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|Classification and external resources|
Molecular structure of thyroxine, the deficiency of which causes the symptoms of hypothyroidism
|Classification and external resources|
Molecular structure of thyroxine, the deficiency of which causes the symptoms of hypothyroidism
Hypothyroidism (//), from hypo- (underactive) and thyroid (the thyroid gland), often called underactive thyroid, is a common endocrine disorder in which the thyroid gland does not produce enough thyroid hormones thyroxine (T4) and triiodothyronine (T3). It can cause a number of symptoms, such as tiredness, cold intolerance and weight gain. In children, hypothyroidism leads to delays in growth and intellectual development, which is called cretinism in severe cases. The diagnosis of hypothyroidism, when suspected clinically, can be confirmed with blood tests measuring thyroid-stimulating hormone (TSH) and thyroxine levels.
Worldwide, not enough iodine in the diet is the most common cause of hypothyroidism. In countries with enough dietary iodine, the most common cause of hypothyroidism is the autoimmune condition Hashimoto's thyroiditis. Less common causes including: previous treatment with radioactive iodine, injury to the hypothalamus or the anterior pituitary gland, certain medications, a lack of a thyroid at birth or surgical removal of a functioning thyroid gland, and other autoimmune problems.
Hypothyroidism can be well treated with manufactured L-thyroxine; the dose is adjusted according to symptoms and normalization of the thyroxine and TSH levels. In Western countries, hypothyroidism occurs in 0.3–0.4% while subclinical hypothyroidism is thought to occur in 4.3–8.5%. It may also happen in dogs and more rarely in cats and horses.
People with hypothyroidism often have no symptoms or only mild symptoms. Numerous symptoms and signs are associated with hypothyroidism, and can relate to the underlying pathological cause of the hypothyroidism, or direct effects of having insufficient thyroid hormones. Hashimoto's thyroiditis may present with the mass effect of a goiter.
|Fatigue||Dry, coarse skin|
|Feeling cold||Cool extremities|
|Poor memory and concentration||Myxedema (mucopolysaccharide deposition in the skin)|
|Weight gain with poor appetite||Slow pulse rate|
|Shortness of breath||Peripheral edema|
|Hoarse voice||Delayed relaxation of tendon reflexes|
|Menorrhagia (and later oligomenorrhea)||Carpal tunnel syndrome|
|Paresthesia||Serous cavity effusions (pleural effusion, ascites, pericardial effusion)|
A number of symptom rating scales are in existence; they provide a degree of objectivity but have limited sensitivity and specificity and cannot be relied upon for diagnosis. Delayed relaxation after testing the ankle jerk reflex is a characteristic sign in hypothyroidism and correlates with the severity of the hormone deficit.
Myxedema coma is a rare but life-threatening state of very severe hypothyroidism. It may occur in those who are known to have hypothyroidism and suffer an intercurrent illness, but it can be the first presentation of hypothyroidism. The illness is characterized by a markedly decreased body temperature without shivering, an altered level of consciousness, a slow heart rate and reduced respiratory effort. There may be physical signs suggestive of hypothyroidism, such as skin changes or enlargement of the tongue.
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), but some may have drowsiness, decreased muscle tone, hoarse-sounding cry, difficulties with feeding, constipation, an enlarged tongue, umbilical hernia, dry skin, a decreased body temperature and jaundice. A goiter is rare, although it may develop later in children who have a thyroid gland that does not produce functioning thyroid hormone. A goiter may also develop in children growing up in areas with iodine deficiency. Normal growth development may be delayed, and untreated neonatal hypothyroidism may lead to an intellectual impairment (IQ 6–15 points lower in severe cases); problems with gross and fine motor skills and coordination, reduced muscle tone, squinting, decreased attention span and delayed speaking.
In older children and adolescents, the symptoms of hypothyroidism may include fatigue, cold intolerance, somnolence, muscle weakness, constipation, a delay in growth, overweight for height, pallor, coarse and thick skin, increased body hair, menstrual irregularities in girls, and delayed puberty. Signs may include delayed relaxation of the ankle reflex and a slow heart beat. A goiter may be present; it is usually diffuse but sometimes asymmetrical and can be pebbly (bosselated) in character.
Even mild or subclinical hypothyroidism has been associated with impaired fertility and an increased risk of miscarriage. Hypothyroidism in early pregnancy, even with limited or no symptoms, may increase the risk of pre-eclampsia, offspring with lower intelligence, and the risk of perinatal mortality. Pregnant women are affected by hypothyroidism in 0.3–0.5% of cases.
Hypothyroidism is caused either by inadequate function of the gland itself (primary hypothyroidsim) or by insufficient stimulation with thyroid-stimulating hormone (central hypothyroidism). Primary hypothyroidism is about a thousandfold more common than central hypothyroidism.
Iodine deficiency is the most common cause of primary hypothyroidism and endemic goiter worldwide. In iodine-replete areas of the world, hypothyroidism is most commonly caused by the autoimmune disease Hashimoto's thyroiditis (chronic autoimmune thyroiditis). 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.
After women give birth, about 5% of women develop postpartum thyroiditis up to nine months afterwards; this is characterized by a period of transient hyperthyroidism followed by transient hypothyroidism; 20–40% remain permanently hypothyroid.
Autoimmune thyroiditis is associated with other immune-mediated diseases such as diabetes mellitus type 1, pernicious anemia, myasthenia gravis, celiac isease, rheumatoid arthritis and systemic lupus erythematosus. It may occur as part of autoimmune polyendocrine syndrome (type 1 and type 2).
|Primary hypothyroidism||Iodine deficiency (developing countries), autoimmune thyroiditis, previous thyroidectomy, previous radioiodine treatment, previous external beam radiotherapy to the neck|
Medication: lithium-based mood stabilizers, amiodarone, interferon alpha, tyrosine kinase inhibitors such as sunitinib
|Central hypothyroidism||Lesions compressing the pituitary (pituitary adenoma, craniopharyngioma, meningioma, glioma, Rathke's cleft cyst, metastasis, empty sella, aneurysm of the internal carotid artery), surgery or radiation to the pituitary, drugs, injury, vascular disorders (pituitary apoplexy, Sheehan syndrome, subarachnoid hemorrhage), autoimmune diseases (lymphocytic hypophysitis, polyglandular disorders), infiltratative diseases (iron overload due to hemochromatosis or thalassemia, sarcoidosis, Langerhans cell histiocytosis), particular inherited congenital disorders, and infections (tuberculosis, mycoses, syphilis)|
|Congenital hypothyroidism||Thyroid dysgenesis (75%), thyroid dyshormonogenesis (20%), maternal antibody or radioiodine transfer|
Syndromes: mutations (in GNAS complex locus, PAX8, TTF-1/NKX2-1, TTF-2/FOXE1), Pendred's syndrome (associated with sensorineural hearing loss)
Transiently: due to maternal iodine deficiency or excess, anti-TSH receptor antibodies, certain congenital disorders, neonatal illness
Central: pituitary dysfunction (idiopathic, septo-optic dysplasia, deficiency of PIT1, isolated TSH deficiency)
Thyroid hormone is required for the normal functioning of numerous tissues in the body. In health, the thyroid gland predominantly secretes thyroxine/T4, which is converted into triiodothyronine/T3 in other organs by the selenium-dependent enzyme iodothyronine deiodinase. Triiodothyronine binds to the thyroid hormone receptor in the nucleus of cells, where it stimulates the transcription of particular genes and the production of specific proteins. Additionally, the hormone binds to integrin αvβ3 on the cell membrane, thereby stimulating the sodium–hydrogen antiporter and processes such as angiogenesis (formation of blood vessels) and cell proliferation. In blood, almost all thyroid hormone (99.97%) is bound to plasma proteins such as thyroxine-binding globulin; only the free unbound fraction is biologically active.
The thyroid gland is the only source of thyroid hormone in the body; the process requires iodine and the amino acid tyrosine. Iodine in the bloodstream is taken up by the gland and incorporated into thyroglobulin molecules. The process is controlled by the thyroid-stimulating hormone (TSH, thyrotropin), which is secreted by the pituitary. Insufficient iodine, or insufficient TSH, can result in decreased production of thyroid hormones.
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 inhibited by thyroxine by a negative feedback process. Insufficiency of TRH, which is uncommon, can lead to deficiency of TSH and thereby to insufficient thyroid hormone production.
Pregnancy leads to marked changes in thyroid hormone physiology. The gland is increased in size by 10%, thyroxine production is increased by 50%, and iodine requirements are increased. Many women have normal thyroid function but immunological evidence of thyroid autoimmunity (as evidenced by autoantibodies) or are iodine deficient develop evidence of hypothyroidism before or after giving birth.
Laboratory evaluation of thyroid stimulating hormone levels in the blood is considered the best initial test for hypothyroidism; a second TSH level is often ordered several weeks later for confirmation of the diagnosis. TSH levels may be abnormal in the context of other illnesses, and TSH testing in hospitalized people is discouraged unless thyroid dysfunction is strongly suspected. If an elevated TSH level is detected, this indicates that the thyroid gland is not producing adequate levels of thyroid hormone and subsequently free T4 levels are often obtained. Determination T3 is discouraged in the assessment for hypothyroidism.
|Normal||Normal||Normal thyroid function|
Many cases of hypothyroidism are associated with mild elevations the activities of creatine kinase and liver enzymes in the blood. They typically normalize when the hypothyroidism has been fully treated. Levels of cholesterol, low-density lipoprotein and lipoprotein (a) can be elevated; the impact of subclinical hypothyroidism on lipid parameters is less well defined.
Very severe hypothyroidism and myxedema coma is characteristically associated with hyponatremia (low sodium levels in the blood) together with elevations in antidiuretic hormone, as well as acute deterioration in kidney function due to a number of causes.
An isolated diagnosis of hypothyroidism without palpable structural anomalies does not merit thyroid imaging; however, if present with a structurally palpable abnormal thyroid gland (e.g. thyroid nodules) on physical examination, diagnostic imaging is then warranted. The presence of antibodies against thyroid peroxidase (TPO) makes it more likely that thyroid nodules are caused by autoimmune thyroiditis, but if there is any doubt a needle biopsy may be required.
If the TSH level is normal or low and serum FT4 levels are low, this is suggestive of central hypothyroidism (insufficient TSH or TRH secretion by the pituitary gland or hypothalamus). There may be other features of hypopituitarism, such as menstrual cycle abnormalities, adrenal insufficiency, and potentially evidence of a pituitary mass (headache, vision changes). Central hypothyroidism should be investigated further as to the underlying cause.
In primary hypothyroidism, TSH levels are high and T4 and T3 levels are low, and TSH usually rises when T4 and T3 levels drop. "Subclinical hypothyroidism" is said to exist when serum TSH levels are elevated but serum free thyroxine is within normal limits. In subclinical hypothyroidism, TSH is elevated but below the limit representing overt hypothyroidism. The presentation of subclinical hypothyroidism is quite variable and classic signs and symptoms of hypothyroidism may not be readily observed. Of people with subclinical hypothyroidism, a proportion will develop overt hypothyroidism each year. In those with detectable antibodies against thyroid peroxidase (TPO), this conversion rate is 4.3%, while those with no detectable antibodies convert at a rate of 2.6%. Those with subclinical hypothyroidism and detectable TPO antibodies who are not requiring treatment should have repeat thyroid function tests more frequently (e.g. yearly) compared with those who do not have antibodies.
In pregnancy, free thyroxine levels may be lower than anticipated due to increased binding to thyroid binding globulin and decreased binding to albumin. They should either be corrected for the stage of pregnancy, or total thyroxine levels should be used instead for diagnosis. TSH values, too, may be lower than normal (particularly in the first trimester), and the normal range should be adjusted for the stage of pregnancy.
In pregnancy, subclinical hypothyroidism is defined as a TSH between 2.5 and 10 mIU/l with a normal thyroxine level, while those with TSH above 10 mIU/l are considered to overtly hypothyroid even if the thyroxine level is normal. Antibodies against TPO may be important in making decisions about treatment (see below), and should therefore be determined in women with abnormal thyroid function tests.
Determination of TPO antibodies may be considered as part of the assessment of recurrent miscarriage, as subtle thyroid dysfunction can be associated with pregnancy loss, but this recommendation is not universal, and presence of thyroid antibodies may not predict future outcome.
Primary prevention of hypothyroidism in populations by addition of iodine to commonly used foods has been a public health intervention that has effectively eliminated childhood hypothyroidism. In addition to stimulating the consumption of iodine-rich foods such as dairy and fish, many countries with moderate iodine deficiency have implemented universal salt iodization (USI). Encouraged by the World Health Organization, 130 countries now have USI, and 70% of the world's population are receiving iodized salt. In some countries, iodized salt is added to bread. Despite this, iodine deficiency has reappeared in some Western countries as a result of attempts to reduce salt intake.
It has been recognized that pregnant and breastfeeding women, whose iodine requirements are higher, may still be deficient. A daily intake of 250 µg is recommended. As many women will not achieve this from dietary sources alone, the American Thyroid Association recommends an oral supplement of 150 µg.
Screening for hypothyroidism at a population level is performed in the newborn period in many countries, generally using TSH. This has led to the early identification of many cases of preventable developmental delay. It is the most widely used newborn screening test worldwide. TSH-based screening will identify the most common causes, but addition of T4 is required to identify the rarer central causes of neonatal hypothyroidism.
In adults, widespread screening of asymptomatic individuals is a matter of debate. Some organisations (such as the United States Preventive Services Task Force) state that routine screening is unnecessary, while others (such as the American Thyroid Association) recommend either intermittent testing above a certain age in both sexes or only in women. Targeted screening may be appropriate in a number of situations where hypothyroidism is common: other autoimmune diseases, a strong family history of thyroid disease, those who have received radioiodine or other radiation therapy to the neck, those who have previously undergone thyroid surgery, those with an abnormal thyroid examination, those with psychiatric disorders, people taking amiodarone or lithium, and those with a number of medical conditions (such as certain heart and skin conditions). Yearly thyroid function tests are recommended in people with Down syndrome, as they are prone to thyroid disease
There is usually no way of directly improving thyroid hormone secretion by the thyroid gland, and most people with symptoms of hypothyroidism and confirmed thyroxine deficiency are therefore treated with a synthetic long-acting form of thyroxine, known as levothyroxine (L-thyroxine). In young and otherwise healthy people with overt hypothyroidism, a full replacement dose (adjusted by weight) can be commenced immediately; in the elderly and people with heart disease a lower starting dose is recommended to prevent oversupplementation and risk of complications. Lower doses may be sufficient in those with subclinical hypothyroidism, while people with central hypothyroidism may require higher than average doses.
Blood free thyroxine and TSH levels are monitored to help determine whether the dose is adequate. This is done 4–8 weeks after the initiation of treatment or a change in levothyroxine dose. Once the adequate replacement dose has been established, the tests can be repeated after 6 and then 12 months, unless there is a change in symptoms. In people with central/secondary hypothyroidism, TSH is not a reliable marker of hormone replacement and decisions are based mainly on the free T4 level.
Addition of liothyroxine (synthetic triiodothyronine/T3) to levothyroxine has been suggested to provide better symptom control, but clinical studies have not confirmed this suggestion. In 2007 the British Thyroid Association issued a statement to the effect that combined T4 and T3 therapy carried a higher rate of side effects and no benefit over T4 monotherapy. Similarly, American professional guidelines discourage combination therapy on the basis of a lack of evidence, although they acknowledge that some people feel better when receiving combination treatment.
Desiccated thyroid extract is an animal-based thyroid gland extract, most commonly from pigs. It is also a combination therapy, containing natural forms of T4 and T3. It also contains calcitonin (a hormone produced in the thyroid gland that is involved in the regulation of calcium levels), T1 and T2; these are not present in synthetic hormone medication. This extract was once a mainstream hypothyroidism treatment, but its use today is unsupported by evidence, and the British Thyroid Association and American professional guidelines discourage its use.
There is limited evidence from clinical studies whether there is definite benefit from treating subclinical hypothyroidism, and whether this offsets the risk of overtreatment and adverse events. Untreated subclinical hypothyroidism may be associated with a possible modest increase in the risk of coronary artery disease. A 2007 meta-analysis by the Cochrane Collaboration found no benefit of thyroid hormone replacement except for "some parameters of lipid profiles and left ventricular function".
Since 2008, consensus American and British opinion has been that in general people with TSH under 10 mIU/l do not require treatment. American guidelines recommend that treatment is considered if the TSH is elevated but below <10 mIU/l in people with symptoms of hypothyroidism, detectable antibodies against thyroid peroxidase, a history of heart disease or are at an increased risk for heart disease.
Myxedema coma usually requires intensive care unit admission for close observation and treatment of abnormalities in breathing, temperature control, blood pressure, and sodium levels. Mechanical ventilation may be required, as well as fluid replacement, vasopressor agents, cautious rewarming, and corticosteroids (for possible adrenal insufficiency which can occur together with hypothyroidism). Careful correction of low sodium levels may be achieved with hypertonic saline solutions or vasopressin receptor antagonists.
To achieve rapid treatment of the hypothyroidism, levothyroxine or liothyronine may be administered intravenously, particularly if the level of consciousness is too low to be able to swallow medication safely.
In woman with known hypothyroidism who become pregnant, it is recommended that serum TSH levels are monitored and kept within the normal range for each trimester when treated with levothyroxine monotherapy. The first trimester normal range is below 2.5 mIU/L and below 3.0 mIU/L in the second and third trimesters. Treatment decisions should be guided by total (rather than free) thyroxine or by the free T4 index; the results are sensitive to the stage of the pregnancy. The levothyroxine dose usually needs to be increased after pregnancy is confirmed.
Women with detectable anti-TPO antibodies who are trying to conceive (naturally or by assisted means) may require thyroid hormone supplementation even if the TSH level is normal, particularly if there have been previous miscarriages or they have been hypothyroid in the past, as the risk of developing hypothyroidism in pregnancy is high. Supplementary levothyroxine may reduce the risk of preterm birth and possibly miscarriage. The recommendation is stronger in pregnant women with subclinical hypothyroidism (defined as TSH 2.5–10 mIU/l) who are anti-TPO positive, in view of the risk of overt hypothyroidism. If a decision is made not to treat, close monitoring of the thyroid function (4-weekly in the first 20 weeks of pregnancy) is recommended. In the absence of anti-TPO positivity, treatment for subclinical hypothyroidism is not currently recommended.
Worldwide about one billion people are estimated to be iodine deficient; however, it is not known how often this results in hypothyroidism. In large population-based studies in iodine-replete Western countries, such as NHANES III, 0.3–0.4% of the population have overt hypothyroidism. A larger proportion of 4.3–8.5% have subclinical hypothyroidism. Of people with subclinical hypothyroidism, 80% have a TSH level below the 10 mIU/l mark that is regarded as the threshold for treatment. Children with subclinical hypothyroidism often revert to normal thyroid function, and a small proportion develops overt hypothyroidism (as predicted by evolving antibody and TSH levels, the presence of celiac disease, and the presence of a goiter).
Women are significantly more likely to develop hypothyroidism than men. In population-based studies, women were seven times more likely than men to have TSH levels above 10 mU/l. 2–4% of people with subclinical hypothyroidism will progress to overt hypothyroidism each year. The risk is higher in those with antibodies against thyroid peroxidase. Subclinical hypothyroidism is estimated to affect approximately 2% of children; in the adult population subclinical hypothyroidism is more common in the elderly, and in Caucasians. There is a much higher rate of thyroid disorders, the most common of which is hypothyroidism, in individuals with Down syndrome and Turner syndrome
Very severe hypothyroidism and myxedema coma is rare, with an estimated incidence of 0.22 per million people a year. The majority of cases occur in women over 60 years of age, although it may occur in all age groups.
Most hypothyroidism is primary in nature. Central/secondary hypothyroidism affects 1:20,0000 to 1:80,0000 of the population, or about one out of every thousand people with hypothyroidism. If T4 determination is included in neonatal screening, this will identify cases of congenital hypothyroidism of central origin in 1:16,000 to 1:160,000 births. Considering these children usually have other pituitary hormone deficiencies, early identification of these cases may prevent complications.
The link between the thyroid gland and myxedema was established in the late 19th century when people and animals who had had their thyroid removed showed improvement in symptoms with transplantation of animal thyroid tissue. Iodine had been discovered in seaweed in 1811 by Bernard Courtois, and iodine intake was linked with goiter size in 1820 by Jean-Francois Coindet. Gaspard Adolphe Chatin postulated in 1852 that endemic goiter was the result of insufficient iodine intake, and Eugen Baumann demonstrated iodine in thyroid tissue in 1896.
In 1891 the English physician George Redmayne Murray introduced subcutaneously injected sheep thyroid extract, followed shortly after by an oral formulation. Purified thyroxine was introduced in 1914 and in the 1930s synthetic thyroxine became available, although desiccated animal thyroid extract remained widely used. Liothyronine was identified in 1952.
In veterinary practice, dogs are the species most commonly affected by hypothyroidism. The majority of cases occurs as a result of primary hypothyroidism, of which two types are recognized: lymphocytic thyroiditis is probably immune-driven and leads to destruction and fibrosis of the thyroid gland, while idiopathic atrophy leads to the gradual replacement of the gland by fatty tissue. There is often lethargy, cold intolerance, exercise intolerance, and weight gain. Furthermore, skin changes and fertility problems are seen in canine hypothyroidism, as well as a number of other symptoms. The signs of myxedema can be seen in dogs, with prominence of skin folds on the forehead, and cases of myxedema coma are encountered. The diagnosis can be confirmed by blood test, as the clinical impression alone may lead to overdiagnosis. Lymphocytic thyroiditis is associated with detectable antibodies against thyroglobulin, although they typically become undetectable in advanced disease. Treatment is with thyroid hormone replacement.
Other species that are less commonly affected include cats and horses, as well as other large domestic animals. In cats, hypothyroidism is usually the result of other medical treatment such as surgery or radiation. In young horses, congenital hypothyroidism has been reported predominantly in Western Canada and has been linked with the mothers diet.