Hypothyroidism

Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, extreme fatigue, muscle aches, constipation, slow heart rate, depression, and weight gain. Occasionally, there may be swelling of the front part of the neck due to goiter. Untrea

Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones.[3] It can cause a number of symptoms, such as poor ability to tolerate cold, extreme fatigue, muscle aches, constipation, slow heart rate, depression, and weight gain.[3] Occasionally, there may be swelling of the front part of the neck due to goiter.[3] Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.[5]

Worldwide, too little iodine in the diet is the most common cause of hypothyroidism.[8][9] Hashimoto's thyroiditis, an autoimmune disease wherein the body's immune system reacts to the thyroid gland,[10] is the most common cause of hypothyroidism in countries with sufficient dietary iodine.[3] Less common causes include previous treatment with radioactive iodine, injury to the hypothalamus or the anterior pituitary gland, certain medications, a lack of a functioning thyroid at birth, or previous thyroid surgery.[3][11] The diagnosis of hypothyroidism, when suspected, can be confirmed with blood tests measuring thyroid-stimulating hormone (TSH) and thyroxine (T4) levels.[3]

Salt iodization has prevented hypothyroidism in many populations.[7] Thyroid hormone replacement with levothyroxine treats hypothyroidism.[3] Medical professionals adjust the dose according to symptoms and normalization of the TSH levels.[12] Thyroid medication is safe in pregnancy.[3] Although an adequate amount of dietary iodine is important, too much may worsen specific forms of hypothyroidism.[3]

Worldwide about one billion people are estimated to be iodine-deficient; however, it is unknown how often this results in hypothyroidism.[13] In the United States, overt hypothyroidism occurs in approximately 0.3–0.4% of people.[8] Subclinical hypothyroidism, a milder form of hypothyroidism characterized by normal thyroxine levels and an elevated TSH level, is thought to occur in 4.3–8.5% of people in the United States.[8] Hypothyroidism is more common in women than in men.[3] People over the age of 60 are more commonly affected.[3] Dogs are also known to develop hypothyroidism, as are cats and horses, albeit more rarely.[14] The word hypothyroidism is from the Greek hypo- ('reduced'), thyreos ('shield'), and eidos ('form'), whereby the two latter parts refer to the thyroid gland.[15]

Signs and symptoms

People with hypothyroidism often have no or only mild symptoms. Numerous symptoms and signs are associated with hypothyroidism and can be related to the underlying cause, or a direct effect of not having enough thyroid hormones.[16][17] Many symptoms of hypothyroidism are otherwise common and do not necessarily indicate thyroid problem.[3] Hashimoto's thyroiditis may present with the mass effect of a goiter (enlarged thyroid gland).[16] In middle-aged women, the symptoms may be mistaken for those of menopause.[12]

Delayed relaxation after testing the ankle jerk reflex is a characteristic sign of hypothyroidism and is associated with the severity of the hormone deficit.[8]

Myxedema coma

Myxedema coma is a rare but life-threatening state of extreme hypothyroidism. It may occur in those with established hypothyroidism when they develop an acute illness. Myxedema coma can be the first presentation of hypothyroidism. People with myxedema coma typically have a low body temperature without shivering, confusion, a slow heart rate and reduced breathing effort. There may be physical signs suggestive of hypothyroidism, such as skin changes or enlargement of the tongue.[19]

Pregnancy

Hypothyroidism when untreated may lead to infertility and an increased risk of miscarriage or infant death around the time of birth, mostly in severe cases of hypothyroidism.[20][21] Women are affected by hypothyroidism in 0.3–0.5% of pregnancies.[22] Subclinical hypothyroidism during pregnancy is associated with birth of the baby before 37 weeks of pregnancy.[23]

Children

Newborn children with hypothyroidism may have normal birth weight and height (although the head may be larger than expected and the posterior fontanelle may be open). Some may have drowsiness, decreased muscle tone, poor weight gain, a hoarse-sounding cry, feeding difficulties, constipation, an enlarged tongue, umbilical hernia, dry skin, a decreased body temperature, and jaundice.[24] A goiter is rare, although it may develop later in children who have a thyroid gland that does not produce functioning thyroid hormone.[24] A goiter may also develop in children growing up in areas with iodine deficiency.[25] Normal growth and development may be delayed, and not treating infants may lead to an intellectual impairment (IQ 6–15 points lower in severe cases). Other problems include the following: difficulty with large scale and fine motor skills and coordination, reduced muscle tone, squinting, decreased attention span, and delayed speaking.[24] Tooth eruption may be delayed.[26]

In older children and adolescents, the symptoms of hypothyroidism may include fatigue, cold intolerance, sleepiness, muscle weakness, constipation, a delay in growth, overweight for height, pallor, coarse and thick skin, increased body hair, irregular menstrual cycles in girls, and delayed puberty. Signs may include delayed relaxation of the ankle reflex and a slow heartbeat.[24] A goiter may be present with a completely enlarged thyroid gland;[24] sometimes only part of the thyroid is enlarged and it can be knobby.[27]

Causes

Hypothyroidism is caused by inadequate function of the gland itself (primary hypothyroidism), inadequate stimulation by thyroid-stimulating hormone from the pituitary gland (secondary hypothyroidism), or inadequate release of thyrotropin-releasing hormone from the brain's hypothalamus (tertiary hypothyroidism).[8][28] Secondary and tertiary hypothyroidism are called "central" hypothyroidism. Primary hypothyroidism is about a thousandfold more common than central hypothyroidism.[11]

Iodine deficiency is the most common cause of primary hypothyroidism and endemic goiter worldwide.[8][9] In areas of the world with sufficient dietary iodine, the autoimmune disease Hashimoto's thyroiditis (chronic autoimmune thyroiditis) is the most common cause of primary hypothyroidism.[8][9] Hashimoto's may be associated with a goiter. It is characterized by infiltration of the thyroid gland with T lymphocytes and autoantibodies against specific thyroid antigens such as thyroid peroxidase, thyroglobulin and the TSH receptor.[8]

Autoimmune thyroiditis (Hashimoto's) is associated with other immune-mediated diseases such as diabetes mellitus type 1, pernicious anemia, myasthenia gravis, celiac disease, rheumatoid arthritis and systemic lupus erythematosus.[8] It may occur as part of autoimmune polyendocrine syndrome (type 1 and type 2).[8]

After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards.[29] This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.[29]

Iatrogenic hypothyroidism can be surgical (a result of thyroidectomy, usually for thyroid nodules or cancer) or following radioiodine ablation (usually for Graves' disease).

Pathophysiology

Thyroid hormone is required for the normal functioning of numerous tissues in the body. In healthy individuals, the thyroid gland predominantly secretes thyroxine (T4), which is converted into triiodothyronine (T3) in other organs by the selenium-dependent enzyme iodothyronine deiodinase.[32] Triiodothyronine binds to the thyroid hormone receptor in the nucleus of cells, where it stimulates the turning on of particular genes and the production of specific proteins.[33] Additionally, the hormone binds to integrin αvβ3 on the cell membrane, thereby stimulating the sodium–hydrogen antiporter and processes such as formation of blood vessels and cell growth.[33] In blood, almost all thyroid hormone (99.97%) are bound to plasma proteins such as thyroxine-binding globulin; only the free unbound thyroid hormone is biologically active.[8]

Electrocardiograms are abnormal in both primary overt hypothyroidism and subclinical hypothyroidism.[34] T3 and TSH are essential for the regulation of cardiac electrical activity.[34] Prolonged ventricular repolarization and atrial fibrillation are often seen in hypothyroidism.[34]

The thyroid gland is the only source of thyroid hormone in the body; the process requires iodine and the amino acid tyrosine. The gland takes up iodine in the bloodstream and incorporates it into thyroglobulin molecules. The process is controlled by the thyroid-stimulating hormone (TSH, thyrotropin), which is secreted by the pituitary. Not enough iodine, or not enough TSH, can decrease thyroid hormone production.[28]

The hypothalamic–pituitary–thyroid axis plays a key role in maintaining thyroid hormone levels within normal limits. Production of TSH by the anterior pituitary gland is stimulated in turn by thyrotropin-releasing hormone (TRH), released from the hypothalamus. Production of TSH and TRH is decreased by thyroxine by a negative feedback process. Not enough TRH, which is uncommon, can lead to insufficient TSH release and therefore insufficient thyroid hormone production.[11]

Pregnancy leads to marked changes in thyroid hormone physiology. The gland increases in size by 10%, thyroxine production increases by 50%, and iodine requirements increase. Many women have normal thyroid function but have immunological evidence of thyroid autoimmunity (as evidenced by autoantibodies) or are iodine-deficient, and develop evidence of hypothyroidism before or after giving birth.[35]