold sore virus) as being involved in FM has conducted a successful Phase III clinical trial, which had been fast-tracked by the [[Food and Drug Administration]] (FDA), of a combination drug that suppresses this virus and also helps with pain. {{See also|Fibromyalgia drugs|Fibromyalgia drugs (see drug trials section for IMC-1)||||}}

On September 5th, 2018, EpicGenetics announced that [http://www.massgeneral.org/ Massachusetts General Hospital] received approval from the FDA to test the [[wikipedia:BCG_vaccine|Bacille Calmette-Guerin (BCG) vaccine]] (an old Tuberculosis vaccine) on patients that tested positive with its FM/a® test.<ref>{{Cite news|url=http://nationalpainreport.com/can-an-existing-vaccine-help-treat-fibromyalgia-8837139.html|title=Can an Existing Vaccine Help Treat Fibromyalgia?|last=Coghlan|first=Ed|date=2018-09-05|work=National Pain Report|access-date=2018-09-10|archive-url=|archive-date=|dead-url=|language=en-US}}</ref><ref>{{Cite web|url=https://www.celestecooper.com/2018/07/the-fma-blood-test-and-participation-in.html#.Wz4nxdJKjIU|title=The FM/a® Blood Test and Participation in Fibromyalgia Vaccine Study|last=Cooper|first=Celeste|date=Jul 5, 2018|website=www.celestecooper.com|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref> <ref>{{Cite news|url=http://www.prohealth.com/library/showArticle.cfm?libid=30644|title=Century-old Vaccine Gives New Hope to Fibromyalgia Community - Prohealth|last=Gregory Burch|first=Donna|date=2017-08-14|work=Prohealth|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref><ref>{{Cite news|url=https://www.prohealth.com/library/century-old-vaccine-gives-new-hope-to-fibromyalgia-community-42689#comment-2286|title=Century-old Vaccine Gives New Hope to Fibromyalgia Community - Prohealth|last=Gregory Burch|first=Donna|date=2017-08-14|work=Prohealth|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|at=See Comments Section: CDW12 says: June 26, 2018 at 2:05 pm|language=en-US}}</ref><ref>{{Cite news|url=http://www.prohealth.com/library/showArticle.cfm?libid=30644|title=Century-old Vaccine Gives New Hope to Fibromyalgia Community - Prohealth|last=Gregory Burch|first=Donna|date=2017-08-14|work=Prohealth|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

Recognizing FM may involve activation of the [[immune system]] researchers performed [[Whole exome sequencing|exome sequencing]] on [[chemokine]] genes in a region of [[chromosome]] 17 identified in a genome-wide family association study. Their conclusion: "SNPs with significant TDTs were found in 36% of the cohort for ''CCL11'' and 12% for ''MEFV'', along with a protein variant in CCL4 (41%) that affects CCR5 down-regulation, supporting an immune involvement for FM."<ref name=":42">{{Cite journal|last=Zhang|first=Zhifang|last2=Feng|first2=Jinong|last3=Mao|first3=Allen|last4=Le|first4=Keith|last5=Placa|first5=Deirdre La|last6=Wu|first6=Xiwei|last7=Longmate|first7=Jeffrey|last8=Marek|first8=Claudia|last9=Amand|first9=R. Paul St|date=2018-06-21|title=SNPs in inflammatory genes CCL11, CCL4 and MEFV in a fibromyalgia family study|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198625|journal=PLOS ONE|language=en|volume=13|issue=6|pages=e0198625|doi=10.1371/journal.pone.0198625|issn=1932-6203|pmid=29927949|via=}}</ref>

=== Brain and spinal cord research ===
A 2004 study by Heffez et al. studied 270 patients with FM and found that 46% had [[cervical spinal stenosis]] and 20% [[chiari malformation]].<ref>{{Cite journal|last=Heffez|first=Dan S.|last2=Ross|first2=Ruth E.|last3=Shade-Zeldow|first3=Yvonne|last4=Kostas|first4=Konstantinos|last5=Shah|first5=Sagar|last6=Gottschalk|first6=Robert|last7=Elias|first7=Dean A.|last8=Shepard|first8=Alan|last9=Leurgans|first9=Sue E.|date=2004-04-09|title=Clinical evidence for cervical myelopathy due to Chiari malformation and spinal stenosis in a non-randomized group of patients with the diagnosis of fibromyalgia|url=https://link.springer.com/article/10.1007/s00586-004-0672-x|journal=European Spine Journal|language=en|volume=13|issue=6|pages=516–523|doi=10.1007/s00586-004-0672-x|issn=0940-6719|pmc=3476600|pmid=15083352|quote=|author-link=|author-link2=|author-link3=|author-link4=|author-link5=|via=}}</ref> In 2007, Heffez et al. saw significant improvement in physical and mental well-being was found in patients with cervical stenosis who received surgery.<ref>{{Cite journal|last=Heffez|first=Dan S.|last2=Ross|first2=Ruth E.|last3=Shade-Zeldow|first3=Yvonne|last4=Kostas|first4=Konstantinos|last5=Morrissey|first5=Mary|last6=Elias|first6=Dean A.|last7=Shepard|first7=Alan|date=2007|title=Treatment of cervical myelopathy in patients with the fibromyalgia syndrome: outcomes and implications|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2200733/|journal=European Spine Journal|volume=16|issue=9|pages=1423–1433|doi=10.1007/s00586-007-0366-2|issn=0940-6719|pmc=2200733|pmid=17426987|quote=|author-link=|author-link2=|author-link3=|author-link4=|author-link5=|via=}}</ref> A second study in 2007 by Andrew Holman found that 71% had cervical [[spinal cord]] compression.<ref>{{Cite journal|date=2008-07-01|title=Positional Cervical Spinal Cord Compression and Fibromyalgia: A Novel Comorbidity With Important Diagnostic and Treatment Implications|url=https://www.sciencedirect.com/science/article/pii/S1526590008004379|journal=The Journal of Pain|language=en|volume=9|issue=7|pages=613–622|doi=10.1016/j.jpain.2008.01.339|issn=1526-5900|last=|first=|quote=|author-link=Andrew Holman|author-link2=|author-link3=|author-link4=|author-link5=|via=}}</ref> It is important to note that in the past many patients were misdiagnosed with FM when further testing would have revealed the true source of their pain; the 2010 (updated in 2016) ACR criteria has helped curb misdiagnoses.<ref>{{Cite news|title=Fibromyalgia Expert Says Misdiagnosis is Rampant|url=http://nationalpainreport.com/fibromyalgia-expert-says-misdiagnosis-is-rampant-8832803.html|work=National Pain Report|date=2017-02-02|access-date=2018-11-26|language=en-US}}</ref><ref>{{Cite news|title=Common Misdiagnoses of Fibromyalgia|url=https://www.webmd.com/fibromyalgia/guide/common-misdiagnoses-of-fibromyalgia#|work=WebMD|access-date=2018-11-26|language=en-US|last=|first=|date=|archive-url=|archive-date=|dead-url=}}</ref><ref>{{Cite web|title=Fibromyalgia Misdiagnosis: What Else Could it Be?|url=https://www.integrativepractitioner.com/topics/news/fibromyalgia-misdiagnosis-what-else-could-it-be|website=www.integrativepractitioner.com|access-date=2018-11-26|language=en|date=Jun 6, 2016|last=|first=|archive-url=|archive-date=|dead-url=}}</ref><ref name=":28" />

Various types of brain imaging are being used to research FM. (''See'': [[Fibromyalgia notable studies]] for images.)

In 2002, an [[Functional magnetic resonance imaging|fMRI]] study conducted by Richard Gracely and Daniel Claw found people with FM "have measurable pain signals in their brains, from a gentle finger squeeze that barely feels unpleasant to people without the disease."<ref>{{Cite web|url=https://www.sciencedaily.com/releases/2002/06/020607073056.htm|title=Fibromyalgia Pain Isn't All In Patient's Heads, New Brain Study Finds|last=|first=|date=Jun 7, 2002|website=sciencedaily.com|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref> A 2007 study by Borsook et al., ''Neuroimaging revolutionizes therapeutic approaches to chronic pain'' found decreased [[gray matter]] density relative to controls in [[cingulate cortex]] (CC), medial [[prefrontal cortex]] (Med. PFC), [[parahippocampal gyrus]] (PHG) and [[insula]].<ref name=":03">{{Cite journal|last=Borsook|first=David|last2=Moulton|first2=Eric A|last3=Schmidt|first3=Karl F|last4=Becerra|first4=Lino R|date=2007-09-11|title=Neuroimaging Revolutionizes Therapeutic Approaches to Chronic Pain|url=https://link.springer.com/article/10.1186/1744-8069-3-25|journal=Molecular Pain|language=en|volume=3|issue=1|pages=1744–8069-3-25|doi=10.1186/1744-8069-3-25|issn=1744-8069|pmid=17848191|via=}}</ref> In 2015, Loggia et al. imaged [[neuroinflammation]] due to [[Glial cell|glial]] activation using [https://www.itnonline.com/article/mrpet-ultimate-imaging-hybrid MR/PET imaging]<ref>{{Cite news|url=https://www.itnonline.com/article/mrpet-ultimate-imaging-hybrid|title=MR/PET: The Ultimate Imaging Hybrid|last=Ros|first=Pablo R.|date=2012-05-29|work=Imaging Technology News|access-date=2018-10-30|archive-url=|archive-date=|dead-url=|language=en}}</ref>.<ref>{{Cite journal|last=Loggia|first=Marco L.|last2=Chonde|first2=Daniel B.|last3=Akeju|first3=Oluwaseun|last4=Arabasz|first4=Grae|last5=Catana|first5=Ciprian|last6=Edwards|first6=Robert R.|last7=Hill|first7=Elena|last8=Hsu|first8=Shirley|last9=Izquierdo-Garcia|first9=David|date=2015-01-08|title=Evidence for brain glial activation in chronic pain patients|url=https://academic.oup.com/brain/article/138/3/604/333527?searchresult=1|journal=Brain|language=en|volume=138|issue=3|pages=604–615|doi=10.1093/brain/awu377|issn=1460-2156}}</ref> In 2017, López-Solà et al. identified three [[brain]] patterns based on [[Functional magnetic resonance imaging|fMRI]] responses to pressure pain and non-painful multisensory stimulation. "These patterns, taken together, discriminate FM from matched healthy controls with 92% sensitivity and 94% specificity."<ref name=":34">{{Cite journal|last=López-Solà|first=Marina|last2=Woo|first2=Choong-Wan|last3=Pujol|first3=Jesus|last4=Deus|first4=Joan|last5=Harrison|first5=Ben J.|last6=Monfort|first6=Jordi|last7=Wager|first7=Tor D.|date=2017|title=Towards a neurophysiological signature for fibromyalgia|url=https://www.ncbi.nlm.nih.gov/pubmed/27583567|journal=Pain|volume=158|issue=1|pages=34–47|doi=10.1097/j.pain.0000000000000707|issn=1872-6623|pmid=27583567|via=}}</ref> In 2018, Albrecht et al used [[Positron emission tomography|PET]] scans to document [[Glial cell|glial]] activation.<ref name=":52">{{Cite journal|last=Albrecht|first=Daniel S.|last2=Forsberg|first2=Anton|last3=Sandstrom|first3=Angelica|last4=Bergan|first4=Courtney|last5=Kadetoff|first5=Diana|last6=Protsenko|first6=Ekaterina|last7=Lampa|first7=Jon|last8=Lee|first8=Yvonne C.|last9=Höglundi|first9=Caroline Olgart|date=2018-09-14|others=Catana, Ciprian; Cervenka, Simon; Akeju, Oluwaseun; Lekander, Mats; Cohen, George; Halldin, Christer; Taylor, Norman; Kim, Minhae; Hooker, Jacob M.; Loggia, Marco L.|title=Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation|url=https://www.sciencedirect.com/science/article/pii/S0889159118302423|journal=Brain, Behavior, and Immunity|language=en|volume=|pages=|doi=10.1016/j.bbi.2018.09.018|issn=0889-1591|via=}}</ref> Also in 2018, Martucci et al. found unbalanced activity between the ventral and dorsal cervical spinal cord. Ventral neural processes were increased and dorsal neural processes were decreased which may reflect the presence of [[central sensitization]] contributing to [[fatigue]] and other bodily symptoms in FM.<ref>{{Cite journal|last=Martucci|first=Katherine T|last2=Weber|first2=Kenneth A|last3=Mackey|first3=Sean C|date=2018-10-03|title=Altered Cervical Spinal Cord Resting State Activity in Fibromyalgia|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/art.40746|journal=Arthritis & Rheumatology|language=en|doi=10.1002/art.40746|issn=2326-5191}}</ref>

===Insulin resistance research ===
* May 2019, [https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216079Is insulin resistance the cause of fibromyalgia? A preliminary report]<ref name="a1cstudy">{{Cite journal|last=Pappolla|first=Miguel A.|last2=Manchikanti|first2=Laxmaiah|last3=Andersen|first3=Clark R.|last4=Greig|first4=Nigel H.|last5=Ahmed|first5=Fawad|last6=Fang|first6=Xiang|last7=Seffinger|first7=Michael A.|last8=Trescot|first8=Andrea M.|date=2019-05-06|title=Is insulin resistance the cause of fibromyalgia? A preliminary report|url=https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216079|journal=PLOS ONE|language=en|volume=14|issue=5|pages=e0216079|doi=10.1371/journal.pone.0216079|issn=1932-6203|pmc=PMC6502334|pmid=31059525}}</ref> [https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216079 (Full text)]
:Age-normalized data was found to show a relationship between insulin resistance/[[pre-diabetes]] and Fibromyalgia. In a preliminary study, Fibromyalgia patients were treated with [[metformin]], a common medication for diabetes, and showed a large improvement in [[myofascial pain]].

=== Fibromyalgia is not depression ===
* Oct 24, 2003, [https://www.webmd.com/depression/news/20031024/fibromyalgia-isnt-depression#1 Fibromyalgia Isn't Depression]<ref name=":40">{{Cite web|url=https://www.webmd.com/depression/news/20031024/fibromyalgia-isnt-depression|title=Fibromyalgia Isn't Depression|last=DeNoon|first=Daniel J.|authorlink=|last2=|first2=|authorlink2=|date=Oct 24, 2003|website=WebMD|language=en|archive-url=|archive-date=|dead-url=|access-date=2019-04-13}}</ref>
<blockquote>[[Depression]] doesn't cause the pain of fibromyalgia, a new study shows.<ref name=":40" /></blockquote>

<blockquote>"People still doubt fibromyalgia is a disease," Giesecke tells WebMD. "Previously, we found that fibromyalgia patients really do have increased central pain processing. Now we can show this is not affected by depression. Something is wrong here, and it is not at all connected with depression."<ref name=":40" /></blockquote>

<blockquote>"Giesecke's group looked at [[brain]] responses to painful stimuli, and then checked to see if there was any difference between depressed and nondepressed fibromyalgia patients. They showed the activation of areas of the brain related to pain were not different in patients with and without depression." But there is a difference between people with and without fibromyalgia, he says.<ref name=":40" /> </blockquote><blockquote>The researchers use an imaging device called [[functional magnetic resonance imaging]], or fMRI, to look at how the brain responds to pain. Study participants get a mildly painful pressure on their thumb, which makes the brain's pain centers "light up" on the image. Thumb pressure -- at a level healthy people hardly feel -- sets off a firestorm in the pain centers of fibromyalgia patients' brains.<ref>{{Cite web|url=https://www.webmd.com/depression/news/20031024/fibromyalgia-isnt-depression|title=Fibromyalgia Isn't Depression|last=DeNoon|first=Daniel J.|authorlink=|last2=|first2=|authorlink2=|date=Oct 24, 2003|website=WebMD|page=2|language=en|archive-url=|archive-date=|dead-url=|access-date=2019-04-13}}</ref></blockquote>
* Jun 30, 2013, [https://www.healthcentral.com/article/psychiatrists-admit-fibromyalgia-is-neuropathic-not-a-form-of-depression Psychiatrists Admit Fibromyalgia is Neuropathic - Not a Form of Depression]<ref name=":41">{{Cite web|url=https://www.healthcentral.com/article/psychiatrists-admit-fibromyalgia-is-neuropathic-not-a-form-of-depression|title=Psychiatrists Admit Fibromyalgia is Neuropathic – Not a Form of Depression - Causes - Chronic Pain {{!}} HealthCentral|last=Lee Richards|first=Karen|authorlink=|last2=|first2=|authorlink2=|date=Jun 30, 2013|website=www.healthcentral.com|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2019-04-13}}</ref>
<blockquote>The study the APA referred to was published in the June issue of [http://brain.oxfordjournals.org/content/136/6/1857.abstract ''Brain''], a journal of neurology. The researchers investigated the function and structure of small nerve fibers in 25 FM patients, 10 patients with monopolar depression without pain and with healthy control subjects. Using three different methods of testing, the researchers found that compared with control subjects, patients with fibromyalgia, but not patients with depression, had impaired small fiber function.<ref name=":41" /></blockquote><blockquote>The ''Psychiatric News'' alert quoted the study authors saying, "This strengthens the notion that fibromyalgia syndrome is not a variant of depression, but rather represents an independent entity that may be associated with depressive symptoms," the researchers said. Furthermore, the findings point "towards a neuropathic nature of pain in fibromyalgia syndrome."<ref name=":41" /></blockquote>
* Jan 10, 2019, [https://themighty.com/2019/01/do-i-have-fibromyalgia-or-depression/ 17 Signs You Have Fibromyalgia, Not 'Just' Depression]<ref name=":43">{{Cite web|url=https://themighty.com/2019/01/do-i-have-fibromyalgia-or-depression/|title=17 Signs You Have Fibromyalgia, Not 'Just' Depression|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=Jan 10, 2019|website=The Mighty|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2019-04-13}}</ref>
<blockquote>Fibromyalgia is [https://themighty.com/2018/05/what-fibromyalgia-gets-misdiagnosed-as/ often misdiagnosed as a number of other illnesses]. Though fibro has its own unique set of diagnostic criteria, many of its symptoms can mimic symptoms of other conditions – both physical and mental, acute and chronic.<ref name=":43" /></blockquote><blockquote>One of the most common conditions fibromyalgia gets mistaken for is depression. While each condition causes a unique set of symptoms, many of them may overlap. Like fibro, depression can cause physical symptoms such as pain, fatigue and brain fog. And living with a chronic physical symptoms can have significant effects on your mood, sometimes causing feelings of hopelessness, anxiety or general discontent – which are also symptoms of depression.<ref name=":43" /></blockquote>

== Comorbidities, overlapping conditions, and common symptoms ==
[[File:Fibromyalgia and comorbid conditions.JPG|700px|thumb|center|Comorbid conditions of fibromyalgia (FM) are [[ME/CFS]] which is the most common;<ref name=":30" /><ref name=":31" /> [[Autoimmune disease|autoimmune disease<nowiki/>s]]; [[Migraine|migraine<nowiki/>s]]; [[Multiple chemical sensitivity|multiple chemical sensitivities]] (MCS); and [[orthostatic intolerance]] (OI) / [[postural orthostatic tachycardia syndrome]] (POTS).<ref name=":30" /><ref name=":33">{{Cite news|url=https://www.verywellhealth.com/fibromyalgia-comorbid-overlapping-conditions-716184|title=Illness That Come Along with Fibromyalgia & Chronic Fatigue Syndrome|last=Dellwo|first=Adrienne|date=Feb 26, 2018|work=Verywell Health|access-date=2018-08-19|archive-url=|archive-date=|dead-url=}}</ref><ref name=":21" /><ref name=":44" /> Overlapping conditions are [[depression]] and [[anxiety]]; [[Digestive problems|digestive conditions]], [[Menstrual|menstrual problems]]; [[Gulf War Illness]] (GWI); [[nervous system]] disorders; [[Hypotension|low blood pressure]] (Low BP); [[Pain#Pain in Fibromyalgia|other pain conditions]]; and [[sleep dysfunction]]/disturbance<ref name=":30" /> <ref name=":33" /><ref name=":21" /><ref name=":05" /><ref name=":46" /><ref name=":47" />]]

*[[Allodynia]]
** [http://chronicfatigue.about.com/od/glossary/g/allodynia.htm Allodynia: A Rare & Distinct Type of Pain in Fibromyalgia & ME/CFS]<ref name=":1">{{Cite news|url=https://www.verywellhealth.com/allodynia-definition-and-types-fibromyalgia-715929|title=Allodynia: A Rare & Distinct Type of Pain in Fibromyalgia & ME/CFS|last=Dellwo|first=Adrienne|date=Feb 23, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref> Types of Allodynia: Tactile; Mechanical; and Thermal. "Type of pain, generally on the skin, that's caused by something that wouldn't normally cause pain."<ref name=":1" />
*[[Autoimmune disease]]<nowiki/>s "Research suggests that RA and other inflammatory diseases may somehow increase the risk for fibromyalgia."<ref>{{Cite news|url=https://www.health.com/health/gallery/0,,20520705,00.html#restless-legs-0|title=7 Conditions Linked to Fibromyalgia|work=Health.com|access-date=2018-08-19|language=en}}</ref>

*[[Body temperature]] (''See:'' [[small fiber peripheral neuropathy]] for temperature sensitivity; burning, tingling, and prickling due to [[paresthesia]]; [[numbness]]; [[Dry eye syndrome|dry eyes]] and [[dry mouth]]; and more.)<ref>{{Cite news|url=https://www.verywellhealth.com/small-fiber-neuropathy-may-cause-fibromyalgia-pain-3972935|title=Does Fibromyalgia Come From Small Nerves in Your Skin?|last=Dellwo|first=Adrienne|date=Feb 23, 2018|work=Verywell Health|access-date=2018-10-04|archive-url=|archive-date=|dead-url=}}</ref><ref>{{Cite news|url=https://www.verywellhealth.com/neuropathy-in-fibromyalgia-cfs-3973033|title=Does Your Pain Come From Damage to Small Nerves?|last=Dellwo|first=Adrienne|date=Feb 1, 2018|work=Verywell Health|access-date=2018-10-04|archive-url=|archive-date=|dead-url=}}</ref><ref name=":02">{{Cite news|url=https://www.healthline.com/health/small-fiber-neuropathy#symptoms|title=Small Fiber Neuropathy: Symptoms, Treatment, Causes, and More|last=Vandergriendt|first=Carly|date=Jan 4, 2018|work=Healthline|access-date=2018-10-04|archive-url=|archive-date=|dead-url=|last2=Weatherspoon|first2=Deborah|language=en}}</ref><ref>{{Cite news|url=https://www.webmd.com/brain/understanding-peripheral-neuropathy-basics#3|title=Peripheral Neuropathy -- Symptoms, Types, and Causes of Peripheral Neuropathy|last=|first=|date=|work=WebMD|access-date=2018-10-04|archive-url=|archive-date=|dead-url=|page=3|language=en-US}}</ref>
**[https://www.verywell.com/temperature-sensitivity-in-fibromyalgia-and-mecfs-716025 Temperature Sensitivity in Fibromyalgia & Chronic Fatigue Syndrome]<ref name=":2">{{Cite news|url=https://www.verywellhealth.com/temperature-sensitivity-in-fibromyalgia-and-mecfs-716025|title=Temperature Sensitivity in Fibromyalgia & ME/CFS|last=Dellwo|first=Adrienne|date=Mar 15, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref>

<blockquote>When you're exposed to heat, does it feel like you're burning up? Does it seem impossible for you to cool off? Or maybe it's cold that bothers you, chilling you to the bone, leaving you unable to warm up? Or are you one of those people with fibromyalgia (FMS) and chronic fatigue syndrome (ME/CFS) who is cold all the time, or hot all the time, or alternately hot or cold while out of sync with the environment?<ref name=":2" /></blockquote>

[[File:Costal cartilages.JPG|200px|thumb|left|Costochondritis is inflammation of the costal cartilages (shown in red) causing chest and ribcage pain. From BodyParts3D/Anatomography (Life Science db.jp), license CC BY-SA 2.1 JP.]]

:* [[Costochondritis]] - What You Need To Know<ref name=":10">{{Cite web|url=https://www.drugs.com/cg/costochondritis.html|title=Costochondritis - What You Need to Know|website=Drugs.com|language=en|access-date=2020-01-27}}</ref>
<blockquote>Costochondritis is a condition that causes pain in the cartilage that connect your ribs to your sternum (breastbone). Cartilage is the tough, bendable tissue that protects your bones where they rub against each other.</blockquote>Costochondritis causes pain in the area where your sternum joins with your ribs. The pain may come and go, and may get worse over time. The pain may be sharp, or dull and aching. It may be painful to touch your chest. The pain may spread to your back, abdomen, or down your arm. It may get worse when you move, breathe deeply, or push or lift an object. The pain may make it hard for you to sleep or do your usual activities.<ref name=":10" /><blockquote>People tend to describe the pain as stabbing, burning, aching, confined to one spot, usually in the very center of the chest, but it may radiate outward.<ref>{{Cite web|url=https://www.medicalnewstoday.com/articles/321635.php|title=Can fibromyalgia cause chest pain?|website=Medical News Today|language=en|access-date=2020-01-27}}</ref></blockquote>

* [[Depression]] and [[Anxiety]]

Fibromyalgia sufferers are "up to three times more likely to have depression at the time of their diagnosis than someone without fibromyalgia."<ref>{{Cite news|url=https://www.webmd.com/fibromyalgia/fibromyalgia-and-depression#1|title=Fibromyalgia and Depression|work=WebMD|access-date=2018-08-19|language=en-US}}</ref> Up to 20 percent of FM patients will have either depression or anxiety.<ref>{{Cite web|url=https://adaa.org/understanding-anxiety/related-illnesses/other-related-conditions/fibromyalgia|title=Fibromyalgia {{!}} Anxiety and Depression Association of America, ADAA|website=adaa.org|language=en|access-date=2018-08-19}}</ref>
* [[Dry eye syndrome]]
** [https://www.news-medical.net/health/Fibromyalgia-and-Dry-Eyes-and-Mouth.aspx Fibromyalgia and Dry Eyes and Mouth]<ref name=":110">{{Cite news|url=https://www.news-medical.net/health/Fibromyalgia-and-Dry-Eyes-and-Mouth.aspx|title=Fibromyalgia and Dry Eyes and Mouth|last=Mandal|first=Ananya|date=2013-06-30|work=News-Medical.net|access-date=2018-10-04|archive-url=|archive-date=|dead-url=|last2=Cashin-Garbutt|first2=April|language=en}}</ref>

* [[Fatigue]]
** [https://www.docsopinion.com/2017/11/08/causes-fatigue-tiredness-chronic-fatigue/ 19 Important Causes of Fatigue – Tiredness and Chronic Fatigue Explained]<ref name=":29">{{Cite web|url=https://www.docsopinion.com/2017/11/08/causes-fatigue-tiredness-chronic-fatigue/|title=19 Important Causes of Fatigue - Tiredness and Chronic Fatigue Explained|website=www.docsopinion.com|access-date=2019-01-30}}</ref> ''See'': 3. Fibromyalgia <blockquote>Fatigue is a universal symptom of fibromyalgia. It is often most marked when arising from sleep in the morning. A typical quote is “''No matter how much sleep I get, it feels like a truck ran me over in the morning'' (20).” Minor activities often seem to aggravate the fatigue.<ref name=":29" /></blockquote>

*[[Fibro fog]] and [[Cognitive dysfunction]]

:*[http://www.news-medical.net/health/What-is-Fibro-Fog-Fibromyalgia-and-Cognitive-Dysfunction.aspx What is Fibro Fog? - Fibromyalgia and Cognitive Dysfunction]<ref name=":3">{{Cite news|url=https://www.news-medical.net/health/What-is-Fibro-Fog-Fibromyalgia-and-Cognitive-Dysfunction.aspx|title=What is Fibro Fog? - Fibromyalgia and Cognitive Dysfunction|last=Mandal|first=Ananya|date=2013-06-03|work=News-Medical.net|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en}}</ref> 'Mental confusion along with difficulty in concentration and loss of memory is often termed “[[fibro fog]]"'.<ref name=":3" />

:* [https://www.verywellhealth.com/brain-fibro-fog-causes-symptoms-possible-treatment-716014 What Is Fibro Fog and ME/CFS Brain Fog?]<ref name=":17" />
:* [https://fibromyalgianewstoday.com/2018/03/21/fibromyalgia-cognitive-dysfunction-study-identifies-main-types/ Study Identifies the Types of Cognitive Dysfunction That Are Most Prevalent in Fibromyalgia]<ref>{{Cite news|url=https://fibromyalgianewstoday.com/2018/03/21/fibromyalgia-cognitive-dysfunction-study-identifies-main-types/|title=Fibromyalgia Study Identifies Main Types of Patients' Cognitive Dysfunction|last=Pena|first=Ana|date=2018-03-21|work=Fibromyalgia News Today|access-date=2018-08-28|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

*[[Gastrointestinal system]]
**[[Irritable bowel syndrome]]: [http://chronicfatigue.about.com/od/whyfmscfsarelinked/a/IBS.htm Irritable Bowel Syndrome in Fibromyalgia & Chronic Fatigue Syndrome - Why Do They Go Together?]<ref name=":4">{{Cite news|url=https://www.verywellhealth.com/irritable-bowel-syndrome-in-fibromyalgia-cfs-716167|title=Irritable Bowel Syndrome in Fibromyalgia & ME/CFS|last=Dellwo|first=Adrienne|date=Jan 28, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref>

:<blockquote>Fibromyalgia, chronic fatigue syndrome and irritable bowel syndrome (IBS) frequently go together. No one really knows why, but we do know that all three conditions can include imbalances of serotonin -- although in fibromyalgia (FMS) and Chronic Fatigue Syndrome (CFS or ME/CFS) it's an imbalance in the brain, while with IBS it's in the gut.<ref name=":4" /></blockquote>
* [[Gulf War Illness]]
**[https://www.publichealth.va.gov/exposures/gulfwar/fibromyalgia.asp Fibromyalgia in Gulf War Veterans]<ref>{{Cite web|url=https://www.publichealth.va.gov/exposures/gulfwar/fibromyalgia.asp|title=Fibromyalgia in Gulf War Veterans - Public Health|last=Administration|first=US Department of Veterans Affairs, Veterans Health|website=www.publichealth.va.gov|language=en|access-date=2018-08-19}}</ref> GWI increases risk of developing fibromyalgia.

*[https://en.wikipedia.org/wiki/Interstitial_cystitis Interstitial Cystitis](Painful bladder)
**[https://www.verywellhealth.com/chronic-fatigue-syndrome-interstitial-cystitis-716168 Fibromyalgia, Chronic Fatigue Syndrome & Interstitial Cystitis]<ref name=":5">{{Cite news|url=https://www.verywellhealth.com/chronic-fatigue-syndrome-interstitial-cystitis-716168|title=Fibromyalgia, Chronic Fatigue Syndrome & Interstitial Cystitis|last=Dellwo|first=Adrienne|date=Feb 16, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref> "Fibromyalgia, chronic fatigue syndrome and interstitial cystitis (IC) -- a painful bladder condition -- frequently occur together. Women may be up to 10 times more likely than men to develop it."<ref name=":5" />
**[[pubmed:20719340|Interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome.]]<ref>{{Cite journal|last=Nickel|first=J. Curtis|last2=Tripp|first2=Dean A.|last3=Pontari|first3=Michel|last4=Moldwin|first4=Robert|last5=Mayer|first5=Robert|last6=Carr|first6=Lesley K.|last7=Doggweiler|first7=Ragi|last8=Yang|first8=Claire C.|last9=Mishra|first9=Nagendra|date=2010|title=Interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20719340|journal=The Journal of Urology|volume=184|issue=4|pages=1358–1363|doi=10.1016/j.juro.2010.06.005|issn=1527-3792|pmid=20719340|via=}}</ref>

*Language Impairment
**[[Word-finding problems]]
:*[https://www.verywellhealth.com/language-impairment-in-fibromyalgia-cfs-716024 Language Impairment in Fibromyalgia and Chronic Fatigue Syndrome Impaired Language in Fibromyalgia & Chronic Fatigue Syndrome]<ref name=":6" /> "Searching their brains for simple words that they just can't remember. On other occasions, individuals with these diagnoses may find it hard to write or even understand language."<ref name=":6">{{Cite news|url=https://www.verywellhealth.com/language-impairment-in-fibromyalgia-cfs-716024|title=Language Impairment in Fibromyalgia and Chronic Fatigue Syndrome|last=Dellwo|first=Adrienne|date=Feb 12, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref>

:*"The diagnosis of [[Aphasia]] is a condition that robs you of the ability to communicate. It can affect your ability to speak, write and understand language, both verbal and written"<ref>{{Cite news|url=http://www.mayoclinic.org/diseases-conditions/aphasia/basics/definition/con-20027061|title=Aphasia - Symptoms and causes|work=Mayo Clinic|access-date=2018-08-09|language=en}}</ref> but with [[dysphasia]] you will have those symptoms and trouble listening and doing numeral calculations.<ref>{{Cite web|url=http://www.ayushveda.com/healthcare/dysphasia.htm|title=Dysphasia - Causes, Symptoms & Treatment|website=www.ayushveda.com|access-date=2018-08-09}}</ref> ''See also'': [[Dyscalculia]].
* [[ME/CFS]]
:*[https://www.verywellhealth.com/fibromyalgia-comorbid-overlapping-conditions-716184 Comorbid Conditions in Fibromyalgia & Chronic Fatigue Syndrome]<ref>{{Cite news|url=https://www.verywellhealth.com/fibromyalgia-comorbid-overlapping-conditions-716184|title=Illness That Come Along with Fibromyalgia & Chronic Fatigue Syndrome|last=Dellwo|first=Adrienne|date=Feb 26, 2018|work=Verywell Health|access-date=2018-08-19|archive-url=|archive-date=|dead-url=}}</ref><ref name=":30" /><ref name=":36" />
* [[Migraine]]
:*[https://migrainecenters.com/blog/migraines-and-fibromyalgia/ Migraines and Fibromyalgia]<ref name=":32" />
<blockquote>Both fibromyalgia and migraine may reflect problems in the brain’s pain processing center. It is believed that both conditions are caused by excitation of the nervous system or an over-response to stimuli. Stress is usually cited as a trigger for both migraine and fibromyalgia attacks.<ref name=":32">{{Cite news|url=https://migrainecenters.com/blog/migraines-and-fibromyalgia/|title=Migraines and Fibromyalgia - Migraine Centers|date=2016-05-06|work=Migraine Centers|access-date=2018-08-19|language=en-US}}</ref></blockquote>
* [[Multiple chemical sensitivity|Multiple Chemical Sensitivity]] (MCS) It is thought that both Fibromyalgia and MCS are [[Central sensitization|central sensitivity]] syndromes.<ref>{{Cite news|url=https://www.verywellhealth.com/chemical-sensitivity-in-fibromyalgia-716170|title=Multiple Chemical Sensitivity in Fibromyalgia & ME/CFS|last=Dellwo|first=Adrienne|date=Jul 23, 2018|work=Verywell Health|access-date=2018-08-19|archive-url=|archive-date=|dead-url=}}</ref>

*OBGYN
**[https://www.verywellhealth.com/menstrual-periods-and-fibromyalgia-715596 Menstrual Periods with Fibromyalgia: Personal Stories]<ref>{{Cite news|url=https://www.verywellhealth.com/menstrual-periods-and-fibromyalgia-715596|title=Menstrual Periods with Fibromyalgia: Personal Stories|last=Dellwo|first=Adrienne|date=May 18, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref>
**[https://www.verywellhealth.com/fibromyalgia-tied-to-hysterectomy-gynecologic-disease-715626 Fibromyalgia Tied to Hysterectomy, Gynecologic Disease].<ref name=":7" />
:<blockquote>You may have heard about a possible link between gynecologic surgery (such as a hysterectomy) and the development of fibromyalgia, and doctors have long suspected that fibromyalgia has strong hormonal ties and triggers. This does not seem surprising as we've long suspected a link between endocrine disorders, gynecological conditions, and autoimmune conditions.<ref name=":7">{{Cite news|url=https://www.verywellhealth.com/fibromyalgia-tied-to-hysterectomy-gynecologic-disease-715626|title=Fibromyalgia Tied to Hysterectomy, Gynecologic Disease|last=Dellwo|first=Adrienne|date=Feb 16, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref></blockquote>

*[[Orthostatic intolerance]] (OI) and [[Postural orthostatic tachycardia syndrome]] (POTS)<ref name=":44">{{Cite journal|last=Yun|first=Dong Joo|last2=Choi|first2=Han Na|last3=Oh|first3=Gun-Sei|date=2013|title=A Case of Postural Orthostatic Tachycardia Syndrome Associated with Migraine and Fibromyalgia|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710947/|journal=The Korean Journal of Pain|volume=26|issue=3|pages=303–306|doi=10.3344/kjp.2013.26.3.303|issn=2005-9159|pmid=23862007|via=}}</ref>

:*[http://drlapp.com/wp-content/uploads/TTT_symptoms.pdf Symptoms Predict the Outcome of Tilt Table Testing in CFS/ME/FM]<ref>{{Cite web|url=http://drlapp.com/wp-content/uploads/TTT_symptoms.pdf|title=Symptoms Predict the Outcome of Tilt Table Testing in CFS/ME/FM|last=Lapp|first=Charles W.|last2=Black|first2=Laura|date=|website=drlapp.com|archive-url=|archive-date=|dead-url=|access-date=|last3=Smith|first3=Rebekah S.}}</ref> (PDF) Symptoms can include low blood pressure and/or sudden high blood pressure, dizziness, fainting.

:*[https://www.healthrising.org/blog/2017/09/21/fibromyalgia-problems-standing-orthostatic-intolerance/ An Overlooked Issue in Fibromyalgia? Study Highlights Problems Standing (Orthostatic Intolerance)]<ref>{{Cite news|url=https://www.healthrising.org/blog/2017/09/21/fibromyalgia-problems-standing-orthostatic-intolerance/|title=An Overlooked Issue in Fibromyalgia? Study Highlights Orthostatic Intolerance - Problems Standing - Health Rising|last=Johnson|first=Cort|date=2017-09-21|work=Health Rising|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>
* [[Raynaud's Syndrome]]
** [https://www.verywellhealth.com/raynauds-syndrome-chronic-fatigue-716185 Raynaud's Syndrome in Fibromyalgia & Chronic Fatigue Syndrome]<ref name=":04">{{Cite news|url=https://www.verywellhealth.com/raynauds-syndrome-chronic-fatigue-716185|title=Cold Hands & Feet? Raynaud's Syndrome in Fibromyalgia & ME/CFS|last=Dellwo|first=Adrienne|date=Jan 28, 2018|work=Verywell Health|access-date=2018-10-11|archive-url=|archive-date=|dead-url=}}</ref> <blockquote>In Raynaud's syndrome, the blood vessels constrict more than they should, which allows less blood to get through. That not only makes your extremities cold, it makes them extremely difficult to warm up. The most commonly affected body parts are the fingers and toes, but your lips, nose, ear lobes, knees, and nipples may also be involved.</blockquote><blockquote>Raynaud's isn't all about the cold, though. The diminished blood flow can cause pain in the affected areas, and it may also cause the skin there to turn blue. Skin ulcers (sores) are possible, since prolonged episodes of low blood flow can damage your tissues.<ref name=":04" /></blockquote>

*[[Sleep dysfunction]]
**[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648619/ Sleep is associated with task-negative brain activity in fibromyalgia participants with comorbid chronic insomnia]<ref name=":23">{{Cite journal|last=Vatthauer|first=Karlyn E|last2=Craggs|first2=Jason G|last3=Robinson|first3=Michael E|last4=Staud|first4=Roland|last5=Berry|first5=Richard B|last6=Perlstein|first6=William M|last7=McCrae|first7=Christina S|date=2015-11-12|title=Sleep is associated with task-negative brain activity in fibromyalgia participants with comorbid chronic insomnia|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648619/|journal=Journal of Pain Research|volume=8|pages=819–827|doi=10.2147/JPR.S87501|issn=1178-7090|pmc=|pmid=26648751|via=|issue=|quote=|author-link=|author-link2=|author-link3=|author-link4=Roland Staud|author-link5=}}</ref>

:<blockquote>The present results of this study suggest that long-term, comorbid pain and sleep disturbance may be associated with increased activation in core default mode brain areas that is above and beyond long-term pain disturbance alone.<ref name=":23" /></blockquote>

:*[http://www.prohealth.com/library/showarticle.cfm?libid=22344 Fibromyalgia and Sleep]<ref name=":8">{{Cite news|url=https://www.prohealth.com/library/fibromyalgia-and-sleep-38954|title=Fibromyalgia and Sleep - Prohealth|date=2016-01-11|work=Prohealth|access-date=2018-08-09|language=en-US}}</ref> "Most people with fibromyalgia have an associated sleep disorder that makes it difficult for them to get the deep, restorative sleep they need."<ref name=":8" />

[[File:Skull_diagram.png|350px|thumb|right|The [[wikipedia:Temporomandibular_joint#Disorders|temporomandibular joint]] is the joint between the mandible (light blue) and the temporal bone (orange) of the skull]]
* [[Temporomandibular joint disorder]] (TMJ/TMD)

:* [https://www.sciencedirect.com/science/article/pii/S2255502114001758 Temporomandibular disorders in fibromyalgia syndrome: a short-communication]<ref>{{Cite journal|last=Soares Gui|first=Maisa|last2=Pimentel|first2=Marcele Jardim|last3=Rizzatti-Barbosa|first3=C'elia Marisa|date=2015-03-01|title=Temporomandibular disorders in fibromyalgia syndrome: a short-communication|url=https://www.sciencedirect.com/science/article/pii/S2255502114001758|journal=Revista Brasileira de Reumatologia (English Edition)|language=en|volume=55|issue=2|pages=189–194|doi=10.1016/j.rbre.2014.07.004|issn=2255-5021|via=ScienceDirect}}</ref><ref>{{Cite news|url=https://www.whitesmilesforlife.com/blog/study-probes-pain-link-between-tmj-fibromyalgia/|title=Study Probes Pain Link Between TMJ, Fibromyalgia|date=2016-05-03|work=Kent E. White, DDS|access-date=2018-08-19|language=en-US}}</ref>

:Other than headaches, the symptoms are quite distinct from symptoms of FMS and ME/CFS.

::They include:
::*Jaw pain
::*Discomfort or difficulty chewing
::*Painful clicking in the jaw
::*Difficulty opening or closing the mouth
::*Headaches
::*Locking jaw
::*Teeth that don't come together properly<ref>{{Cite news|url=https://www.verywellhealth.com/tmj-in-fibromyalgia-chronic-fatigue-syndrome-716175|title=TMJ in Fibromyalgia and Chronic Fatigue Syndrome|last=Dellwo|first=Adrienne|date=Mar 31, 2018|work=Verywell Health|access-date=2018-08-22|archive-url=|archive-date=|dead-url=}}</ref>

*[[Thyroid disease]]
**[https://www.verywellhealth.com/relationship-between-cfs-fibromyalgia-and-aitd-3231677 Chronic Fatigue Syndrome, Fibromyalgia, and Autoimmune Thyroid Disease]<ref name=":9">{{Cite news|url=https://www.verywellhealth.com/relationship-between-cfs-fibromyalgia-and-aitd-3231677|title=A Comparison of Chronic Fatigue, Fibromyalgia, and Thyroid Disease|last=Shomon|first=Mary|date=Feb 21, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref>

:<blockquote>People with Hashimoto's autoimmune thyroid disease often experience significant fatigue and body aches. While these symptoms are common in Hashimoto's, they can also be markers of other diseases, like chronic fatigue syndrome or fibromyalgia.<ref name=":9" /></blockquote>

*Other symptoms
**[http://chronicfatigue.about.com/od/whatisfibromyalgia/a/fibrosymptoms.htm Symptoms of Fibromyalgia]<ref>{{Cite news|url=https://www.verywellhealth.com/fibromyalgia-symptoms-716139|title=Symptoms of Fibromyalgia|last=Dellwo|first=Adrienne|date=May 16, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref> (On all the many symptoms and conditions of and related to fibromyalgia.)
**''Fibromyalgia Syndrome: An Overview of Pathophysiology, Diagnosis and Management'' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394355/ Conditions associated with fibromyalgia. (Table 1)]<ref name=":21" />

==Treatment==

===United States===
'''Rheumatology and primary care providers: Diagnosing and treatment'''

*2012, [https://www.mayoclinicproceedings.org/article/S0025-6196(12)00299-6/abstract A Framework for Fibromyalgia Management for Primary Care Providers]<ref>{{Cite journal|last=Arnold|first=Lesley M.|last2=Clauw|first2=Daniel J.|last3=Dunegan|first3=L. Jean|last4=Turk|first4=Dennis C.|date=2012|title=A Framework for Fibromyalgia Management for Primary Care Providers|url=https://www.mayoclinicproceedings.org/article/S0025-6196(12)00299-6/abstract|journal=Mayo Clinic Proceedings|language=English|volume=87|issue=5|pages=488–496|doi=10.1016/j.mayocp.2012.02.010|issn=0025-6196|via=}}</ref> Rheumatologists stopped treating fibromyalgia patients and primary care providers began treatment managment although rheumatologists are most often the specialist to diagnose. (Please see [http://me-pedia.org/wiki/Fibromyalgia#Disability disability] heading about ''primary provider'' and ''specialists'' for disability cases.)

=== '''Drugs (See main article link below)''' ===
{{Main article |page_name = Fibromyalgia drugs}}

=== Therapies ===

==== Exercise ====
''Please Note'': These treatments are for fibromyalgia patients and '''not''' [[ME/CFS]] sufferers due to it's hallmark symptom of [[post-exertional malaise]].
[[File:Warm water exercise.JPG|200px|thumb|left|Warm water exercise is best for fibromyalgia. Start slow and don't push through the pain<ref name=":11" />]]

*[https://www.verywellhealth.com/warm-water-exercise-for-fibromyalgia-716059 Warm Water Exercise for Fibromyalgia]<ref name=":11">{{Cite news|url=http://chronicfatigue.about.com/od/treatingfmscfs/a/warmwaterFMS.htm|title=Warm Water Exercise for Fibromyalgia|last=Dellwo|first=Adrienne|date=Nov 19, 2017|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref><ref>{{Cite journal|last=Munguía-Izquierdo|first=D.|last2=Legaz-Arrese|first2=A.|date=2007|title=Exercise in warm water decreases pain and improves cognitive function in middle-aged women with fibromyalgia|url=https://www.ncbi.nlm.nih.gov/pubmed/18173915|journal=Clinical and Experimental Rheumatology|volume=25|issue=6|pages=823–830|issn=0392-856X|pmid=18173915|via=}}</ref><ref>{{Cite news|url=https://www.prohealth.com/fibromyalgia/library/aquatic-exercise-training-fibromyalgia-85081?utm_campaign=Social%20Media%20-%20Fibromyalgia&utm_content=76595810&utm_medium=social&utm_source=twitter|title=Aquatic exercise training for fibromyalgia. - Prohealth|date=2018-08-29|work=Prohealth|access-date=2018-09-01|language=en-US}}</ref><ref>{{Cite journal|last=Bidonde|first=Julia|last2=Busch|first2=Angela J.|last3=Webber|first3=Sandra C.|last4=Schachter|first4=Candice L.|last5=Danyliw|first5=Adrienne|last6=Overend|first6=Tom J.|last7=Richards|first7=Rachel S.|last8=Rader|first8=Tamara|date=2014-10-28|title=Aquatic exercise training for fibromyalgia|url=https://www.ncbi.nlm.nih.gov/pubmed/25350761|journal=The Cochrane Database of Systematic Reviews|issue=10|pages=CD011336|doi=10.1002/14651858.CD011336|issn=1469-493X|pmid=25350761}}</ref>

<blockquote>Several studies have found that warm-water pool exercise is a beneficial treatment for fibromyalgia. A very large survey of patients found that 26% have used pool therapy, rating it as very effective.<ref name=":45">{{Cite journal|last=Bennett|first=Robert M.|author-link=Robert Bennett|last2=Jones|first2=Jessie|author-link2=Jessie Jones|last3=Turk|first3=Dennis C.|author-link3=Dennis Turk|last4=Russell|first4=I. Jon|author-link4=I. Jon Russell|last5=Matallana|first5=Lynne|author-link5=Lynne Matallana|date=Mar 9, 2007|title=An internet survey of 2,596 people with fibromyalgia|url=https://doi.org/10.1186/1471-2474-8-27|journal=BMC Musculoskeletal Disorders|volume=8|issue=1|pages=27|doi=10.1186/1471-2474-8-27|issn=1471-2474|pmc=1829161|pmid=17349056|quote=|via=}}</ref> The same survey found 74% of patients found heat helpful - either warm water or heat packs.<ref name=":45" /> Warm water especially important in FMS because many people with the condition are intolerant of cold. A warm-water pool is one that's kept around 89.6 degrees Fahrenheit (32 Celsius), which is several degrees warmer than most heated pools.<ref name=":11" /></blockquote>

* Moderate aerobic exercise and weights with six to eight reps and then a day or two of rest in between. Do not start a program if you are in a flare.<ref>{{Cite web|url=http://www.arthritis.org/living-with-arthritis/tools-resources/expert-q-a/fibromyalgia-questions/fibromyalgia-exercise.php|title=Fibromyalgia Exercise {{!}} Exercising with Fibromyalgia|last=Ronenn|first=Roubenoff|date=|website=www.arthritis.org|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref>

*[https://www.youtube.com/watch?v=BauJYuJwFsI Easy fibromyalgia exercises and motivation to keep you healthy!]<ref>{{Cite web|url=https://www.youtube.com/watch?v=BauJYuJwFsI|title=Easy Fibromyalgia exercises and motivation to keep you healthy!|last=Suarez|first=Eric|date=Jun 21, 2011|website=YouTube|archive-url=|archive-date=|dead-url=|access-date=Aug 9, 2018}}</ref> Video

*[http://chronicfatigue.about.com/od/whatisfibromyalgia/a/Fibromyalgia-Myth-Vs-Fact.htm Fibromyalgia Myth vs. Fact]<ref name=":15">{{Cite news|url=https://www.verywellhealth.com/fibromyalgia-myth-vs-fact-716131|title=Fibromyalgia: What's Myth, What's Fact?|last=Dellwo|first=Adrienne|date=Jun 8, 2016|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|at=Myth #3 People With Fibromyalgia Need More Exercise}}</ref> Heading: ''Myth #3: People With Fibromyalgia Need More Exercise''. Appropriate exercise, which each patient needs to gauge for themselves.<ref name=":15" />

==== Massage ====

*2014, [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930706/ Massage Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials]<ref>{{Cite journal|last=Li|first=Yan-hui|last2=Wang|first2=Feng-yun|last3=Feng|first3=Chun-qing|last4=Yang|first4=Xia-feng|last5=Sun|first5=Yi-hua|date=2014-02-20|title=Massage Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930706/|journal=PLoS ONE|volume=9|issue=2|doi=10.1371/journal.pone.0089304|issn=1932-6203|pmc=|pmid=24586677|pages=|via=}}</ref>

*2016, [http://chronicfatigue.about.com/od/alternativetreatments/a/bodywork.htm Massage, Rolfing & Other Bodywork - Are They Effective Fibromyalgia & Chronic Fatigue Syndrome Treatments?]<ref>{{Cite news|url=https://www.verywellhealth.com/massage-rolfing-other-bodywork-715645|title=Massage, Rolfing, Reiki: Do They Work for Fibromyalgia & ME/CFS?|last=Dellwo|first=Adrienne|date=Aug 10, 2017|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref>

==== Acupuncture ====

*2004, [[U.S. Department of Health and Human Services]] (HHS) and [https://en.wikipedia.org/wiki/Centers_for_Medicare_and_Medicaid_Services Centers for Medicare and Medicaid Services] (CMS) ruled April 16, 2004, a noncoverage determination for acupuncture.<ref>{{Cite web|url=https://www.cms.gov/Regulations-and-Guidance/Guidance/Transmittals/downloads/R11NCD.pdf|title=CMS Manual System Pub. 100-03 Medicare National Coverage Determinations|last=|first=|date=Apr 16, 2004|website=CMS.gov|format=PDF|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

*2005, [http://acupunctureschoolonline.com/acupuncture-good-for-fibromyalgia.html Acupuncture Good for Fibromyalgia?] <ref name=":16">{{Cite web|url=http://acupunctureschoolonline.com/acupuncture-good-for-fibromyalgia.html|title=Acupuncture Good for Fibromyalgia?|last=|first=|date=Oct 2, 2012|website=Acupuncture School Online|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref> "Acupuncture gave no significant pain relief to fibromyalgia patients."<ref name=":16" />

*2016, [http://www.sciencedirect.com/science/article/pii/S2095496416602352 Short-term complementary and alternative medicine on quality of life in women with fibromyalgia] <ref name=":25">{{Cite journal|date=2016-01-01|title=Short-term complementary and alternative medicine on quality of life in women with fibromyalgia|url=https://www.sciencedirect.com/science/article/pii/S2095496416602352|journal=Journal of Integrative Medicine|language=en|volume=14|issue=1|pages=29–35|doi=10.1016/S2095-4964(16)60235-2|issn=2095-4964}}</ref> "There was no significant improvement in pain or reduction of tender points in any of the groups studied, at the end of the 8th session."<ref name=":25" />

*2016, [https://fibromyalgianewstoday.com/2016/02/01/acupuncture-does-not-reduce-pain-for-women-with-fibromyalgia/ Acupuncture Does Not Appear to Relieve Pain in Fibromyalgia Patients]<ref>{{Cite news|url=https://fibromyalgianewstoday.com/2016/02/01/acupuncture-does-not-reduce-pain-for-women-with-fibromyalgia/|title=Acupuncture Does Not Appear to Relieve Pain in Fibromyalgia Patients - Fibromyalgia News Today|last=Semedo|first=Daniela|date=2016-02-01|work=Fibromyalgia News Today|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

== '''Disability: SSI/SSD and LTD (See main article link below)''' ==
{{Main article |page_name = Fibromyalgia disability process}}

== '''Notable studies (See main article link below)''' ==
{{Main article |page_name = Fibromyalgia notable studies}}

== Controversy ==
=== Dr. Frederick Wolfe ===
Dr. [http://rheummd.org/members/fwolfe Frederick Wolfe], the director of the [https://www.arthritis-research.org/ National Databank for Rheumatic Diseases] and the lead author of the 1990 paper that first defined the diagnostic guidelines for fibromyalgia, says he has become cynical and discouraged about the diagnosis. He now considers the condition a physical response to stress, depression, and economic and social anxiety.<ref>{{Cite news|url=http://www.nytimes.com/2008/01/14/health/14pain.html?_r=0|title=Drug Approved. Is Disease Real?|last=Berenson|first=Alex|date=Jan 14, 2008|work=The Wall Street Journal|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en}}</ref><ref>{{Cite journal|last=Wolfe|first=Frederick|last2=Walitt|first2=Brian|date=2016|title=Fibromyalgia: A Short Commentary|url=http://headache.imedpub.com/fibromyalgia-a-short-commentary.pdf|journal=Journal of Headache & Pain Management|volume=1|issue=No. 3:27|pages=|via=iMedPubJournals}}</ref><ref>{{Cite news|url=https://www.news-medical.net/news/20130322/Fibromyalgia-an-interview-with-Dr-Frederick-Wolfe-University-of-Kansas-School-of-Medicine.aspx|title=Fibromyalgia: an interview with Dr Frederick Wolfe, University of Kansas School of Medicine|last=Cashin-Garbutt|first=April|date=2013-03-22|work=News-Medical.net|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en}}</ref>

=== Fibromyalgia vs Chiari malformation ===
Some individuals diagnosed with FMS were undergoing surgery for [[chiari malformation]] (CM). These are two separate conditions; FMS cannot be resolved by undergoing a risky CM surgery.

*2011, [https://www.ncbi.nlm.nih.gov/pubmed/21135714 Is Chiari I malformation associated with fibromyalgia?]<ref>{{Cite journal|last=Watson|first=Nathaniel F.|last2=Buchwald|first2=Dedra|last3=Goldberg|first3=Jack|last4=Maravilla|first4=Kenneth R.|last5=Noonan|first5=Carolyn|last6=Guan|first6=Qingyan|last7=Ellenbogen|first7=Richard G.|date=2011|title=Is Chiari I malformation associated with fibromyalgia?|url=https://www.ncbi.nlm.nih.gov/pubmed/21135714|journal=Neurosurgery|volume=68|issue=2|pages=443–448; discussion 448–449|doi=10.1227/NEU.0b013e3182039a31|issn=1524-4040|pmid=21135714|via=}}</ref>
::Conclusion: Most patients with FM do not have [[CIM]] pathology. Future studies should focus on dynamic neuroimaging of craniocervical neuroanatomy in patients with FM.
*2015, [https://www.massmecfs.org/resource-library/9-treatment/172-cfidsfm-and-chiari-malformation-surgery CFS/FM and Chiari Malformation Surgery]<ref>{{Cite web|url=https://www.massmecfs.org/resource-library/9-treatment/172-cfidsfm-and-chiari-malformation-surgery|title=CFS/FM and Chiari Malformation Surgery|last=Casanova|first=Ken|date=Nov 15, 2015|website=www.massmecfs.org|language=en-GB|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref>

==See also==
*[[Fibromyalgia disability process]]
* [[Fibromyalgia drugs]]
* [[Fibromyalgia notable studies]]
* [[Influenza vaccine]]
*[[Lady Gaga]]
*''[[Mayo Clinic Guide to Fibromyalgia: Strategies to Take Back Your Life]] - Medical guide book (2019)''

== Learn more ==
*[https://dx.doi.org/10.4065%2Fmcp.2011.0206 The Science of Fibromyalgia] - Daniel Clauw, Lesley Arnold, and Bill McCarber for the FibroCollaborative
*[https://www.s4me.info/forums/fibromyalgia-and-connective-tissue-disorders.35/ Forum: Fibromyalgia and Connective Tissue Disorders] at [[Science for ME]]
*[[Verywell FMS/CFS]]

=== Ongoing process of diagnosing and categorizing ===

*2014, [http://www.medpagetoday.com/Rheumatology/Fibromyalgia/49114 Lyme Disease, Fibromyalgia Link Evaporates]<ref>{{Cite news|url=https://www.medpagetoday.com/Rheumatology/Fibromyalgia/49114|title=Lyme Disease, Fibromylagia Link Evaporates|last=Kuznar|first=Wayne|date=2014-12-14|work=|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en}}</ref> (See also: [[Chronic lyme disease]])

*2015, [http://www.news-medical.net/news/20150518/Fibromyalgia-now-considered-as-a-lifelong-central-nervous-system-disorder.aspx Fibromyalgia now considered as a lifelong central nervous system disorder]<ref>{{Cite news|url=https://www.news-medical.net/news/20150518/Fibromyalgia-now-considered-as-a-lifelong-central-nervous-system-disorder.aspx|title=Fibromyalgia now considered as a lifelong central nervous system disorder|date=2015-05-18|work=News-Medical.net|access-date=2018-08-09|language=en}}</ref>

*2015, [http://nationalpainreport.com/foundation-of-fibromyalgia-is-altered-central-nervous-system-new-study-validates-8827896.html Foundation of Fibromyalgia Is Altered Central Nervous System, New Study Validates]<ref>{{Cite news|url=http://nationalpainreport.com/foundation-of-fibromyalgia-is-altered-central-nervous-system-new-study-validates-8827896.html|title=Foundation of Fibromyalgia Is Altered Central Nervous System, New Study Validates|date=2015-10-24|work=National Pain Report|access-date=2018-08-09|language=en-US}}</ref>

*2015, ''Question:'' [http://fmcfstriggerpoints.blogspot.com/2015/09/is-fibromyalgia-psychosomatic-illness.html 'Is Fibromyalgia a Psychosomatic Illness?'] ''Answer:'' "Fibromyalgia is NOT a psychosomatic illness."<ref>{{Cite web|url=http://fmcfstriggerpoints.blogspot.com/2015/09/is-fibromyalgia-psychosomatic-illness.html|title=Is Fibromyalgia a Psychosomatic Illness? Med Student Asks Celeste Cooper|last=Cooper|first=Celeste|date=Sep 4, 2015|website=fmcfstriggerpoints.blogspot.com|archive-url=|archive-date=|dead-url=|access-date=2018-09-15}}</ref>

*2016, [http://fibromyalgianewstoday.com/2016/09/09/fibromyalgia-diagnosis-using-noninvasive-eye-examination Diagnosing Fibromyalgia May Be Possible Using Noninvasive Eye Examination]<ref>{{Cite news|url=https://fibromyalgianewstoday.com/2016/09/09/fibromyalgia-diagnosis-using-noninvasive-eye-examination|title=Diagnosing Fibromyalgia May Be Possible with Noninvasive Eye Exam|date=2016-09-09|work=Fibromyalgia News Today|access-date=2018-08-09|language=en-US}}</ref>

*2016, [https://www.verywellhealth.com/microglia-in-fibromyalgia-chronic-fatigue-syndrome-3862780 Microglia in Fibromyalgia & Chronic Fatigue Syndrome]<ref>{{Cite news|url=https://www.verywellhealth.com/microglia-in-fibromyalgia-chronic-fatigue-syndrome-3862780|title=Microglia in Fibromyalgia and Chronic Fatigue Syndrome|last=Dellwo|first=Adrienne|date=Feb 21, 2018|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref>

*2016, [http://simmaronresearch.com/2016/03/are-chronic-fatigue-syndrome-mecfs-and-fibromyalgia-immune-exhaustion-disorders/ Are Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Immune Exhaustion Disorders?]<ref>{{Cite news|url=http://simmaronresearch.com/2016/03/are-chronic-fatigue-syndrome-mecfs-and-fibromyalgia-immune-exhaustion-disorders/|title=Are Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Immune Exhaustion Disorders? - Simmaron Research|date=2016-03-21|work=Simmaron Research|access-date=2018-08-09|language=en-US}}</ref>

*2016, [https://consultqd.clevelandclinic.org/2016/03/why-fibromyalgia-is-neuropathic/?utm_campaign=qd+tweets&utm_medium=social&utm_source=twitter&utm_content=160308+fibromyalgia+neuropathic&dynid=twitter-_-qd+tweets-_-social-_-social-_-160308+fibromyalgia+neuropathic Why Fibromyalgia Is Neuropathic]<ref>{{Cite news|url=https://consultqd.clevelandclinic.org/why-fibromyalgia-is-neuropathic/?utm_campaign=qd+tweets&utm_medium=social&utm_source=twitter&utm_content=160308+fibromyalgia+neuropathic&dynid=twitter-_-qd+tweets-_-social-_-social-_-160308+fibromyalgia+neuropathic|title=Why Fibromyalgia Is Neuropathic|date=2016-03-08|work=Consult QD|access-date=2018-08-09|language=en-US}}</ref>

*2017, [http://nationalpainreport.com/study-reveals-new-treatment-target-for-fibromyalgia-inflammation-in-the-brain-8833354.html Study Reveals New Treatment Target for Fibromyalgia: Inflammation in the Brain]<ref>{{Cite news|url=http://nationalpainreport.com/study-reveals-new-treatment-target-for-fibromyalgia-inflammation-in-the-brain-8833354.html|title=Study Reveals New Treatment Target for Fibromyalgia: Inflammation in the Brain|last=Liptan|first=Ginevra|date=2017-04-11|work=National Pain Report|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>
*2017, [https://qz.com/1349854/ai-can-spot-the-pain-from-a-disease-some-doctors-still-think-is-fake/?mc_cid=669d3db241&mc_eid=c75cd86947 AI can spot the pain from a disease some doctors still think is fake]<ref>{{Cite news|url=https://qz.com/1349854/ai-can-spot-the-pain-from-a-disease-some-doctors-still-think-is-fake/?mc_cid=669d3db241&mc_eid=c75cd86947|title=AI can spot the pain from a disease some doctors still think is fake|last=Goldhill|first=Olivia|date=Aug 9, 2018|work=Quartz|access-date=2018-08-15|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>
*2018, [https://www.verywellhealth.com/fibromyalgia-pain-physiological-evidence-716141 Understanding the Pathophysiology of Fibromyalgia]<ref>{{Cite news|url=https://www.verywellhealth.com/fibromyalgia-pain-physiological-evidence-716141|title=What Is the Pathophysiology of Fibromyalgia?|last=Dellwo|first=Adrienne|date=Sep 18, 2018|work=Verywell Health|access-date=2018-09-19|archive-url=|archive-date=|dead-url=}}</ref>
*2018, [https://www.prohealth.com/fibromyalgia/library/fibromyalgia-central-sensitization-syndrome-87957?utm_campaign=Social%20Media%20-%20Fibromyalgia&utm_content=80329422&utm_medium=social&utm_source=twitter Fibromyalgia: Central Sensitization Syndrome - Characterizing classes of fibromyalgia within the continuum of central sensitization syndrome.]<ref>{{Cite news|url=https://www.prohealth.com/fibromyalgia/library/fibromyalgia-central-sensitization-syndrome-87957?utm_campaign=Social%20Media%20-%20Fibromyalgia&utm_content=80329422&utm_medium=social&utm_source=twitter|title=Fibromyalgia: Central Sensitization Syndrome - Prohealth|last=Davis|first=F|date=2018-11-18|work=Prohealth|access-date=2018-11-25|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

=== Blood tests ===

*2013, [http://nationalpainreport.com/new-fibromyalgia-blood-test-is-99-accurate-8821072.html New Fibromyalgia Blood Test is 99% Accurate]<ref>{{Cite news|url=http://nationalpainreport.com/new-fibromyalgia-blood-test-is-99-accurate-8821072.html|title=New Fibromyalgia Blood Test is 99% Accurate|date=2013-07-31|work=National Pain Report|access-date=2018-08-09|language=en-US}}</ref>

*2014, [http://www.prohealth.com/library/showarticle.cfm?libid=18837 Pridgen Reports Fibromyalgia Antiviral Trial Results “Very Positive”: Predicts New Approach Will Be “Game-Changer”]<ref>{{Cite news|url=https://www.prohealth.com/library/pridgen-reports-fibromyalgia-antiviral-trial-results-very-positive-predicts-new-approach-will-be-game-changer-32620|title=Pridgen Reports Fibromyalgia Antiviral Trial Results “Very Positive”: Predicts New Approach Will Be “Game-Changer”|last=|first=|date=2014-03-25|work=Prohealth|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

*2016, [https://www.celestecooper.com/2016/05/blood-test-for-fibromyalgia-fma-test-is.html Blood Test for Fibromyalgia: FM/a Test Ⓡ is now available, Q&A]<ref>{{Cite web|url=https://www.celestecooper.com/2016/05/blood-test-for-fibromyalgia-fma-test-is.html|title=Blood Test for Fibromyalgia: FM/a Test ® Is Real, Q&A|last=Cooper|first=Celeste|date=May 3, 2016|website=www.celestecooper.com|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref>

*2016, [http://www.liveinsurancenews.com/fibromyalgia-blood-testing-covered-rising-number-insurance-companies/ Fibromyalgia blood testing covered by rising number of insurance companies]<ref>{{Cite news|url=http://www.liveinsurancenews.com/fibromyalgia-blood-testing-covered-rising-number-insurance-companies/|title=Fibromyalgia blood testing covered more of insurance companies|last=Campbell|first=Julie|date=2016-04-08|work=Live Insurance News|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

*2017, [http://www.businesswire.com/news/home/20170419005324/en/EpicGenetics-Assistance-Leading-Medical-Centers-Expands-Clinical EpicGenetics, with the Assistance of Leading Medical Centers, Expands Clinical Study of FM/a® Test to Diagnose Fibromyalgia, Identify Genetic Markers Unique to the Disorder and Explore Direct Treatment Approaches]<ref>{{Cite news|url=https://www.businesswire.com/news/home/20170419005324/en/EpicGenetics-Assistance-Leading-Medical-Centers-Expands-Clinical|title=EpicGenetics, with the Assistance of Leading Medical Centers, Expands Clinical Study of FM/a® Test to Diagnose Fibromyalgia, Identify Genetic Markers Unique to the Disorder and Explore Direct Treatment Approaches|last=|first=|date=Apr 19, 2017|work=Business Wire|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en}}</ref>

=== Brain scans ===

*2002, [http://www.anapsid.org/cnd/diagnosis/brainpain.html Fibromyalgia Pain Isn't All In Patient's Heads, New Brain Study Finds]<ref>{{Cite web|url=http://www.anapsid.org/cnd/diagnosis/brainpain.html|title=Fibromyalgia Pain Isn't All In Patient's Heads, New Brain Study Finds|last=Kaplan|first=Melissa|date=Jan 1, 2014|website=www.anapsid.org|publisher=ANAPSID|via=Chronic Neuroimmune Diseases|archive-url=|archive-date=|dead-url=|access-date=2018-08-09}}</ref>

*2012, [https://www.sciencedaily.com/releases/2012/11/121111153426.htm Fibromyalgia and the brain: New clues reveal how pain and therapies are processed]<ref>{{Cite news|url=https://www.sciencedaily.com/releases/2012/11/121111153426.htm|title=Fibromyalgia and the brain: New clues reveal how pain and therapies are processed|last=|first=|date=Nov 11, 2012|work=ScienceDaily|access-date=2018-08-09|archive-url=|archive-date=|dead-url=|language=en}}</ref>

*2015, [https://www.verywellhealth.com/how-lyrica-changes-the-fibromyalgia-brain-715767 How Lyrica Changes the Fibromyalgia Brain]<ref>{{Cite news|url=https://www.verywellhealth.com/how-lyrica-changes-the-fibromyalgia-brain-715767|title=How Lyrica Changes the Fibromyalgia Brain|last=Dellwo|first=Adrienne|date=Apr 30, 2016|work=Verywell Health|access-date=2018-08-09|archive-url=|archive-date=|dead-url=}}</ref>
*2018, [https://ki.se/en/news/people-with-fibromyalgia-have-inflammation-of-the-brain People with fibromyalgia have inflammation of the brain]<ref>{{Cite web|url=https://ki.se/en/news/people-with-fibromyalgia-have-inflammation-of-the-brain|title=People with fibromyalgia have inflammation of the brain|last=|first=|date=Sep 25, 2018|website=ki.se|language=en|archive-url=|archive-date=|dead-url=|access-date=2018-09-26}}</ref>
*2018, [https://fibromyalgianewstoday.com/2018/10/11/brain-inflammation-imaged-first-time-fibromyalgia-patients-study/ Brain Inflammation Imaged for First Time in Fibromyalgia Patients, Study Reports]<ref>{{Cite news|url=https://fibromyalgianewstoday.com/2018/10/11/brain-inflammation-imaged-first-time-fibromyalgia-patients-study/|title=In Fibromyalgia Patients, Brain Inflammation Imaged for First Time in Study|last=Inacio|first=Patricia|date=2018-10-11|work=Fibromyalgia News Today|access-date=2018-10-30|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

==References==
{{reflist}}

[[Category:Diagnoses]]
[[Category:Potential comorbidities]]
[[Category:Musculoskeletal diseases and disorders]]
[[Category:Neurological diseases and disorders]]

Ehlers-Danlos syndrome

2020-05-30T10:53:07Z

FatigueTrackerBot:.

'''Ehlers-Danlos syndromes''' (EDS) is a group of inherited disorders that affects [[Connective tissue|connective tissues]] — primarily skin, joints, and blood vessel walls.<ref>{{Cite news|url=http://www.mayoclinic.org/diseases-conditions/ehlers-danlos-syndrome/basics/definition/con-20033656|title=Ehlers-Danlos syndrome - Symptoms and causes|work=Mayo Clinic|access-date=2018-08-17|language=en}}</ref> It is a genetic disease that causes a defect in the production of [[collagen]].<ref name=":2" /> It is characterized by joint hypermobility, skin hyperextensibility, and tissue fragility, and ranges widely in severity.<ref>{{Cite news|url=https://www.ehlers-danlos.com/what-is-eds/|title=What are the Ehlers-Danlos Syndromes? {{!}} The Ehlers Danlos Society|work=The Ehlers Danlos Society|access-date=2018-10-07|language=en-US}}</ref>

== Symptoms and presentation ==
[[File:Hypermobile (double jointed) phalangeal joints.JPG|300px|thumb|right|An 18 years old patient with EDS can extend his fingers back to almost touching the forearm due to hypermobile [[wikipedia:Phalanx_bone|phalangeal]] joints]]Symptoms vary widely between individuals, based on the sub-type of EDS they have. EDS affects connective tissues, which results in symptoms that range from mild joint effects to life-threatening complications.<ref>{{Cite journal|date=2018-10-17|title=Ehlers–Danlos syndromes|url=https://en.wikipedia.org/w/index.php?title=Ehlers%E2%80%93Danlos_syndromes&oldid=864500626|journal=Wikipedia|language=en}}</ref>
* [[joint hypermobility]] (stretch further than normal)
* loose/unstable joints, prone to subluxations/dislocations
* [[Arthralgia|joint pain]]
* joints that move beyond the normal range (hyperextensibility)
* early onset of [[arthritis]]
* soft, velvety-like skin
* fragile skin that tears or bruises easily
* severe scarring
* slow and poor wound healing
* development of [[molluscoid psuedo tumors]]
* [[Musculoskeletal system|musculoskeletal]] pain
* poor [[muscle]] tone (less common)

== Sub-types ==
<div style="max-width:270px;float:right;margin:0;padding-bottom: 3em;clear:both">
<gallery style="font-size:1.em;margin:0;padding:0;" widths="350" mode="slideshow">
File:Beighton Score - Thumb Reaches Forearm.JPG|Hypermobile EDS, cEDS, and clEDS can be diagnosed using [https://www.ehlers-danlos.com/assessing-joint-hypermobility/ The Beighton Scoring System] along with [https://www.ehlers-danlos.com/eds-types/ EDS Types] criteria. Here, thumb reaches forearm in one of its measurements|alt=
File:PMC3504533 1471-2415-12-47-2 (cropped).png|Hyperelastic skin in a person with cEDS|alt=
File:PMC3567970 1752-1947-7-35-1 (cropped).png|Translucent skin in Vascular EDS (VEDS)|alt=
File:751768.fig.002a.jpg|Atrophic scar found in cEDS, clEDS, Dermatosparaxis, and some other types|alt=
File:Marfan.JPG|"Marfanoid habitus" (resembling Marfans Syndrome) long slender fingers of Kyphoscoliosis Type EDS|alt=
File:Ehlers-danlos.png|4 y/o diagnosed by swelling of eyelids, corneas protruded anteriorly, blue sclerae, high myopia, and keratoconus. EDS, Rare Types: Brittle Cornea Syndrome (BCS)|alt=
</gallery>
</div>
There are currently thirteen sub-types of EDS. These include six distinct types of EDS and sub-types, as well as five presentations that fit into an 'other' category.<ref name=":1">{{Cite web|url=https://rarediseases.info.nih.gov/diseases/6322/ehlers-danlos-syndromes|title=Ehlers-Danlos syndromes {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|website=rarediseases.info.nih.gov|language=en|access-date=2018-10-06}}</ref><ref name=":0">{{Cite news|url=http://ehlers-danlos.com/eds-types/|title=The Types of EDS|work=The Ehlers Danlos Society|access-date=2018-08-17|language=en-US}}</ref><ref name=":2" /> They are:
* [https://rarediseases.info.nih.gov/diseases/2081/ehlers-danlos-syndrome-hypermobility-type Hypermobile EDS] (hEDS) - the most dominant clinical manifestation; presents with joint hypermobility, resulting into dislocations, [[bruising]] and [[chronic pain]], often out of proportion to physical and radiological findings.

*[https://rarediseases.info.nih.gov/diseases/2088/ehlers-danlos-syndrome-classic-type Classical (cEDS)] and [https://www.ehlers-danlos.com/eds-types/#clEDS Classical-like (clEDS)] presents with marked skin hyperextensibility, joint hypermobility, and in clEDS easy [[bruising]].
*[https://rarediseases.info.nih.gov/diseases/2082/ehlers-danlos-syndrome-vascular-type Vascular EDS (VEDS)] and [https://www.ehlers-danlos.com/eds-types/#cvEDS Cardiac-valvular EDS (cvEDS)] - presents with arterial/intestinal/uterine fragility with possibility of arterial or organ rupture; often presents with thin or translucent skin with veins being visible thru the skin and in cvEDS severe progressive cardiac-valvular problems.
*[https://rarediseases.info.nih.gov/diseases/2083/ehlers-danlos-syndrome-kyphoscoliosis-type Kyphoscoliosis Type] - presents with scoliosis, joint laxity, and severe muscle hypotonia at birth; scoliosis is progressive and may result in the loss of the ability to walk in one's 20's or 30's. Other common features include a "marfanoid habitus" characterized by long, slender fingers; unusually long limbs; and a sunken chest or protruding chest.
*[https://rarediseases.info.nih.gov/diseases/2084/ehlers-danlos-syndrome-arthrochalasia-type Arthrochalasia Type] - presents with congenital hip dislocation and generalized joint hypermobility; may also have skin hyperextensibility, tissue fragility, kyphoscoliosis, and muscle hypotonia.
*[https://rarediseases.info.nih.gov/diseases/2089/ehlers-danlos-syndrome-dermatosparaxis-type Dermatosparaxis Type] - presents with severe skin fragility and substantial [[bruising]].
*Other Types - [https://www.ehlers-danlos.com/eds-types/#BCS Brittle Cornea Syndrome (BCS)]; [https://www.ehlers-danlos.com/eds-types/#spEDS Spondylodysplastic EDS (spEDS)],[https://www.ehlers-danlos.com/eds-types/#mcEDS Musculocontractural EDS (mcEDS)], [https://www.ehlers-danlos.com/eds-types/#mEDS Myopathic EDS (mEDS)], [https://www.ehlers-danlos.com/eds-types/#pEDS Periodontal EDS (pEDS)] - this category groups the rarest genetic presentations sometimes only seen in one family.<ref name=":1" /><ref name=":0" />

== Prevalence ==
Ehlers-Danlos syndrome affects both males and females.<ref name=":0" />

1 in 5,000 have all types of EDS worldwide. Hypermobile and classical forms are most common. Hypermobile may affect as many as 1 in 5,000 to 20,000 people, while the classical type probably occurs in 1 in 20,000 to 40,000 people. Other forms are rare, often with only a few cases or affected families in the world.<ref>{{Cite web|url=https://ghr.nlm.nih.gov/condition/ehlers-danlos-syndrome#statistics|title=Ehlers-Danlos syndrome|last=Reference|first=Genetics Home|website=Genetics Home Reference|language=en|access-date=2018-10-07}}</ref>

== Risk factors ==
Ehlers-Danlos syndrome is a hereditary disease cause by a genetic mutation in one or more of the genes involved in the synthesis of collagen,<ref name=":2" /> an important protein found in muscle, skin, ligaments, tendons, cartilage, bones, blood vessels, and other other body tissue.<ref>{{Cite journal|date=2018-08-09|title=Collagen|url=https://en.wikipedia.org/w/index.php?title=Collagen&oldid=854113611|journal=Wikipedia|language=en}}</ref><ref name=":2" />

== Diagnosis ==
Diagnosis is made through physical examination which includes a test for hypermobility, such as the Beighton Scoring System<ref>{{Cite news|url=http://ehlers-danlos.com/assessing-joint-hypermobility/|title=Assessing Joint Hypermobility {{!}} The Ehlers Danlos Society|work=The Ehlers Danlos Society|access-date=2018-08-17|language=en-US}}</ref> or the Brighton Criteria.<ref>{{Cite web|url=http://hypermobility.org/help-advice/hypermobility-syndromes/the-brighton-score/|title=Hypermobility Syndromes Association » The Brighton Criteria for JHS|website=hypermobility.org|access-date=2018-08-17}}</ref>

== Pathophysiology ==
EDS is a diverse group of inherited connective-tissue disorders. Joint hypermobility, skin fragility, and hyperextensibility characterize the disorders. Collagen defect has been identified in at least six types.<ref name=":2">{{Cite journal|last=|first=|date=Jan 11, 2018|title=Ehlers-Danlos Syndrome: Background, Pathophysiology, Etiology|url=https://emedicine.medscape.com/article/1114004-overview#a5|format=Login Needed|journal=Medscape|volume=|pages=|at=Pathophysiology|via=}}</ref>

The vascular form is characterized by a decreased amount of type III collagen. It is [https://medlineplus.gov/ency/article/002049.htm autosomal dominant] (AD), one parent with a defective gene are needed to pass on this form of EDS and is caused by mutations in COL3A1. This results in increased fragility of connective tissue with arterial, intestinal, and uterine ruptures and premature death.<ref>{{Cite web|url=https://reference.medscape.com/medline/abstract/23489429|title=A new COL3A1 mutation in Ehlers-Danlos syndrome type IV.|last=Eder|first=J|last2=Laccone|first2=F|date=|website=reference.medscape.com|publisher=Medscape|format=Login Needed|issn=|archive-url=|archive-date=|dead-url=|access-date=2018-10-06|last3=Rohrbach|first3=M|last4=Guinta|first4=C|last5=Aumayr|first5=K|last6=Reichel|first6=C|last7=Trautinger|first7=F}}</ref>

In EDS types I and II, cEDS and clEDS, causative mutations may involved the ''COL5A1, COL5A2,'' and ''tenascin-X'' genes and are implied to be in the ''COL1A2'' gene. "Although half of the mutations that cause Ehlers-Danlos syndrome types I and II are likely to affect the ''COL5A1'' gene, a significant portion of the mutations result in low levels of mRNA from the mutant allele as a consequence of nonsense-mediated mRNA decay."<ref name=":2" /> <ref>{{Cite web|url=https://reference.medscape.com/medline/abstract/10796876|title=Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II).|last=Schwarze|first=U|last2=Atkinson|first2=M|date=|website=reference.medscape.com|publisher=Medscape|format=Login Needed|issn=|archive-url=|archive-date=|dead-url=|access-date=2018-10-06|last3=Hoffman|first3=GG|last4=Greenspan|first4=DS|last5=Byers|first5=PH}}</ref>

Kyphoscoliotic (type VI) is characterized by generalized joint laxity, skin fragility, and severe muscle hypotonia at birth. It is [https://medlineplus.gov/ency/article/002052.htm autosomal recessive] (AR), both parents with defective genes are needed to pass on this form of EDS. More than 20 mutations are identified in the LH1 gene that contributes to LH deficiency and clinical EDS type VI.<ref name=":2" /><ref>{{Cite web|url=https://reference.medscape.com/medline/abstract/11001813|title=Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI.|last=Yeowell|first=HN|last2=Walker|first2=LC|date=|website=reference.medscape.com|publisher=Medscape|format=Login Needed|issn=1096-7192|archive-url=|archive-date=|dead-url=|access-date=2018-10-06}}</ref>

Impaired wound healing is a typical feature of EDS.<ref name=":2" />

Pediatric patients have deficiencies in three genes of glutathione S-transferase family (''GSTM1, GSTT1, GSTP1'').<ref name=":2" /><ref>{{Cite web|url=https://reference.medscape.com/medline/abstract/18683505|title=Polymorphism of detoxification genes and cell resistance to mutagens in patients with Ehlers-Danlos syndrome.|last=Kuz'mina|first=NS|last2=Shipaeva|first2=EV|date=|website=reference.medscape.com|publisher=Medscape|format=Login Needed|issn=0007-4888|archive-url=|archive-date=|dead-url=|access-date=2018-10-06|last3=Semyachkina|first3=AN|last4=Vasil'eva|first4=IM|last5=Kovalenko|first5=LP|last6=Durnev|first6=LP|last7=Zasukhina|first7=GD}}</ref>

Reduced activity of beta4GalT-7 is associated with the progeriform (causing children to age rapidly) EDS.<ref name=":2" />

"Biallelic mutations in ''FKBP14'' may result in a recessive form of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, hearing loss, and, possibly, an increased risk for vascular complications."<ref name=":2" /><ref>{{Cite web|url=https://reference.medscape.com/medline/abstract/24677762|title=FKBP14-related Ehlers-Danlos syndrome: expansion of the phenotype to include vascular complications.|last=Murray|first=ML|last2=Yang|first2=M|date=|website=reference.medscape.com|publisher=Medscape|format=Login Needed|issn=|archive-url=|archive-date=|dead-url=|access-date=2018-10-06|last3=Frauth|first3=C|last4=Byers|first4=PH}}</ref>

An ''[https://www.ehlers-danlos.com/eds-types/#chart EDS Types Chart]''<ref>{{Cite news|url=https://www.ehlers-danlos.com/eds-types/#chart|title=The Types of EDS|last=|first=|date=|work=The Ehlers Danlos Society|access-date=2018-10-06|archive-url=|archive-date=|dead-url=|at=EDS Types Chart|language=en-US}}</ref> with AD/AR inheritance pattern (IP), genetic basis, and protein involved are provided by [https://www.ehlers-danlos.com/ The Ehlers Danlos Society].

== Systems affected by EDS ==
Systems affected by EDS include:
* [[anxiety]] disorders and [[depression]]
* bladder
* bleeding
* [[brain]] and spine
* circulatory system, [[Cardiovascular system|cardiovascular]]
* dental, oral, and voice problems
* [[Digestive problems|digestive disorders]]
* diverticulitis
* heart and valve leakage
* hernia
* joint, musculoskeletal
* ocular
* reproductive
* skin
* subluxations and dislocations<ref>{{Cite web|url=https://www.ehlers-danlos.org/what-is-eds/information-on-eds/mental-health/|title=Mental health – The Ehlers-Danlos Support UK|website=www.ehlers-danlos.org|language=en|access-date=2018-10-06}}</ref><ref>{{Cite web|url=https://www.ehlers-danlos.org/what-is-eds/information-on-eds/brain-and-spine/|title=Brain and spine – The Ehlers-Danlos Support UK|website=www.ehlers-danlos.org|language=en|access-date=2018-10-07}}</ref><ref>{{Cite web|url=https://www.ehlers-danlos.org/what-is-eds/information-on-eds/dental-oral-and-voice-problems/|title=Dental, oral and voice problems – The Ehlers-Danlos Support UK|website=www.ehlers-danlos.org|language=en|access-date=2018-10-07}}</ref><ref>{{Cite web|url=https://www.ehlers-danlos.org/what-is-eds/information-on-eds/digestive-disorders/|title=Digestive disorders – The Ehlers-Danlos Support UK|website=www.ehlers-danlos.org|language=en|access-date=2018-10-07}}</ref><ref>{{Cite web|url=https://www.chronicpainpartners.com/ehlers-danlos-syndrome-common-associated-health-problems/|title=Ehlers-Danlos Syndrome Commonly Associated Health Problems {{!}} EDSAwareness.com|website=www.chronicpainpartners.com|language=en|access-date=2018-10-06}}</ref><ref>{{Cite web|url=https://www.ehlers-danlos.org/what-is-eds/information-on-eds/joint-problems/|title=Joint problems – The Ehlers-Danlos Support UK|website=www.ehlers-danlos.org|language=en|access-date=2018-10-07}}</ref><ref>{{Cite news|url=https://totaleyecare.com/ocular-complications-ehlers-danlos-syndrome/|title=Ocular Complications of Ehlers Danlos Syndrome - Total Eye Care|work=Total Eye Care|access-date=2018-10-06|language=en-US}}</ref><ref>{{Cite news|url=https://www.msdmanuals.com/home/children-s-health-issues/connective-tissue-disorders-in-children/ehlers-danlos-syndrome|title=Ehlers-Danlos Syndrome - Children's Health Issues - MSD Manual Consumer Version|work=MSD Manual Consumer Version|access-date=2018-10-07|language=en}}</ref><ref>{{Cite web|url=https://www.ehlers-danlos.org/what-is-eds/information-on-eds/postural-tachycardia-syndrome-pots/|title=Postural tachycardia syndrome (PoTS) – The Ehlers-Danlos Support UK|website=www.ehlers-danlos.org|language=en|access-date=2018-10-07}}</ref><ref>{{Cite news|url=https://www.healthline.com/health/erectile-dysfunction|title=Erectile Dysfunction (ED): Causes, Treatment, and More|work=Healthline|access-date=2018-10-07|language=en}}</ref><ref>{{Cite journal|last=Hurst|first=B.S.|last2=Lang|first2=M.B.|last3=Kullstam|first3=S.M.|last4=Usadi|first4=R.S.|last5=Matthews|first5=M.L.|last6=Marshburn|first6=P.B.|date=2012|title=Reproductive challenges in women with Ehlers-Danlos syndrome: survey results from over 1350 respondents from the Ehlers-Danlos National Foundation|url=https://www.fertstert.org/article/S0015-0282(12)01145-4/fulltext|journal=Fertility and Sterility|language=English|volume=98|issue=3|pages=S112|doi=10.1016/j.fertnstert.2012.07.411|issn=0015-0282|via=}}</ref><ref>{{Cite web|url=https://www.ehlers-danlos.org/what-is-eds/information-on-eds/skin/|title=Skin – The Ehlers-Danlos Support UK|website=www.ehlers-danlos.org|language=en|access-date=2018-10-07}}</ref><ref>{{Cite news|url=https://www.ehlers-danlos.com/dislocation-subluxation-management/|title=Dislocation/Subluxation Management|work=The Ehlers Danlos Society|access-date=2018-10-07|language=en-US}}</ref>

==Comorbidities & complications ==

===ME/CFS ===
A 1999 case series by Dr. [[Peter Rowe]] of adolescents referred to his chronic fatigue syndrome clinic found 12 patients who also met the criteria for Ehlers-Danlos Syndrome and had orthostatic intolerance (postural orthostatic tachycardia or neurally-mediated hypotension). He concluded that “Among patients with CFS and orthostatic intolerance, a subset also has EDS.”<ref name=":5">{{Cite journal|last=Rowe|first=Peter C.|last2=Barron|first2=Diana F.|last3=Calkins|first3=Hugh|last4=Maumenee|first4=Irene H.|last5=Tong|first5=Patrick Y.|last6=Geraghty|first6=Michael T.|date=1999-10-01|title=Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome|url=http://www.sciencedirect.com/science/article/pii/S0022347699701733|journal=The Journal of Pediatrics|volume=135|issue=4|pages=494–499|doi=10.1016/S0022-3476(99)70173-3|issn=0022-3476}}</ref> He also found joint hypermobility (Beighton score > 4) in 60% of pediatric ME/CFS patients viruses 24% of healthy controls.<ref>{{Cite journal|last=Barron|first=Diana F.|last2=Cohen|first2=Bernard A.|last3=Geraghty|first3=Michael T.|last4=Violand|first4=Rick|last5=Rowe|first5=Peter C.|date=2002-09-01|title=Joint hypermobility is more common in children with chronic fatigue syndrome than in healthy controls|url=http://www.sciencedirect.com/science/article/pii/S0022347602001105|journal=The Journal of Pediatrics|volume=141|issue=3|pages=421–425|doi=10.1067/mpd.2002.127496|issn=0022-3476}}</ref>

A Swedish study of 234 ME/CFS patients meeting the [[Canadian Consensus Criteria]] found that 49% of patients had hypermobility and 20% met the criteria for hEDS.<ref>{{Cite web|url=https://osf.io/qwn5h/|website=Center for Open Science|access-date=2019-12-03|title=Bragee Bertilson et al. - ME CFS and Intracranial Hypertension|date=Nov 27, 2019|last=|first=|authorlink=|last2=|first2=|authorlink2=|archive-url=|archive-date=|dead-url=}}</ref>

=== Other ===
* [[Dysautonomia]]
* [[Mast cell activation syndrome]]
* [[Postural orthostatic tachycardia syndrome]]<ref>{{Cite web|url=https://www.inspire.com/groups/ehlers-danlos-syndromes-and-related-disorders/discussion/the-ehlers-danlos-society-is-forming-a-comorbid-condition-coalition/|title=The Ehlers-Danlos Society is forming a Comorbid Condition Coalition! - Inspire|last=|first=|date=Nov 8, 2017|website=www.inspire.com|archive-url=|archive-date=|dead-url=|access-date=2018-10-07}}</ref><ref>{{Cite news|url=http://www.thepainrelieffoundation.com/craniocervical-instability/|title=What is Craniocervical Instability? - The Pain Relief Foundation|work=The Pain Relief Foundation|access-date=2018-10-07|language=en-US}}</ref><ref>{{Cite news|url=https://www.ehlers-danlos.com/2017-eds-classification-non-experts/neurological-spinal-manifestations-ehlers-danlos-syndromes/|title=Neurological and Spinal Manifestations of the Ehlers-Danlos Syndromes (for Non-experts) {{!}} The Ehlers Danlos Society|work=The Ehlers Danlos Society|access-date=2018-10-07|language=en-US}}</ref>
* [[Chiari malformation]]<ref name=":4">{{Cite journal|last=Henderson|first=Fraser C.|last2=Austin|first2=Claudiu|last3=Benzel|first3=Edward|last4=Bolognese|first4=Paolo|last5=Ellenbogen|first5=Richard|last6=Francomano|first6=Clair A.|last7=Ireton|first7=Candace|last8=Klinge|first8=Petra|last9=Koby|first9=Myles|date=2017-02-21|title=Neurological and spinal manifestations of the Ehlers-Danlos syndromes|url=https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.c.31549|journal=American Journal of Medical Genetics Part C: Seminars in Medical Genetics|language=en|volume=175|issue=1|pages=195–211|doi=10.1002/ajmg.c.31549|issn=1552-4868}}</ref>
* [[Syringomyelia]]<ref name=":4" />
* [[Craniocervical instability]]<ref name=":4" />
* [[Atlantoaxial instability]]<ref name=":4" />

* [[Intracranial hypertension]]<ref name=":4" />
* [[Kyphosis]]<ref name=":4" /> and [[Scoliosis]]<ref name=":4" />
* [[Tethered cord]]<ref name=":4" />
* [[Dystonia]]<ref name=":4" />
* [[Tarlov cyst]]<ref name=":4" />
* [[Mitral valve prolapse]]

== Treatment ==

'''Medications'''

There is no cure for EDS and treatments are limited to over-the-counter pain relievers such as acetaminophen (Tylenol and others) ibuprofen (Advil, Motrin IB, others), and naproxen sodium (Aleve). Prescription medications are used for acute injuries. Blood pressure medications are sometimes used to keep pressure low to relieve stress on vessels.<ref name=":3">{{Cite web|url=https://www.mayoclinic.org/diseases-conditions/ehlers-danlos-syndrome/diagnosis-treatment/drc-20362149|title=Ehlers-Danlos syndrome - Diagnosis and treatment - Mayo Clinic|website=www.mayoclinic.org|language=en|access-date=2018-10-07}}</ref>

'''Physical therapy'''

Because dislocations occur in EDS, exercise to strengthen the muscles and stabilize joints are the primary treatment. Braces help prevent joint dislocations.<ref name=":3" />

'''Surgical and other procedures'''

Surgery may be recommended to repair joints damaged by dislocations but connective tissue may not heal properly. Ruptured blood vessels or organs for patients with VEDS may also be necessary.<ref name=":3" />

== See also ==
* [[Collagen]]
*[[Joint hypermobility|Joint hypermobility and hypermobility syndromes]]

==Learn more==
* [http://www.rcgp.org.uk/clinical-and-research/resources/toolkits/ehlers-danlos-syndromes-toolkit.aspx Ehlers-Danlos Syndrome Toolkit]<ref>{{Cite web|url=http://www.rcgp.org.uk/clinical-and-research/resources/toolkits/ehlers-danlos-syndromes-toolkit.aspx|title=Ehlers Danlos Syndromes Toolkit|last=|first=|date=|website=www.rcgp.org.uk|publisher=Royal College of General Practitioners|language=en|archive-url=|archive-date=|dead-url=|access-date=2018-10-29}}</ref>
* [https://www.ehlers-danlos.org/information/pregnancy-birth-feeding-and-hypermobile-ehlers-danlos-syndrome-hypermobility-spectrum-disorders/ Pregnancy, birth, feeding and hypermobile Ehlers-Danlos syndrome / hypermobility spectrum disorders]<ref>{{Cite web|url=https://www.ehlers-danlos.org/information/pregnancy-birth-feeding-and-hypermobile-ehlers-danlos-syndrome-hypermobility-spectrum-disorders/|title=Pregnancy, birth, feeding and hypermobile Ehlers-Danlos syndrome / hypermobility spectrum disorders – The Ehlers-Danlos Support UK|website=www.ehlers-danlos.org|language=en|access-date=2018-10-07}}</ref>

*2016, [http://www.healthrising.org/blog/2016/07/01/chronic-fatigue-fibromyalgia-ehlers-danlos-syndrome-diagnosis/ Another Piece of the Puzzle: An ME/CFS/FM Patient Gets an Ehlers Danlos Syndrome Diagnosis]<ref>{{Cite news|url=http://www.healthrising.org/blog/2016/07/01/chronic-fatigue-fibromyalgia-ehlers-danlos-syndrome-diagnosis/|title=Another Piece of the Puzzle: An ME/CFS/FM Patient Gets an Ehlers Danlos Syndrome Diagnosis - Health Rising|last=Burns|first=Darden|date=2016-07-01|work=Health Rising|access-date=2018-08-17|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>
*[https://www.lecturio.com/magazine/wall_structure_of_arteries_and_veins/ Blood Vessels — Wall Structure of Arteries and Veins]

== References==
{{reflist}}

[[Category:Diagnoses]]
[[Category:Potential comorbidities]]

Bruising

2020-05-30T10:46:52Z

FatigueTrackerBot:Create and redirect

#REDIRECT [[Capillary fragility]]

Capillary fragility

2020-05-29T23:02:12Z

FatigueTrackerBot:Added link

Capillary fragility is manifested by the appearance of extensive point hemorrhagic spots (petechiae, bruises and hematomas).
This may occur especially on the face and legs. The condition is determined by the tendency of the capillaries to spontaneously break, releasing the blood content in the surrounding area.

Alterations in capillary fragility (ACF) can be determined by different causes and be associated with many diseases; these can be congenital, alterations caused by drugs, microtraumas or other diseases such as collagen diseases.

==See also==
*[[Collagen]]
*[[Encephalitis lethargica]]

References:

Romano C1, Costa M2, Rapisarda M2, Messina M2 and Bertini M3, Treatment of Capillary Fragility in Subjects with Spontaneous Hematomas J Clin Case Rep 2018, 8:7 DOI: 10.4172/2165-7920.10001152,Journal of Clinical Case Reports

Edward E.Brown, Diseases associated with low capillary resistance , American Heart Journal
Volume 34, Issue 2, August 1947, Pages 241-248

Capillary fragility

2020-05-29T22:42:26Z

FatigueTrackerBot:Added link

Capillary fragility is manifested by the appearance of extensive point hemorrhagic spots (petechiae, bruises and hematomas).
This may occur especially on the face and legs. The condition is determined by the tendency of the capillaries to spontaneously break, releasing the blood content in the surrounding area.

Alterations in capillary fragility (ACF) can be determined by different causes and be associated with many diseases; these can be congenital, alterations caused by drugs, microtraumas or other diseases such as collagen diseases.

==See also==
*[[Collagen]]

References:

Romano C1, Costa M2, Rapisarda M2, Messina M2 and Bertini M3, Treatment of Capillary Fragility in Subjects with Spontaneous Hematomas J Clin Case Rep 2018, 8:7 DOI: 10.4172/2165-7920.10001152,Journal of Clinical Case Reports

Edward E.Brown, Diseases associated with low capillary resistance , American Heart Journal
Volume 34, Issue 2, August 1947, Pages 241-248

Capillary fragility

2020-05-29T22:38:18Z

FatigueTrackerBot:Added ref

Capillary fragility is manifested by the appearance of extensive point hemorrhagic spots (petechiae, bruises and hematomas).
This may occur especially on the face and legs. The condition is determined by the tendency of the capillaries to spontaneously break, releasing the blood content in the surrounding area.

Alterations in capillary fragility (ACF) can be determined by different causes and be associated with many diseases; these can be congenital, alterations caused by drugs, microtraumas or other diseases such as collagen diseases.

References:

Romano C1, Costa M2, Rapisarda M2, Messina M2 and Bertini M3, Treatment of Capillary Fragility in Subjects with Spontaneous Hematomas J Clin Case Rep 2018, 8:7 DOI: 10.4172/2165-7920.10001152,Journal of Clinical Case Reports

Edward E.Brown, Diseases associated with low capillary resistance , American Heart Journal
Volume 34, Issue 2, August 1947, Pages 241-248

Capillary fragility

2020-05-29T22:24:57Z

FatigueTrackerBot:Creating page

Capillary fragility is manifested by the appearance of extensive point hemorrhagic spots (petechiae, bruises and hematomas).
This may occur especially on the face and legs. The condition is determined by the tendency of the capillaries to spontaneously break, releasing the blood content in the surrounding area.

Alterations in capillary fragility (ACF) can be determined by different causes and be associated with many diseases; these can be congenital, alterations caused by drugs, microtraumas or other diseases such as collagen diseases.

References:

Romano C1, Costa M2, Rapisarda M2, Messina M2 and Bertini M3, Treatment of Capillary Fragility in Subjects with Spontaneous Hematomas J Clin Case Rep 2018, 8:7 DOI: 10.4172/2165-7920.10001152,
Journal of Clinical Case Reports

Vitamin C

2020-05-06T20:28:27Z

FatigueTrackerBot:Added research on discrepancies on RDA

'''Vitamin C''', also known as '''ascorbic acid''', is a water-soluble vitamin found particularly in citrus fruits and green vegetables. It is essential for [[collagen]], [[catecholamine]], and [[carnitine]] biosynthesis.<ref>{{Cite journal|last=Michels|first=Alexander J.|last2=Hagen|first2=Tory M.|last3=Frei|first3=Balz|date=2013|title=Human Genetic Variation Influences Vitamin C Homeostasis by Altering Vitamin C Transport and Antioxidant Enzyme Function|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357493/|journal=Annual review of nutrition|volume=33|pages=45–70|doi=10.1146/annurev-nutr-071812-161246|issn=0199-9885|pmc=4357493|pmid=23642198}}</ref>

One of its roles is as an antioxidant, that is, it helps to protect cells from damage by oxidative stress and also improves mitochondrial function. Another role is as a cofactor for several enzymes.<ref>{{Cite book|url=https://www.worldcat.org/oclc/55641398|title=Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids : a report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine.|date=2000|publisher=National Academy Press|others=National Research Council (U.S.), Institute of Medicine (U.S.)|isbn=0309597196|location=Washington, D.C.|oclc=55641398}}</ref> After absorption, Vitamin C is present throughout the whole body.

Large cross-sectional population studies confirm that vitamin C deficiency is common in humans, affecting 5%–10% of adults in the industrialized world. Moreover, significant associations between poor vitamin C status and increased morbidity and mortality have consistently been observed. However, the absorption, distribution and elimination kinetics of vitamin C ''in vivo'' are highly complex, due to dose-dependent non-linearity, and the specific regulatory mechanisms are not fully understood.<ref name="lindblad2013" /> In addition, the optimal daily intake as well as the typical total body pool of vitamin C during health and disease remain unknown.<ref name="ginter1979" /><ref name="ginter1980" /><ref name="ginter1982" /><ref name="lykkesfeldt2019" /> There are also discrepancies in global vitamin C
recommendations, and the various national authorities recommend the minimum amount of vitamin C, however, this is likely not meeting the health needs of various subpopulations. For example, smokers and people with obesity have higher requirements than the general population, and national authorities should reassess their dietary recommendations.<ref name="carr2020" />

[[File:Nutrients-05-02860-g001.jpg|right|300x300px]]

==Biology==
Vitamin C is found in the whole body, even skin tissue.<ref name="padayatty2016" /><ref name="pullar2017" /> High levels of vitamin C are found in the [[eyes]], [[pituitary]], [[adrenal gland]], [[pancreas]], [[liver]], [[spleen]] and [[brain]]. Vitamin C is also found in relative high levels in the [[bone marrow]], [[muscles]] and [[skin]].<ref name="pullar2017" /><ref>{{Cite journal|last=|first=|date=|title=Vitamin neurotoxicity|url=https://www.ncbi.nlm.nih.gov/pubmed/1463588|journal=Mol Neurobiology|volume=|pages=|via=}}</ref> Bone marrow is probably also involved in the vitamin C homeostasis process.<ref name="padayatty2016" /><ref name="seftel1966" /><ref name="aghajanian2015" />
[[File:VitCinskinPullar2017.jpg|right|300x300px]]

The adrenal gland can inject vitamin C into the blood.<ref name="padayatty2016" />

Too much sun exposure may deplete the Vitamin C stores in the skin tissue.<ref name="pullar2017" />

== In human disease ==
Vitamin C is important in [[mast cell activation disorder]] for its role in the breakdown of [[histamine]] and as a [[mast cell]] stabilizer. Vitamin C is also a co-factor in [[collagen]] synthesis, making it a potentially important nutrient in [[Ehlers-Danlos syndrome]] and other [[connective tissue]] disorders.<ref>{{Cite journal|last=Mantle|first=D.|last2=Wilkins|first2=R. M.|last3=Preedy|first3=V.|date=2005-01-01|title=A novel therapeutic strategy for Ehlers–Danlos syndrome based on nutritional supplements|url=http://www.sciencedirect.com/science/article/pii/S0306987704004566|journal=Medical Hypotheses|volume=64|issue=2|pages=279–283|doi=10.1016/j.mehy.2004.07.023|issn=0306-9877}}</ref><ref>{{Cite journal|last=Dembure|first=Philip P.|last2=Janko|first2=Anita R.|last3=Priest|first3=Jean H.|last4=Elsas|first4=Louis J.|date=1987-07-01|title=Ascorbate regulation of collagen biosynthesis in Ehlers-Danlos syndrome, type VI|url=http://www.sciencedirect.com/science/article/pii/0026049587901557|journal=Metabolism|volume=36|issue=7|pages=687–691|doi=10.1016/0026-0495(87)90155-7|issn=0026-0495}}</ref><ref>{{Cite journal|last=Elsas|first=Louis J.|last2=Miller|first2=Robert L.|last3=Pinnell|first3=Sheldon R.|date=1978-03-01|title=Inherited human collagen lysyl hydroxylase deficiency: Ascorbic acid response|url=http://www.sciencedirect.com/science/article/pii/S0022347678804235|journal=The Journal of Pediatrics|volume=92|issue=3|pages=378–384|doi=10.1016/S0022-3476(78)80423-5|issn=0022-3476}}</ref><ref>{{Cite journal|last=Kanof|first=Abram|date=1952-02-01|title=EHLERS-DANLOS SYNDROME: Report of a Case with Suggestion of a Possible Causal Mechanism|url=https://jamanetwork.com/journals/jamapediatrics/fullarticle/495523|journal=A.M.A. American Journal of Diseases of Children|language=en|volume=83|issue=2|pages=197–202|doi=10.1001/archpedi.1952.02040060063007|issn=0096-8994}}</ref><ref>{{Cite journal|last=Ringsdorf|first=W. M.|last2=Cheraskin|first2=E.|date=1982-03-01|title=Vitamin C and human wound healing|url=http://www.sciencedirect.com/science/article/pii/003042208290295X|journal=Oral Surgery, Oral Medicine, Oral Pathology|volume=53|issue=3|pages=231–236|doi=10.1016/0030-4220(82)90295-X|issn=0030-4220}}</ref><ref>{{Cite book|url=https://books.google.com/books?hl=en&lr=&id=x-Z-cXUGlL8C&oi=fnd&pg=PR5&ots=FzzS-w8isY&sig=vY_ard7hUgYcNfbXatqmS7ltZGA#v=onepage&q&f=false|title=Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects|last=Royce|first=Peter M.|last2=Steinmann|first2=Beat|date=2003-04-14|publisher=John Wiley & Sons|isbn=978-0-471-46117-3|language=en}}</ref> Deficiency of vitamin C may contribute to [[osteoporosis]].<ref name="seftel1966" /><ref name="aghajanian2015" />

Vitamin C deficiency leads to altered function of [[procollagen-proline dioxygenase]] and [[lysyl hydroxylase]] enzymes. Each are essential for collagen synthesis and require Vitamin C as a cofactor.<ref>{{Cite journal|last=Wu|first=Marlyn|last2=Crane|first2=Jonathan S.|date=2019|title=Biochemistry, Collagen Synthesis|url=http://www.ncbi.nlm.nih.gov/books/NBK507709/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29939531}}</ref>

=== Mast cell activation disorder ===
Numerous studies have found Vitamin C to be inversely correlated with histamine and that the administration of Vitamin C reduces blood [[histamine]] levels.<ref name="clemetson1980" /><ref name="johnston1992" /><ref>{{Cite journal|last=Johnston|first=CS|date=December 1996|title=Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults|url=https://www.ncbi.nlm.nih.gov/pubmed/8951736|journal=J Am Coll Nutr.|volume=|pages=|via=}}</ref> It does this potentially through several mechanisms: by inhibiting mast cell production; by increasing [[diamine oxidase]] (an [[enzyme]] that breaks down histamine); by inhibiting mast cell degranulation and the release of histamine in the first place (i.e., as a mast cell stabilizer),<ref name=":0">{{Cite journal|last=Mio|first=M|date=1999|title=Ultraviolet B (UVB) light-induced histamine release from rat peritoneal mast cells and its augmentation by certain phenothiazine compounds|url=https://www.sciencedirect.com/science/article/pii/S0162310998000538|journal=Immunopharmacology|volume=|pages=|via=}}</ref> and by inhibiting [[histidine decarboxylase]] (the enzyme that forms histamine).<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903110/|title=Pharmacological treatment options for mast cell activation disease|last=Molderings|first=Gerhard|date=2016|journal=Naunyn Schmiedebergs Arch Pharmacol|volume=|pages=|via=}}</ref>

[[File:Nihms-754526-f0008.jpg|right|300x300px]]

=== Ehlers-Danlos Syndrome ===
A case study found improved wound healing in a patient with vascular [[Ehlers-Danlos Syndrome]] who was given high-dose (4g/day) oral vitamin C supplementation for two years.<ref>{{Cite journal|last=Ringsdorf|first=W. M.|last2=Cheraskin|first2=E.|date=1982-03-01|title=Vitamin C and human wound healing|url=http://www.sciencedirect.com/science/article/pii/003042208290295X|journal=Oral Surgery, Oral Medicine, Oral Pathology|volume=53|issue=3|pages=231–236|doi=10.1016/0030-4220(82)90295-X|issn=0030-4220}}</ref> A case study of two patients with Kyphoscoliotic EDS received high-dose Vitamin C (5g/day). After one year, they had reduced bleeding time and improve wound healing, and muscle strength.<ref>{{Cite journal|last=Dembure|first=Philip P.|last2=Janko|first2=Anita R.|last3=Priest|first3=Jean H.|last4=Elsas|first4=Louis J.|date=1987-07-01|title=Ascorbate regulation of collagen biosynthesis in Ehlers-Danlos syndrome, type VI|url=http://www.sciencedirect.com/science/article/pii/0026049587901557|journal=Metabolism|volume=36|issue=7|pages=687–691|doi=10.1016/0026-0495(87)90155-7|issn=0026-0495}}</ref>

== Supplementation ==
Several studies indicates the recovery from Vitamin C depletion will require several months of treatment. <ref name="padayatty2016" />

== Notable studies ==
* 2014, Mitochondrial dysfunction and chronic disease: treatment with natural supplements<ref>{{Cite journal|last=Nicolson|first=Garth L.|author-link=Garth Nicolson|author-link2=|author-link3=|author-link4=|author-link5=|date=2014|title=Mitochondrial dysfunction and chronic disease: treatment with natural supplements|url=https://www.ncbi.nlm.nih.gov/pubmed/24473982|journal=Alternative Therapies in Health and Medicine|volume=20 Suppl 1|issue=|pages=18–25|issn=1078-6791|pmid=24473982|quote=|via=}}</ref> [https://www.researchgate.net/publication/259960416_Mitochondrial_Dysfunction_and_Chronic_Disease_Treatment_With_Natural_Supplements (Full text)]

==See also==
*[[Vitamin C Deficiency without Scurvy hypothesis]]
*[[Collagen]]
*[[Mast cell activation syndrome]]
*[[Scurvy]]
*[[Vitamin]]
*[[Irritable bowel syndrome]]
*[[Osteoporosis]]
*[[Diet]]

==Learn more==

*[http://lpi.oregonstate.edu/mic/vitamins/vitamin-C Linus Pauling Institute Micronutrient Information Center - Vitamin C]

==References==
<references>
<ref name="ginter1979">{{Citation| issue = 33| pages = 104-141| last = Ginter| first = Emil| title = Chronic marginal vitamin C deficiency: biochemistry and pathophysiology.| journal = World Rev Nutr Diet| date = 1979|doi=10.1159/000402551|url=https://www.ncbi.nlm.nih.gov/pubmed/392953}}</ref>
<ref name="ginter1980">{{Citation| volume = 33| issue = 3| pages = 538-539| last = Ginter| first = Emil| title = What is truly the maximum body pool size of ascorbic acid in man?| journal = Am J Clin Nutr| date = Mar 1980|doi=10.1093/ajcn/33.3.538|url=https://www.ncbi.nlm.nih.gov/pubmed/6986762}}</ref>
<ref name="ginter1982">{{Citation| volume = 1| issue = 2| pages = 66-77| last = Ginter| first = Emil| title = Optimum Intake of Vitamin C for the Human Organism| journal = Nutrition and Health| date = Apr 1982|doi=10.1177/026010608200100202|url=https://journals.sagepub.com/doi/10.1177/026010608200100202}}</ref><ref name="lindblad2013">{{Citation| issn = 2072-6643| issue = 5| pages = 2860-2879| last = Lindblad| first = Maiken|last2 = Tveden-Nyborg| first2 = Pernille| last3 = Lykkesfeldt| first3 = Jens| title = Regulation of Vitamin C Homeostasis during Deficiency| journal = Nutrients| date = May 2013|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775232}}</ref>
<ref name="lykkesfeldt2019">{{Citation| volume = 11| issue = 10| last2 = Tveden-Nyborg| first2 = Pernille| last = Lykkesfeldt| first = Jens| title = The Pharmacokinetics of Vitamin C| journal = Nutrients| date = Oct 2019|doi=10.3390/nu11102412|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835439}}</ref>
<ref name="padayatty2016">{{Citation|volume = 22| issue = 6| pages = 463-93| last = Padayatty| first = Sebastian| last2 = Levine| first2 = Mark| title = Vitamin C: the known and the unknown and Goldilocks| journal = Oral Disease| date = June 2016|url = https://www.ncbi.nlm.nih.gov/pubmed/26808119}}</ref>
<ref name="clemetson1980">{{Citation| issn = 0022-3166| volume = 110| issue = 4| pages = 662–668| last = Clemetson| first = C. A.| title = Histamine and ascorbic acid in human blood| journal = The Journal of Nutrition| date = April 1980| pmid = 7365537}}</ref>
<ref name="johnston1992">{{Citation| issn = 0731-5724| volume = 11| issue = 2| pages = 172–176| last1 = Johnston| first1 = C. S.| last2 = Martin| first2 = L. J.| last3 = Cai| first3 = X.| title = Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis| journal = Journal of the American College of Nutrition| date = April 1992| pmid = 1578094}}</ref>
<ref name="seftel1966">{{Citation| volume = 1| issue = 5488| pages = 642-644| last1 = Seftel| first1 = H| last2 = Malkin| first2 = C| last3 = Schmaman| first3 = A| last4 = Abrahams| first4 = C| last5 = Lynch| first5 = S| last6 = Charlton| first6 = S| last7 = Bothwell| first7 = T| title = Osteoporosis, Scurvy, and Siderosis in Johannesburg Bantu| journal = Br Med J|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1843929/}}</ref>
<ref name="aghajanian2015">{{Citation| volume = 30| issue = 11| pages = 1945–1955| last1 = Aghajanian| first1 = P| last2 = Hall| first2 = S.| last3 = Wongworawat| first3 = MD| last4 = Mohan| first4 = S| title = The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments| journal = J Bone Miner Res| date = 2015|url=https://www.ncbi.nlm.nih.gov/pubmed/26358868}}</ref>
<ref name="carr2020">{{Citation| volume = 30| issue = 3| pages = 1-14| last1 = Carr| first1 = AC| last2 = Lykkesfeldt| first2 = J| title = Discrepancies in global vitamin C recommendations: a review of RDA criteria and underlying health perspectives|journal = Crit Rev Food Sci Nutr| date = 2020|url=https://www.ncbi.nlm.nih.gov/pubmed/32223303 }}</ref>
<ref name="pullar2017">{{Citation| volume = 9| issue = 8| pages = 866| last1 = Pullar| first1 = JM| last2 = Carr| first2 = AC| last3 = Vissers| first3 = MCM| title = The Roles of Vitamin C in Skin Health| journal = Nutrients| date = 2017|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579659}}</ref>
</references>

[[Category:Potential treatments]]
[[Category:Supplements]]
[[Category:Vitamins]]
[[Category:Nutrients]]

Vitamin C deficiency

2020-01-04T16:45:46Z

FatigueTrackerBot:/* See also */ Added link

{{Cleanup|reason=Grammar and image violating copyright. |talk=TALKPAGENAME }}
'''Hypovitaminosis C''' is also when in-hospital highly prevalent but almost completely unrecognized. Medical awareness of this potentially important disorder is hindered by the inability of most hospital laboratories to determine plasma [[Vitamin C]] concentrations. The availability of a simple, reliable method for analyzing plasma vitamin C could increase opportunities for routine plasma vitamin C analysis in clinical medicine.<ref name="Robitaille2016" />

This is also described in<ref name="Levine1996" /> will give the following symptoms: lassitude, fatigue and irritability.

== Evidence ==
The disease of terminal vitamin C deficiency – [[Scurvy]] – is first suspected on clinical grounds. The diagnosis is confirmed by documenting a plasma vitamin C concentration < 11.4 μmol/L and observing prompt clinical improvement after appropriate vitamin C provision. [[Scurvy]] is rare in the modern world, but hypovitaminosis C (plasma vitamin C concentration < 28.4 μmol/L ) or marginal vitamin C deficiency (plasma vitamin C concentration < 28.4 μmol/L but > 11.4 μmol/L ) is not. Hypovitaminosis C occurs in ~ 10% of the general population , in ~ 30 % of cigarette smokers and ~ 60% of acutely hospitalized patients, in whom it could contribute to fatigue and mood disturbance, immune system dysfunction, impaired wound healing, the complex regional pain syndrome and the complications of cardiovascular disease.<ref name="Robitaille2016" />

Cited from <ref name="Levine1996" /> : Subclinical Vitamin C Deficiency: Clinical Application. Six of seven volunteers noted mild but distinct fatigue and/or irritability at depletion, without scurvy. Symptoms disappeared within several days of the 30- or 60-mg daily dose. Although fatigue and irritability have myriad causes, vitamin C deficiency without scurvy should be an additional consideration. Since fatigue and irritability are common symptoms and were so easily reversible, physicians should ask patients with these symptoms about vitamin C ingestion from foods or supplements. [[File:60mgperday.jpg|300px|thumb|left|Steady state plateau ascorbic acid concentration in plasma. Data are an example of plateau determination from volonteer 6 at the 60mg dose.]]

== Blood test ==
The blood test procedure for Vitamin C deficiency is highly advanced.<ref name="Levine1996" /> A simpler but less accurate is proposed in <ref name="Robitaille2016" />

==Notable studies==
*1996, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance<ref name="Levine1996" /> [https://www.pnas.org/content/pnas/93/8/3704.full.pdf (Full Text)]

==See also==
*[[Collagen]]
*[[Irritable bowel syndrome]]
*[[Osteoporosis]]
*[[Scurvy]]
*[[Vitamin C]]

== Learn more ==

==References==
<references>
<ref name="Levine1996">{{Citation
| last1 = Levine | first1 = Mark
| last2 = Conry-Cantilena | first2 = Cathy
| last3 = Wang | first3 = Yaohui
| last4 = Welch | first4 = Richard W.
| last5 = Washko | first5 = Louis R.
| last6 = Dhariwal | last7 = Park | last8 = Lazarev | last9 = Graumlich | last10 = King | last11 = Cantilena | title = Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance
| journal = Proc Natl Acad Sci U S A | volume = 93 | issue = 8 | page = 3704-9
| date = 1996
| url = https://www.pnas.org/content/93/8/3704.long

}}
</ref>
<ref name="Robitaille2016">{{Citation
| last1 = Robitaille | first1 = Line
| last2 = Hoffer | first2 = L John
| title = A simple method for plasma total vitamin C analysis suitable for routine clinical laboratory use
| journal = Nutrition Journal | volume = 15 | issue = 40
| date = 21 April 2016
| url = https://nutritionj.biomedcentral.com/articles/10.1186/s12937-016-0158-9

}}
</ref>
</references>
[[Category:Diagnoses]]
[[Category:Vitamins]]

Collagen

2020-01-04T16:44:16Z

FatigueTrackerBot:/* See also */ Added link

'''Collagen''' is the main component of [[connective tissue]] and the most abundant protein in the human body. It is mostly found in fibrous tissues such as tendons, ligaments and skin.

== Types ==
There are over 28 types of collagen found in the human body.<ref name=":3">{{Cite journal|last=Wu|first=Marlyn|last2=Crane|first2=Jonathan S.|date=2019|title=Biochemistry, Collagen Synthesis|url=http://www.ncbi.nlm.nih.gov/books/NBK507709/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29939531}}</ref> Over 90% is made of of these fives types<ref name=":3" />:
* Type I: skin, tendon, vasculature, organs, bone (main component of the organic part of bone)
* Type II: cartilage (main collagenous component of cartilage)
* Type III: reticulate (main component of reticular fibers), commonly found alongside type I.
* Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.
* Type V: cell surfaces, hair, and placenta
The main collagen in ligaments is collagen type I, which comprises 70% of the dry weight of a ligament.<ref>{{Cite web|url=https://www.orthobullets.com/basic-science/9016/ligaments|title=Ligaments|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=www.orthobullets.com|archive-url=|archive-date=|dead-url=|access-date=2019-09-16}}</ref> Elastin is also found at 4–9% of the dry weight in ligaments.<ref>{{Cite journal|last=Zitnay|first=Jared L.|last2=Weiss|first2=Jeffrey A.|date=Dec 2018|title=Load Transfer, Damage and Failure in Ligaments and Tendons|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454883/|journal=Journal of orthopaedic research : official publication of the Orthopaedic Research Society|volume=36|issue=12|pages=3093–3104|doi=10.1002/jor.24134|issn=0736-0266|pmc=6454883|pmid=30175857}}</ref>

== Biology ==

=== Components ===
Collagen is made up primarily of the amino acids [[glycine]] and [[proline]]. The primary amino acid sequence of collagen is glycine-proline-X or glycine-X-hydroxyproline.<ref>{{Cite journal|last=Szulc|first=Pawel|date=Oct 2018|title=Bone turnover: Biology and assessment tools|url=https://www.ncbi.nlm.nih.gov/pubmed/30449551|journal=Best Practice & Research. Clinical Endocrinology & Metabolism|volume=32|issue=5|pages=725–738|doi=10.1016/j.beem.2018.05.003|issn=1878-1594|pmid=30449551|last2=|first2=|pmc=|quote=|last3=|first3=|last4=|first4=|last5=|first5=|last6=|first6=|last7=|first7=|last8=|first8=|author-link=|author-link2=|access-date=|author-link3=|author-link4=|author-link5=|author-link6=|via=}}</ref> X can be any of the other 17 amino acids. Every third amino acid is glycine.<ref name=":3" />

=== Co-factors ===
[[Vitamin C]] is a co-factor of many of the chemical reactions involved in collagen production. Vitamin C is also a [[mast cell]] stabilizer. Vitamin C deficiency can result in impaired collagen synthesis and [[scurvy]].{{Citation needed|reason=}}

=== Structure ===
Collagen is composed of three chains that wind together to form a triple helix.<ref name=":3" />

=== Biosynthesis ===
Collagen synthesis occurs mainly in [[Fibroblast|fibroblasts]], cells whose many function is the synthesis of collagen and [[stroma]].<ref name=":3" /> Synthesis occurs in both intracellular and extracellular spaces.<ref name=":3" />

== Collagen-degrading factors ==

=== Pathogens ===
Infection can degrade collagen via direct secretion<ref name=":1">{{Cite journal|last=Harrington|first=D J|date=Jun 1996|title=Bacterial collagenases and collagen-degrading enzymes and their potential role in human disease.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC174012/|journal=Infection and Immunity|volume=64|issue=6|pages=1885–1891|issn=0019-9567|pmid=8675283}}</ref> of collagenases and other [[Enzyme|enzymes]] (in the case of [[bacteria]]) or increased host production of [[Matrix metalloproteinase|matrix metalloproteinases]] (MMPs) as part of the normal [[immune response]] (in the case of bacteria and [[Virus|viruses]]). Numerous bacteria secrete their own [[collagenase|collagenases]].<ref name=":1" /><ref>{{Cite journal|last=Duarte|first=Ana Sofia|last2=Correia|first2=Antonio|last3=Esteves|first3=Ana Cristina|date=2016|title=Bacterial collagenases - A review|url=https://www.ncbi.nlm.nih.gov/pubmed/24754251|journal=Critical Reviews in Microbiology|volume=42|issue=1|pages=106–126|doi=10.3109/1040841X.2014.904270|issn=1549-7828|pmid=24754251}}</ref> [[Borrelia]] spirochetes upregulate production of human collagenase (MMP-1) and [[gelatinase B]] (MMP-9)<ref>{{Cite journal|last=Gebbia|first=Joseph A.|last2=Coleman|first2=James L.|last3=Benach|first3=Jorge L.|date=2001-01-01|title=Borrelia Spirochetes Upregulate Release and Activation of Matrix Metalloproteinase Gelatinase B (MMP-9) and Collagenase 1 (MMP-1) in Human Cells|url=https://iai.asm.org/content/69/1/456|journal=Infection and Immunity|language=en|volume=69|issue=1|pages=456–462|doi=10.1128/IAI.69.1.456-462.2001|issn=0019-9567|pmid=11119537}}</ref>, an enzyme that can degrade both [[elastin]] and collagen.<ref>{{Cite web|url=https://www.sciencedirect.com/topics/neuroscience/gelatinase-b|title=ScienceDirect|website=www.sciencedirect.com|access-date=2018-11-09}}</ref> MMP-8 and MMP-9 are upregulated in bacterial [[meningitis]] and the latter is associated with an increased risk of [[blood-brain barrier]] breakdown and neurological sequale such as [[epilepsy]] and [[Cognitive dysfunction|cognitive impairment]].<ref>{{Cite journal|last=Tiveron|first=Marcos Gradim|last2=Pomerantzeff|first2=Pablo Maria Alberto|last3=de Lourdes Higuchi|first3=Maria|last4=Reis|first4=Marcia Martins|last5=de Jesus Pereira|first5=Jaqueline|last6=Kawakami|first6=Joyce Tieko|last7=Ikegami|first7=Renata Nishiyama|last8=de Almeida Brandao|first8=Carlos Manuel|last9=Jatene|first9=Fabio Biscegli|date=2017-04-21|title=Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study|url=https://www.ncbi.nlm.nih.gov/pubmed/28431520|journal=BMC infectious diseases|volume=17|issue=1|pages=297|doi=10.1186/s12879-017-2387-8|issn=1471-2334|pmc=5399830|pmid=28431520}}</ref> [[Herpes simplex virus]]<ref name=":2">{{Cite journal|date=2006-12-13|title=Herpes-simplex virus encephalitis is characterized by an early MMP-9 increase and collagen type IV degradation|url=https://www.sciencedirect.com/science/article/pii/S0006899306029246|journal=Brain Research|language=en|volume=1125|issue=1|pages=155–162|doi=10.1016/j.brainres.2006.09.093|issn=0006-8993}}</ref>, [[Human herpesvirus 6|HHV-6]]<ref>{{Cite journal|date=2014-11-01|title=Serum levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in human herpesvirus-6–infected infants with or without febrile seizures|url=https://www.sciencedirect.com/science/article/pii/S1341321X14002682|journal=Journal of Infection and Chemotherapy|language=en|volume=20|issue=11|pages=716–721|doi=10.1016/j.jiac.2014.07.017|issn=1341-321X}}</ref> and [[Coxsackie B]]<ref>{{Cite journal|last=De Palma|first=Armando M.|last2=Verbeken|first2=Erik|last3=Van Aelst|first3=Ilse|last4=Van den Steen|first4=Philippe E.|last5=Opdenakker|first5=Ghislain|last6=Neyts|first6=Johan|date=2008-12-05|title=Increased gelatinase B/matrix metalloproteinase 9 (MMP-9) activity in a murine model of acute coxsackievirus B4-induced pancreatitis|url=https://www.ncbi.nlm.nih.gov/pubmed/18929380|journal=Virology|volume=382|issue=1|pages=20–27|doi=10.1016/j.virol.2008.08.046|issn=1096-0341|pmid=18929380}}</ref><ref>{{Cite journal|date=2006-03-01|title=Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis|url=https://www.sciencedirect.com/science/article/pii/S1054880705001729|journal=Cardiovascular Pathology|language=en|volume=15|issue=2|pages=63–74|doi=10.1016/j.carpath.2005.11.008|issn=1054-8807}}</ref> infection result in increased production of MMP-9, which is associated with Type IV and Type V collagen degradation.<ref name=":2" /><ref>{{Cite journal|last=Zeng|first=Z. S.|last2=Cohen|first2=A. M.|last3=Guillem|first3=J. G.|date=May 1999|title=Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis|url=https://www.ncbi.nlm.nih.gov/pubmed/10334190|journal=Carcinogenesis|volume=20|issue=5|pages=749–755|issn=0143-3334|pmid=10334190}}</ref><ref>{{Cite journal|last=Van den Steen|first=Philippe E.|last2=Dubois|first2=Bénédicte|last3=Nelissen|first3=Inge|last4=Rudd|first4=Pauline M.|last5=Dwek|first5=Raymond A.|last6=Opdenakker|first6=Ghislain|date=Jan 2002|title=Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9)|url=https://www.tandfonline.com/doi/abs/10.1080/10409230290771546|journal=Critical Reviews in Biochemistry and Molecular Biology|language=en|volume=37|issue=6|pages=375–536|doi=10.1080/10409230290771546|issn=1040-9238}}</ref> Coxsackie B infection induces immune cells to secrete MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12.<ref>{{Cite journal|last=Cheung|first=Caroline|last2=Luo|first2=Honglin|last3=Yanagawa|first3=Bobby|last4=Leong|first4=Hon Sing|last5=Samarasekera|first5=Dinesh|last6=Lai|first6=John C. K.|last7=Suarez|first7=Agripina|last8=Zhang|first8=Jingchun|last9=McManus|first9=Bruce M.|date=Mar 2006|title=Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis|url=https://www.ncbi.nlm.nih.gov/pubmed/16533694|journal=Cardiovascular Pathology: The Official Journal of the Society for Cardiovascular Pathology|volume=15|issue=2|pages=63–74|doi=10.1016/j.carpath.2005.11.008|issn=1054-8807|pmid=16533694}}</ref><ref>{{Cite journal|last=Meng|first=Xiao-hui|last2=Wang|first2=Yi|last3=Zhuang|first3=Jian-xin|last4=Han|first4=Xiu-zhen|last5=Chen|first5=Yao|last6=Jin|first6=You-peng|last7=Wang|first7=Yu-lin|last8=Yu|first8=Yong-hui|last9=Spires|first9=James P.|date=Aug 2004|title=Dynamic changes in myocardial matrix metalloproteinase activity in mice with viral myocarditis|url=https://www.ncbi.nlm.nih.gov/pubmed/15361294|journal=Chinese Medical Journal|volume=117|issue=8|pages=1195–1199|issn=0366-6999|pmid=15361294}}</ref><ref>{{Cite journal|last=Rutschow|first=Susanne|last2=Leschka|first2=Sebastian|last3=Westermann|first3=Dirk|last4=Puhl|first4=Kerstin|last5=Weitz|first5=Anneke|last6=Ladyszenskij|first6=Leonid|last7=Jaeger|first7=Sebastian|last8=Zeichhardt|first8=Heinz|last9=Noutsias|first9=Michel|date=2010-03-25|title=Left ventricular enlargement in coxsackievirus-B3 induced chronic myocarditis--ongoing inflammation and an imbalance of the matrix degrading system|url=https://www.ncbi.nlm.nih.gov/pubmed/20035743|journal=European Journal of Pharmacology|volume=630|issue=1-3|pages=145–151|doi=10.1016/j.ejphar.2009.12.019|issn=1879-0712|pmid=20035743}}</ref>
==== Infection and Ehlers-Danlos Syndrome ====
[[Ehlers-Danlos syndrome|Ehlers-Danlos Syndrome]] is a group connective tissue disorders caused by genetic defects in the production of collagen. Type III, [[hypermobile EDS]] (hEDS), is also thought to be genetic but as a genetic marker has not yet been identified; it is diagnosed via signs and symptoms. A 2018 case study of a patient who met the diagnostic criteria for hEDS and had a chronic Bartonella infection found their hEDS symptoms resolved with antibiotic treatment for Bartonella.<ref name=":0">{{Cite journal|last=Mozayeni|first=Bobak Robert|last2=Maggi|first2=Ricardo Guillermo|last3=Bradley|first3=Julie Meredith|last4=Breitschwerdt|first4=Edward Bealmear|date=Apr 2018|title=Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias|url=https://journals.lww.com/md-journal/Pages/articleviewer.aspx?year=2018&issue=04270&article=00032&type=Fulltext|journal=Medicine|language=en-US|volume=97|issue=17|pages=e0465|doi=10.1097/MD.0000000000010465|issn=0025-7974}}</ref> [[Mycoplasma pneumoniae]] has been associated with [[mitral valve]] degeneration, a complication of EDS.<ref>{{Cite journal|last=Tiveron|first=Marcos Gradim|last2=Pomerantzeff|first2=Pablo Maria Alberto|last3=de Lourdes Higuchi|first3=Maria|last4=Reis|first4=Marcia Martins|last5=de Jesus Pereira|first5=Jaqueline|last6=Kawakami|first6=Joyce Tieko|last7=Ikegami|first7=Renata Nishiyama|last8=de Almeida Brandao|first8=Carlos Manuel|last9=Jatene|first9=Fabio Biscegli|date=2017-04-21|title=Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study|url=https://www.ncbi.nlm.nih.gov/pubmed/28431520|journal=BMC infectious diseases|volume=17|issue=1|pages=297|doi=10.1186/s12879-017-2387-8|issn=1471-2334|pmc=5399830|pmid=28431520}}</ref>

=== Fluoroquinolone antibiotics ===
“Fluoroquinolones upregulate cell matrix metalloproteinases, resulting in a reduction of collagen fibrils of types I and III collagen.”<ref>{{Cite web|url=https://www.jwatch.org/na48248/2019/02/13/adverse-effects-fluoroquinolones-where-do-we-stand|title=NEJM Journal Watch: Summaries of and commentary on original medical and scientific articles from key medical journals|website=www.jwatch.org|access-date=2019-06-18}}</ref> A longitudinal study found Fluoroquinolones increased the risk of collagen-related adverse events like tendon ruptured and detached retinas.<ref>{{Cite journal|last=Redelmeier|first=Donald A.|last2=Lu|first2=Hong|last3=Daneman|first3=Nick|date=2015-11-01|title=Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study|url=https://bmjopen.bmj.com/content/5/11/e010077|journal=BMJ Open|language=en|volume=5|issue=11|pages=e010077|doi=10.1136/bmjopen-2015-010077|issn=2044-6055|pmid=26582407}}</ref> In December 2018, the FDA recommended against its use in patients with connective tissue disorders like Ehlers-Danlos Syndrome and Marfan Syndrome.<ref>{{Cite journal|last=Research|first=Center for Drug Evaluation and|date=2019-04-15|title=FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients|url=http://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics|journal=FDA|language=en}}</ref>

[[Doxycycline]], by contrast, inhibits MMP production.<ref name=":02">{{Cite journal|last=De Paiva|first=Cintia S.|last2=Corrales|first2=Rosa M.|last3=Villarreal|first3=Arturo L.|last4=Farley|first4=William J.|last5=Li|first5=De-Quan|last6=Stern|first6=Michael E.|last7=Pflugfelder|first7=Stephen C.|date=2006-09-01|title=Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye|url=http://www.sciencedirect.com/science/article/pii/S0014483506001709|journal=Experimental Eye Research|volume=83|issue=3|pages=526–535|doi=10.1016/j.exer.2006.02.004|issn=0014-4835}}</ref><ref>{{Cite journal|last=Roach|first=D. M|last2=Fitridge|first2=R. A|last3=Laws|first3=P. E|last4=Millard|first4=S. H|last5=Varelias|first5=A|last6=Cowled|first6=P. A|date=2002-03-01|title=Up-regulation of MMP-2 and MMP-9 Leads to Degradation of Type IV Collagen During Skeletal Muscle Reperfusion Injury; Protection by the MMP Inhibitor, Doxycycline|url=http://www.sciencedirect.com/science/article/pii/S1078588402915984|journal=European Journal of Vascular and Endovascular Surgery|volume=23|issue=3|pages=260–269|doi=10.1053/ejvs.2002.1598|issn=1078-5884}}</ref><ref>{{Cite journal|last=Niedzwiecki|first=A.|last2=Rath|first2=M.|last3=Kalinovsky|first3=T.|last4=Monterrey|first4=J. C.|last5=Roomi|first5=M. W.|date=2010-03-01|title=In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors|url=http://www.spandidos-publications.com/or/23/3/605/abstract|journal=Oncology Reports|volume=23|issue=3|pages=605–614|doi=10.3892/or_00000675|issn=1021-335X}}</ref><ref>{{Cite journal|last=Choi|first=Dong-Hoon|last2=Moon|first2=Ik-Sang|last3=Choi|first3=Bong-Kyu|last4=Paik|first4=Jeong-Won|last5=Kim|first5=Yoon-Sik|last6=Choi|first6=Seong-Ho|last7=Kim|first7=Chong-Kwan|date=2004|title=Effects of sub-antimicrobial dose doxycycline therapy on crevicular fluid MMP-8, and gingival tissue MMP-9, TIMP-1 and IL-6 levels in chronic periodontitis|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0765.2004.00696.x|journal=Journal of Periodontal Research|language=en|volume=39|issue=1|pages=20–26|doi=10.1111/j.1600-0765.2004.00696.x|issn=1600-0765}}</ref><ref>{{Cite journal|last=Li|first=De-Quan|last2=Lokeshwar|first2=Balakrishna L|last3=Solomon|first3=Abraham|last4=Monroy|first4=Dagoberto|last5=Ji|first5=Zhonghua|last6=Pflugfelder|first6=Stephen C|date=2001-10-01|title=Regulation of MMP-9 Production by Human Corneal Epithelial Cells|url=http://www.sciencedirect.com/science/article/pii/S0014483501910541|journal=Experimental Eye Research|volume=73|issue=4|pages=449–459|doi=10.1006/exer.2001.1054|issn=0014-4835}}</ref><ref>{{Cite journal|last=Brown David L.|last2=Desai Kavita K.|last3=Vakili Babak A.|last4=Nouneh Chadi|last5=Lee Hsi-Ming|last6=Golub Lorne M.|date=2004-04-01|title=Clinical and Biochemical Results of the Metalloproteinase Inhibition with Subantimicrobial Doses of Doxycycline to Prevent Acute Coronary Syndromes (MIDAS) Pilot Trial|url=https://www.ahajournals.org/doi/full/10.1161/01.ATV.0000121571.78696.dc|journal=Arteriosclerosis, Thrombosis, and Vascular Biology|volume=24|issue=4|pages=733–738|doi=10.1161/01.ATV.0000121571.78696.dc}}</ref>

=== Mold ===
''[[Stachybotrys chartarum]]'' (black [[mold]]) release proteinases that can hydrolyze [[gelatin]] and collagen I and IV.<ref>{{Cite journal|last=Yike|first=Iwona|last2=Rand|first2=Thomas|last3=Dearborn|first3=Dorr G.|date=2007-07-03|title=The role of fungal proteinases in pathophysiology of Stachybotrys chartarum|url=https://doi.org/10.1007/s11046-007-9037-4|journal=Mycopathologia|language=en|volume=164|issue=4|pages=171|doi=10.1007/s11046-007-9037-4|issn=1573-0832}}</ref> Three [[Mycotoxin|mycotoxins]], deoxynivalenol (DON), nivalenol (NIV) and T-2 toxin, were study in an the context of an experimental cartilage model. They were found to increase the expression of MMPs and result in the loss of [[aggrecan]] and type II collagen. Selenium partially inhibited the effects of these mycotoxins.<ref>{{Cite journal|last=Caterson|first=Bruce|last2=Li|first2=Jin|last3=Wang|first3=Jiali|last4=Luo|first4=Mingxiu|last5=Liu|first5=Jiayuan|last6=Zhang|first6=Zengtie|last7=Fu|first7=Qiang|last8=Chen|first8=Jinghong|last9=Li|first9=Siyuan|date=2012|title=The Effects of Mycotoxins and Selenium Deficiency on Tissue-Engineered Cartilage|url=https://www.karger.com/Article/FullText/335046|journal=Cells Tissues Organs|language=english|volume=196|issue=3|pages=241–250|doi=10.1159/000335046|issn=1422-6405|pmid=22538829}}</ref>

=== Sex hormones ===
Several animal studies of collagen in muscle and the aorta have found that [[estrogen]] decreases and [[testosterone]] collagen and elastin.<ref>{{Cite journal|last=Fischer|first=G. M.|last2=Swain|first2=M. L.|date=1977-06-01|title=Effect of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats|url=https://www.physiology.org/doi/abs/10.1152/ajpheart.1977.232.6.H617|journal=American Journal of Physiology-Heart and Circulatory Physiology|volume=232|issue=6|pages=H617–H621|doi=10.1152/ajpheart.1977.232.6.H617|issn=0363-6135}}</ref><ref>{{Cite journal|last=Cembrano|first=JosÉ|last2=Lillo|first2=Manuel|last3=Val|first3=JosÉ|last4=Mardones|first4=Jorge|date=1960-05-01|title=Influence of Sex Difference and Hormones on Elastine and Collagen in the Aorta of Chickens|url=http://insights.ovid.com/|journal=Circulation Research|language=ENGLISH|volume=8|issue=3|pages=527–529|issn=0009-7330|pmid=13808759}}</ref><ref>{{Cite journal|last=Fischer|first=Grace M.|last2=Swain|first2=Margaret L.|date=1980-08-01|title=Influence of contraceptive and other sex steroids on aortic collagen and elastin|url=http://www.sciencedirect.com/science/article/pii/0014480080900039|journal=Experimental and Molecular Pathology|volume=33|issue=1|pages=15–24|doi=10.1016/0014-4800(80)90003-9|issn=0014-4800}}</ref><ref>{{Cite journal|last=Fischer|first=G. M.|last2=Swain|first2=M. L.|date=1985-02-01|title=Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas|url=http://www.sciencedirect.com/science/article/pii/0021915085901777|journal=Atherosclerosis|volume=54|issue=2|pages=177–185|doi=10.1016/0021-9150(85)90177-7|issn=0021-9150}}</ref><ref>{{Cite journal|last=Fischer|first=Grace M.|date=1972-11-01|title=In Vivo EflEects of Estradiol on Collagen and Elastin Dynamics in Rat Aorta|url=https://academic.oup.com/endo/article/91/5/1227/2621144|journal=Endocrinology|language=en|volume=91|issue=5|pages=1227–1232|doi=10.1210/endo-91-5-1227|issn=0013-7227}}</ref> A study of collagen in male cows found that collagen synthesis increased with puberty, possibly as a result of testosterone.<ref>{{Cite journal|last=Cross|first=H. R.|last2=Schanbacher|first2=B. D.|last3=Crouse|first3=J. D.|date=1984-01-01|title=Sex, age and breed related changes in bovine testosterone and intramuscular collagen|url=http://www.sciencedirect.com/science/article/pii/0309174084900214|journal=Meat Science|volume=10|issue=3|pages=187–195|doi=10.1016/0309-1740(84)90021-4|issn=0309-1740}}</ref> Another, that intramuscular collagen was higher in bulls than in steers (castrated cattle).<ref>{{Cite journal|last=Judge|first=M. D.|last2=Diekman|first2=M. A.|last3=Lemenager|first3=R. P.|last4=Aberle|first4=E. D.|last5=Jones|first5=S. J.|last6=Gerrard|first6=D. E.|date=1987-11-01|title=Collagen Stability, Testosterone Secretion and Meat Tenderness in Growing Bulls and Steers|url=https://academic.oup.com/jas/article/65/5/1236/4662470|journal=Journal of Animal Science|language=en|volume=65|issue=5|pages=1236–1242|doi=10.2527/jas1987.6551236x|issn=0021-8812}}</ref> An ''in vitro'' study of rat cartilage cells found that testosterone stimulated collagen synthesis, but only in male cells.<ref>{{Cite journal|last=Boyan|first=B. D.|last2=Soskolne|first2=W. A.|last3=Brooks|first3=B. P.|last4=Ornoy|first4=A.|last5=Nasatzky|first5=E.|last6=Schwartz|first6=Z.|date=1994-04-01|title=Gender-specific, maturation-dependent effects of testosterone on chondrocytes in culture|url=https://academic.oup.com/endo/article/134/4/1640/3035468|journal=Endocrinology|language=en|volume=134|issue=4|pages=1640–1647|doi=10.1210/endo.134.4.8137726|issn=0013-7227}}</ref>

== In human disease ==
=== Ehlers-Danlos Syndrome ===
{{Main article|page_name=Ehlers-Danlos Syndrome}}

=== Mast cell activation syndrome ===
{{Main article|page_name=Mast cell activation syndrome}}

=== ME/CFS ===
{{Main article|page_name=Myalgic encephalomyelitis}}

Preliminary data from the [[UK ME/CFS biobank]] show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of [[prolyl 4-hydroxylase]] subunit alpha 1 (P4HA1), which encodes for [[procollagen-proline dioxygenase]], an enzyme involved in the production of collagen that also plays a role in the regulation of [[energy metabolism]] via downregulation of [[pyruvate dehydrogenase]] during [[hypoxia]].<ref>{{Cite journal|last=Schneider|first=Martin|last2=Harnoss|first2=Jonathan Michael|last3=Strowitzki|first3=Moritz J.|last4=Radhakrishnan|first4=Praveen|last5=Platzer|first5=Lisa|last6=Harnoss|first6=Julian Camill|last7=Hank|first7=Thomas|last8=Cai|first8=Jun|last9=Ulrich|first9=Alexis|date=Jan 2015|title=Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges|url=https://www.dovepress.com/therapeutic-inhibition-of-prolyl-hydroxylase-domain-containing-enzymes-peer-reviewed-fulltext-article-HP|journal=Hypoxia|language=English|volume=3|pages=1|doi=10.2147/HP.S60872|issn=2324-1128}}</ref> The data are based on self-reported diagnosis of [[chronic fatigue syndrome]] and involve a sample size that is very small for genome-wide association studies (n=1829), making confidence intervals difficult to estimate.<ref>{{Cite news|url=https://mecfsresearchreview.me/2018/06/11/analysis-of-data-from-500000-individuals-in-uk-biobank-demonstrates-an-inherited-component-to-me-cfs/amp/?__twitter_impression=true|title=Analysis of data from 500,000 individuals in UK Biobank demonstrates an inherited component to ME/CFS|date=2018-06-11|work=ME/CFS Research Review|access-date=2018-11-11|language=en-US}}</ref>

Elevated levels of [[hydroxyproline]], a marker of collagen breakdown, was found by [[Wenzhong Xiao]] in the [[Severely Ill Patient Study]].<ref>{{Citation|last=Open Medicine Foundation - OMF|title=Wenzhong Xiao, PhD {{!}} Results from the Severely Ill Patient Study (SIPS)|date=2018-11-07|url=https://www.youtube.com/watch?v=_N1o2gbaCl4&feature=youtu.be&t=853|access-date=2019-07-16}}</ref> [[Robert Naviaux]]’s work has suggested it as a possible [[Diagnostic biomarker|biomarker]] for female [[ME/CFS]] patients.<ref>{{Cite journal|last=Gordon|first=Eric|last2=Anderson|first2=Wayne|last3=Nathan|first3=Neil|last4=Baxter|first4=Asha|last5=Wang|first5=Lin|last6=Alaynick|first6=William A.|last7=Bright|first7=A. Taylor|last8=Li|first8=Kefeng|last9=Naviaux|first9=Jane C.|date=2016-09-13|title=Metabolic features of chronic fatigue syndrome|url=https://www.pnas.org/content/113/37/E5472|journal=Proceedings of the National Academy of Sciences|language=en|volume=113|issue=37|pages=E5472–E5480|doi=10.1073/pnas.1607571113|issn=0027-8424|pmid=27573827}}</ref> [[Maureen Hanson]] failed to find elevated hydroxyproline in her metabolomics study.{{Citation needed|reason=}}

==As a supplement==
When hydrolyzed, collagen is reduced to small [[peptide]]s, which can be ingested in the form of [[dietary supplement]] or [[functional food]]s and beverages with the intent to aid joint and bone health and enhance skin health.<ref>{{Cite journal|last=Guillerminet|first=Fanny|last2=Beaupied|first2=Hélène|last3=Fabien-Soulé|first3=Véronique|last4=Tomé|first4=Daniel|last5=Benhamou|first5=Claude-Laurent|last6=Roux|first6=Christian|last7=Blais|first7=Anne|date=2010-03-01|title=Hydrolyzed collagen improves bone metabolism and biomechanical parameters in ovariectomized mice: An in vitro and in vivo study|url=http://www.thebonejournal.com/article/S8756-3282(09)02003-1/abstract|journal=Bone|language=English|volume=46|issue=3|pages=827–834|doi=10.1016/j.bone.2009.10.035|issn=8756-3282}}</ref><ref>{{Cite journal|last=Guillerminet|first=F.|last2=Fabien-Soulé|first2=V.|last3=Even|first3=P. C.|last4=Tomé|first4=D.|last5=Benhamou|first5=C.-L.|last6=Roux|first6=C.|last7=Blais|first7=A.|date=2012-07-01|title=Hydrolyzed collagen improves bone status and prevents bone loss in ovariectomized C3H/HeN mice|url=https://link.springer.com/article/10.1007/s00198-011-1788-6|journal=Osteoporosis International|language=en|volume=23|issue=7|pages=1909–1919|doi=10.1007/s00198-011-1788-6|issn=0937-941X}}</ref><ref>{{Cite journal|last=Daneault|first=A.|date=2014-04-01|title=Hydrolyzed collagen contributes to osteoblast differentiation in vitro and subsequent bone health in vivo|url=http://www.oarsijournal.com/article/S1063-4584(14)00280-5/fulltext|journal=Osteoarthritis and Cartilage|language=English|volume=22|pages=S131|doi=10.1016/j.joca.2014.02.240|issn=1063-4584}}</ref><ref>{{Cite journal|last=Daneault|first=Audrey|last2=Prawitt|first2=Janne|last3=Fabien Soulé|first3=Véronique|last4=Coxam|first4=Véronique|last5=Wittrant|first5=Yohann|date=2017-06-13|title=Biological effect of hydrolyzed collagen on bone metabolism|journal=Critical Reviews in Food Science and Nutrition|volume=57|issue=9|pages=1922–1937|doi=10.1080/10408398.2015.1038377|issn=1549-7852|pmid=25976422|url=https://zenodo.org/record/889529|deadurl=no|archiveurl=https://web.archive.org/web/20170913183348/https://zenodo.org/record/889529|archivedate=2017-09-13|df=}}</ref><ref>{{Cite journal|last=Jiang|first=J.X.|date=2014|title=Collagen peptides improve knee osteoarthritis in elderly women: A 6-month randomized, double-blind, placebo-controlled study|url=http://old.teknoscienze.com//articles/agro-food-industry-hi-tech-collagen-peptides-improve-knee-osteoarthritis-in-elderly-women-a.aspx#.WXCW-oSGNtR|journal=Agro FOOD Indusrty Hi Tech|volume=25|pages=19–23|via=|deadurl=no|archiveurl=https://web.archive.org/web/20170913183401/http://old.teknoscienze.com//articles/agro-food-industry-hi-tech-collagen-peptides-improve-knee-osteoarthritis-in-elderly-women-a.aspx#.WXCW-oSGNtR|archivedate=2017-09-13|df=}}</ref><ref>{{Cite journal|last=Dar|first=Qurratul-Ain|last2=Schott|first2=Eric M.|last3=Catheline|first3=Sarah E.|last4=Maynard|first4=Robert D.|last5=Liu|first5=Zhaoyang|last6=Kamal|first6=Fadia|last7=Farnsworth|first7=Christopher W.|last8=Ketz|first8=John P.|last9=Mooney|first9=Robert A.|date=2017-04-06|title=Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174705|journal=PLOS ONE|volume=12|issue=4|pages=e0174705|doi=10.1371/journal.pone.0174705|issn=1932-6203|pmc=5383229|pmid=28384173|deadurl=no|archiveurl=https://web.archive.org/web/20170913184032/http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0174705|archivedate=2017-09-13|df=|bibcode=2017PLoSO..1274705D}}</ref><ref>{{Cite journal|last=Asserin|first=Jérome|last2=Lati|first2=Elian|last3=Shioya|first3=Toshiaki|last4=Prawitt|first4=Janne|date=2015-12-01|title=The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo‐controlled clinical trials|url=http://onlinelibrary.wiley.com/doi/10.1111/jocd.12174/full|journal=Journal of Cosmetic Dermatology|language=en|volume=14|issue=4|pages=291–301|doi=10.1111/jocd.12174|issn=1473-2165|deadurl=no|archiveurl=https://web.archive.org/web/20170910193750/http://onlinelibrary.wiley.com/doi/10.1111/jocd.12174/full|archivedate=2017-09-10|df=}}</ref> These [[hydroxyproline]]-containing peptides are transported into the target tissues (e.g., skin, bones, and cartilage), where they act as building blocks for local cells and help boost the production of new collagen fibers.<ref>{{Cite journal|last=Ichikawa|first=Satomi|last2=Morifuji|first2=Masashi|last3=Ohara|first3=Hiroki|last4=Matsumoto|first4=Hitoshi|last5=Takeuchi|first5=Yasuo|last6=Sato|first6=Kenji|date=2010-02-01|title=Hydroxyproline-containing dipeptides and tripeptides quantified at high concentration in human blood after oral administration of gelatin hydrolysate|url=https://dx.doi.org/10.3109/09637480903257711|journal=International Journal of Food Sciences and Nutrition|volume=61|issue=1|pages=52–60|doi=10.3109/09637480903257711|issn=0963-7486|pmid=19961355}}</ref><ref>{{Cite journal|last=Shigemura|first=Yasutaka|last2=Kubomura|first2=Daiki|last3=Sato|first3=Yoshio|last4=Sato|first4=Kenji|date=2014-09-15|title=Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion|url=http://www.sciencedirect.com/science/article/pii/S0308814614002763|journal=Food Chemistry|volume=159|pages=328–332|doi=10.1016/j.foodchem.2014.02.091}}</ref><ref>{{Cite journal|last=Watanabe-Kamiyama|first=Mari|last2=Shimizu|first2=Muneshige|last3=Kamiyama|first3=Shin|last4=Taguchi|first4=Yasuki|last5=Sone|first5=Hideyuki|last6=Morimatsu|first6=Fumiki|last7=Shirakawa|first7=Hitoshi|last8=Furukawa|first8=Yuji|last9=Komai|first9=Michio|date=2010-01-27|title=Absorption and Effectiveness of Orally Administered Low Molecular Weight Collagen Hydrolysate in Rats|url=https://dx.doi.org/10.1021/jf9031487|journal=Journal of Agricultural and Food Chemistry|volume=58|issue=2|pages=835–841|doi=10.1021/jf9031487|issn=0021-8561}}</ref>

== Potential modulators ==
The following are compounds that can or might increase collagen synthesis, inhibit collagen destruction, or improve collagen strength. Compounds proven to promote connective tissue repair in vivo, or proven to reduce connective tissue-degrading [[matrix metalloproteinase]] (MMP) enzymes in vivo, are indicated by the "shown effective in vivo" column.

{| class="wikitable"
!Compound
!Type
!Shown effective in vivo
!
!Mechanism of action
|-
|[[Aloe vera]]
|[[Polysaccharide]]
|
|Promotes synthesis, and inhibits destruction
|Stimulates fibroblast proliferation and collagen synthesis. Inhibits MMP-2 and MMP-9 in vitro.<ref name=":4">{{Cite journal|last=Kudalkar|first=Mithun D.|last2=Nayak|first2=Aarati|last3=Bhat|first3=Kishore S.|last4=Nayak|first4=Ranganath N.|date=Jan 2014|title=Effect of Azadirachta indica (Neem) and Aloe vera as compared to subantimicrobial dose doxycycline on matrix metalloproteinases (MMP)-2 and MMP-9: An in-vitro study|url=https://www.ncbi.nlm.nih.gov/pubmed/25364206|journal=Ayu|volume=35|issue=1|pages=85–89|doi=10.4103/0974-8520.141947|issn=0974-8520|pmc=4213975|pmid=25364206}}</ref>
|-
|[[Pentadecapeptide BPC 157]]
|[[Peptide]]
|Yes
|Promotes synthesis
|Stimulates growth factor receptors on fibroblasts.<ref>{{Cite journal|last=Gwyer|first=Daniel|last2=Wragg|first2=Nicholas M.|last3=Wilson|first3=Samantha L.|date=Aug 2019|title=Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing|url=https://www.ncbi.nlm.nih.gov/pubmed/30915550|journal=Cell and Tissue Research|volume=377|issue=2|pages=153–159|doi=10.1007/s00441-019-03016-8|issn=1432-0878|pmid=30915550}}</ref><ref>{{Cite journal|last=Staresinic|first=M.|last2=Sebecic|first2=B.|last3=Patrlj|first3=L.|last4=Jadrijevic|first4=S.|last5=Suknaic|first5=S.|last6=Perovic|first6=D.|last7=Aralica|first7=G.|last8=Zarkovic|first8=N.|last9=Borovic|first9=S.|date=Nov 2003|title=Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth|url=https://www.ncbi.nlm.nih.gov/pubmed/14554208|journal=Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society|volume=21|issue=6|pages=976–983|doi=10.1016/S0736-0266(03)00110-4|issn=0736-0266|pmid=14554208}}</ref>
|-
|[[GABA]]
|Supplement
|Yes
|Promotes synthesis
|GABA dramatically increases the formation of elastic fibers and up-regulates the expression of type I collagen in human dermal fibroblasts.<ref>{{Cite journal|last=Uehara|first=Eriko|last2=Hokazono|first2=Hideki|last3=Hida|first3=Mariko|last4=Sasaki|first4=Takako|last5=Yoshioka|first5=Hidekatsu|last6=Matsuo|first6=Noritaka|date=Jun 2017|title=GABA promotes elastin synthesis and elastin fiber formation in normal human dermal fibroblasts (HDFs)|url=https://www.ncbi.nlm.nih.gov/pubmed/28485217|journal=Bioscience, Biotechnology, and Biochemistry|volume=81|issue=6|pages=1198–1205|doi=10.1080/09168451.2017.1290518|issn=1347-6947|pmid=28485217}}</ref> GABA 100 mg daily is shown to increase skin skin elasticity in women.<ref>{{Cite journal|last=絵理子|first=上原|last2=英樹|first2=外薗|date=2016-07-15|title=γ-アミノ酪酸の経口摂取による皮膚状態改善効果|url=https://www.jstage.jst.go.jp/article/nskkk/63/7/63_306/_article/-char/en|journal=日本食品科学工学会誌|language=ja|volume=63|issue=7|pages=306–311|doi=10.3136/nskkk.63.306|issn=1341-027X}}</ref>
|-
|Thymosin beta 4 (TB-500)
|Peptide
|Yes
|Promotes synthesis
|Helps repair ligaments.<ref>{{Cite journal|last=Xu|first=Bo|last2=Yang|first2=Mowen|last3=Li|first3=Zhaozhu|last4=Zhang|first4=Yubo|last5=Jiang|first5=Zhitao|last6=Guan|first6=Shengyang|last7=Jiang|first7=Dapeng|date=2013-06-10|title=Thymosin β4 enhances the healing of medial collateral ligament injury in rat|url=https://www.ncbi.nlm.nih.gov/pubmed/23523891|journal=Regulatory Peptides|volume=184|pages=1–5|doi=10.1016/j.regpep.2013.03.026|issn=1873-1686|pmid=23523891}}</ref>
|-
|Collagen peptides
|[[Amino acid]]
|
|Co-factor essential for synthesis
|Contains proline, lysine and other amino acids necessary for collagen synthesis.
|-
|[[Vitamin C]]
|[[Vitamin]]
|
|Co-factor essential for synthesis
|Catalyzes the enzymes [[procollagen-proline dioxygenase]] and lysl hydroxylase.
|-
|[[Copper]]
|[[Mineral]]
|
|Co-factor essential for synthesis
|Catalyzes the enzyme [[lysyl dioxidase]].
|-
|[[Doxycycline]]
|[[Antibiotic]]
|Yes
|Inhibits destruction
|Inhibits matrix metalloproteinases MMP-1, 2, 7, 8, 9, 12 and 13, and is effective at MMP inhibition at a low dose of 20 mg twice daily.<ref>{{Cite journal|last=Del Buono|first=Angelo|last2=Oliva|first2=Francesco|last3=Osti|first3=Leonardo|last4=Maffulli|first4=Nicola|date=2013-05-21|title=Metalloproteases and tendinopathy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676164/|journal=Muscles, Ligaments and Tendons Journal|volume=3|issue=1|pages=51–57|doi=10.11138/mltj/2013.3.1.051|issn=2240-4554|pmc=3676164|pmid=23885345}}</ref> Sold as the drug Periostat, which is the only FDA approved MMP inhibitor.
|-
|[[Fish oil]]
|Supplement
|Yes
|Inhibits destruction
|Fish oil 9.6 grams per day reduced MMP-9 secretion from immune cells by 58% after 3 months in multiple sclerosis patients.<ref>{{Cite journal|last=Shinto|first=L.|last2=Marracci|first2=G.|last3=Baldauf-Wagner|first3=S.|last4=Strehlow|first4=A.|last5=Yadav|first5=V.|last6=Stuber|first6=L.|last7=Bourdette|first7=D.|date=Feb 2009|title=Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/19171471|journal=Prostaglandins, Leukotrienes, and Essential Fatty Acids|volume=80|issue=2-3|pages=131–136|doi=10.1016/j.plefa.2008.12.001|issn=0952-3278|pmc=2692605|pmid=19171471}}</ref>
|-
|Q10
|Supplement
|Yes
|Inhibits destruction
|Q10 at 500 mg daily reduced MMP-9 in multiple sclerosis patients.<ref>{{Cite journal|last=Sanoobar|first=Meisam|last2=Eghtesadi|first2=Shahryar|last3=Azimi|first3=Amirreza|last4=Khalili|first4=Mohammad|last5=Khodadadi|first5=Behnam|last6=Jazayeri|first6=Shima|last7=Gohari|first7=Mahmood Reza|last8=Aryaeian|first8=Nahid|date=May 2015|title=Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/24621064|journal=Nutritional Neuroscience|volume=18|issue=4|pages=169–176|doi=10.1179/1476830513Y.0000000106|issn=1476-8305|pmid=24621064}}</ref>
|-
|Ecklonia cava
|Supplement
|Yes
|Inhibits destruction
|Ecklonia cava, an edible marine brown alga sold as a supplement, inhibits MMP-2 and MMP-9 and in a rat study reduced periodontitis.<ref>{{Cite journal|last=Kim|first=Seonyoung|last2=Choi|first2=Soo-Im|last3=Kim|first3=Gun-Hee|last4=Imm|first4=Jee-Young|date=2019-05-22|title=Anti-Inflammatory Effect of Ecklonia cava Extract on Porphyromonas gingivalis Lipopolysaccharide-Stimulated Macrophages and a Periodontitis Rat Model|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566535/|journal=Nutrients|volume=11|issue=5|doi=10.3390/nu11051143|issn=2072-6643|pmc=6566535|pmid=31121899}}</ref>
|-
|Captopril
|Drug
|Yes
|Inhibits destruction
|Angiotensin-converting enzyme (ACE) inhibitor captopril inhibits serum MMP-9 in patients with Kawasaki disease (this disease is likely caused by infection).<ref>{{Cite journal|last=Inoue|first=Nao|last2=Takai|first2=Shinji|last3=Jin|first3=Denan|last4=Okumura|first4=Kenichi|last5=Okamura|first5=Naoyuki|last6=Kajiura|first6=Mitsugu|last7=Yoshikawa|first7=Sosuke|last8=Kawamura|first8=Naohisa|last9=Tamai|first9=Hiroshi|date=Feb 2010|title=Effect of angiotensin-converting enzyme inhibitor on matrix metalloproteinase-9 activity in patients with Kawasaki disease|url=https://www.ncbi.nlm.nih.gov/pubmed/19945447/|journal=Clinica Chimica Acta; International Journal of Clinical Chemistry|volume=411|issue=3-4|pages=267–269|doi=10.1016/j.cca.2009.11.020|issn=1873-3492|pmid=19945447}}</ref>
|-
|Losartan
|Drug
|Yes
|Inhibits destruction
|Angiotensin II receptor blocker drug losartan decreases MMP-2 and MMP-9.<ref>{{Cite journal|last=Derosa|first=Giuseppe|last2=Maffioli|first2=Pamela|last3=Ferrari|first3=Ilaria|last4=Palumbo|first4=Ilaria|last5=Randazzo|first5=Sabrina|last6=Fogari|first6=Elena|last7=D'Angelo|first7=Angela|last8=Cicero|first8=Arrigo F. G.|date=Jan 2011|title=Different actions of losartan and ramipril on adipose tissue activity and vascular remodeling biomarkers in hypertensive patients|url=https://www.ncbi.nlm.nih.gov/pubmed/21107327|journal=Hypertension Research: Official Journal of the Japanese Society of Hypertension|volume=34|issue=1|pages=145–151|doi=10.1038/hr.2010.205|issn=1348-4214|pmid=21107327}}</ref>
|-
|Neem
|Herb
|
|Inhibits destruction
|Inhibits MMP-2 and MMP-9 in vitro.<ref name=":4" />
|-
|Magnesium
|[[Mineral]]
|
|Inhibits destruction
|An in vitro study found magnesium reduces MMP-2.
|-
|Glucosamine sulfate
|Supplement
|
|Inhibits destruction
|Glucosamine sulfate inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells in vitro.<ref>{{Cite journal|last=Rajapakse|first=Niranjan|last2=Mendis|first2=Eresha|last3=Kim|first3=Moon-Moo|last4=Kim|first4=Se-Kwon|date=2007-07-15|title=Sulfated glucosamine inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells|url=https://www.ncbi.nlm.nih.gov/pubmed/17498959|journal=Bioorganic & Medicinal Chemistry|volume=15|issue=14|pages=4891–4896|doi=10.1016/j.bmc.2007.04.048|issn=0968-0896|pmid=17498959}}</ref>
|-
|Triphala
|Herbal formula
|
|Inhibits destruction
|Inhibits MMP-9 in vitro.<ref>{{Cite journal|last=Abraham|first=Sajith|last2=Kumar|first2=M. Senthil|last3=Sehgal|first3=P. K.|last4=Nitish|first4=S.|last5=Jayakumar|first5=N. D.|date=Apr 2005|title=Evaluation of the inhibitory effect of triphala on PMN-type matrix metalloproteinase (MMP-9)|url=https://www.ncbi.nlm.nih.gov/pubmed/15857087/|journal=Journal of Periodontology|volume=76|issue=4|pages=497–502|doi=10.1902/jop.2005.76.4.497|issn=0022-3492|pmid=15857087}}</ref>
|-
|Vitamin K2
|Supplement
|
|
|Inhibits MMP-1 in vitro
|-
|Glucuronolactone
|Supplement
|
|Structural component
|Glucuronolactone is an important structural component of connective tissues in tendons, ligaments and cartilage. A 250 ml can of Red Bull contains 600 mg of glucuronolactone.
|-
|[[Hyaluronic acid]]
|
|
|
|
|}

== See also ==

* [[Ehlers-Danlos syndrome]]
* [[Mast cell activation syndrome]]
* [[Extracellular matrix]]
* [[Mast cell]]
* [[Osteoporosis]]
*[[Hypovitaminosis C]]
* [[Vitamin C]]

== References ==
<references />
[[Category:Proteins]]
[[Category:Biochemistry and cell biology]]

Irritable bowel syndrome

2020-01-04T16:40:05Z

FatigueTrackerBot:/* See also */ Added link to Collagen and Diet

'''Irritable bowel syndrome''' (IBS) is a group of symptoms that occur together including pain or discomfort in your abdomen along with changes in your bowel movements. Also called a functional gastrointestinal (GI) disorder; "when your GI tract behaves in an abnormal way without evidence of damage due to a disease."<ref>{{Cite news|url=https://www.niddk.nih.gov/health-information/digestive-diseases/irritable-bowel-syndrome/definition-facts|title=Definition & Facts for Irritable Bowel Syndrome {{!}} NIDDK|work=National Institute of Diabetes and Digestive and Kidney Diseases|access-date=2018-11-20|language=en-US}}</ref>

IBS affects 10 to 15 percent of US adults. Only 5-7 percent of US adults have received a diagnosis of IBS.<ref>[http://www.niddk.nih.gov/health-information/health-topics/digestive-diseases/irritable-bowel-syndrome/Pages/definition-facts.aspx How Common is IBS - NIH Health Topics]</ref>

== Four types of IBS ==
Stool consistency dictates the four types.<ref>[http://www.niddk.nih.gov/health-information/health-topics/digestive-diseases/irritable-bowel-syndrome/Pages/definition-facts.aspx Definition and Facts for Irritable Bowel Syndrome - IBS - NIH Health Topics]</ref>

*IBS with constipation
*IBS with diarrhea
*Mixed IBS
*Unsubtyped IBS

== ME/CFS and IBS ==
*[https://www.verywell.com/irritable-bowel-syndrome-in-fibromyalgia-cfs-716167 Irritable Bowel Syndrome in Fibromyalgia & Chronic Fatigue Syndrome - Why Do They Go Together?]

:"[[Fibromyalgia]], [[chronic fatigue syndrome]] and irritable bowel syndrome (IBS) frequently go together. No one really knows why, but we do know that all three conditions can include imbalances of serotonin -- although in fibromyalgia (FMS) and chronic fatigue syndrome ([[CFS]] or [[ME/CFS]]) it's an imbalance in the brain, while with IBS it's in the gut."<ref>[http://chronicfatigue.about.com/od/whyfmscfsarelinked/a/IBS.htm Irritable Bowel Syndrome in Fibromyalgia & Chronic Fatigue Syndrome - Why Do They Go Together? - About.com Health FMS/ME/CFS]</ref>

*[https://www.ncbi.nlm.nih.gov/pubmed/25433843 Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without irritable bowel syndrome (IBS).]

:The findings show that is a characteristic of a subset of patients with ME/CFS and that increased bacterial translocation (leaky gut) is associated with IBS symptoms. This study has defined a pathway phenotype, i.e bacterial translocation, that is related to [[ME/CFS]] and [[IBS]] and that may drive systemic inflammatory processes.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/25433843 Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome.- NCBI,(2014) Study]</ref>

*[https://www.amazon.co.uk/Running-Empty-Complete-Chronic-Syndrome/dp/0897931912/ Prevalence of 50-90% for IBS symptoms in ME/CFS patients.]

:Katrina Berne reports a prevalence of 50-90% for IBS symptoms (including diarrhea, nausea, gas, and abdominal pain) in ME/CFS patients.<ref>{{citation |last= Berne |first= Katrina |date= 1 Dec 1995 |title= Running on Empty: The Complete Guide to Chronic Fatigue Syndrome (CFIDS), 2nd ed. |url= https://www.amazon.co.uk/Running-Empty-Complete-Chronic-Syndrome/dp/0897931912/ |publisher= Hunter House |page= 58 |isbn= 978-0897931915}}</ref>

== Tests and diagnosis ==
Mayo Clinic provides the following information on IBS, ''Tests and Diagnosis''<ref>[http://www.mayoclinic.org/diseases-conditions/irritable-bowel-syndrome/basics/tests-diagnosis/CON-20024578 Irritable Bowel Syndrome - Tests and Diagnosis - Mayo Clinic]</ref>

''Excerpt:''
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description= "What it's Like to Have a Flexible Sigmoidoscopy. By Cancer Research UK">https://www.youtube.com/watch?v=FPCar0b5_mk</embedvideo>
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description= "What happens during and after a colonoscopy? By You and Colonoscopy">https://www.youtube.com/watch?v=mh90RPA-C10</embedvideo>
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description= "CT (Computed Tomography) Scan: What to expect By UW Medicine">https://www.youtube.com/watch?v=uHu9aa0QDiE</embedvideo>
:*'''Rome criteria'''. According to these criteria, you must have certain signs and symptoms before a doctor diagnoses irritable bowel syndrome. The most important are abdominal pain and discomfort lasting at least three days a month in the last three months, associated with two or more of following: improvement with defecation, altered frequency of stool or altered consistency of stool.

:*'''Manning criteria'''. These criteria focus on pain relieved by defecation, having incomplete bowel movements, mucus in the stool and changes in stool consistency. The more symptoms present, the greater the likelihood of IBS.

:Some red flag signs and symptoms that suggest a need for additional testing include:

:*New onset after age 50
:*Weight loss
:*Rectal bleeding
:*Fever
:*Nausea or recurrent vomiting
:*Abdominal pain, especially if it's not completely relieved by a bowel movement, or occurs at night
:*Diarrhea that is persistent or awakens you from sleep
:*Anemia related to low iron

Imaging:
*Additional Tests:
*Flexible sigmoidoscopy
*Colonoscopy
*X-ray (radiography)
*Computerized tomography (CT) scan
*Lower GI series<ref>[http://www.mayoclinic.org/diseases-conditions/irritable-bowel-syndrome/basics/tests-diagnosis/CON-20024578 Irritable Bowel Syndrome - Tests and Diagnosis - Mayo Clinic]</ref>

Laboratory tests:

*Lactose intolerance
*Breath
*Blood
*Stool<ref>[http://www.mayoclinic.org/diseases-conditions/irritable-bowel-syndrome/basics/tests-diagnosis/CON-20024578 Irritable Bowel Syndrome - Tests and Diagnosis - Mayo Clinic]</ref>

== See also ==
*[[Collagen]]
*[[Diet]]
*[[Low FODMAP diet|Low FODMAP Diet]] - an effective treatment for IBS
*[[Gastroparesis]]
*[[Vitamin C]]
*[[Vitamin C Deficiency without Scurvy hypothesis]]
*[[Scurvy]]

== Learn more ==
*[http://www.newsweek.com/ibs-mind-study-brain-gut-microbes-flora-microbiome-606848 Is IBS All In Your Mind? New Study Hints at Close Ties Between the Brain and the Gut] (2017) Newsweek Tech & science (Article w/ Video)
*[https://jcoynester.wordpress.com/2016/05/21/no-irritable-bowel-syndrome-is-not-all-in-your-head/ Blog entry - "No, irritable bowel syndrome is not all in your head"]

== References ==

[[Category:Diagnoses]]
[[Category:Potential comorbidities]]
[[Category:Signs and symptoms]]
[[Category:Digestive signs and symptoms]]
<references />

Vitamin C

2020-01-04T16:36:43Z

FatigueTrackerBot:/* See also */ Added link to Diet

'''Vitamin C''', also known as '''ascorbic acid''', is a water-soluble vitamin found particularly in citrus fruits and green vegetables. It is essential for [[collagen]], [[catecholamine]], and [[carnitine]] biosynthesis.<ref>{{Cite journal|last=Michels|first=Alexander J.|last2=Hagen|first2=Tory M.|last3=Frei|first3=Balz|date=2013|title=Human Genetic Variation Influences Vitamin C Homeostasis by Altering Vitamin C Transport and Antioxidant Enzyme Function|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357493/|journal=Annual review of nutrition|volume=33|pages=45–70|doi=10.1146/annurev-nutr-071812-161246|issn=0199-9885|pmc=4357493|pmid=23642198}}</ref>

One of its roles is as an antioxidant, that is, it helps to protect cells from damage by oxidative stress and also improves mitochondrial function. Another role is as a cofactor for several enzymes.<ref>{{Cite book|url=https://www.worldcat.org/oclc/55641398|title=Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids : a report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine.|date=2000|publisher=National Academy Press|others=National Research Council (U.S.), Institute of Medicine (U.S.)|isbn=0309597196|location=Washington, D.C.|oclc=55641398}}</ref> After absorption, Vitamin C is present throughout the whole body.

Large cross-sectional population studies confirm that vitamin C deficiency is common in humans, affecting 5%–10% of adults in the industrialized world. Moreover, significant associations between poor vitamin C status and increased morbidity and mortality have consistently been observed. However, the absorption, distribution and elimination kinetics of vitamin C ''in vivo'' are highly complex, due to dose-dependent non-linearity, and the specific regulatory mechanisms are not fully understood.<ref name="lindblad2013" /> In addition, the optimal daily intake as well as the typical total body pool of vitamin C during health and disease remain unknown.<ref name="ginter1979" /><ref name="ginter1980" /><ref name="ginter1982" /><ref name="lykkesfeldt2019" />

[[File:Nutrients-05-02860-g001.jpg|right|300x300px]]

==Biology==
Vitamin C is found in the whole body, even skin tissue.<ref name="padayatty2016" /><ref name="pullar2017" /> High levels of vitamin C are found in the [[eyes]], [[pituitary]], [[adrenal gland]], [[pancreas]], [[liver]], [[spleen]] and [[brain]]. Vitamin C is also found in relative high levels in the [[bone marrow]], [[muscles]] and [[skin]].<ref name="pullar2017" /><ref>{{Cite journal|last=|first=|date=|title=Vitamin neurotoxicity|url=https://www.ncbi.nlm.nih.gov/pubmed/1463588|journal=Mol Neurobiology|volume=|pages=|via=}}</ref> Bone marrow is probably also involved in the vitamin C homeostasis process.<ref name="padayatty2016" /><ref name="seftel1966" /><ref name="aghajanian2015" />
[[File:VitCinskinPullar2017.jpg|right|300x300px]]

The adrenal gland can inject vitamin C into the blood.<ref name="padayatty2016" />

Too much sun exposure may deplete the Vitamin C stores in the skin tissue.<ref name="pullar2017" />

== In human disease ==
Vitamin C is important in [[mast cell activation disorder]] for its role in the breakdown of [[histamine]] and as a [[mast cell]] stabilizer. Vitamin C is also a co-factor in [[collagen]] synthesis, making it a potentially important nutrient in [[Ehlers-Danlos syndrome]] and other [[connective tissue]] disorders.<ref>{{Cite journal|last=Mantle|first=D.|last2=Wilkins|first2=R. M.|last3=Preedy|first3=V.|date=2005-01-01|title=A novel therapeutic strategy for Ehlers–Danlos syndrome based on nutritional supplements|url=http://www.sciencedirect.com/science/article/pii/S0306987704004566|journal=Medical Hypotheses|volume=64|issue=2|pages=279–283|doi=10.1016/j.mehy.2004.07.023|issn=0306-9877}}</ref><ref>{{Cite journal|last=Dembure|first=Philip P.|last2=Janko|first2=Anita R.|last3=Priest|first3=Jean H.|last4=Elsas|first4=Louis J.|date=1987-07-01|title=Ascorbate regulation of collagen biosynthesis in Ehlers-Danlos syndrome, type VI|url=http://www.sciencedirect.com/science/article/pii/0026049587901557|journal=Metabolism|volume=36|issue=7|pages=687–691|doi=10.1016/0026-0495(87)90155-7|issn=0026-0495}}</ref><ref>{{Cite journal|last=Elsas|first=Louis J.|last2=Miller|first2=Robert L.|last3=Pinnell|first3=Sheldon R.|date=1978-03-01|title=Inherited human collagen lysyl hydroxylase deficiency: Ascorbic acid response|url=http://www.sciencedirect.com/science/article/pii/S0022347678804235|journal=The Journal of Pediatrics|volume=92|issue=3|pages=378–384|doi=10.1016/S0022-3476(78)80423-5|issn=0022-3476}}</ref><ref>{{Cite journal|last=Kanof|first=Abram|date=1952-02-01|title=EHLERS-DANLOS SYNDROME: Report of a Case with Suggestion of a Possible Causal Mechanism|url=https://jamanetwork.com/journals/jamapediatrics/fullarticle/495523|journal=A.M.A. American Journal of Diseases of Children|language=en|volume=83|issue=2|pages=197–202|doi=10.1001/archpedi.1952.02040060063007|issn=0096-8994}}</ref><ref>{{Cite journal|last=Ringsdorf|first=W. M.|last2=Cheraskin|first2=E.|date=1982-03-01|title=Vitamin C and human wound healing|url=http://www.sciencedirect.com/science/article/pii/003042208290295X|journal=Oral Surgery, Oral Medicine, Oral Pathology|volume=53|issue=3|pages=231–236|doi=10.1016/0030-4220(82)90295-X|issn=0030-4220}}</ref><ref>{{Cite book|url=https://books.google.com/books?hl=en&lr=&id=x-Z-cXUGlL8C&oi=fnd&pg=PR5&ots=FzzS-w8isY&sig=vY_ard7hUgYcNfbXatqmS7ltZGA#v=onepage&q&f=false|title=Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects|last=Royce|first=Peter M.|last2=Steinmann|first2=Beat|date=2003-04-14|publisher=John Wiley & Sons|isbn=978-0-471-46117-3|language=en}}</ref> Deficiency of vitamin C may contribute to [[osteoporosis]].<ref name="seftel1966" /><ref name="aghajanian2015" />

Vitamin C deficiency leads to altered function of [[procollagen-proline dioxygenase]] and [[lysyl hydroxylase]] enzymes. Each are essential for collagen synthesis and require Vitamin C as a cofactor.<ref>{{Cite journal|last=Wu|first=Marlyn|last2=Crane|first2=Jonathan S.|date=2019|title=Biochemistry, Collagen Synthesis|url=http://www.ncbi.nlm.nih.gov/books/NBK507709/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29939531}}</ref>

=== Mast cell activation disorder ===
Numerous studies have found Vitamin C to be inversely correlated with histamine and that the administration of Vitamin C reduces blood [[histamine]] levels.<ref name="clemetson1980" /><ref name="johnston1992" /><ref>{{Cite journal|last=Johnston|first=CS|date=December 1996|title=Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults|url=https://www.ncbi.nlm.nih.gov/pubmed/8951736|journal=J Am Coll Nutr.|volume=|pages=|via=}}</ref> It does this potentially through several mechanisms: by inhibiting mast cell production; by increasing [[diamine oxidase]] (an [[enzyme]] that breaks down histamine); by inhibiting mast cell degranulation and the release of histamine in the first place (i.e., as a mast cell stabilizer),<ref name=":0">{{Cite journal|last=Mio|first=M|date=1999|title=Ultraviolet B (UVB) light-induced histamine release from rat peritoneal mast cells and its augmentation by certain phenothiazine compounds|url=https://www.sciencedirect.com/science/article/pii/S0162310998000538|journal=Immunopharmacology|volume=|pages=|via=}}</ref> and by inhibiting [[histidine decarboxylase]] (the enzyme that forms histamine).<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903110/|title=Pharmacological treatment options for mast cell activation disease|last=Molderings|first=Gerhard|date=2016|journal=Naunyn Schmiedebergs Arch Pharmacol|volume=|pages=|via=}}</ref>

[[File:Nihms-754526-f0008.jpg|right|300x300px]]

=== Ehlers-Danlos Syndrome ===
A case study found improved wound healing in a patient with vascular [[Ehlers-Danlos Syndrome]] who was given high-dose (4g/day) oral vitamin C supplementation for two years.<ref>{{Cite journal|last=Ringsdorf|first=W. M.|last2=Cheraskin|first2=E.|date=1982-03-01|title=Vitamin C and human wound healing|url=http://www.sciencedirect.com/science/article/pii/003042208290295X|journal=Oral Surgery, Oral Medicine, Oral Pathology|volume=53|issue=3|pages=231–236|doi=10.1016/0030-4220(82)90295-X|issn=0030-4220}}</ref> A case study of two patients with Kyphoscoliotic EDS received high-dose Vitamin C (5g/day). After one year, they had reduced bleeding time and improve wound healing, and muscle strength.<ref>{{Cite journal|last=Dembure|first=Philip P.|last2=Janko|first2=Anita R.|last3=Priest|first3=Jean H.|last4=Elsas|first4=Louis J.|date=1987-07-01|title=Ascorbate regulation of collagen biosynthesis in Ehlers-Danlos syndrome, type VI|url=http://www.sciencedirect.com/science/article/pii/0026049587901557|journal=Metabolism|volume=36|issue=7|pages=687–691|doi=10.1016/0026-0495(87)90155-7|issn=0026-0495}}</ref>

== Supplementation ==
Several studies indicates the recovery from Vitamin C depletion will require several months of treatment. <ref name="padayatty2016" />

== Notable studies ==
* 2014, Mitochondrial dysfunction and chronic disease: treatment with natural supplements<ref>{{Cite journal|last=Nicolson|first=Garth L.|author-link=Garth Nicolson|author-link2=|author-link3=|author-link4=|author-link5=|date=2014|title=Mitochondrial dysfunction and chronic disease: treatment with natural supplements|url=https://www.ncbi.nlm.nih.gov/pubmed/24473982|journal=Alternative Therapies in Health and Medicine|volume=20 Suppl 1|issue=|pages=18–25|issn=1078-6791|pmid=24473982|quote=|via=}}</ref> [https://www.researchgate.net/publication/259960416_Mitochondrial_Dysfunction_and_Chronic_Disease_Treatment_With_Natural_Supplements (Full text)]

==See also==
*[[Vitamin C Deficiency without Scurvy hypothesis]]
*[[Collagen]]
*[[Mast cell activation syndrome]]
*[[Scurvy]]
*[[Vitamin]]
*[[Irritable bowel syndrome]]
*[[Osteoporosis]]
*[[Diet]]

==Learn more==

*[http://lpi.oregonstate.edu/mic/vitamins/vitamin-C Linus Pauling Institute Micronutrient Information Center - Vitamin C]

==References==
<references>
<ref name="ginter1979">{{Citation| issue = 33| pages = 104-141| last = Ginter| first = Emil| title = Chronic marginal vitamin C deficiency: biochemistry and pathophysiology.| journal = World Rev Nutr Diet| date = 1979|doi=10.1159/000402551|url=https://www.ncbi.nlm.nih.gov/pubmed/392953}}</ref>
<ref name="ginter1980">{{Citation| volume = 33| issue = 3| pages = 538-539| last = Ginter| first = Emil| title = What is truly the maximum body pool size of ascorbic acid in man?| journal = Am J Clin Nutr| date = Mar 1980|doi=10.1093/ajcn/33.3.538|url=https://www.ncbi.nlm.nih.gov/pubmed/6986762}}</ref>
<ref name="ginter1982">{{Citation| volume = 1| issue = 2| pages = 66-77| last = Ginter| first = Emil| title = Optimum Intake of Vitamin C for the Human Organism| journal = Nutrition and Health| date = Apr 1982|doi=10.1177/026010608200100202|url=https://journals.sagepub.com/doi/10.1177/026010608200100202}}</ref><ref name="lindblad2013">{{Citation| issn = 2072-6643| issue = 5| pages = 2860-2879| last = Lindblad| first = Maiken|last2 = Tveden-Nyborg| first2 = Pernille| last3 = Lykkesfeldt| first3 = Jens| title = Regulation of Vitamin C Homeostasis during Deficiency| journal = Nutrients| date = May 2013|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775232}}</ref>
<ref name="lykkesfeldt2019">{{Citation| volume = 11| issue = 10| last2 = Tveden-Nyborg| first2 = Pernille| last = Lykkesfeldt| first = Jens| title = The Pharmacokinetics of Vitamin C| journal = Nutrients| date = Oct 2019|doi=10.3390/nu11102412|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835439}}</ref>
<ref name="padayatty2016">{{Citation|volume = 22| issue = 6| pages = 463-93| last = Padayatty| first = Sebastian| last2 = Levine| first2 = Mark| title = Vitamin C: the known and the unknown and Goldilocks| journal = Oral Disease| date = June 2016|url = https://www.ncbi.nlm.nih.gov/pubmed/26808119}}</ref>
<ref name="clemetson1980">{{Citation| issn = 0022-3166| volume = 110| issue = 4| pages = 662–668| last = Clemetson| first = C. A.| title = Histamine and ascorbic acid in human blood| journal = The Journal of Nutrition| date = April 1980| pmid = 7365537}}</ref>
<ref name="johnston1992">{{Citation| issn = 0731-5724| volume = 11| issue = 2| pages = 172–176| last1 = Johnston| first1 = C. S.| last2 = Martin| first2 = L. J.| last3 = Cai| first3 = X.| title = Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis| journal = Journal of the American College of Nutrition| date = April 1992| pmid = 1578094}}</ref>
<ref name="seftel1966">{{Citation| volume = 1| issue = 5488| pages = 642-644| last1 = Seftel| first1 = H| last2 = Malkin| first2 = C| last3 = Schmaman| first3 = A| last4 = Abrahams| first4 = C| last5 = Lynch| first5 = S| last6 = Charlton| first6 = S| last7 = Bothwell| first7 = T| title = Osteoporosis, Scurvy, and Siderosis in Johannesburg Bantu| journal = Br Med J|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1843929/}}</ref>
<ref name="aghajanian2015">{{Citation| volume = 30| issue = 11| pages = 1945–1955| last1 = Aghajanian| first1 = P| last2 = Hall| first2 = S.| last3 = Wongworawat| first3 = MD| last4 = Mohan| first4 = S| title = The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments| journal = J Bone Miner Res| date = 2015|url=https://www.ncbi.nlm.nih.gov/pubmed/26358868}}</ref>
<ref name="pullar2017">{{Citation| volume = 9| issue = 8| pages = 866| last1 = Pullar| first1 = JM| last2 = Carr| first2 = AC| last3 = Vissers| first3 = MCM| title = The Roles of Vitamin C in Skin Health| journal = Nutrients| date = 2017|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579659}}</ref>
</references>

[[Category:Potential treatments]]
[[Category:Supplements]]
[[Category:Vitamins]]
[[Category:Nutrients]]

Osteoporosis

2020-01-04T16:31:20Z

FatigueTrackerBot:/* Notable studies */ Added review article

{{stub}}
'''Osteoporosis''', a condition where bones thin and weaken, usually in older adults, resulting in increase risk of bone fractures, especially stress fractures. The risk of developing osteoporosis is considered higher in people with ME/CFS.<ref>{{Cite web|url=https://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/|title=Chronic Fatigue Syndrome and Osteoporosis|date=2009-07-14|website=The Optimum Health Clinic|language=en-US|access-date=2019-10-10}}</ref>

A study in 2014, showed that patients without osteoporosis in the CFS cohort exhibited a 1.16-fold higher risk of fracture than did those in the non-CFS cohort. The researches concluded that although the cause remains unclear, CFS-related fracture might not be associated with osteoporosis.<ref name=":0">{{Cite journal|last=Kao|first=C.-H.|last2=Kuo|first2=C.-N.|last3=Chen|first3=H.-J.|last4=Yang|first4=T.-Y.|last5=Lin|first5=W.-M.|last6=Chen|first6=C.-S.|date=2014-08-01|title=Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study|url=https://academic.oup.com/qjmed/article/107/8/635/2948336|journal=QJM: An International Journal of Medicine|language=en|volume=107|issue=8|pages=635–641|doi=10.1093/qjmed/hcu037|issn=1460-2725}}</ref>

==Presentation==
Fractures and their causative and repair mechanisms have been topics subject to various forms of investigation for several decades.

==Osteoporosis in ME/CFS==

==Possible causes==

==Potential treatments==

Vitamin C can inhibit osteoporosis by promoting osteoblast formation and blocking osteoclastogenesis through the activation of signaling pathways. Therefore, it is suggested that vitamin C improves bone regeneration.{{Citation needed|reason=|date=4 January 2020}}

==Notable studies==
*2014, Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study<ref name=":0" /> - [https://academic.oup.com/qjmed/article/107/8/635/2948336 (Full text)]

*2019, Vitamin C Activates Osteoblastogenesis and Inhibits Osteoclastogenesis via Wnt/β-Catenin/ATF4 Signaling Pathways{{Citation needed|reason=|date=4 January 2020}}

*2019, Will the Elderly Benefit from a Fruit and Vegetable Nutritional Program? The Case of Vitamin C and Bone Health

==See also==
* [[Collagen]]
* [[Diet]]
* [[Vitamin C]]
* [[Vitamin D]]

==Learn more==
*[http://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/ Chronic Fatigue Syndrome and Osteoporosis]
*[http://drmyhill.co.uk/wiki/Osteoporosis_-_a_long_term_complication_of_CFS Osteoporosis - a long term complication of CFS]
*[https://youtu.be/78RBpWSOl08 Bone remodeling]
==References==
{{reflist}}

[[Category:Diagnoses]]
[[Category:Potential comorbidities]]
[[Category:Musculoskeletal diseases and disorders]]

Osteoporosis

2020-01-04T16:28:29Z

FatigueTrackerBot:/* Presentation */ from review article

{{stub}}
'''Osteoporosis''', a condition where bones thin and weaken, usually in older adults, resulting in increase risk of bone fractures, especially stress fractures. The risk of developing osteoporosis is considered higher in people with ME/CFS.<ref>{{Cite web|url=https://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/|title=Chronic Fatigue Syndrome and Osteoporosis|date=2009-07-14|website=The Optimum Health Clinic|language=en-US|access-date=2019-10-10}}</ref>

A study in 2014, showed that patients without osteoporosis in the CFS cohort exhibited a 1.16-fold higher risk of fracture than did those in the non-CFS cohort. The researches concluded that although the cause remains unclear, CFS-related fracture might not be associated with osteoporosis.<ref name=":0">{{Cite journal|last=Kao|first=C.-H.|last2=Kuo|first2=C.-N.|last3=Chen|first3=H.-J.|last4=Yang|first4=T.-Y.|last5=Lin|first5=W.-M.|last6=Chen|first6=C.-S.|date=2014-08-01|title=Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study|url=https://academic.oup.com/qjmed/article/107/8/635/2948336|journal=QJM: An International Journal of Medicine|language=en|volume=107|issue=8|pages=635–641|doi=10.1093/qjmed/hcu037|issn=1460-2725}}</ref>

==Presentation==
Fractures and their causative and repair mechanisms have been topics subject to various forms of investigation for several decades.

==Osteoporosis in ME/CFS==

==Possible causes==

==Potential treatments==

Vitamin C can inhibit osteoporosis by promoting osteoblast formation and blocking osteoclastogenesis through the activation of signaling pathways. Therefore, it is suggested that vitamin C improves bone regeneration.{{Citation needed|reason=|date=4 January 2020}}

==Notable studies==
*2014, Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study<ref name=":0" /> - [https://academic.oup.com/qjmed/article/107/8/635/2948336 (Full text)]

*2019, Vitamin C Activates Osteoblastogenesis and Inhibits Osteoclastogenesis via Wnt/β-Catenin/ATF4 Signaling Pathways{{Citation needed|reason=|date=4 January 2020}}

==See also==
* [[Collagen]]
* [[Diet]]
* [[Vitamin C]]
* [[Vitamin D]]

==Learn more==
*[http://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/ Chronic Fatigue Syndrome and Osteoporosis]
*[http://drmyhill.co.uk/wiki/Osteoporosis_-_a_long_term_complication_of_CFS Osteoporosis - a long term complication of CFS]
*[https://youtu.be/78RBpWSOl08 Bone remodeling]
==References==
{{reflist}}

[[Category:Diagnoses]]
[[Category:Potential comorbidities]]
[[Category:Musculoskeletal diseases and disorders]]

Osteoporosis

2020-01-04T16:21:55Z

FatigueTrackerBot:/* See also */ Added links

{{stub}}
'''Osteoporosis''', a condition where bones thin and weaken, usually in older adults, resulting in increase risk of bone fractures, especially stress fractures. The risk of developing osteoporosis is considered higher in people with ME/CFS.<ref>{{Cite web|url=https://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/|title=Chronic Fatigue Syndrome and Osteoporosis|date=2009-07-14|website=The Optimum Health Clinic|language=en-US|access-date=2019-10-10}}</ref>

A study in 2014, showed that patients without osteoporosis in the CFS cohort exhibited a 1.16-fold higher risk of fracture than did those in the non-CFS cohort. The researches concluded that although the cause remains unclear, CFS-related fracture might not be associated with osteoporosis.<ref name=":0">{{Cite journal|last=Kao|first=C.-H.|last2=Kuo|first2=C.-N.|last3=Chen|first3=H.-J.|last4=Yang|first4=T.-Y.|last5=Lin|first5=W.-M.|last6=Chen|first6=C.-S.|date=2014-08-01|title=Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study|url=https://academic.oup.com/qjmed/article/107/8/635/2948336|journal=QJM: An International Journal of Medicine|language=en|volume=107|issue=8|pages=635–641|doi=10.1093/qjmed/hcu037|issn=1460-2725}}</ref>

==Presentation==

==Osteoporosis in ME/CFS==

==Possible causes==

==Potential treatments==

Vitamin C can inhibit osteoporosis by promoting osteoblast formation and blocking osteoclastogenesis through the activation of signaling pathways. Therefore, it is suggested that vitamin C improves bone regeneration.{{Citation needed|reason=|date=4 January 2020}}

==Notable studies==
*2014, Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study<ref name=":0" /> - [https://academic.oup.com/qjmed/article/107/8/635/2948336 (Full text)]

*2019, Vitamin C Activates Osteoblastogenesis and Inhibits Osteoclastogenesis via Wnt/β-Catenin/ATF4 Signaling Pathways{{Citation needed|reason=|date=4 January 2020}}

==See also==
* [[Collagen]]
* [[Diet]]
* [[Vitamin C]]
* [[Vitamin D]]

==Learn more==
*[http://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/ Chronic Fatigue Syndrome and Osteoporosis]
*[http://drmyhill.co.uk/wiki/Osteoporosis_-_a_long_term_complication_of_CFS Osteoporosis - a long term complication of CFS]
*[https://youtu.be/78RBpWSOl08 Bone remodeling]
==References==
{{reflist}}

[[Category:Diagnoses]]
[[Category:Potential comorbidities]]
[[Category:Musculoskeletal diseases and disorders]]

Collagen

2020-01-04T16:20:10Z

FatigueTrackerBot:Added links

'''Collagen''' is the main component of [[connective tissue]] and the most abundant protein in the human body. It is mostly found in fibrous tissues such as tendons, ligaments and skin.

== Types ==
There are over 28 types of collagen found in the human body.<ref name=":3">{{Cite journal|last=Wu|first=Marlyn|last2=Crane|first2=Jonathan S.|date=2019|title=Biochemistry, Collagen Synthesis|url=http://www.ncbi.nlm.nih.gov/books/NBK507709/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29939531}}</ref> Over 90% is made of of these fives types<ref name=":3" />:
* Type I: skin, tendon, vasculature, organs, bone (main component of the organic part of bone)
* Type II: cartilage (main collagenous component of cartilage)
* Type III: reticulate (main component of reticular fibers), commonly found alongside type I.
* Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.
* Type V: cell surfaces, hair, and placenta
The main collagen in ligaments is collagen type I, which comprises 70% of the dry weight of a ligament.<ref>{{Cite web|url=https://www.orthobullets.com/basic-science/9016/ligaments|title=Ligaments|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=www.orthobullets.com|archive-url=|archive-date=|dead-url=|access-date=2019-09-16}}</ref> Elastin is also found at 4–9% of the dry weight in ligaments.<ref>{{Cite journal|last=Zitnay|first=Jared L.|last2=Weiss|first2=Jeffrey A.|date=Dec 2018|title=Load Transfer, Damage and Failure in Ligaments and Tendons|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454883/|journal=Journal of orthopaedic research : official publication of the Orthopaedic Research Society|volume=36|issue=12|pages=3093–3104|doi=10.1002/jor.24134|issn=0736-0266|pmc=6454883|pmid=30175857}}</ref>

== Biology ==

=== Components ===
Collagen is made up primarily of the amino acids [[glycine]] and [[proline]]. The primary amino acid sequence of collagen is glycine-proline-X or glycine-X-hydroxyproline.<ref>{{Cite journal|last=Szulc|first=Pawel|date=Oct 2018|title=Bone turnover: Biology and assessment tools|url=https://www.ncbi.nlm.nih.gov/pubmed/30449551|journal=Best Practice & Research. Clinical Endocrinology & Metabolism|volume=32|issue=5|pages=725–738|doi=10.1016/j.beem.2018.05.003|issn=1878-1594|pmid=30449551|last2=|first2=|pmc=|quote=|last3=|first3=|last4=|first4=|last5=|first5=|last6=|first6=|last7=|first7=|last8=|first8=|author-link=|author-link2=|access-date=|author-link3=|author-link4=|author-link5=|author-link6=|via=}}</ref> X can be any of the other 17 amino acids. Every third amino acid is glycine.<ref name=":3" />

=== Co-factors ===
[[Vitamin C]] is a co-factor of many of the chemical reactions involved in collagen production. Vitamin C is also a [[mast cell]] stabilizer. Vitamin C deficiency can result in impaired collagen synthesis and [[scurvy]].{{Citation needed|reason=}}

=== Structure ===
Collagen is composed of three chains that wind together to form a triple helix.<ref name=":3" />

=== Biosynthesis ===
Collagen synthesis occurs mainly in [[Fibroblast|fibroblasts]], cells whose many function is the synthesis of collagen and [[stroma]].<ref name=":3" /> Synthesis occurs in both intracellular and extracellular spaces.<ref name=":3" />

== Collagen-degrading factors ==

=== Pathogens ===
Infection can degrade collagen via direct secretion<ref name=":1">{{Cite journal|last=Harrington|first=D J|date=Jun 1996|title=Bacterial collagenases and collagen-degrading enzymes and their potential role in human disease.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC174012/|journal=Infection and Immunity|volume=64|issue=6|pages=1885–1891|issn=0019-9567|pmid=8675283}}</ref> of collagenases and other [[Enzyme|enzymes]] (in the case of [[bacteria]]) or increased host production of [[Matrix metalloproteinase|matrix metalloproteinases]] (MMPs) as part of the normal [[immune response]] (in the case of bacteria and [[Virus|viruses]]). Numerous bacteria secrete their own [[collagenase|collagenases]].<ref name=":1" /><ref>{{Cite journal|last=Duarte|first=Ana Sofia|last2=Correia|first2=Antonio|last3=Esteves|first3=Ana Cristina|date=2016|title=Bacterial collagenases - A review|url=https://www.ncbi.nlm.nih.gov/pubmed/24754251|journal=Critical Reviews in Microbiology|volume=42|issue=1|pages=106–126|doi=10.3109/1040841X.2014.904270|issn=1549-7828|pmid=24754251}}</ref> [[Borrelia]] spirochetes upregulate production of human collagenase (MMP-1) and [[gelatinase B]] (MMP-9)<ref>{{Cite journal|last=Gebbia|first=Joseph A.|last2=Coleman|first2=James L.|last3=Benach|first3=Jorge L.|date=2001-01-01|title=Borrelia Spirochetes Upregulate Release and Activation of Matrix Metalloproteinase Gelatinase B (MMP-9) and Collagenase 1 (MMP-1) in Human Cells|url=https://iai.asm.org/content/69/1/456|journal=Infection and Immunity|language=en|volume=69|issue=1|pages=456–462|doi=10.1128/IAI.69.1.456-462.2001|issn=0019-9567|pmid=11119537}}</ref>, an enzyme that can degrade both [[elastin]] and collagen.<ref>{{Cite web|url=https://www.sciencedirect.com/topics/neuroscience/gelatinase-b|title=ScienceDirect|website=www.sciencedirect.com|access-date=2018-11-09}}</ref> MMP-8 and MMP-9 are upregulated in bacterial [[meningitis]] and the latter is associated with an increased risk of [[blood-brain barrier]] breakdown and neurological sequale such as [[epilepsy]] and [[Cognitive dysfunction|cognitive impairment]].<ref>{{Cite journal|last=Tiveron|first=Marcos Gradim|last2=Pomerantzeff|first2=Pablo Maria Alberto|last3=de Lourdes Higuchi|first3=Maria|last4=Reis|first4=Marcia Martins|last5=de Jesus Pereira|first5=Jaqueline|last6=Kawakami|first6=Joyce Tieko|last7=Ikegami|first7=Renata Nishiyama|last8=de Almeida Brandao|first8=Carlos Manuel|last9=Jatene|first9=Fabio Biscegli|date=2017-04-21|title=Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study|url=https://www.ncbi.nlm.nih.gov/pubmed/28431520|journal=BMC infectious diseases|volume=17|issue=1|pages=297|doi=10.1186/s12879-017-2387-8|issn=1471-2334|pmc=5399830|pmid=28431520}}</ref> [[Herpes simplex virus]]<ref name=":2">{{Cite journal|date=2006-12-13|title=Herpes-simplex virus encephalitis is characterized by an early MMP-9 increase and collagen type IV degradation|url=https://www.sciencedirect.com/science/article/pii/S0006899306029246|journal=Brain Research|language=en|volume=1125|issue=1|pages=155–162|doi=10.1016/j.brainres.2006.09.093|issn=0006-8993}}</ref>, [[Human herpesvirus 6|HHV-6]]<ref>{{Cite journal|date=2014-11-01|title=Serum levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in human herpesvirus-6–infected infants with or without febrile seizures|url=https://www.sciencedirect.com/science/article/pii/S1341321X14002682|journal=Journal of Infection and Chemotherapy|language=en|volume=20|issue=11|pages=716–721|doi=10.1016/j.jiac.2014.07.017|issn=1341-321X}}</ref> and [[Coxsackie B]]<ref>{{Cite journal|last=De Palma|first=Armando M.|last2=Verbeken|first2=Erik|last3=Van Aelst|first3=Ilse|last4=Van den Steen|first4=Philippe E.|last5=Opdenakker|first5=Ghislain|last6=Neyts|first6=Johan|date=2008-12-05|title=Increased gelatinase B/matrix metalloproteinase 9 (MMP-9) activity in a murine model of acute coxsackievirus B4-induced pancreatitis|url=https://www.ncbi.nlm.nih.gov/pubmed/18929380|journal=Virology|volume=382|issue=1|pages=20–27|doi=10.1016/j.virol.2008.08.046|issn=1096-0341|pmid=18929380}}</ref><ref>{{Cite journal|date=2006-03-01|title=Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis|url=https://www.sciencedirect.com/science/article/pii/S1054880705001729|journal=Cardiovascular Pathology|language=en|volume=15|issue=2|pages=63–74|doi=10.1016/j.carpath.2005.11.008|issn=1054-8807}}</ref> infection result in increased production of MMP-9, which is associated with Type IV and Type V collagen degradation.<ref name=":2" /><ref>{{Cite journal|last=Zeng|first=Z. S.|last2=Cohen|first2=A. M.|last3=Guillem|first3=J. G.|date=May 1999|title=Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis|url=https://www.ncbi.nlm.nih.gov/pubmed/10334190|journal=Carcinogenesis|volume=20|issue=5|pages=749–755|issn=0143-3334|pmid=10334190}}</ref><ref>{{Cite journal|last=Van den Steen|first=Philippe E.|last2=Dubois|first2=Bénédicte|last3=Nelissen|first3=Inge|last4=Rudd|first4=Pauline M.|last5=Dwek|first5=Raymond A.|last6=Opdenakker|first6=Ghislain|date=Jan 2002|title=Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9)|url=https://www.tandfonline.com/doi/abs/10.1080/10409230290771546|journal=Critical Reviews in Biochemistry and Molecular Biology|language=en|volume=37|issue=6|pages=375–536|doi=10.1080/10409230290771546|issn=1040-9238}}</ref> Coxsackie B infection induces immune cells to secrete MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12.<ref>{{Cite journal|last=Cheung|first=Caroline|last2=Luo|first2=Honglin|last3=Yanagawa|first3=Bobby|last4=Leong|first4=Hon Sing|last5=Samarasekera|first5=Dinesh|last6=Lai|first6=John C. K.|last7=Suarez|first7=Agripina|last8=Zhang|first8=Jingchun|last9=McManus|first9=Bruce M.|date=Mar 2006|title=Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis|url=https://www.ncbi.nlm.nih.gov/pubmed/16533694|journal=Cardiovascular Pathology: The Official Journal of the Society for Cardiovascular Pathology|volume=15|issue=2|pages=63–74|doi=10.1016/j.carpath.2005.11.008|issn=1054-8807|pmid=16533694}}</ref><ref>{{Cite journal|last=Meng|first=Xiao-hui|last2=Wang|first2=Yi|last3=Zhuang|first3=Jian-xin|last4=Han|first4=Xiu-zhen|last5=Chen|first5=Yao|last6=Jin|first6=You-peng|last7=Wang|first7=Yu-lin|last8=Yu|first8=Yong-hui|last9=Spires|first9=James P.|date=Aug 2004|title=Dynamic changes in myocardial matrix metalloproteinase activity in mice with viral myocarditis|url=https://www.ncbi.nlm.nih.gov/pubmed/15361294|journal=Chinese Medical Journal|volume=117|issue=8|pages=1195–1199|issn=0366-6999|pmid=15361294}}</ref><ref>{{Cite journal|last=Rutschow|first=Susanne|last2=Leschka|first2=Sebastian|last3=Westermann|first3=Dirk|last4=Puhl|first4=Kerstin|last5=Weitz|first5=Anneke|last6=Ladyszenskij|first6=Leonid|last7=Jaeger|first7=Sebastian|last8=Zeichhardt|first8=Heinz|last9=Noutsias|first9=Michel|date=2010-03-25|title=Left ventricular enlargement in coxsackievirus-B3 induced chronic myocarditis--ongoing inflammation and an imbalance of the matrix degrading system|url=https://www.ncbi.nlm.nih.gov/pubmed/20035743|journal=European Journal of Pharmacology|volume=630|issue=1-3|pages=145–151|doi=10.1016/j.ejphar.2009.12.019|issn=1879-0712|pmid=20035743}}</ref>
==== Infection and Ehlers-Danlos Syndrome ====
[[Ehlers-Danlos syndrome|Ehlers-Danlos Syndrome]] is a group connective tissue disorders caused by genetic defects in the production of collagen. Type III, [[hypermobile EDS]] (hEDS), is also thought to be genetic but as a genetic marker has not yet been identified; it is diagnosed via signs and symptoms. A 2018 case study of a patient who met the diagnostic criteria for hEDS and had a chronic Bartonella infection found their hEDS symptoms resolved with antibiotic treatment for Bartonella.<ref name=":0">{{Cite journal|last=Mozayeni|first=Bobak Robert|last2=Maggi|first2=Ricardo Guillermo|last3=Bradley|first3=Julie Meredith|last4=Breitschwerdt|first4=Edward Bealmear|date=Apr 2018|title=Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias|url=https://journals.lww.com/md-journal/Pages/articleviewer.aspx?year=2018&issue=04270&article=00032&type=Fulltext|journal=Medicine|language=en-US|volume=97|issue=17|pages=e0465|doi=10.1097/MD.0000000000010465|issn=0025-7974}}</ref> [[Mycoplasma pneumoniae]] has been associated with [[mitral valve]] degeneration, a complication of EDS.<ref>{{Cite journal|last=Tiveron|first=Marcos Gradim|last2=Pomerantzeff|first2=Pablo Maria Alberto|last3=de Lourdes Higuchi|first3=Maria|last4=Reis|first4=Marcia Martins|last5=de Jesus Pereira|first5=Jaqueline|last6=Kawakami|first6=Joyce Tieko|last7=Ikegami|first7=Renata Nishiyama|last8=de Almeida Brandao|first8=Carlos Manuel|last9=Jatene|first9=Fabio Biscegli|date=2017-04-21|title=Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study|url=https://www.ncbi.nlm.nih.gov/pubmed/28431520|journal=BMC infectious diseases|volume=17|issue=1|pages=297|doi=10.1186/s12879-017-2387-8|issn=1471-2334|pmc=5399830|pmid=28431520}}</ref>

=== Fluoroquinolone antibiotics ===
“Fluoroquinolones upregulate cell matrix metalloproteinases, resulting in a reduction of collagen fibrils of types I and III collagen.”<ref>{{Cite web|url=https://www.jwatch.org/na48248/2019/02/13/adverse-effects-fluoroquinolones-where-do-we-stand|title=NEJM Journal Watch: Summaries of and commentary on original medical and scientific articles from key medical journals|website=www.jwatch.org|access-date=2019-06-18}}</ref> A longitudinal study found Fluoroquinolones increased the risk of collagen-related adverse events like tendon ruptured and detached retinas.<ref>{{Cite journal|last=Redelmeier|first=Donald A.|last2=Lu|first2=Hong|last3=Daneman|first3=Nick|date=2015-11-01|title=Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study|url=https://bmjopen.bmj.com/content/5/11/e010077|journal=BMJ Open|language=en|volume=5|issue=11|pages=e010077|doi=10.1136/bmjopen-2015-010077|issn=2044-6055|pmid=26582407}}</ref> In December 2018, the FDA recommended against its use in patients with connective tissue disorders like Ehlers-Danlos Syndrome and Marfan Syndrome.<ref>{{Cite journal|last=Research|first=Center for Drug Evaluation and|date=2019-04-15|title=FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients|url=http://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics|journal=FDA|language=en}}</ref>

[[Doxycycline]], by contrast, inhibits MMP production.<ref name=":02">{{Cite journal|last=De Paiva|first=Cintia S.|last2=Corrales|first2=Rosa M.|last3=Villarreal|first3=Arturo L.|last4=Farley|first4=William J.|last5=Li|first5=De-Quan|last6=Stern|first6=Michael E.|last7=Pflugfelder|first7=Stephen C.|date=2006-09-01|title=Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye|url=http://www.sciencedirect.com/science/article/pii/S0014483506001709|journal=Experimental Eye Research|volume=83|issue=3|pages=526–535|doi=10.1016/j.exer.2006.02.004|issn=0014-4835}}</ref><ref>{{Cite journal|last=Roach|first=D. M|last2=Fitridge|first2=R. A|last3=Laws|first3=P. E|last4=Millard|first4=S. H|last5=Varelias|first5=A|last6=Cowled|first6=P. A|date=2002-03-01|title=Up-regulation of MMP-2 and MMP-9 Leads to Degradation of Type IV Collagen During Skeletal Muscle Reperfusion Injury; Protection by the MMP Inhibitor, Doxycycline|url=http://www.sciencedirect.com/science/article/pii/S1078588402915984|journal=European Journal of Vascular and Endovascular Surgery|volume=23|issue=3|pages=260–269|doi=10.1053/ejvs.2002.1598|issn=1078-5884}}</ref><ref>{{Cite journal|last=Niedzwiecki|first=A.|last2=Rath|first2=M.|last3=Kalinovsky|first3=T.|last4=Monterrey|first4=J. C.|last5=Roomi|first5=M. W.|date=2010-03-01|title=In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors|url=http://www.spandidos-publications.com/or/23/3/605/abstract|journal=Oncology Reports|volume=23|issue=3|pages=605–614|doi=10.3892/or_00000675|issn=1021-335X}}</ref><ref>{{Cite journal|last=Choi|first=Dong-Hoon|last2=Moon|first2=Ik-Sang|last3=Choi|first3=Bong-Kyu|last4=Paik|first4=Jeong-Won|last5=Kim|first5=Yoon-Sik|last6=Choi|first6=Seong-Ho|last7=Kim|first7=Chong-Kwan|date=2004|title=Effects of sub-antimicrobial dose doxycycline therapy on crevicular fluid MMP-8, and gingival tissue MMP-9, TIMP-1 and IL-6 levels in chronic periodontitis|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0765.2004.00696.x|journal=Journal of Periodontal Research|language=en|volume=39|issue=1|pages=20–26|doi=10.1111/j.1600-0765.2004.00696.x|issn=1600-0765}}</ref><ref>{{Cite journal|last=Li|first=De-Quan|last2=Lokeshwar|first2=Balakrishna L|last3=Solomon|first3=Abraham|last4=Monroy|first4=Dagoberto|last5=Ji|first5=Zhonghua|last6=Pflugfelder|first6=Stephen C|date=2001-10-01|title=Regulation of MMP-9 Production by Human Corneal Epithelial Cells|url=http://www.sciencedirect.com/science/article/pii/S0014483501910541|journal=Experimental Eye Research|volume=73|issue=4|pages=449–459|doi=10.1006/exer.2001.1054|issn=0014-4835}}</ref><ref>{{Cite journal|last=Brown David L.|last2=Desai Kavita K.|last3=Vakili Babak A.|last4=Nouneh Chadi|last5=Lee Hsi-Ming|last6=Golub Lorne M.|date=2004-04-01|title=Clinical and Biochemical Results of the Metalloproteinase Inhibition with Subantimicrobial Doses of Doxycycline to Prevent Acute Coronary Syndromes (MIDAS) Pilot Trial|url=https://www.ahajournals.org/doi/full/10.1161/01.ATV.0000121571.78696.dc|journal=Arteriosclerosis, Thrombosis, and Vascular Biology|volume=24|issue=4|pages=733–738|doi=10.1161/01.ATV.0000121571.78696.dc}}</ref>

=== Mold ===
''[[Stachybotrys chartarum]]'' (black [[mold]]) release proteinases that can hydrolyze [[gelatin]] and collagen I and IV.<ref>{{Cite journal|last=Yike|first=Iwona|last2=Rand|first2=Thomas|last3=Dearborn|first3=Dorr G.|date=2007-07-03|title=The role of fungal proteinases in pathophysiology of Stachybotrys chartarum|url=https://doi.org/10.1007/s11046-007-9037-4|journal=Mycopathologia|language=en|volume=164|issue=4|pages=171|doi=10.1007/s11046-007-9037-4|issn=1573-0832}}</ref> Three [[Mycotoxin|mycotoxins]], deoxynivalenol (DON), nivalenol (NIV) and T-2 toxin, were study in an the context of an experimental cartilage model. They were found to increase the expression of MMPs and result in the loss of [[aggrecan]] and type II collagen. Selenium partially inhibited the effects of these mycotoxins.<ref>{{Cite journal|last=Caterson|first=Bruce|last2=Li|first2=Jin|last3=Wang|first3=Jiali|last4=Luo|first4=Mingxiu|last5=Liu|first5=Jiayuan|last6=Zhang|first6=Zengtie|last7=Fu|first7=Qiang|last8=Chen|first8=Jinghong|last9=Li|first9=Siyuan|date=2012|title=The Effects of Mycotoxins and Selenium Deficiency on Tissue-Engineered Cartilage|url=https://www.karger.com/Article/FullText/335046|journal=Cells Tissues Organs|language=english|volume=196|issue=3|pages=241–250|doi=10.1159/000335046|issn=1422-6405|pmid=22538829}}</ref>

=== Sex hormones ===
Several animal studies of collagen in muscle and the aorta have found that [[estrogen]] decreases and [[testosterone]] collagen and elastin.<ref>{{Cite journal|last=Fischer|first=G. M.|last2=Swain|first2=M. L.|date=1977-06-01|title=Effect of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats|url=https://www.physiology.org/doi/abs/10.1152/ajpheart.1977.232.6.H617|journal=American Journal of Physiology-Heart and Circulatory Physiology|volume=232|issue=6|pages=H617–H621|doi=10.1152/ajpheart.1977.232.6.H617|issn=0363-6135}}</ref><ref>{{Cite journal|last=Cembrano|first=JosÉ|last2=Lillo|first2=Manuel|last3=Val|first3=JosÉ|last4=Mardones|first4=Jorge|date=1960-05-01|title=Influence of Sex Difference and Hormones on Elastine and Collagen in the Aorta of Chickens|url=http://insights.ovid.com/|journal=Circulation Research|language=ENGLISH|volume=8|issue=3|pages=527–529|issn=0009-7330|pmid=13808759}}</ref><ref>{{Cite journal|last=Fischer|first=Grace M.|last2=Swain|first2=Margaret L.|date=1980-08-01|title=Influence of contraceptive and other sex steroids on aortic collagen and elastin|url=http://www.sciencedirect.com/science/article/pii/0014480080900039|journal=Experimental and Molecular Pathology|volume=33|issue=1|pages=15–24|doi=10.1016/0014-4800(80)90003-9|issn=0014-4800}}</ref><ref>{{Cite journal|last=Fischer|first=G. M.|last2=Swain|first2=M. L.|date=1985-02-01|title=Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas|url=http://www.sciencedirect.com/science/article/pii/0021915085901777|journal=Atherosclerosis|volume=54|issue=2|pages=177–185|doi=10.1016/0021-9150(85)90177-7|issn=0021-9150}}</ref><ref>{{Cite journal|last=Fischer|first=Grace M.|date=1972-11-01|title=In Vivo EflEects of Estradiol on Collagen and Elastin Dynamics in Rat Aorta|url=https://academic.oup.com/endo/article/91/5/1227/2621144|journal=Endocrinology|language=en|volume=91|issue=5|pages=1227–1232|doi=10.1210/endo-91-5-1227|issn=0013-7227}}</ref> A study of collagen in male cows found that collagen synthesis increased with puberty, possibly as a result of testosterone.<ref>{{Cite journal|last=Cross|first=H. R.|last2=Schanbacher|first2=B. D.|last3=Crouse|first3=J. D.|date=1984-01-01|title=Sex, age and breed related changes in bovine testosterone and intramuscular collagen|url=http://www.sciencedirect.com/science/article/pii/0309174084900214|journal=Meat Science|volume=10|issue=3|pages=187–195|doi=10.1016/0309-1740(84)90021-4|issn=0309-1740}}</ref> Another, that intramuscular collagen was higher in bulls than in steers (castrated cattle).<ref>{{Cite journal|last=Judge|first=M. D.|last2=Diekman|first2=M. A.|last3=Lemenager|first3=R. P.|last4=Aberle|first4=E. D.|last5=Jones|first5=S. J.|last6=Gerrard|first6=D. E.|date=1987-11-01|title=Collagen Stability, Testosterone Secretion and Meat Tenderness in Growing Bulls and Steers|url=https://academic.oup.com/jas/article/65/5/1236/4662470|journal=Journal of Animal Science|language=en|volume=65|issue=5|pages=1236–1242|doi=10.2527/jas1987.6551236x|issn=0021-8812}}</ref> An ''in vitro'' study of rat cartilage cells found that testosterone stimulated collagen synthesis, but only in male cells.<ref>{{Cite journal|last=Boyan|first=B. D.|last2=Soskolne|first2=W. A.|last3=Brooks|first3=B. P.|last4=Ornoy|first4=A.|last5=Nasatzky|first5=E.|last6=Schwartz|first6=Z.|date=1994-04-01|title=Gender-specific, maturation-dependent effects of testosterone on chondrocytes in culture|url=https://academic.oup.com/endo/article/134/4/1640/3035468|journal=Endocrinology|language=en|volume=134|issue=4|pages=1640–1647|doi=10.1210/endo.134.4.8137726|issn=0013-7227}}</ref>

== In human disease ==
=== Ehlers-Danlos Syndrome ===
{{Main article|page_name=Ehlers-Danlos Syndrome}}

=== Mast cell activation syndrome ===
{{Main article|page_name=Mast cell activation syndrome}}

=== ME/CFS ===
{{Main article|page_name=Myalgic encephalomyelitis}}

Preliminary data from the [[UK ME/CFS biobank]] show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of [[prolyl 4-hydroxylase]] subunit alpha 1 (P4HA1), which encodes for [[procollagen-proline dioxygenase]], an enzyme involved in the production of collagen that also plays a role in the regulation of [[energy metabolism]] via downregulation of [[pyruvate dehydrogenase]] during [[hypoxia]].<ref>{{Cite journal|last=Schneider|first=Martin|last2=Harnoss|first2=Jonathan Michael|last3=Strowitzki|first3=Moritz J.|last4=Radhakrishnan|first4=Praveen|last5=Platzer|first5=Lisa|last6=Harnoss|first6=Julian Camill|last7=Hank|first7=Thomas|last8=Cai|first8=Jun|last9=Ulrich|first9=Alexis|date=Jan 2015|title=Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges|url=https://www.dovepress.com/therapeutic-inhibition-of-prolyl-hydroxylase-domain-containing-enzymes-peer-reviewed-fulltext-article-HP|journal=Hypoxia|language=English|volume=3|pages=1|doi=10.2147/HP.S60872|issn=2324-1128}}</ref> The data are based on self-reported diagnosis of [[chronic fatigue syndrome]] and involve a sample size that is very small for genome-wide association studies (n=1829), making confidence intervals difficult to estimate.<ref>{{Cite news|url=https://mecfsresearchreview.me/2018/06/11/analysis-of-data-from-500000-individuals-in-uk-biobank-demonstrates-an-inherited-component-to-me-cfs/amp/?__twitter_impression=true|title=Analysis of data from 500,000 individuals in UK Biobank demonstrates an inherited component to ME/CFS|date=2018-06-11|work=ME/CFS Research Review|access-date=2018-11-11|language=en-US}}</ref>

Elevated levels of [[hydroxyproline]], a marker of collagen breakdown, was found by [[Wenzhong Xiao]] in the [[Severely Ill Patient Study]].<ref>{{Citation|last=Open Medicine Foundation - OMF|title=Wenzhong Xiao, PhD {{!}} Results from the Severely Ill Patient Study (SIPS)|date=2018-11-07|url=https://www.youtube.com/watch?v=_N1o2gbaCl4&feature=youtu.be&t=853|access-date=2019-07-16}}</ref> [[Robert Naviaux]]’s work has suggested it as a possible [[Diagnostic biomarker|biomarker]] for female [[ME/CFS]] patients.<ref>{{Cite journal|last=Gordon|first=Eric|last2=Anderson|first2=Wayne|last3=Nathan|first3=Neil|last4=Baxter|first4=Asha|last5=Wang|first5=Lin|last6=Alaynick|first6=William A.|last7=Bright|first7=A. Taylor|last8=Li|first8=Kefeng|last9=Naviaux|first9=Jane C.|date=2016-09-13|title=Metabolic features of chronic fatigue syndrome|url=https://www.pnas.org/content/113/37/E5472|journal=Proceedings of the National Academy of Sciences|language=en|volume=113|issue=37|pages=E5472–E5480|doi=10.1073/pnas.1607571113|issn=0027-8424|pmid=27573827}}</ref> [[Maureen Hanson]] failed to find elevated hydroxyproline in her metabolomics study.{{Citation needed|reason=}}

==As a supplement==
When hydrolyzed, collagen is reduced to small [[peptide]]s, which can be ingested in the form of [[dietary supplement]] or [[functional food]]s and beverages with the intent to aid joint and bone health and enhance skin health.<ref>{{Cite journal|last=Guillerminet|first=Fanny|last2=Beaupied|first2=Hélène|last3=Fabien-Soulé|first3=Véronique|last4=Tomé|first4=Daniel|last5=Benhamou|first5=Claude-Laurent|last6=Roux|first6=Christian|last7=Blais|first7=Anne|date=2010-03-01|title=Hydrolyzed collagen improves bone metabolism and biomechanical parameters in ovariectomized mice: An in vitro and in vivo study|url=http://www.thebonejournal.com/article/S8756-3282(09)02003-1/abstract|journal=Bone|language=English|volume=46|issue=3|pages=827–834|doi=10.1016/j.bone.2009.10.035|issn=8756-3282}}</ref><ref>{{Cite journal|last=Guillerminet|first=F.|last2=Fabien-Soulé|first2=V.|last3=Even|first3=P. C.|last4=Tomé|first4=D.|last5=Benhamou|first5=C.-L.|last6=Roux|first6=C.|last7=Blais|first7=A.|date=2012-07-01|title=Hydrolyzed collagen improves bone status and prevents bone loss in ovariectomized C3H/HeN mice|url=https://link.springer.com/article/10.1007/s00198-011-1788-6|journal=Osteoporosis International|language=en|volume=23|issue=7|pages=1909–1919|doi=10.1007/s00198-011-1788-6|issn=0937-941X}}</ref><ref>{{Cite journal|last=Daneault|first=A.|date=2014-04-01|title=Hydrolyzed collagen contributes to osteoblast differentiation in vitro and subsequent bone health in vivo|url=http://www.oarsijournal.com/article/S1063-4584(14)00280-5/fulltext|journal=Osteoarthritis and Cartilage|language=English|volume=22|pages=S131|doi=10.1016/j.joca.2014.02.240|issn=1063-4584}}</ref><ref>{{Cite journal|last=Daneault|first=Audrey|last2=Prawitt|first2=Janne|last3=Fabien Soulé|first3=Véronique|last4=Coxam|first4=Véronique|last5=Wittrant|first5=Yohann|date=2017-06-13|title=Biological effect of hydrolyzed collagen on bone metabolism|journal=Critical Reviews in Food Science and Nutrition|volume=57|issue=9|pages=1922–1937|doi=10.1080/10408398.2015.1038377|issn=1549-7852|pmid=25976422|url=https://zenodo.org/record/889529|deadurl=no|archiveurl=https://web.archive.org/web/20170913183348/https://zenodo.org/record/889529|archivedate=2017-09-13|df=}}</ref><ref>{{Cite journal|last=Jiang|first=J.X.|date=2014|title=Collagen peptides improve knee osteoarthritis in elderly women: A 6-month randomized, double-blind, placebo-controlled study|url=http://old.teknoscienze.com//articles/agro-food-industry-hi-tech-collagen-peptides-improve-knee-osteoarthritis-in-elderly-women-a.aspx#.WXCW-oSGNtR|journal=Agro FOOD Indusrty Hi Tech|volume=25|pages=19–23|via=|deadurl=no|archiveurl=https://web.archive.org/web/20170913183401/http://old.teknoscienze.com//articles/agro-food-industry-hi-tech-collagen-peptides-improve-knee-osteoarthritis-in-elderly-women-a.aspx#.WXCW-oSGNtR|archivedate=2017-09-13|df=}}</ref><ref>{{Cite journal|last=Dar|first=Qurratul-Ain|last2=Schott|first2=Eric M.|last3=Catheline|first3=Sarah E.|last4=Maynard|first4=Robert D.|last5=Liu|first5=Zhaoyang|last6=Kamal|first6=Fadia|last7=Farnsworth|first7=Christopher W.|last8=Ketz|first8=John P.|last9=Mooney|first9=Robert A.|date=2017-04-06|title=Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174705|journal=PLOS ONE|volume=12|issue=4|pages=e0174705|doi=10.1371/journal.pone.0174705|issn=1932-6203|pmc=5383229|pmid=28384173|deadurl=no|archiveurl=https://web.archive.org/web/20170913184032/http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0174705|archivedate=2017-09-13|df=|bibcode=2017PLoSO..1274705D}}</ref><ref>{{Cite journal|last=Asserin|first=Jérome|last2=Lati|first2=Elian|last3=Shioya|first3=Toshiaki|last4=Prawitt|first4=Janne|date=2015-12-01|title=The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo‐controlled clinical trials|url=http://onlinelibrary.wiley.com/doi/10.1111/jocd.12174/full|journal=Journal of Cosmetic Dermatology|language=en|volume=14|issue=4|pages=291–301|doi=10.1111/jocd.12174|issn=1473-2165|deadurl=no|archiveurl=https://web.archive.org/web/20170910193750/http://onlinelibrary.wiley.com/doi/10.1111/jocd.12174/full|archivedate=2017-09-10|df=}}</ref> These [[hydroxyproline]]-containing peptides are transported into the target tissues (e.g., skin, bones, and cartilage), where they act as building blocks for local cells and help boost the production of new collagen fibers.<ref>{{Cite journal|last=Ichikawa|first=Satomi|last2=Morifuji|first2=Masashi|last3=Ohara|first3=Hiroki|last4=Matsumoto|first4=Hitoshi|last5=Takeuchi|first5=Yasuo|last6=Sato|first6=Kenji|date=2010-02-01|title=Hydroxyproline-containing dipeptides and tripeptides quantified at high concentration in human blood after oral administration of gelatin hydrolysate|url=https://dx.doi.org/10.3109/09637480903257711|journal=International Journal of Food Sciences and Nutrition|volume=61|issue=1|pages=52–60|doi=10.3109/09637480903257711|issn=0963-7486|pmid=19961355}}</ref><ref>{{Cite journal|last=Shigemura|first=Yasutaka|last2=Kubomura|first2=Daiki|last3=Sato|first3=Yoshio|last4=Sato|first4=Kenji|date=2014-09-15|title=Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion|url=http://www.sciencedirect.com/science/article/pii/S0308814614002763|journal=Food Chemistry|volume=159|pages=328–332|doi=10.1016/j.foodchem.2014.02.091}}</ref><ref>{{Cite journal|last=Watanabe-Kamiyama|first=Mari|last2=Shimizu|first2=Muneshige|last3=Kamiyama|first3=Shin|last4=Taguchi|first4=Yasuki|last5=Sone|first5=Hideyuki|last6=Morimatsu|first6=Fumiki|last7=Shirakawa|first7=Hitoshi|last8=Furukawa|first8=Yuji|last9=Komai|first9=Michio|date=2010-01-27|title=Absorption and Effectiveness of Orally Administered Low Molecular Weight Collagen Hydrolysate in Rats|url=https://dx.doi.org/10.1021/jf9031487|journal=Journal of Agricultural and Food Chemistry|volume=58|issue=2|pages=835–841|doi=10.1021/jf9031487|issn=0021-8561}}</ref>

== Potential modulators ==
The following are compounds that can or might increase collagen synthesis, inhibit collagen destruction, or improve collagen strength. Compounds proven to promote connective tissue repair in vivo, or proven to reduce connective tissue-degrading [[matrix metalloproteinase]] (MMP) enzymes in vivo, are indicated by the "shown effective in vivo" column.

{| class="wikitable"
!Compound
!Type
!Shown effective in vivo
!
!Mechanism of action
|-
|[[Aloe vera]]
|[[Polysaccharide]]
|
|Promotes synthesis, and inhibits destruction
|Stimulates fibroblast proliferation and collagen synthesis. Inhibits MMP-2 and MMP-9 in vitro.<ref name=":4">{{Cite journal|last=Kudalkar|first=Mithun D.|last2=Nayak|first2=Aarati|last3=Bhat|first3=Kishore S.|last4=Nayak|first4=Ranganath N.|date=Jan 2014|title=Effect of Azadirachta indica (Neem) and Aloe vera as compared to subantimicrobial dose doxycycline on matrix metalloproteinases (MMP)-2 and MMP-9: An in-vitro study|url=https://www.ncbi.nlm.nih.gov/pubmed/25364206|journal=Ayu|volume=35|issue=1|pages=85–89|doi=10.4103/0974-8520.141947|issn=0974-8520|pmc=4213975|pmid=25364206}}</ref>
|-
|[[Pentadecapeptide BPC 157]]
|[[Peptide]]
|Yes
|Promotes synthesis
|Stimulates growth factor receptors on fibroblasts.<ref>{{Cite journal|last=Gwyer|first=Daniel|last2=Wragg|first2=Nicholas M.|last3=Wilson|first3=Samantha L.|date=Aug 2019|title=Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing|url=https://www.ncbi.nlm.nih.gov/pubmed/30915550|journal=Cell and Tissue Research|volume=377|issue=2|pages=153–159|doi=10.1007/s00441-019-03016-8|issn=1432-0878|pmid=30915550}}</ref><ref>{{Cite journal|last=Staresinic|first=M.|last2=Sebecic|first2=B.|last3=Patrlj|first3=L.|last4=Jadrijevic|first4=S.|last5=Suknaic|first5=S.|last6=Perovic|first6=D.|last7=Aralica|first7=G.|last8=Zarkovic|first8=N.|last9=Borovic|first9=S.|date=Nov 2003|title=Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth|url=https://www.ncbi.nlm.nih.gov/pubmed/14554208|journal=Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society|volume=21|issue=6|pages=976–983|doi=10.1016/S0736-0266(03)00110-4|issn=0736-0266|pmid=14554208}}</ref>
|-
|[[GABA]]
|Supplement
|Yes
|Promotes synthesis
|GABA dramatically increases the formation of elastic fibers and up-regulates the expression of type I collagen in human dermal fibroblasts.<ref>{{Cite journal|last=Uehara|first=Eriko|last2=Hokazono|first2=Hideki|last3=Hida|first3=Mariko|last4=Sasaki|first4=Takako|last5=Yoshioka|first5=Hidekatsu|last6=Matsuo|first6=Noritaka|date=Jun 2017|title=GABA promotes elastin synthesis and elastin fiber formation in normal human dermal fibroblasts (HDFs)|url=https://www.ncbi.nlm.nih.gov/pubmed/28485217|journal=Bioscience, Biotechnology, and Biochemistry|volume=81|issue=6|pages=1198–1205|doi=10.1080/09168451.2017.1290518|issn=1347-6947|pmid=28485217}}</ref> GABA 100 mg daily is shown to increase skin skin elasticity in women.<ref>{{Cite journal|last=絵理子|first=上原|last2=英樹|first2=外薗|date=2016-07-15|title=γ-アミノ酪酸の経口摂取による皮膚状態改善効果|url=https://www.jstage.jst.go.jp/article/nskkk/63/7/63_306/_article/-char/en|journal=日本食品科学工学会誌|language=ja|volume=63|issue=7|pages=306–311|doi=10.3136/nskkk.63.306|issn=1341-027X}}</ref>
|-
|Thymosin beta 4 (TB-500)
|Peptide
|Yes
|Promotes synthesis
|Helps repair ligaments.<ref>{{Cite journal|last=Xu|first=Bo|last2=Yang|first2=Mowen|last3=Li|first3=Zhaozhu|last4=Zhang|first4=Yubo|last5=Jiang|first5=Zhitao|last6=Guan|first6=Shengyang|last7=Jiang|first7=Dapeng|date=2013-06-10|title=Thymosin β4 enhances the healing of medial collateral ligament injury in rat|url=https://www.ncbi.nlm.nih.gov/pubmed/23523891|journal=Regulatory Peptides|volume=184|pages=1–5|doi=10.1016/j.regpep.2013.03.026|issn=1873-1686|pmid=23523891}}</ref>
|-
|Collagen peptides
|[[Amino acid]]
|
|Co-factor essential for synthesis
|Contains proline, lysine and other amino acids necessary for collagen synthesis.
|-
|[[Vitamin C]]
|[[Vitamin]]
|
|Co-factor essential for synthesis
|Catalyzes the enzymes [[procollagen-proline dioxygenase]] and lysl hydroxylase.
|-
|[[Copper]]
|[[Mineral]]
|
|Co-factor essential for synthesis
|Catalyzes the enzyme [[lysyl dioxidase]].
|-
|[[Doxycycline]]
|[[Antibiotic]]
|Yes
|Inhibits destruction
|Inhibits matrix metalloproteinases MMP-1, 2, 7, 8, 9, 12 and 13, and is effective at MMP inhibition at a low dose of 20 mg twice daily.<ref>{{Cite journal|last=Del Buono|first=Angelo|last2=Oliva|first2=Francesco|last3=Osti|first3=Leonardo|last4=Maffulli|first4=Nicola|date=2013-05-21|title=Metalloproteases and tendinopathy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676164/|journal=Muscles, Ligaments and Tendons Journal|volume=3|issue=1|pages=51–57|doi=10.11138/mltj/2013.3.1.051|issn=2240-4554|pmc=3676164|pmid=23885345}}</ref> Sold as the drug Periostat, which is the only FDA approved MMP inhibitor.
|-
|[[Fish oil]]
|Supplement
|Yes
|Inhibits destruction
|Fish oil 9.6 grams per day reduced MMP-9 secretion from immune cells by 58% after 3 months in multiple sclerosis patients.<ref>{{Cite journal|last=Shinto|first=L.|last2=Marracci|first2=G.|last3=Baldauf-Wagner|first3=S.|last4=Strehlow|first4=A.|last5=Yadav|first5=V.|last6=Stuber|first6=L.|last7=Bourdette|first7=D.|date=Feb 2009|title=Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/19171471|journal=Prostaglandins, Leukotrienes, and Essential Fatty Acids|volume=80|issue=2-3|pages=131–136|doi=10.1016/j.plefa.2008.12.001|issn=0952-3278|pmc=2692605|pmid=19171471}}</ref>
|-
|Q10
|Supplement
|Yes
|Inhibits destruction
|Q10 at 500 mg daily reduced MMP-9 in multiple sclerosis patients.<ref>{{Cite journal|last=Sanoobar|first=Meisam|last2=Eghtesadi|first2=Shahryar|last3=Azimi|first3=Amirreza|last4=Khalili|first4=Mohammad|last5=Khodadadi|first5=Behnam|last6=Jazayeri|first6=Shima|last7=Gohari|first7=Mahmood Reza|last8=Aryaeian|first8=Nahid|date=May 2015|title=Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/24621064|journal=Nutritional Neuroscience|volume=18|issue=4|pages=169–176|doi=10.1179/1476830513Y.0000000106|issn=1476-8305|pmid=24621064}}</ref>
|-
|Ecklonia cava
|Supplement
|Yes
|Inhibits destruction
|Ecklonia cava, an edible marine brown alga sold as a supplement, inhibits MMP-2 and MMP-9 and in a rat study reduced periodontitis.<ref>{{Cite journal|last=Kim|first=Seonyoung|last2=Choi|first2=Soo-Im|last3=Kim|first3=Gun-Hee|last4=Imm|first4=Jee-Young|date=2019-05-22|title=Anti-Inflammatory Effect of Ecklonia cava Extract on Porphyromonas gingivalis Lipopolysaccharide-Stimulated Macrophages and a Periodontitis Rat Model|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566535/|journal=Nutrients|volume=11|issue=5|doi=10.3390/nu11051143|issn=2072-6643|pmc=6566535|pmid=31121899}}</ref>
|-
|Captopril
|Drug
|Yes
|Inhibits destruction
|Angiotensin-converting enzyme (ACE) inhibitor captopril inhibits serum MMP-9 in patients with Kawasaki disease (this disease is likely caused by infection).<ref>{{Cite journal|last=Inoue|first=Nao|last2=Takai|first2=Shinji|last3=Jin|first3=Denan|last4=Okumura|first4=Kenichi|last5=Okamura|first5=Naoyuki|last6=Kajiura|first6=Mitsugu|last7=Yoshikawa|first7=Sosuke|last8=Kawamura|first8=Naohisa|last9=Tamai|first9=Hiroshi|date=Feb 2010|title=Effect of angiotensin-converting enzyme inhibitor on matrix metalloproteinase-9 activity in patients with Kawasaki disease|url=https://www.ncbi.nlm.nih.gov/pubmed/19945447/|journal=Clinica Chimica Acta; International Journal of Clinical Chemistry|volume=411|issue=3-4|pages=267–269|doi=10.1016/j.cca.2009.11.020|issn=1873-3492|pmid=19945447}}</ref>
|-
|Losartan
|Drug
|Yes
|Inhibits destruction
|Angiotensin II receptor blocker drug losartan decreases MMP-2 and MMP-9.<ref>{{Cite journal|last=Derosa|first=Giuseppe|last2=Maffioli|first2=Pamela|last3=Ferrari|first3=Ilaria|last4=Palumbo|first4=Ilaria|last5=Randazzo|first5=Sabrina|last6=Fogari|first6=Elena|last7=D'Angelo|first7=Angela|last8=Cicero|first8=Arrigo F. G.|date=Jan 2011|title=Different actions of losartan and ramipril on adipose tissue activity and vascular remodeling biomarkers in hypertensive patients|url=https://www.ncbi.nlm.nih.gov/pubmed/21107327|journal=Hypertension Research: Official Journal of the Japanese Society of Hypertension|volume=34|issue=1|pages=145–151|doi=10.1038/hr.2010.205|issn=1348-4214|pmid=21107327}}</ref>
|-
|Neem
|Herb
|
|Inhibits destruction
|Inhibits MMP-2 and MMP-9 in vitro.<ref name=":4" />
|-
|Magnesium
|[[Mineral]]
|
|Inhibits destruction
|An in vitro study found magnesium reduces MMP-2.
|-
|Glucosamine sulfate
|Supplement
|
|Inhibits destruction
|Glucosamine sulfate inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells in vitro.<ref>{{Cite journal|last=Rajapakse|first=Niranjan|last2=Mendis|first2=Eresha|last3=Kim|first3=Moon-Moo|last4=Kim|first4=Se-Kwon|date=2007-07-15|title=Sulfated glucosamine inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells|url=https://www.ncbi.nlm.nih.gov/pubmed/17498959|journal=Bioorganic & Medicinal Chemistry|volume=15|issue=14|pages=4891–4896|doi=10.1016/j.bmc.2007.04.048|issn=0968-0896|pmid=17498959}}</ref>
|-
|Triphala
|Herbal formula
|
|Inhibits destruction
|Inhibits MMP-9 in vitro.<ref>{{Cite journal|last=Abraham|first=Sajith|last2=Kumar|first2=M. Senthil|last3=Sehgal|first3=P. K.|last4=Nitish|first4=S.|last5=Jayakumar|first5=N. D.|date=Apr 2005|title=Evaluation of the inhibitory effect of triphala on PMN-type matrix metalloproteinase (MMP-9)|url=https://www.ncbi.nlm.nih.gov/pubmed/15857087/|journal=Journal of Periodontology|volume=76|issue=4|pages=497–502|doi=10.1902/jop.2005.76.4.497|issn=0022-3492|pmid=15857087}}</ref>
|-
|Vitamin K2
|Supplement
|
|
|Inhibits MMP-1 in vitro
|-
|Glucuronolactone
|Supplement
|
|Structural component
|Glucuronolactone is an important structural component of connective tissues in tendons, ligaments and cartilage. A 250 ml can of Red Bull contains 600 mg of glucuronolactone.
|-
|[[Hyaluronic acid]]
|
|
|
|
|}

== See also ==

* [[Ehlers-Danlos syndrome]]
* [[Mast cell activation syndrome]]
* [[Extracellular matrix]]
* [[Mast cell]]
* [[Osteoporosis]]
* [[Vitamin C]]

== References ==
<references />
[[Category:Proteins]]
[[Category:Biochemistry and cell biology]]

Vitamin C

2020-01-04T16:11:10Z

FatigueTrackerBot:Added link to collagen

'''Vitamin C''', also known as '''ascorbic acid''', is a water-soluble vitamin found particularly in citrus fruits and green vegetables. It is essential for [[collagen]], [[catecholamine]], and [[carnitine]] biosynthesis.<ref>{{Cite journal|last=Michels|first=Alexander J.|last2=Hagen|first2=Tory M.|last3=Frei|first3=Balz|date=2013|title=Human Genetic Variation Influences Vitamin C Homeostasis by Altering Vitamin C Transport and Antioxidant Enzyme Function|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357493/|journal=Annual review of nutrition|volume=33|pages=45–70|doi=10.1146/annurev-nutr-071812-161246|issn=0199-9885|pmc=4357493|pmid=23642198}}</ref>

One of its roles is as an antioxidant, that is, it helps to protect cells from damage by oxidative stress and also improves mitochondrial function. Another role is as a cofactor for several enzymes.<ref>{{Cite book|url=https://www.worldcat.org/oclc/55641398|title=Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids : a report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine.|date=2000|publisher=National Academy Press|others=National Research Council (U.S.), Institute of Medicine (U.S.)|isbn=0309597196|location=Washington, D.C.|oclc=55641398}}</ref> After absorption, Vitamin C is present throughout the whole body.

Large cross-sectional population studies confirm that vitamin C deficiency is common in humans, affecting 5%–10% of adults in the industrialized world. Moreover, significant associations between poor vitamin C status and increased morbidity and mortality have consistently been observed. However, the absorption, distribution and elimination kinetics of vitamin C ''in vivo'' are highly complex, due to dose-dependent non-linearity, and the specific regulatory mechanisms are not fully understood.<ref name="lindblad2013" /> In addition, the optimal daily intake as well as the typical total body pool of vitamin C during health and disease remain unknown.<ref name="ginter1979" /><ref name="ginter1980" /><ref name="ginter1982" /><ref name="lykkesfeldt2019" />

[[File:Nutrients-05-02860-g001.jpg|right|300x300px]]

==Biology==
Vitamin C is found in the whole body, even skin tissue.<ref name="padayatty2016" /><ref name="pullar2017" /> High levels of vitamin C are found in the [[eyes]], [[pituitary]], [[adrenal gland]], [[pancreas]], [[liver]], [[spleen]] and [[brain]]. Vitamin C is also found in relative high levels in the [[bone marrow]], [[muscles]] and [[skin]].<ref name="pullar2017" /><ref>{{Cite journal|last=|first=|date=|title=Vitamin neurotoxicity|url=https://www.ncbi.nlm.nih.gov/pubmed/1463588|journal=Mol Neurobiology|volume=|pages=|via=}}</ref> Bone marrow is probably also involved in the vitamin C homeostasis process.<ref name="padayatty2016" /><ref name="seftel1966" /><ref name="aghajanian2015" />
[[File:VitCinskinPullar2017.jpg|right|300x300px]]

The adrenal gland can inject vitamin C into the blood.<ref name="padayatty2016" />

Too much sun exposure may deplete the Vitamin C stores in the skin tissue.<ref name="pullar2017" />

== In human disease ==
Vitamin C is important in [[mast cell activation disorder]] for its role in the breakdown of [[histamine]] and as a [[mast cell]] stabilizer. Vitamin C is also a co-factor in [[collagen]] synthesis, making it a potentially important nutrient in [[Ehlers-Danlos syndrome]] and other [[connective tissue]] disorders.<ref>{{Cite journal|last=Mantle|first=D.|last2=Wilkins|first2=R. M.|last3=Preedy|first3=V.|date=2005-01-01|title=A novel therapeutic strategy for Ehlers–Danlos syndrome based on nutritional supplements|url=http://www.sciencedirect.com/science/article/pii/S0306987704004566|journal=Medical Hypotheses|volume=64|issue=2|pages=279–283|doi=10.1016/j.mehy.2004.07.023|issn=0306-9877}}</ref><ref>{{Cite journal|last=Dembure|first=Philip P.|last2=Janko|first2=Anita R.|last3=Priest|first3=Jean H.|last4=Elsas|first4=Louis J.|date=1987-07-01|title=Ascorbate regulation of collagen biosynthesis in Ehlers-Danlos syndrome, type VI|url=http://www.sciencedirect.com/science/article/pii/0026049587901557|journal=Metabolism|volume=36|issue=7|pages=687–691|doi=10.1016/0026-0495(87)90155-7|issn=0026-0495}}</ref><ref>{{Cite journal|last=Elsas|first=Louis J.|last2=Miller|first2=Robert L.|last3=Pinnell|first3=Sheldon R.|date=1978-03-01|title=Inherited human collagen lysyl hydroxylase deficiency: Ascorbic acid response|url=http://www.sciencedirect.com/science/article/pii/S0022347678804235|journal=The Journal of Pediatrics|volume=92|issue=3|pages=378–384|doi=10.1016/S0022-3476(78)80423-5|issn=0022-3476}}</ref><ref>{{Cite journal|last=Kanof|first=Abram|date=1952-02-01|title=EHLERS-DANLOS SYNDROME: Report of a Case with Suggestion of a Possible Causal Mechanism|url=https://jamanetwork.com/journals/jamapediatrics/fullarticle/495523|journal=A.M.A. American Journal of Diseases of Children|language=en|volume=83|issue=2|pages=197–202|doi=10.1001/archpedi.1952.02040060063007|issn=0096-8994}}</ref><ref>{{Cite journal|last=Ringsdorf|first=W. M.|last2=Cheraskin|first2=E.|date=1982-03-01|title=Vitamin C and human wound healing|url=http://www.sciencedirect.com/science/article/pii/003042208290295X|journal=Oral Surgery, Oral Medicine, Oral Pathology|volume=53|issue=3|pages=231–236|doi=10.1016/0030-4220(82)90295-X|issn=0030-4220}}</ref><ref>{{Cite book|url=https://books.google.com/books?hl=en&lr=&id=x-Z-cXUGlL8C&oi=fnd&pg=PR5&ots=FzzS-w8isY&sig=vY_ard7hUgYcNfbXatqmS7ltZGA#v=onepage&q&f=false|title=Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects|last=Royce|first=Peter M.|last2=Steinmann|first2=Beat|date=2003-04-14|publisher=John Wiley & Sons|isbn=978-0-471-46117-3|language=en}}</ref> Deficiency of vitamin C may contribute to [[osteoporosis]].<ref name="seftel1966" /><ref name="aghajanian2015" />

Vitamin C deficiency leads to altered function of [[procollagen-proline dioxygenase]] and [[lysyl hydroxylase]] enzymes. Each are essential for collagen synthesis and require Vitamin C as a cofactor.<ref>{{Cite journal|last=Wu|first=Marlyn|last2=Crane|first2=Jonathan S.|date=2019|title=Biochemistry, Collagen Synthesis|url=http://www.ncbi.nlm.nih.gov/books/NBK507709/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29939531}}</ref>

=== Mast cell activation disorder ===
Numerous studies have found Vitamin C to be inversely correlated with histamine and that the administration of Vitamin C reduces blood [[histamine]] levels.<ref name="clemetson1980" /><ref name="johnston1992" /><ref>{{Cite journal|last=Johnston|first=CS|date=December 1996|title=Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults|url=https://www.ncbi.nlm.nih.gov/pubmed/8951736|journal=J Am Coll Nutr.|volume=|pages=|via=}}</ref> It does this potentially through several mechanisms: by inhibiting mast cell production; by increasing [[diamine oxidase]] (an [[enzyme]] that breaks down histamine); by inhibiting mast cell degranulation and the release of histamine in the first place (i.e., as a mast cell stabilizer),<ref name=":0">{{Cite journal|last=Mio|first=M|date=1999|title=Ultraviolet B (UVB) light-induced histamine release from rat peritoneal mast cells and its augmentation by certain phenothiazine compounds|url=https://www.sciencedirect.com/science/article/pii/S0162310998000538|journal=Immunopharmacology|volume=|pages=|via=}}</ref> and by inhibiting [[histidine decarboxylase]] (the enzyme that forms histamine).<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903110/|title=Pharmacological treatment options for mast cell activation disease|last=Molderings|first=Gerhard|date=2016|journal=Naunyn Schmiedebergs Arch Pharmacol|volume=|pages=|via=}}</ref>

[[File:Nihms-754526-f0008.jpg|right|300x300px]]

=== Ehlers-Danlos Syndrome ===
A case study found improved wound healing in a patient with vascular [[Ehlers-Danlos Syndrome]] who was given high-dose (4g/day) oral vitamin C supplementation for two years.<ref>{{Cite journal|last=Ringsdorf|first=W. M.|last2=Cheraskin|first2=E.|date=1982-03-01|title=Vitamin C and human wound healing|url=http://www.sciencedirect.com/science/article/pii/003042208290295X|journal=Oral Surgery, Oral Medicine, Oral Pathology|volume=53|issue=3|pages=231–236|doi=10.1016/0030-4220(82)90295-X|issn=0030-4220}}</ref> A case study of two patients with Kyphoscoliotic EDS received high-dose Vitamin C (5g/day). After one year, they had reduced bleeding time and improve wound healing, and muscle strength.<ref>{{Cite journal|last=Dembure|first=Philip P.|last2=Janko|first2=Anita R.|last3=Priest|first3=Jean H.|last4=Elsas|first4=Louis J.|date=1987-07-01|title=Ascorbate regulation of collagen biosynthesis in Ehlers-Danlos syndrome, type VI|url=http://www.sciencedirect.com/science/article/pii/0026049587901557|journal=Metabolism|volume=36|issue=7|pages=687–691|doi=10.1016/0026-0495(87)90155-7|issn=0026-0495}}</ref>

== Supplementation ==
Several studies indicates the recovery from Vitamin C depletion will require several months of treatment. <ref name="padayatty2016" />

== Notable studies ==
* 2014, Mitochondrial dysfunction and chronic disease: treatment with natural supplements<ref>{{Cite journal|last=Nicolson|first=Garth L.|author-link=Garth Nicolson|author-link2=|author-link3=|author-link4=|author-link5=|date=2014|title=Mitochondrial dysfunction and chronic disease: treatment with natural supplements|url=https://www.ncbi.nlm.nih.gov/pubmed/24473982|journal=Alternative Therapies in Health and Medicine|volume=20 Suppl 1|issue=|pages=18–25|issn=1078-6791|pmid=24473982|quote=|via=}}</ref> [https://www.researchgate.net/publication/259960416_Mitochondrial_Dysfunction_and_Chronic_Disease_Treatment_With_Natural_Supplements (Full text)]

==See also==
*[[Vitamin C Deficiency without Scurvy hypothesis]]
*[[Collagen]]
*[[Mast cell activation syndrome]]
*[[Scurvy]]
*[[Vitamin]]
*[[Irritable bowel syndrome]]
*[[Osteoporosis]]

==Learn more==

*[http://lpi.oregonstate.edu/mic/vitamins/vitamin-C Linus Pauling Institute Micronutrient Information Center - Vitamin C]

==References==
<references>
<ref name="ginter1979">{{Citation| issue = 33| pages = 104-141| last = Ginter| first = Emil| title = Chronic marginal vitamin C deficiency: biochemistry and pathophysiology.| journal = World Rev Nutr Diet| date = 1979|doi=10.1159/000402551|url=https://www.ncbi.nlm.nih.gov/pubmed/392953}}</ref>
<ref name="ginter1980">{{Citation| volume = 33| issue = 3| pages = 538-539| last = Ginter| first = Emil| title = What is truly the maximum body pool size of ascorbic acid in man?| journal = Am J Clin Nutr| date = Mar 1980|doi=10.1093/ajcn/33.3.538|url=https://www.ncbi.nlm.nih.gov/pubmed/6986762}}</ref>
<ref name="ginter1982">{{Citation| volume = 1| issue = 2| pages = 66-77| last = Ginter| first = Emil| title = Optimum Intake of Vitamin C for the Human Organism| journal = Nutrition and Health| date = Apr 1982|doi=10.1177/026010608200100202|url=https://journals.sagepub.com/doi/10.1177/026010608200100202}}</ref><ref name="lindblad2013">{{Citation| issn = 2072-6643| issue = 5| pages = 2860-2879| last = Lindblad| first = Maiken|last2 = Tveden-Nyborg| first2 = Pernille| last3 = Lykkesfeldt| first3 = Jens| title = Regulation of Vitamin C Homeostasis during Deficiency| journal = Nutrients| date = May 2013|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775232}}</ref>
<ref name="lykkesfeldt2019">{{Citation| volume = 11| issue = 10| last2 = Tveden-Nyborg| first2 = Pernille| last = Lykkesfeldt| first = Jens| title = The Pharmacokinetics of Vitamin C| journal = Nutrients| date = Oct 2019|doi=10.3390/nu11102412|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835439}}</ref>
<ref name="padayatty2016">{{Citation|volume = 22| issue = 6| pages = 463-93| last = Padayatty| first = Sebastian| last2 = Levine| first2 = Mark| title = Vitamin C: the known and the unknown and Goldilocks| journal = Oral Disease| date = June 2016|url = https://www.ncbi.nlm.nih.gov/pubmed/26808119}}</ref>
<ref name="clemetson1980">{{Citation| issn = 0022-3166| volume = 110| issue = 4| pages = 662–668| last = Clemetson| first = C. A.| title = Histamine and ascorbic acid in human blood| journal = The Journal of Nutrition| date = April 1980| pmid = 7365537}}</ref>
<ref name="johnston1992">{{Citation| issn = 0731-5724| volume = 11| issue = 2| pages = 172–176| last1 = Johnston| first1 = C. S.| last2 = Martin| first2 = L. J.| last3 = Cai| first3 = X.| title = Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis| journal = Journal of the American College of Nutrition| date = April 1992| pmid = 1578094}}</ref>
<ref name="seftel1966">{{Citation| volume = 1| issue = 5488| pages = 642-644| last1 = Seftel| first1 = H| last2 = Malkin| first2 = C| last3 = Schmaman| first3 = A| last4 = Abrahams| first4 = C| last5 = Lynch| first5 = S| last6 = Charlton| first6 = S| last7 = Bothwell| first7 = T| title = Osteoporosis, Scurvy, and Siderosis in Johannesburg Bantu| journal = Br Med J|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1843929/}}</ref>
<ref name="aghajanian2015">{{Citation| volume = 30| issue = 11| pages = 1945–1955| last1 = Aghajanian| first1 = P| last2 = Hall| first2 = S.| last3 = Wongworawat| first3 = MD| last4 = Mohan| first4 = S| title = The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments| journal = J Bone Miner Res| date = 2015|url=https://www.ncbi.nlm.nih.gov/pubmed/26358868}}</ref>
<ref name="pullar2017">{{Citation| volume = 9| issue = 8| pages = 866| last1 = Pullar| first1 = JM| last2 = Carr| first2 = AC| last3 = Vissers| first3 = MCM| title = The Roles of Vitamin C in Skin Health| journal = Nutrients| date = 2017|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579659}}</ref>
</references>

[[Category:Potential treatments]]
[[Category:Supplements]]
[[Category:Vitamins]]
[[Category:Nutrients]]

Osteoporosis

2020-01-04T11:11:42Z

FatigueTrackerBot:Added info

{{stub}}
'''Osteoporosis''', a condition where bones thin and weaken, usually in older adults, resulting in increase risk of bone fractures, especially stress fractures. The risk of developing osteoporosis is considered higher in people with ME/CFS.<ref>{{Cite web|url=https://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/|title=Chronic Fatigue Syndrome and Osteoporosis|date=2009-07-14|website=The Optimum Health Clinic|language=en-US|access-date=2019-10-10}}</ref>

A study in 2014, showed that patients without osteoporosis in the CFS cohort exhibited a 1.16-fold higher risk of fracture than did those in the non-CFS cohort. The researches concluded that although the cause remains unclear, CFS-related fracture might not be associated with osteoporosis.<ref name=":0">{{Cite journal|last=Kao|first=C.-H.|last2=Kuo|first2=C.-N.|last3=Chen|first3=H.-J.|last4=Yang|first4=T.-Y.|last5=Lin|first5=W.-M.|last6=Chen|first6=C.-S.|date=2014-08-01|title=Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study|url=https://academic.oup.com/qjmed/article/107/8/635/2948336|journal=QJM: An International Journal of Medicine|language=en|volume=107|issue=8|pages=635–641|doi=10.1093/qjmed/hcu037|issn=1460-2725}}</ref>

==Presentation==

==Osteoporosis in ME/CFS==

==Possible causes==

==Potential treatments==

Vitamin C can inhibit osteoporosis by promoting osteoblast formation and blocking osteoclastogenesis through the activation of signaling pathways. Therefore, it is suggested that vitamin C improves bone regeneration.{{Citation needed|reason=|date=4 January 2020}}

==Notable studies==
*2014, Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study<ref name=":0" /> - [https://academic.oup.com/qjmed/article/107/8/635/2948336 (Full text)]

*2019, Vitamin C Activates Osteoblastogenesis and Inhibits Osteoclastogenesis via Wnt/β-Catenin/ATF4 Signaling Pathways{{Citation needed|reason=|date=4 January 2020}}

==See also==
* [[Vitamin C]]
* [[Vitamin D]]
==Learn more==
*[http://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/ Chronic Fatigue Syndrome and Osteoporosis]
*[http://drmyhill.co.uk/wiki/Osteoporosis_-_a_long_term_complication_of_CFS Osteoporosis - a long term complication of CFS]
*[https://youtu.be/78RBpWSOl08 Bone remodeling]
==References==
{{reflist}}

[[Category:Diagnoses]]
[[Category:Potential comorbidities]]
[[Category:Musculoskeletal diseases and disorders]]

Osteoporosis

2020-01-04T00:22:35Z

FatigueTrackerBot:/* Potential treatments */ typos

{{stub}}
'''Osteoporosis''', a condition where bones thin and weaken, usually in older adults, resulting in increase risk of bone fractures, especially stress fractures. The risk of developing osteoporosis is considered higher in people with ME/CFS.<ref>{{Cite web|url=https://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/|title=Chronic Fatigue Syndrome and Osteoporosis|date=2009-07-14|website=The Optimum Health Clinic|language=en-US|access-date=2019-10-10}}</ref>

A study in 2014, showed that patients without osteoporosis in the CFS cohort exhibited a 1.16-fold higher risk of fracture than did those in the non-CFS cohort. The researches concluded that although the cause remains unclear, CFS-related fracture might not be associated with osteoporosis.<ref name=":0">{{Cite journal|last=Kao|first=C.-H.|last2=Kuo|first2=C.-N.|last3=Chen|first3=H.-J.|last4=Yang|first4=T.-Y.|last5=Lin|first5=W.-M.|last6=Chen|first6=C.-S.|date=2014-08-01|title=Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study|url=https://academic.oup.com/qjmed/article/107/8/635/2948336|journal=QJM: An International Journal of Medicine|language=en|volume=107|issue=8|pages=635–641|doi=10.1093/qjmed/hcu037|issn=1460-2725}}</ref>

==Presentation==

==Osteoporosis in ME/CFS==

==Possible causes==

==Potential treatments==

Vitamin C can inhibit osteoporosis by promoting osteoblast formation and blocking osteoclastogenesis through the activation of signaling pathways. Therefore, it is suggested that vitamin C improves bone regeneration.

==Notable studies==
*2014, Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study<ref name=":0" /> - [https://academic.oup.com/qjmed/article/107/8/635/2948336 (Full text)]

*2019, Vitamin C Activates Osteoblastogenesis and Inhibits Osteoclastogenesis via Wnt/β-Catenin/ATF4 Signaling Pathways

==See also==
* [[Vitamin C]]
* [[Vitamin D]]
==Learn more==
*[http://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/ Chronic Fatigue Syndrome and Osteoporosis]
*[http://drmyhill.co.uk/wiki/Osteoporosis_-_a_long_term_complication_of_CFS Osteoporosis - a long term complication of CFS]

==References==
{{reflist}}

[[Category:Diagnoses]]
[[Category:Potential comorbidities]]
[[Category:Musculoskeletal diseases and disorders]]

Osteoporosis

2020-01-04T00:19:13Z

FatigueTrackerBot:/* Notable studies */ adferd VitC study

{{stub}}
'''Osteoporosis''', a condition where bones thin and weaken, usually in older adults, resulting in increase risk of bone fractures, especially stress fractures. The risk of developing osteoporosis is considered higher in people with ME/CFS.<ref>{{Cite web|url=https://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/|title=Chronic Fatigue Syndrome and Osteoporosis|date=2009-07-14|website=The Optimum Health Clinic|language=en-US|access-date=2019-10-10}}</ref>

A study in 2014, showed that patients without osteoporosis in the CFS cohort exhibited a 1.16-fold higher risk of fracture than did those in the non-CFS cohort. The researches concluded that although the cause remains unclear, CFS-related fracture might not be associated with osteoporosis.<ref name=":0">{{Cite journal|last=Kao|first=C.-H.|last2=Kuo|first2=C.-N.|last3=Chen|first3=H.-J.|last4=Yang|first4=T.-Y.|last5=Lin|first5=W.-M.|last6=Chen|first6=C.-S.|date=2014-08-01|title=Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study|url=https://academic.oup.com/qjmed/article/107/8/635/2948336|journal=QJM: An International Journal of Medicine|language=en|volume=107|issue=8|pages=635–641|doi=10.1093/qjmed/hcu037|issn=1460-2725}}</ref>

==Presentation==

==Osteoporosis in ME/CFS==

==Possible causes==

==Potential treatments==

This study is the first to show that vitamin C can inhibit osteoporosis by promoting osteoblast formation and blocking osteoclastogenesis through the activation of wingless-type MMTV integration site family/β-catenin/activating transcription factor 4 signaling, which is achieved through the serine/threonine kinase and mitogen-activated protein kinase signaling pathways. Therefore, our results suggest that vitamin C improves bone regeneration.

==Notable studies==
*2014, Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study<ref name=":0" /> - [https://academic.oup.com/qjmed/article/107/8/635/2948336 (Full text)]

*2019, Vitamin C Activates Osteoblastogenesis and Inhibits Osteoclastogenesis via Wnt/β-Catenin/ATF4 Signaling Pathways

==See also==
* [[Vitamin C]]
* [[Vitamin D]]
==Learn more==
*[http://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/ Chronic Fatigue Syndrome and Osteoporosis]
*[http://drmyhill.co.uk/wiki/Osteoporosis_-_a_long_term_complication_of_CFS Osteoporosis - a long term complication of CFS]

==References==
{{reflist}}

[[Category:Diagnoses]]
[[Category:Potential comorbidities]]
[[Category:Musculoskeletal diseases and disorders]]

Osteoporosis

2020-01-04T00:16:45Z

FatigueTrackerBot:Adferd VitC treatment

{{stub}}
'''Osteoporosis''', a condition where bones thin and weaken, usually in older adults, resulting in increase risk of bone fractures, especially stress fractures. The risk of developing osteoporosis is considered higher in people with ME/CFS.<ref>{{Cite web|url=https://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/|title=Chronic Fatigue Syndrome and Osteoporosis|date=2009-07-14|website=The Optimum Health Clinic|language=en-US|access-date=2019-10-10}}</ref>

A study in 2014, showed that patients without osteoporosis in the CFS cohort exhibited a 1.16-fold higher risk of fracture than did those in the non-CFS cohort. The researches concluded that although the cause remains unclear, CFS-related fracture might not be associated with osteoporosis.<ref name=":0">{{Cite journal|last=Kao|first=C.-H.|last2=Kuo|first2=C.-N.|last3=Chen|first3=H.-J.|last4=Yang|first4=T.-Y.|last5=Lin|first5=W.-M.|last6=Chen|first6=C.-S.|date=2014-08-01|title=Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study|url=https://academic.oup.com/qjmed/article/107/8/635/2948336|journal=QJM: An International Journal of Medicine|language=en|volume=107|issue=8|pages=635–641|doi=10.1093/qjmed/hcu037|issn=1460-2725}}</ref>

==Presentation==

==Osteoporosis in ME/CFS==

==Possible causes==

==Potential treatments==

This study is the first to show that vitamin C can inhibit osteoporosis by promoting osteoblast formation and blocking osteoclastogenesis through the activation of wingless-type MMTV integration site family/β-catenin/activating transcription factor 4 signaling, which is achieved through the serine/threonine kinase and mitogen-activated protein kinase signaling pathways. Therefore, our results suggest that vitamin C improves bone regeneration.

==Notable studies==
*2014, Chronic fatigue syndrome is associated with the risk of fracture: a nationwide cohort study<ref name=":0" /> - [https://academic.oup.com/qjmed/article/107/8/635/2948336 (Full text)]

==See also==
* [[Vitamin C]]
* [[Vitamin D]]
==Learn more==
*[http://www.theoptimumhealthclinic.com/2009/07/chronic-fatigue-syndrome-and-osteoporosis/ Chronic Fatigue Syndrome and Osteoporosis]
*[http://drmyhill.co.uk/wiki/Osteoporosis_-_a_long_term_complication_of_CFS Osteoporosis - a long term complication of CFS]

==References==
{{reflist}}

[[Category:Diagnoses]]
[[Category:Potential comorbidities]]
[[Category:Musculoskeletal diseases and disorders]]

User:FatigueTrackerBot

2020-01-02T01:08:52Z

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2020-01-02T01:04:39Z

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2020-01-02T01:03:15Z

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2020-01-02T01:01:16Z

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2020-01-02T00:48:52Z

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Expert in [[wiki|Cybernetics]]. Performing research within the area of [[wiki|biocybernetics]]. Focusing on available and relevant research regarding various causes for fatigue.