Thyroid hormone

Thyroid hormones are a group of hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are primarily responsible for regulation of metabolism, and thus act on nearly every cell in the body.

Thyroid hormone production is regulated by the pituitary gland, which releases thyroid stimulating hormone (TSH).

Over production of thyroid hormones (hyperthyroidism) can accelerate your body's metabolism causing sudden weight loss, a rapid or irregular heartbeat, sweating, nervousness or irritability, and other symptoms. Under production of thyroid hormones (hypothyroidism) can lower your body's metabolism causing obesity, fatigue, muscle weakness, thinning hair, slowed heart rate, depression and other symptoms.

Thyroxine (T4) (90%)
Thyroxine (abbreviated as T4) accounts for 90% of the hormone produced by the thyroid gland. It is physiological inactive and must be converted to T3 in the liver and kidneys.

Triiodothyronine (T3) (9%)
Triiodothyronine (abbreviated as T3) is the active form of the hormone. Only 9% of the thyroid hormone produced by the thyroid glad is T3. The rest of the physiologically required T3 is converted from T4 within liver and kidney cells by deiodinases, which are selenium-dependent enzymes. Selenium sufficiency is therefore important for the proper conversion of T4 to T3. Genetic differences can deiodinase production and therefore conversion ability.

Reverse T3 (rT3) (0.9%)
Reverse T3 is an isomer of T3, that is it has the same chemical formula but a different shape and is physiologically inactive. It is also made from T4 and plays a role in euthyroid sick syndrome, where rT3 levels are elevated in presence of normal T4 and TSH levels.

Diiodothyronine (T2)
The physiological functions of diiodothyronine (T2), including 3,5-diiodo-L-thyronine, are less well-understood.

Peripheral
T4 is a prohormone and a reservoir for the biologically active T3. T4 is converted to T3 by deiodinase enzymes.

There are three types of deiodinase enzymes:


 * Type 1 (D1) deiodinates T4 to the biologically active T3 as well as the hormonally inactive and possibly inhibitory rT3. Breaks down rT3 into T2. Encoded by DIO1 gene. In humans, it is found in liver, kidney, thyroid, and pituitary.
 * Type 2 (D2) converts T4 into T3, and breaks down rT3 into T2. Encoded by DIO2 gene. In humans, it is found in skeletal muscle, central nervous system, pituitary, thyroid, heart, and brown adipose tissue.
 * Type 3 (D3) produces rT3 from T4, and breaks down T3 into T2. Encoded by DIO3 gene. In humans, it has been found in the central nervous system and placenta in adults and in many additional tissues in the fetus.

Genetic factors
It is estimated that 40–65% of the inter-individual variation in serum TSH and FT4 levels is determined by genetic factors. Genetic factors may influence individual variation in the ability to convert T4 to T3. Several SNPs of the DIO1 gene, which encodes for the D1 enzyme, and DIO2 gene, which encodes for the D2 enzyme, have been studied.

D1O1
rs2235544: The homozygous mutant allele (C:C) is associated decreased deiodinase function, resulting in a lower FT3/FT4 ratio, lower T3 and high T4 compared to wild type.

D2O2
rs225014: Also known as Thr92Ala, represents a variant in the deiodinase, iodothyronine, type II DIO2 gene on chromosome 14. A study of 102 patients pre- and post- total thyroidectomy showed that after receiving T4-only hormone replacement, 34% of patients had lower reduced Free T3 levels (FT3) than they had pre-surgery. Those with mutant alleles of Thr92Ala had lower levels of Free T3 hormone than wild type (Thr/Thr) / (T;T) patients. The percentage of reduced post-surgery FT3 levels was directly correlated with the presence and severity of the polymorphism: 58.3% in homozygous (Ala/Ala) / (C;C) patients vs 36.5% in heterozygous (Thr/Ala) / (T;C) subjects.

rs12885300: In a study of patients after thyroidectomy, patients with appeared to have an "have an altered set point of the hypothalamus-pituitary-thyroid axis" with a weaker negative feedback of FT4 on TSH in patients with homozygous mutant alleles (C;C).

Transport
Thyroxine binding globulin is a transport protein responsible for carrying T4 and T3 in the bloodstream.

Function and metabolic effects
Thyroid hormones are essential for regulating a number of biological processes, including growth, neurodevelopment, carbohydrate metabolism, oxygen consumption and protein synthesis.

Mitochondrial function
T3 plays an important role in the regulation of mitochondrial function as well as in mitochondrial biogenesis. T3 rapidly stimulates an increase in cellular respiration within minutes to hours after hormone treatment. One to several days after hormone treatment, changes in gene expression as well as direct binding of hormone to receptors induces mitochondrial biogenesis and changes to mitochondrial mass. T3 stimulates the expression of an inner membrane mitochondrial protein called uncoupling protein, resulting in increased inner membrane proton leak. It also induces changes in phospholipid turnover. ATP synthesis and turnover reactions are also affected.

Uncoupling protein is responsible for thermogenesis, which is why hyperthyroidism results in excess heat while hypothyroidism results in cold intolerance.

Citric acid cycle
T3 increases oxygen , glucose and pyruvate   utilization, shifting metabolism from an anaerobic to more aerobic state.

T2 also plays a role in regulating energy metabolism, although its role is less studied. 3,5-diiodo-L-thyronine influences resting metabolic rate.

Cholesterol
Triiodothyronine reduces cholesterol.

Testing
Standard commercial laboratory testing for thyroid hormones is via immunoassay. However, these tests are shown to be unreliable in the low-normal and high-normal range when compared to mass spectrometry. In addition, most clinicians do not test for reverse T3.

Hypothyrodism
Hypothyrodism is when the thyroid produces excess levels of hormone. It can have a number of causes including:


 * Hashimoto's thyroiditis

Hyperthyrodism
Hyperthyroidism is when the thyroid produces excess levels of hormone. It can have a number of causes including:


 * Graves' disease, an autoimmune disorder

Low T3 Syndrome
Also known as euthyroid sick syndrome, Low T3 syndrome is characterized by decreased serum T3 and/or thyroxin (T4) levels, increased reverse T3 (rT3), and no significant increase in TSH. Low T3 syndrome is often seen in cases of acute and chronic illness, including myocardial infarction, fasting, starvation and sepsis. There is no evidence that supplementation with T3 is of benefit.

Nutrition
Sufficient iodine, selenium, and iron are crucial for normal thyroid hormone function. Thyroid hormones are partially comprised of iodine and a deficiency of iodine in the diet can lead to decreased production of these hormones. If left uncorrected the thyroid tissue can enlarge, resulting in a pronounced swelling in the neck, called a 'simple goitre.' Selenium is required for the production of deiodinase enzymes, and thus the conversion of T4 to T3. Iron is needed for heme-dependent thyroid peroxidase.

Hormone replacement
Patients with hypothyrodism may need hormone replacement. The standard replacement therapy is Levothyroxine, a synthetic form of T4. However, some patients on Levothyroxine report continuing symptoms of hypothyrodism despite normal laboratory results, owing to poor conversion of T4 to T3. In these cases, patients may add a T3 replacement hormone drug, such as Cytomel, or Armour thyroid, which is whole desiccated thyroid gland from pigs.

Chronic Fatigue Syndrome
A study of 99 patients with a diagnosis of Chronic Fatigue Syndrome found similar levels of TSH to healthy controls but lower free triiodothyronine (FT3), total thyroxine (TT4), total triiodothyronine (TT3), %TT3 (4.7%), deiodinase activity, secretory capacity of the thyroid gland, lower 24-h urinary iodine (27.6%), and higher % reverse T3 (rT3). "Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels. The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state."

Fibromyalgia
A series of small N trials found significant improvement in symptoms in euthyroid patients given T3.

Small intestinal bacterial overgrowth
In one study, 54% of patients with hypothyroidism tested positive for small intestinal bacterial overgrowth (SIBO) as compared to 5% of controls. SIBO is also associated with Levothyroxine usage, possibly owing to the secondary hypothyroidism seen in patients who are poor converters.

Notable studies

 * 2018, Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study Full Text)

Learn more

 * American Thyroid Association webpage