Hypothyroidism

Back

Practice Essentials

Hypothyroidism is a common endocrine disorder resulting from deficiency of thyroid hormone. In the United States and other areas of adequate iodine intake, autoimmune thyroid disease (Hashimoto disease) is the most common cause of hypothyroidism; worldwide, iodine deficiency remains the foremost cause.

The image below depicts the hypothalamic-pituitary-thyroid axis.



View Image

The hypothalamic-pituitary-thyroid axis. Levels of circulating thyroid hormones are regulated by a complex feedback system involving the hypothalamus ....

See 21 Hidden Clues to Diagnosing Nutritional Deficiencies, a Critical Images slideshow, to help identify clues to conditions associated with malnutrition.

Signs and symptoms

Hypothyroidism commonly manifests as a slowing in physical and mental activity but may be asymptomatic. Symptoms and signs are often subtle and neither sensitive nor specific.

The following are symptoms of hypothyroidism:

The following are symptoms more specific to Hashimoto thyroiditis:

Physical signs of hypothyroidism include the following:

Myxedema coma is a severe form of hypothyroidism that most commonly occurs in individuals with undiagnosed or untreated hypothyroidism who are subjected to an external stress. Features are as follows:

See Clinical Presentation for more detail.

Diagnosis

Third-generation thyroid-stimulating hormone (TSH) assays are generally the most sensitive screening tool for primary hypothyroidism.[1] If TSH levels are above the reference range, the next step is to measure free thyroxine (T4) or the free thyroxine index (FTI), which serves as a surrogate of the free hormone level. Routine measurement of triiodothyronine (T3) is not recommended.

Results in patients with hypothyroidism are as follows:

Abnormalities in the complete blood count and metabolic profile that may be found in patients with hypothyroidism include the following[2] :

No universal screening recommendations exist for thyroid disease for adults. The American Thyroid Association recommends screening at age 35 years and every 5 years thereafter, with closer attention to patients who are at high risk, such as the following[3] :

See Workup for more detail.

Management

Monotherapy with levothyroxine (LT4) remains the treatment of choice for hypothyroidism. Aspects of LT4 treatment are as follows:

After dose stabilization, patients can be monitored with annual clinical evaluations and TSH monitoring. Patients should be monitored for symptoms and signs of overtreatment, which include the following:

In patients who continue to have symptoms (eg, weight gain, fatigue) despite normalization of their TSH level, consideration should be given to causes other than hypothyroidism. In some cases, however, the persistence of symptoms results from impaired conversion of T4 to T3 in the brain; these patients may benefit from combination LT4/liothyronine (LT3) therapy.[4]

The updated guidelines on hypothyroidism issued by the American Thyroid Association in 2014 maintain the recommendation of levothyroxine as the preparation of choice for hypothyroidism, with the following considerations:[5, 6]

Updated recommendations concerning hypothyroidism treatment in pregnant women are as follows:[5, 6]

Treatment of myxedema coma is as follows:

See Treatment and Medication for more detail.

Background

Hypothyroidism is a common endocrine disorder resulting from deficiency of thyroid hormone. It usually is a primary process in which the thyroid gland is unable to produce sufficient amounts of thyroid hormone.

Hypothyroidism can also be secondary—that is, the thyroid gland itself is normal, but it receives insufficient stimulation because of low secretion of thyrotropin (ie, thyroid-stimulating hormone [TSH]) from the pituitary gland. In tertiary hypothyroidism, inadequate secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus leads to insufficient release of TSH, which in turn causes inadequate thyroid stimulation.

Worldwide, iodine deficiency remains the foremost cause of hypothyroidism. In the United States and other areas of adequate iodine intake, autoimmune thyroid disease (Hashimoto disease) is the most common cause. Hypothyroidism may also be drug-induced or otherwise iatrogenic. (See Etiology.)

The patient’s presentation may vary from asymptomatic to myxedema coma with multisystem organ failure. Because nearly all metabolically active cells require thyroid hormone, deficiency of the hormone has a wide range of effects. Classic signs and symptoms, such as cold intolerance, puffiness, decreased sweating, and coarse skin, may not be present, especially in younger patients. (See Presentation.)

Third-generation TSH assays are readily available and are generally the most sensitive screening tool for primary hypothyroidism. The generally accepted reference range for normal serum TSH is 0.40-4.2 mIU/L.

If TSH levels are above the reference range, the next step would be to measure free thyroxine (T4). Subclinical hypothyroidism, also referred to as mild hypothyroidism, is defined as normal serum levels of free T4 and triiodothyronine (T3) with a slightly high serum TSH concentration. (See Workup.)

For hypothyroidism, thyroid hormone is administered to supplement or replace endogenous production. In general, hypothyroidism can be adequately treated with a constant daily dose of levothyroxine (LT4). (See Treatment and Medication.)

Congenital hypothyroidism, which affects 1 of every 4000 newborns, is due to congenital maldevelopment of the thyroid (see Pediatric Hypothyroidism). This disorder is included in the newborn screening panel in the United States and many other countries, and it is readily treatable once detected. Cretinism refers to severe hypothyroidism in an infant or child. This is classically the result of maternal iodine deficiency, and thankfully is increasingly rare.

Pathophysiology

The hypothalamic-pituitary-thyroid axis governs thyroid hormone secretion (see the image below).



View Image

The hypothalamic-pituitary-thyroid axis. Levels of circulating thyroid hormones are regulated by a complex feedback system involving the hypothalamus ....

Although hypothalamic or pituitary disorders can affect thyroid function, localized disease of the thyroid gland that results in decreased thyroid hormone production is the most common cause of hypothyroidism. Under normal circumstances, the thyroid releases 100-125 nmol of T4 daily and only small amounts of T3. The half-life of T4 is approximately 7-10 days. T4, a prohormone, is converted to T3, the active form of thyroid hormone, in the peripheral tissues by 5’-deiodination.

Early in the disease process, compensatory mechanisms maintain T3 levels. Decreased production of T4 causes an increase in the secretion of TSH by the pituitary gland. TSH stimulates hypertrophy and hyperplasia of the thyroid gland and 5’-deiodinase activity, thereby increasing T3 production.

Deficiency of thyroid hormone has a wide range of effects. Systemic effects are the result of either derangements in metabolic processes or direct effects by myxedematous infiltration (ie, accumulation of glucosaminoglycans in the tissues).

The hypothyroid changes in the heart result in decreased contractility, cardiac enlargement, pericardial effusion, decreased pulse, and decreased cardiac output. A Swedish study, by Mourtzinis et al, found the rates of hypothyroidism and hyperthyroidism in patients with atrial fibrillation to be 5.9% and 2.3%, respectively, compared with 3.7% and 0.8%, respectively, in controls.[7]

In the gastrointestinal (GI) tract, achlorhydria and prolonged intestinal transit time with gastric stasis can occur in hypothyroidism. Delayed puberty, anovulation, menstrual irregularities, and infertility are common. TSH screening should be a routine part of any investigation into menstrual irregularities or infertility.

Decreased thyroid hormone effect can cause increased levels of total cholesterol and low-density lipoprotein (LDL) cholesterol and a possible change in high-density lipoprotein (HDL) cholesterol because of a change in metabolic clearance. In addition, hypothyroidism may result in an increase in insulin resistance.

Etiology

In the United States and other areas of adequate iodine intake, autoimmune thyroid disease (Hashimoto disease) is the most common cause of hypothyroidism. The prevalence of antibodies is higher in women and increases with age.

Primary hypothyroidism

Types of primary hypothyroidism include the following:

Chronic lymphocytic (autoimmune) thyroiditis

The most frequent cause of acquired hypothyroidism is chronic lymphocytic (autoimmune) thyroiditis (Hashimoto thyroiditis). The body considers the thyroid antigens as foreign, and a chronic immune reaction ensues, resulting in lymphocytic infiltration of the gland and progressive destruction of functional thyroid tissue.

The majority of affected individuals will have circulating antibodies to thyroid tissue. Anti–thyroid peroxidase (anti-TPO) antibodies are the hallmark of this disease. It should be noted that antibody levels can vary over time, may not be present early in the disease process, and usually disappear over time. Given this change in antibody concentration, it should be understood that the absence of antibodies does not exclude the diagnosis of chronic lymphocytic (autoimmune) thyroiditis.

A study by Bothra et al reported that, compared with the general population, first-degree relatives of persons with Hashimoto thyroiditis have a nine-fold greater risk of developing it.[8]

Postpartum thyroiditis

Up to 10% of postpartum women may develop lymphocytic thyroiditis (postpartum thyroiditis) in the 2-12 months after delivery. The frequency may be as high as 25% in women with type 1 diabetes mellitus. Although a short course of treatment with levothyroxine (LT4) may be necessary, the condition is usually transient (2-4 months). However, patients with postpartum thyroiditis (anti-TPO–positive) are at increased risk of permanent hypothyroidism or recurrence of postpartum thyroiditis with future pregnancies.

The hypothyroid state can be preceded by a short thyrotoxic state. High titers of anti-TPO antibodies during pregnancy have been reported to have high sensitive and specificity for postpartum autoimmune thyroid disease.

In a 12-year longitudinal study, Stuckey et al found that hypothyroidism developed in 27 of 71 women (38%) who had a past history of postpartum thyroid dysfunction (PPTD). In comparison, only 14 of 338 women (4%) who had not had PPTD developed hypothyroidism.[9]

Subacute granulomatous thyroiditis

Also known as de Quervain disease, subacute granulomatous thyroiditis is a relatively uncommon disease that occurs most frequently in middle-aged women. Disease features include low grade fever, thyroid pain, dysphagia, and elevated erythrocyte sedimentation rate (ESR).

The disease is usually self-limited and does not normally result in longstanding thyroid dysfunction. It is important to note that inflammatory conditions or viral syndromes may be associated with transient hyperthyroidism followed by transient hypothyroidism (ie, de Quervain or painful thyroiditis and subacute thyroiditis).

Drug-induced and iatrogenic hypothyroidism

The following medications reportedly have the potential to cause hypothyroidism:

Use of radioactive iodine (I-131) for treatment of Graves disease generally results in permanent hypothyroidism within 3-6 months after therapy. The frequency of hypothyroidism after I-131 treatment is much lower in patients with toxic nodular goiters and those with autonomously functioning thyroid nodules. Patients treated with radioiodine should be monitored for clinical and biochemical evidence of hypothyroidism.

External neck irradiation (for head and neck neoplasms, breast cancer, or Hodgkin disease) may result in hypothyroidism. Patients who have received these treatments require monitoring of thyroid function.

Thyroidectomy of course results in hypothyroidism. Patients who undergo a thyroid lobectomy, with or without isthmectomy, have an approximately 15-30% chance of developing thyroid insufficiency.

Genetics

Genome-wide association studies have suggested that a single-nucleotide polymorphism located near the FOXE1 gene is associated with risk of developing thyroid disease and that the strongest association is with hypothyroidism. Persons found to have GG at the described location had an odds ratio (OR) of 1.35 for development of hypothyroidism, whereas persons found to have AG at the location had an OR of 1.00, and persons found to have AA at the location had an OR of 0.74.[12]

Approximately 10% of patients with congenital hypothyroidism have an error in thyroid hormone synthesis.[13] Mutations in the TPO gene appear to be the most common error of hormone synthesis, causing failure to produce adequate amounts of TPO.[14]

Mutations in the TSHR and PAX8 genes are known to cause congenital hypothyroidism without goiter.[15, 16] Mutations in the TSHR gene can cause hypothyroidism due to insensitivity to TSH, though most cases are notable for a clinically euthyroid state despite abnormal laboratory test results (elevated TSH with normal serum thyroid hormone concentrations). Mutations in the PAX8 gene cause hypothyroidism due to dysgenesis or agenesis of the gland .

Syndromic forms of hypothyroidism are also well described. Pendred syndrome is caused by a mutation in the SLC26A4 gene, which causes a defect in the organification of iodine (ie, incorporation into thyroid hormone), congenital sensorineural hearing loss, and, usually, an enlarged thyroid gland. It is inherited in an autosomal recessive manner.[17]

Autoimmune polyendocrinopathy type I is caused by a mutation in the AIRE gene and is characterized by the presence of Addison disease, hypoparathyroidism, and mucocutaneous candidiasis. A subset of patients with this disease also have a high prevalence of autoimmune thyroiditis and hypothyroidism and a novel mutation in the AIRE gene that is inherited in an autosomal dominant fashion.[18] Autoimmune polyendocrinopathy type 2 (Schmidt syndrome) is associated with adrenal insufficiency and hypothyroidism.

Iodine deficiency or excess

Worldwide, iodine deficiency is the most common cause of hypothyroidism. Excess iodine, as in radiocontrast dyes, amiodarone, health tonics (herbal and dietary supplements), and seaweed, can transiently inhibit iodide organification and thyroid hormone synthesis (the Wolff-Chiakoff effect). Most healthy individuals have a physiologic escape from this effect. In patients with iodine overload, the sodium-iodide symporter shuts down, and this allows intracellular iodine levels to drop and hormone secretion to resume.

The Wolff-Chiakoff effect is short-lived because the sodium-iodide symporter is capable of rapidly downregulation. However, exposure to excess iodine can produce more profound and sustained hypothyroidism in individuals with abnormal thyroid glands (eg, from autoimmune thyroiditis, subtotal thyroidectomy, or prior radioiodine therapy).[19]

Central hypothyroidism

Central hypothyroidism (secondary or tertiary) results when the hypothalamic-pituitary axis is damaged. The following potential causes should be considered[20, 21] :

Tumors in or around the pituitary cause impaired pituitary function by exerting pressure on normal pituitary cells and thereby affect the secretion of TRH, TSH, or both. Radiation, hypophysitis, and Sheehan syndrome cause death of these cells. Drugs such as dopamine and corticosteroids result in decreased TSH secretion.

Congenital nongoiterous hypothyroidism type 4 is caused by a mutation in the TSHB gene and is inherited in an autosomal recessive pattern. Patients have hypothyroidism and a low TSH level that does not rise with administration of TRH. Many patients with this condition were the products of consanguineous unions.[22]

TRH resistance is caused by a mutation in the TRHR gene and is inherited in an autosomal recessive manner. Patients with this condition have hypothyroidism and, unsurprisingly, have insensitivity to thyrotropin secretion.[23] That only a handful of cases of TRH resistance have been reported in the literature suggests that this is a rare condition.

TRH deficiency is caused by mutation in the TRH gene and is inherited in an autosomal recessive manner.[24] The index case was a girl evaluated for short stature who was found to have an isolated deficiency of TRH.[25]

Epidemiology

The National Health and Nutrition Examination Survey (NHANES 1999-2002) of 4392 individuals reflecting the US population reported hypothyroidism (defined as TSH levels exceeding 4.5 mIU/L) in 3.7% of the population.[26] Hypothyroidism is more common in women with small body size at birth and low body mass index during childhood.[27]

Iodine deficiency as a cause of hypothyroidism is more common in less-developed countries. Routine supplementation of salt, flour, and other food staples with iodine has decreased the rates of iodine deficiency.

World Health Organization (WHO) data from 130 countries taken from January 1994 through December 2006 found inadequate iodine nutrition in 30.6% of the population. The WHO recommends urinary iodine concentrations between 100 and 199 μg/L in the general population and a range of 150-249 μg/L in pregnant women. In developed countries, death caused by hypothyroidism is uncommon.

Age-related demographics

The frequency of hypothyroidism, goiters, and thyroid nodules increases with age. Hypothyroidism is most prevalent in elderly populations, with 2-20% of older age groups having some form of hypothyroidism. The Framingham study found hypothyroidism (TSH > 10 mIU/L) in 5.9% of women and 2.4% of men older than 60 years.[28] In NHANES 1999-2002, the odds of having hypothyroidism were 5 times greater in persons aged 80 years and older than in individuals aged 12-49 years.[26]

Sex-related demographics

Community studies use slightly different criteria for determining hypothyroidism; therefore, female-to-male ratios vary. Generally, thyroid disease is much more common in females than in males, with reported prevalences ranging from 2 to 8 times higher in females.

Race-related demographics

NHANES 1999-2002 reported that the prevalence of hypothyroidism (including the subclinical form) was higher in whites (5.1%) and Mexican Americans than in African Americans (1.7%). African Americans tend to have lower median TSH values.[26]

Prognosis

Undertreatment of hypothyroidism leads to disease progression, with gradual worsening of symptoms and further metabolic derangements. Ultimately, untreated hypothyroidism can cause profound coma or even death. Untreated hypothyroidism in infants can cause irreversible mental retardation.

In most patients, fortunately, thyroid hormone treatment reverses the signs and symptoms of hypothyroidism. With treatment, other secondarily affected laboratory values (eg, circulating lipid levels and elevated prolactin levels) should improve.

Using disease-specific (ThyPRO questionnaire) and generic (36-item Short Form Health Survey [SF-36]) measures of health-related quality of life (HRQL), Winther et al discovered that levothyroxine treatment resulted in improvement in some, but not all, aspects of HRQL in patients with hypothyroidism resulting from autoimmune thyroiditis. This included significant improvements in nine of 13 ThyPRO scales after 6 weeks of therapy.[29]

A study by Chang et al suggested that subclinical and overt hypothyroidism are linked to reduced renal function, with subclinical hypothyroidism raising the risk of chronic kidney disease (estimated glomerular filtration rate of below 60 mL/min/1.73m2) by 2.03-fold, and overt hypothyroidism increasing the risk by 7.68-fold. The increased risk remained significant even after other potential risk factors for chronic kidney disease were taken into account. The study also indicated, however, that subclinical and overt hypothyroidism have a lesser effect on proteinuria risk.[30]

A study by Sato et al suggested that in patients with heart failure, those with subclinical hypothyroidism have a worse prognosis, finding a significant increase in the rates of cardiac events and all-cause mortality in heart failure patients in the study with subclinical hypothyroidism compared with those who were euthyroid.[31]

Patient Education

Emphasize proper compliance at each visit. Clearly discuss the lifelong nature of hypothyroidism, the need for lifelong levothyroxine therapy, the proper way to take medicine, and the need for TSH testing at least annually.

Patients should take thyroid hormone as a single daily dose. Thyroid hormone is better absorbed in the small bowel; therefore, absorption can be affected by malabsorptive states, small bowel disease (eg, celiac sprue), and the patient’s age. Many drugs (eg, iron, calcium carbonate, calcium acetate aluminum hydroxide, sucralfate, raloxifene, and proton pump inhibitors) can interfere with absorption and therefore should not be taken within 2-4 hours of LT4 administration.[32]

Estrogen/progestin oral contraceptives and pregnancy are associated with changes in thyroid-binding globulin. These changes may impact thyroid hormone dosing.

For patient education information, see the Thyroid & Metabolism Center as well as Thyroid Problems and Chronic Fatigue Syndrome.

History

Hypothyroidism commonly manifests as a slowing in physical and mental activity but may be asymptomatic. Symptoms and signs of this disease are often subtle and neither sensitive nor specific. Classic signs and symptoms (eg, cold intolerance, puffiness, decreased sweating, and coarse skin) may not be present as commonly as was once believed.

Many of the more common symptoms are nonspecific and difficult to attribute to a particular cause. Individuals can also present with obstructive sleep apnea (secondary to macroglossia) or carpal tunnel syndrome. Women can present with galactorrhea and menstrual disturbances. Consequently, the diagnosis of hypothyroidism is based on clinical suspicion and confirmed by laboratory testing.

Myxedema coma is a severe form of hypothyroidism that results in an altered mental status, hypothermia, bradycardia, hypercarbia, and hyponatremia. Cardiomegaly, pericardial effusion, cardiogenic shock, and ascites may be present. Myxedema coma most commonly occurs in individuals with undiagnosed or untreated hypothyroidism who are subjected to an external stress, such as low temperature, infection, myocardial infarction, stroke, or medical intervention (eg, surgery or hypnotic drugs).

The following are symptoms of hypothyroidism:

Hashimoto thyroiditis is difficult to distinguish clinically, but the following symptoms are more specific to this condition:

Physical Examination

Signs found in hypothyroidism are usually subtle, and their detection requires a careful physical examination. Moreover, such signs are often dismissed as part of aging; however, clinicians should consider a diagnosis of hypothyroidism when they are present.

Physical signs of hypothyroidism include the following:

Additional signs specific to different causes of hypothyroidism, such as diffuse or nodular goiter and pituitary enlargement or tumor, can occur.

A study by Piantanida et al indicated that an increased risk of masked hypertension exists with subclinical and overt hypothyroidism. The study included 64 newly diagnosed hypothyroid patients, with masked hypertension found in 26.3% of those with the subclinical condition and 15.4% of those with overt hypothyroidism, compared with 10% of controls.[33]

Laboratory Studies

Third-generation thyroid-stimulating hormone (TSH) assays are readily available and are generally the most sensitive screening tool for primary hypothyroidism.[1] The generally accepted reference range for normal serum TSH is 0.40-4.2 mIU/L.

In the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994), of 17,353 people evaluated, 80.8% had a serum TSH below 2.5 mIU/L; TSH concentrations rose with advancing age.[34] Certain physiologic conditions, such as illness, psychiatric disorders, and significant physical stress (eg, running a marathon), exposure to extremes in temperature, negative energy balance), can produce marked variations in TSH levels.

If TSH levels are above the reference range, the next step is measure free thyroxine (T4). Another option is to measure total T4 and binding proteins. T4 is highly protein-bound (99.97%), with approximately 85% bound to thyroid-binding globulin (TBG), approximately 10% bound to transthyretin or thyroid-binding prealbumin, and the remainder bound loosely to albumin.

The levels of these binding proteins can vary by hormonal status, inheritance, and in various disease states. Hence, free T4 assays, which measure unbound (ie, free) hormone, are becoming popular. However, free T4 assays can be unreliable in the setting of severe illness or pregnancy.

Free T4 can be directly measured via equilibrium dialysis. Results are independent of binding protein concentrations. However, this test is more costly and generally takes longer to return. Free thyroid hormone levels can be estimated by calculating the percentage of available thyroid hormone-binding sites (triiodothyronine [T3] resin uptake, or thyroid hormone binding ratio [THBR]) or by measuring the TBG concentration. A free T4 index (FTI) serves as a surrogate of the free hormone level. The FTI is the product of T3 resin uptake and total T4 levels.

In pregnancy, the variation in the results of commercially available free T4 assays has led the American Thyroid Association to recommend using method-specific and trimester-specific reference ranges for serum free T4. If these specific ranges are not available, TSH, total T4, and FTI can be used to monitor the pregnant patient.

Patients with primary hypothyroidism have elevated TSH levels and decreased free hormone levels. Patients with elevated TSH levels (usually 4.5-10.0 mIU/L) but normal free hormone levels or estimates are considered to have mild or subclinical hypothyroidism.

Primary hypothyroidism is virtually the only disease that is characterized by sustained rises in TSH levels. As the TSH level increases early in the disease, conversion of T4 to T3 increases, maintaining T3 levels. In early hypothyroidism, TSH levels are elevated, T4 levels are normal to low, and T3 levels are normal. Given this early protection of the T3 level, routine checking of T3 is not recommended if one suspects that a patient is hypothyroid. Drawing a reverse T3 is also not recommended as a routine part of the hypothyroidism workup.

Assays for anti–thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg) antibodies may be helpful in determining the etiology of hypothyroidism or in predicting future hypothyroidism. However, once a patient has been found to be antibody positive, repeated antibody testing adds little to the clinical picture and thus is not recommended. In addition, anti-TPO antibodies have been associated with increased risk of infertility and miscarriage; levothyroxine (LT4) treatment may lower this risk.[35]

In patients with nonthyroidal disease, TSH secretion is normal or decreased, total T4 levels are normal or decreased, and total T3 levels are decreased to markedly decreased. This scenario can be confused with secondary hypothyroidism. In these patients, the primary abnormality is decreased peripheral production of T3 from T4. They have an increased reverse T3, which can be measured. (See Euthyroid Sick Syndrome.)

Other abnormalities seen in patients who are critically ill include decreased TBG levels and abnormalities in the hypothalamic-pituitary axis. During recovery, some patients have transient elevations in serum TSH concentrations (up to 20 mIU/L). Hence, thyroid function should not be evaluated in a critically ill person unless thyroid dysfunction is strongly suspected, and if evaluation is warranted, screening with TSH alone is insufficient. When needed, however, multiple thyroid hormone measurements over time may assist with interpretation.

In patients with hypothalamic or pituitary dysfunction, TSH levels do not increase in appropriate relation to the low free T4 levels. The absolute levels may be in the reference range or even slightly elevated while still being inappropriately low for the severity of the hypothyroid state. Hence, when secondary or tertiary hypothyroidism is suspected, measurement of serum TSH alone is inadequate; free T4 should also be measured.

The TRH stimulation test is an older and rarely needed test for helping to assess pituitary and hypothalamic dysfunction. With the improvements in TSH and free T4 assays, TRH stimulation has become outmoded. In the United States, this medication is available only at the National Institutes of Health (NIH).

The complete blood count and metabolic profile may show abnormalities in patients with hypothyroidism. These include anemia, dilutional hyponatremia, hyperlipidemia, and reversible increases in serum creatinine.[2] Elevations in transaminases and creatinine kinase have also been found.

Primary hypothyroidism causes an elevation of TRH, which can cause an elevation of prolactin along with TSH. Prolactin levels in patients with hypothyroidism tend to be lower than those usually seen with prolactinomas (the latter are usually 150-200 ng/mL or higher).

Imaging Studies

Ultrasonography of the neck and thyroid can be used to detect nodules and infiltrative disease. It has little use in hypothyroidism per se unless a secondary anatomic lesion in the gland is of clinical concern. Hashimoto thyroiditis is usually associated with a diffusely heterogeneous ultrasonographic image. In rare cases, it may be associated with lymphoma of the thyroid. Serial images with fine-needle aspiration (FNA) of suspicious nodules may be useful.

The use of color flow Doppler scanning allows assessment of vascularity, which can help to distinguish thyroiditis from Graves disease. Glands with the former will have decreased flow, whereas glands with the latter will have increased flow.

Any thyroid nodules noted on imaging studies should undergo standard evaluation.

Radioactive iodine uptake (RAIU) and thyroid scanning are not useful in hypothyroidism, because these tests require some level of endogenous thyroid function if they are to provide useful information. Patients with Hashimoto thyroiditis may have relatively high early uptake (after 4 hours) but do not have the usual doubling of uptake at 24 hours consistent with an organification defect.

Patients undergoing whole-body F18-fluorodeoxyglucose positron emission tomography (FDG-PET) for nonthyroid disease often show significant thyroid uptake as an incidental finding.[36] In general, diffuse uptake by the thyroid on FDG-PET is considered a benign finding and is typical of thyroiditis.

Screening

Governmental bodies frequently mandate screening of neonates for hypothyroidism so as to prevent delay in the recognition and treatment of cretinism. No universal screening recommendations exist for thyroid disease for adults. The American Thyroid Association recommends screening at age 35 years and every 5 years thereafter, with closer attention to patients who are at high risk, such as the following[3] :

Screening recommendations from other groups are as follows:

Fine-Needle Aspiration Biopsy

Thyroid nodules are often found incidentally during physical examination or on chest radiography, computed tomography (CT), or magnetic resonance imaging (MRI). Thyroid nodules can be found in patients who are hypothyroid, euthyroid, or hyperthyroid. FNA biopsy is the procedure of choice for evaluating suspicious nodules, usually with ultrasound guidance. Risk factors for thyroid nodules include age greater than 60 years, history of head or neck irradiation, and a family history of thyroid cancer.

About 5-15% of solitary nodules are malignant. Suspicious nodules are those with sonographic features such as irregular margins, hypoechoic parenchyma, or microcalcifications.

Histologic Findings

Autoimmune thyroiditis causes a decrease in intrathyroidal iodine stores, increased iodine turnover, and defective organification. Chronic inflammation of the gland causes progressive destruction of the functional tissue with widespread infiltration by lymphocytes and plasma cells with epithelial cell abnormalities. In time, dense fibrosis and atrophic thyroid follicles replace the initial lymphocytic hyperplasia and vacuoles.

Other causes of functional tissue destruction and infiltration include the following:

Approach Considerations

The treatment goals for hypothyroidism are to reverse clinical progression and correct metabolic derangements, as evidenced by normal blood levels of thyroid-stimulating hormone (TSH) and free thyroxine (T4). Thyroid hormone is administered to supplement or replace endogenous production. In general, hypothyroidism can be adequately treated with a constant daily dose of levothyroxine (LT4).

Thyroid hormone can be started at anticipated full replacement doses in individuals who are young and otherwise healthy. In elderly patients and those with known ischemic heart disease, treatment should begin with one fourth to one half the expected dosage, and the dosage should be adjusted in small increments after no less than 4-6 weeks. For most cases of mild to moderate hypothyroidism, a starting levothyroxine dosage of 50-75 µg/day will suffice.

Clinical benefits begin in 3-5 days and level off after 4-6 weeks. Achieving a TSH level within the reference range may take several months because of delayed readaptation of the hypothalamic-pituitary axis. In patients receiving treatment with LT4, dosing changes should be made every 6-8 weeks until the patient’s TSH is in target range.

In patients with central (ie, pituitary or hypothalamic) hypothyroidism, T4 levels rather than TSH levels are used to guide treatment. In most cases, the free T4 level should be kept in the upper third of the reference range.

After dosage stabilization, patients can be monitored with annual or semiannual clinical evaluations and TSH monitoring. Patients should be monitored for symptoms and signs of overtreatment, which include the following:

The updated guidelines on hypothyroidism issued by the American Thyroid Association in 2014 maintain the recommendation of levothyroxine as the preparation of choice for hypothyroidism, with the following considerations:[5, 6]

A meta-analysis of randomized, controlled trials of T4-triiodothyronine (T3) combination therapy versus T4 monotherapy for treatment of clinical hypothyroidism found no difference in effectiveness between combination therapy and monotherapy with respect to side effects such as bodily pain, depression, fatigue, body weight, anxiety, quality of life, and total low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglyceride levels.[42]

A study of athyrotic patients found a high heterogeneity in these patients’ ability to produce T3 when treated with levothyroxine. Approximately 20% of these athyrotic patients did not maintain normal free T4 or free T3 values despite a normal TSH.[43] However, it is unclear whether more physiologic treatments offer any benefit, even in subgroups of hypothyroid patients.

In patients who continue to have symptoms (eg, weight gain and fatigue) despite normalization of the TSH level, one should consider causes other than hypothyroidism, rather than simply increasing the thyroid hormone dose on the basis of symptoms alone (see DDx). In some cases, however, symptom persistence is the result of a polymorphism of the deiodinase 2 enzyme, which converts T4 to T3 in the brain; these patients may benefit from combined LT4-liothyronine (LT3) therapy, using a physiologic LT4-to-LT3 ratio in the range of 10-14:1.[4]

Most patients with hypothyroidism can be treated in an ambulatory care setting. Patients who require long-term continuous tube feeding routinely require intravenous (IV) LT4 replacement because the absorption of oral agents is impaired by the contents of tube feeds. Alternatively, tube feeds can be withheld for 1 hour while the patient receives an oral preparation of LT4. It should be noted that oral and IV preparations of LT4 are not equivalent; consequently, great care must be taken in switching between these formulations.

Patients with severe hypothyroidism requiring hospitalization (eg, myxedema) may require aggressive management. Overreplacement or aggressive replacement with any thyroid hormone may precipitate tachyarrhythmias or, very rarely, thyroid storm and should be balanced against the need for urgent replacement. Risk is higher with T3 therapy.

Surgery is rarely needed in patients with hypothyroidism; it is more commonly required in the treatment of hyperthyroidism. However, surgery is indicated for large goiters that compromise tracheoesophageal function.

Hypothyroidism in Pregnancy

The updated guidelines on hypothyroidism issued by the American Thyroid Association in 2014 concerning hypothyroidism treatment in pregnant women are as follows:[5, 6]

Hypothyroidism in pregnancy can produce an array of obstetric complications. Even mild disease may have adverse effects on the offspring. Adverse effects of hypothyroidism in pregnancy include the following:

Despite the possibility of poor fetal outcomes, routine screening for thyroid dysfunction is not performed in the United States and remains a controversial topic. A study reviewing the records of pregnant women screened between June 2005 and May 2008 found that only 23% of these women were tested for hypothyroidism.[45] The study also found a 15% prevalence of hypothyroidism among pregnant women, a figure that is significantly higher than the 2-3% frequently cited in older literature.[45]

Increased thyroid hormone dosage requirements should be anticipated during pregnancy, especially in the first and second trimesters. Studies have suggested that in pregnant women with hypothyroidism, the LT4 dose should be increased by 30% at the confirmation of pregnancy and subsequently adjusted in accordance with TSH levels.

In addition, iodine demands are higher with pregnancy and lactation. Iodine needs rise from approximately 150 µg/day in the nonpregnant woman to 240-290 µg/day with pregnancy and lactation. Guidelines from the American Thyroid Association recommend that all pregnant and lactating women ingest a minimum of 250 mg iodine daily—optimally, in the form of potassium iodide, to ensure consistent delivery.[46]

For pregnant women with previously diagnosed hypothyroidism, serum TSH levels should be measured every 3-4 weeks during the first half of pregnancy and every 6-10 weeks thereafter. The LT4 dose should be adjusted so as to keep the serum TSH below 2.5 mIU/L. TSH and free T4 levels should be measured 3-4 weeks after every dosage adjustment.[47]

Autoimmune thyroid disease without overt hypothyroidism has been associated with a higher miscarriage rate. Negro et al showed that euthyroid Caucasian women with positive anti−thyroid peroxidase (anti-TPO) antibodies who were treated with LT4 during the first trimester had lower miscarriage rates than those who were not treated. These women also had lower rates of premature delivery, comparable to rates in women without thyroid antibodies.[48]

In a meta-analysis of 3 studies involving 220 women with subclinical hypothyroidism or thyroid autoimmunity who were undergoing assisted reproduction technologies, Velkeniers et al concluded that treatment with LT4 should be recommended to improve pregnancy outcomes.[49] In pooled analyses, LT4 treatment resulted in a significantly higher delivery rate and a significantly lower miscarriage rate.

Such findings, if confirmed by sufficient data, would provide an indication for treating euthyroid pregnant women who have thyroid antibodies.

LT4 should not be taken with prenatal vitamin preparations containing iron and calcium. After delivery, the LT4 dose can be reduced to the prepregnancy level, and TSH should be checked in 6 weeks.

In a study of 77 pregnant women with newly diagnosed subclinical (64 women) or overt (13 women) hypothyroidism, Abalovich et al determined the specific levothyroxine (LT4) dosages required to return these patients to a euthyroid state. The investigators found that the most successful dosages, as follow, varied according to baseline levels of thyroid stimulating hormone (TSH)[50, 51] :

These dosages proved appropriate in 89% and 77% of patients with subclinical or overt hypothyroidism, respectively, and were recommended by the study's authors for pregnant patients with hypothyroidism that has been newly diagnosed during pregnancy.

Subclinical Hypothyroidism

Significant controversy persists regarding the treatment of patients with mild hypothyroidism.[52] Some have argued that treatment of these patients improves symptoms, prevents progression to overt hypothyroidism, and may have cardioprotective benefits. Reviews by the US Preventive Services Task Force[41] and an independent expert panel[53] found inconclusive evidence to recommend aggressive treatment of patients with TSH levels of 4.5-10 mIU/L.

The Endocrine Society recommends T4 replacement in pregnant women with subclinical hypothyroidism.[54] The American College of Obstetricians and Gynecologists does not recommend it as a routine measure.[55]

Ultrasonography may have prognostic value in subclinical hypothyroidism. In an Italian study, progression to overt hypothyroidism occurred more often in patients whose ultrasonographic thyroid scan showed diffuse hypoechogenicity (an indication of chronic thyroiditis).[56]

In nonpregnant patients, following subclinical hypothyroidism and treating on a case-by-case basis is reasonable. Treatment of subclinical hypothyroidism has been shown to reduce total cholesterol, non-HDL cholesterol, and apolipoprotein B levels[57] and to decrease arterial stiffness and systolic blood pressure.[58] In patients with concomitant subclinical hypothyroidism and iron deficiency anemia, iron supplementation may be ineffective if LT4 is not given.[59]

Guidelines from the American Association of Clinical Endocrinologists (AACE) recommend treatment in patients with TSH levels higher than 10 mIU/L and in patients with TSH levels of 5-10 mIU/L in conjunction with goiter or positive anti-TPO antibodies; these patients have the highest rates of progression to overt hypothyroidism. An initial LT4 dosage of 50-75 µg/day can be used, which can be titrated every 6-8 weeks to achieve a target TSH of between 0.3 and 3 mIU/L.[40]

A literature review by Abreu et al suggested that levothyroxine therapy can hinder the development of coronary artery disease in subclinical hypothyroidism. Evaluating randomized, placebo-controlled trials, the investigators reported that patients receiving levothyroxine experienced significant reductions in serum TSH and in total and low-density lipoprotein cholesterol compared with patients receiving placebo.[60]

Myxedema Coma

In patients with myxedema coma, an effective approach consists of the following:

If adrenal insufficiency is suspected (eg, in a patient with hypothyroidism secondary to panhypopituitarism), that diagnosis should be investigated. If adrenal insufficiency is confirmed, stress doses of IV glucocorticoids should be given before hypothyroidism is treated. If the patient’s condition is critical and there is no time to complete the workup for adrenal insufficiency before the necessary use of IV LT4, the patient must be given stress-dose glucocorticoids to prevent the catastrophic complication of adrenal crisis.

Use of IV LT3 is controversial and based on expert opinion. It is associated with a higher frequency of adverse cardiac events and is generally reserved for patients who are not improving clinically on LT4. LT3 can be given initially as a 10 µg IV bolus, which is repeated every 8-12 hours until the patient can take maintenance oral doses of T4.

Advanced age, high-dose T4 therapy, and cardiac complications have the highest associations with mortality in myxedema coma (see Hypothyroidism and Myxedema Coma in Emergency Medicine).[61]

Complications of Treatment

Thyroid hormone replacement can precipitate adrenal crises in patients with untreated adrenal insufficiency by enhancing hepatic corticosteroid metabolism. If adrenal insufficiency is suspected, it should be confirmed or ruled out; if confirmed, it should be treated before treatment of hypothyroidism.

Aggressive replacement of thyroid hormone may compromise cardiac function in patients with existing cardiac disease. In these patients, administer smaller initial doses of LT4, and titrate the dosage upward in small increments.

Subclinical hyperthyroidism is a more common complication of treatment with LT4. The relationship of overtreatment to osteoporosis and fracture is not consistent and is best studied in postmenopausal women.

A large population-based nested case-control study demonstrated a 2-fold to 3-fold increase in fractures in LT4 users older than 70 years; the increase was dose-related.[62] Because thyroid function studies were not performed, the relation between subclinical hyperthyroidism and osteoporosis requires further evaluation. However, this study does support careful dose titration, especially in elderly patients.

Nonetheless, patients at risk for osteoporosis (eg, women who are estrogen-deficient) and individuals receiving a long-term suppressive dose of LT4 (eg, patients with differentiated thyroid cancer) should be closely monitored. It should be noted that patients with thyroid cancer are usually on a higher dose of LT4. The desired TSH depends on the staging of the cancer and on the evidence (or lack of evidence) of active disease. In patients with stage IV thyroid cancer, it is desirable to keep the TSH below 0.1 mIU/L in the long term.

Patients should be advised that in rare cases, vision may temporarily worsen when hormone therapy is initiated. Pseudotumor cerebri may occur, albeit uncommonly. Patients with depression may develop mania, and psychosis may be exacerbated in patients with severe psychological illness.

Because most brain growth occurs in the first 2 years of life, untreated hypothyroidism in infants can cause irreversible mental retardation. Older infants are spared nervous system damage but continue to have slowed physical and linear bone growth. They also have delayed dental development.

Diet and Activity

No specific diets are required for hypothyroidism. Subclinical hypothyroidism has been seen in increased frequency in patients with greater iodine intake. The World Health Organization (WHO) recommends a daily dietary iodine intake of 150 µg for adults, 200 µg for pregnant and lactating women, and 50-120 µg for children.

Patients who have hypothyroidism have generalized hypotonia and may be at risk for ligamentous injury, particularly from excessive force across joints. Thus, patients should exercise caution with certain activities, such as contact sports and heavy physical labor.

Patients with uncontrolled hypothyroidism may have difficulty maintaining concentration in low-stimulus activities and may have slowed reaction times. Patients should use caution when engaging in an activity that poses a risk of injury (eg, operating presses or heavy equipment and driving).

Consultations

Indications for referral to an endocrinologist include any of the following[1] :

Some patients with subacute or postpartum thyroiditis can develop thyrotoxicosis (or symptoms consistent with hyperthyroidism) before developing hypothyroidism. These patients also may benefit from consultation with an endocrinologist.

Suspected myxedema coma is a medical emergency with a high risk of mortality, and it necessitates requires initiation of IV LT4 and glucocorticoid therapy before laboratory confirmation. An urgent endocrinology consultation should be obtained.

Rarely, an increase in size of a goiter in a patient with autoimmune thyroid disease could indicate a lymphoma. These patients should be evaluated by an endocrinologist.

Long-Term Monitoring

Once an appropriate therapeutic dosage is arrived at, patients can be monitored annually or semiannually with laboratory evaluation and physical examination. In addition, monitor patients for signs of excess dosing (eg, nervousness, palpitations, diarrhea, excessive sweating, heat intolerance, chest pain, or insomnia). Monitor pulse rate, blood pressure, and vital signs. In children, sleeping pulse rate and basal temperature can be used as guides to the adequacy of the clinical response to treatment.

Guidelines Summary

European Thyroid Association guidelines on central hypothyroidism

The following guidelines on the diagnosis and management of central hypothyroidism (CeH) were released in October 2018 by the European Thyroid Association[63] :

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Thyroid hormone is administered to supplement or replace endogenous production.

Levothyroxine (Synthroid, Levoxyl, Levothroid, Unithroid, Tirosint)

Clinical Context:  Thyroid hormone influences growth and maturation of tissues. It is involved in normal growth, metabolism, and development. Levothyroxine (LT4) is generally considered to be the treatment of choice for patients with hypothyroidism.

Liothyronine (Cytomel, Triostat)

Clinical Context:  Liothyronine (LT3) is a synthetic form of the natural thyroid hormone (T3) converted from T4. It is not intended for use as sole maintenance therapy, but in rare cases it can be used together with LT4 in small doses (5-15 µg/day).The recommended ratio of T4 to T3 is 10-14:1. T3 has a short duration of activity (half-life, 12-24 hours), which allows quick dosage adjustments in the event of overdosage.

Theoretically, LT3 may be preferred when gastrointestinal (GI) absorption is impaired (95% of this hormone is absorbed, compared with 50-80% of T4) or if peripheral conversion is impaired. Dosage recommendations are for short-term use in special circumstances (eg, myxedema coma), under the guidance of an endocrinologist. Dosage should be determined in consultation with an endocrinologist.

Dosage recommendations are for short-term use in special circumstances (see above) with the guidance of an endocrinologist.

Thyroid desiccated (Armour Thyroid, Nature-Throid, Westhroid)

Clinical Context:  Desiccated thyroid is derived from extracts of bovine or porcine thyroid glands. Some manufacturers standardize their formulations on the basis of bioassays, whereas others use iodine content.

Desiccated thyroid is referred to as natural thyroid and generally contains T3 and T4 in a 1:4 ratio. It is made in a range of strengths, with tablets including 1/8, 1/4, 1/2, 1, 2, 3, 4, or 5 grains. One grain (60 mg) contains about 38 µg of T4 and 9 µg of T3. Because these preparations contain variable quantities of T3, they should not be prescribed for patients with known or suspected cardiac disease and are generally avoided. They also are not preferred in pregnancy, because they produce relatively lower T4 levels.

Class Summary

Thyroid hormone influences growth and maturation of tissues. It is involved in normal growth, metabolism, and development. Levothyroxine (LT4) is generally considered to be the treatment of choice for patients with hypothyroidism.

What is hypothyroidism?What are the symptoms of hypothyroidism?What symptoms of hypothyroidism are specific to Hashimoto thyroiditis?What are physical signs of hypothyroidism?What is myxedema coma?What is the role of third-generation thyroid-stimulating hormone (TSH) assays in the diagnosis of hypothyroidism?Which abnormalities on CBC count are associated with hypothyroidism?Which patients are candidates for hypothyroidism screening?Which medication is the drug of choice for hypothyroidism treatment, and what are the key aspects of initiating therapy?What are the symptoms and signs of levothyroxine (LT4) overtreatment in hypothyroidism?What action should be taken if hypothyroidism symptoms continue to occur after treatment?What are the ATA guidelines on the use of levothyroxine (LT4) as the drug of choice for the treatment of hypothyroidism?What are the recommendations on treating hypothyroidism in pregnant women?How is myxedema coma treated?Which classic signs and symptoms are commonly observed in hypothyroidism?What causes hypothyroidism?What are the causes of secondary and tertiary hypothyroidism?What are the most common causes of hypothyroidism?Which assay is commonly used to screen for hypothyroidism, and what is the normal reference range of TSH?How is thyroid hormone supplemented or replaced in hypothyroidism treatment?What causes congenital hypothyroidism and is it treatable?What is cretinism, and what causes it?What is the pathophysiology of hypothyroidism?What are the effects of thyroid hormone deficiency?What is central hypothyroidism, and what are the potential causes?What is the most common cause of hypothyroidism in areas of adequate iodine intake?What are the types of primary hypothyroidism?What is chronic lymphocytic (autoimmune) thyroiditis (Hashimoto thyroiditis), and which antibodies are most commonly associated with it?What is postpartum thyroiditis, and how is it treated?What is subacute granulomatous thyroiditis (de Quervain disease)?Which medications may cause hypothyroidism?Can radioactive iodine (I-131) cause hypothyroidism?Can external neck irradiation cause hypothyroidism?Can thyroidectomy or thyroid lobectomy result in hypothyroidism?Which genes are associated with a risk of developing hypothyroidism?Which genetic mutations are most commonly associated with congenital hypothyroidism?What is Pendred syndrome?What is autoimmune polyendocrinopathy?What is the role of iodine in hypothyroidism?How do tumors in or around the pituitary affect TRH and TSH?What is congenital nongoiterous hypothyroidism type 4, and what causes it?Which genetic mutation causes TRH resistance?Which genetic mutation causes TRH deficiency?What is the prevalence of hypothyroidism in the US?What is the most common cause of hypothyroidism in developing countries, and what has been done to decrease the incidence?What are the WHO recommendations for urinary iodine concentrations?Which age group has the highest prevalence of hypothyroidism?Is hypothyroidism more common in males or females?Does hypothyroidism have racial predilection?What is the prognosis of hypothyroidism?What educational information should be provided to patients with hypothyroidism?What are the manifestations of hypothyroidism?What is myxedema coma, and what signs and symptoms are associated with it?What are the symptoms of hypothyroidism?Which symptoms of hypothyroidism are more specific to Hashimoto thyroiditis?What are the physical signs of hypothyroidism?What is the role of hypothyroidism in masked hypertension?Which conditions should be considered in the differential diagnoses of hypothyroidism?What are the differential diagnoses for Hypothyroidism?Which screening assay is the recommended test for hypothyroidism?Other than hypothyroidism, which physiologic conditions can cause variations in TSH levels?What steps should be taken in screening for hypothyroidism if TSH levels are above the reference range?What factors can contribute to variation in free thyroxine (T4) levels?How is free T4 measured, and how is the free T4 index (FTI) calculated?How is free T4 measured and monitored in pregnancy?What do TSH levels and free hormone levels indicate in hypothyroidism diagnoses?What are the roles of anti-thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg) assays in the diagnosis of hypothyroidism?Which TSH, T3, and T4 levels are characteristic of nonthyroidal disease (euthyroid sick syndrome)?What is the role of thyroid evaluations in a critically ill person?What is the role of testing T4 levels in hypothalamic or pituitary dysfunction in the evaluation of hypothyroidism?What is the TRH stimulation test?Which CBC count and metabolic profile results suggest hypothyroidism?How does primary hypothyroidism affect TRH and prolactin levels?What is the role of ultrasonography in the workup for hypothyroidism?What is the role of color flow Doppler scanning in the workup for hypothyroidism?Should thyroid nodules noted on imaging studies be evaluated?What is the role of radioactive iodine uptake (RAIU) and thyroid scanning in the workup for hypothyroidism?What is the role of whole-body F18- FDG-PET scanning in the workup for hypothyroidism?Who should be screened for hypothyroidism?How are thyroid nodules typically identified?Which procedures are used to evaluate thyroid nodules?Which risk factors are associated with thyroid nodules?What percentage of thyroid nodules are malignant, and which sonographic features should raise suspicion?How does autoimmune thyroiditis cause functional tissue destruction?Other than autoimmune thyroiditis, which conditions can cause functional tissue destruction and infiltration?How is hypothyroidism treated, and what are the treatment goals?How is thyroid hormone replacement therapy initiated in the treatment of hypothyroidism?How soon do hypothyroidism signs and symptoms improve after treatment begins?Should T4 or TSH levels be used to guide treatment of central hypothyroidism?What is the standard surveillance of patients with hypothyroidism once hormone levels have stabilized, and what are the signs and symptoms of overtreatment?What are the ATA guidelines on the use of levothyroxine (LT4) as the treatment of choice for hypothyroidism?What is the difference in side effects of T4-triiodothyronine (T3) combination therapy versus T4 monotherapy in the treatment of clinical hypothyroidism?Does levothyroxine (LT4) normalize free T4 or T3 levels in athyrotic patients?What factors may contribute to ongoing symptoms of hypothyroidism despite normalization of the TSH level?What is the approach for treating patients with hypothyroidism who are on long-term continuous tube feeding?How is severe hypothyroidism, such as myxedema, treated?When is surgery indicated in hypothyroidism?What are the ATA guidelines for the treatment of hypothyroidism in pregnant women?What are the potential obstetric complications of hypothyroidism in pregnancy?What is the role of routine screening for thyroid dysfunction in pregnant women?What medication adjustments should be made in the management of hypothyroidism in pregnant and lactating women, and how often should serum TSH levels be measured?What are the potential effects of autoimmune thyroid disease on pregnancy?Should levothyroxine (LT4) be used in women with subclinical hypothyroidism or thyroid autoimmunity who undergo fertility treatment?What are the recommended dosages of levothyroxine (LT4) for pregnant women newly diagnosed with subclinical or overt hypothyroidism?What is the recommended treatment of mild (subclinical) hypothyroidism?What is the recommended treatment of mild (subclinical) hypothyroidism in pregnant women?What is the role of ultrasonography in subclinical hypothyroidism?What is the recommended treatment of subclinical hypothyroidism in nonpregnant patients?According to the AACE, what TSH levels indicate the need for hypothyroidism treatment?How does levothyroxine (LT4) therapy protect against coronary artery disease (CAD) in patients with subclinical hypothyroidism?What is the treatment for myxedema coma?How is adrenal insufficiency treated in cases of myxedema coma?What is the role of IV LT3 in the treatment of myxedema coma?Which risk factors have the highest associations with mortality in myxedema coma?What is the role of thyroid hormone replacement in hypothyroidism and adrenal crisis?When might thyroid hormone replacement compromise cardiac function in hypothyroidism?Can thyroid hormone replacement cause subclinical hyperthyroidism?What is the relationship between levothyroxine (LT4) treatment for hypothyroidism and osteoporosis in elderly patients?Which patients should be closely monitored for overtreatment of hypothyroidism?Is hypothyroidism treatment associated with vision loss?Is hypothyroidism treatment associated with pseudotumor cerebri?Which complications of hypothyroidism treatment can develop in patients with depression or severe psychological illness?Which complications of hypothyroidism may occur in untreated infants?Are there specific dietary restrictions or recommendations for patients with hypothyroidism?Which kinds of physical activity should be avoided by patients with hypothyroidism?When is consultation with an endocrinologist indicated for patients with hypothyroidism?What is the role of long-term monitoring in hypothyroidism, and what should be included?Which medications in the drug class Thyroid Products are used in the treatment of Hypothyroidism?

Author

Philip R Orlander, MD, Director and Professor, Division of Endocrinology, Associate Dean for Educational Programs, Vice-Chair of Medicine for Education, Program Director, Internal Medicine Residency Program, University of Texas Health Science Center at Houston

Disclosure: Nothing to disclose.

Coauthor(s)

Jeena M Varghese, MD, Assistant Professor, Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center

Disclosure: Nothing to disclose.

Lance M Freeman, MD, Fellow, Division of Endocrinology, University of Texas Health Science Center at Houston

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Anu Bhalla Davis, MD Assistant Professor, Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Texas Medical School at Houston

Disclosure: Nothing to disclose.

Shikha Bharaktiya, MD Physician in Endocrinology, Diabetes, and Metabolism, Endocrinology Clinics of Texas, PA

Disclosure: Nothing to disclose.

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Nutrition, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, American Society for Bone and Mineral Research, Endocrine Society, and International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Walter R Woodhouse, MD, MSA Associate Clinical Professor, Department of Family Practice, Medical College of Ohio

Walter R Woodhouse, MD, MSA is a member of the following medical societies: American Academy of Family Physicians, American Academy of Pain Medicine, and Society of Teachers of Family Medicine

Disclosure: Nothing to disclose.

Frederick H Ziel, MD Associate Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group

Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, andInternational Society for Clinical Densitometry

Disclosure: Nothing to disclose.

References

  1. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012 Dec. 22(12):1200-35. [View Abstract]
  2. Kreisman SH, Hennessey JV. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch Intern Med. 1999 Jan 11. 159(1):79-82. [View Abstract]
  3. Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med. 2000 Jun 12. 160(11):1573-5. [View Abstract]
  4. McDermott MT. Does combination T4 and T3 therapy make sense?. Endocr Pract. 2012 Sep-Oct. 18(5):750-7. [View Abstract]
  5. [Guideline] Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014 Dec. 24(12):1670-751. [View Abstract]
  6. Melville NA. New ATA guidelines stick with levothyroxine for hypothyroidism. Medscape Medical News from WebMD. October 02, 2014. Available at http://www.medscape.com/viewarticle/832682. Accessed: February 19, 2015.
  7. Mourtzinis G, Adamsson Eryd S, Rosengren A, et al. Primary aldosteronism and thyroid disorders in atrial fibrillation: A Swedish nationwide case-control study. Eur J Prev Cardiol. 2018 Jan 1. 2047487318759853. [View Abstract]
  8. Bothra N, Shah N, Goroshi M, et al. Hashimoto's thyroiditis: Relative recurrence risk ratio and implications for screening of first degree relatives. Clin Endocrinol (Oxf). 2017 Mar 8. [View Abstract]
  9. Stuckey BG, Kent GN, Ward LC, Brown SJ, Walsh JP. Postpartum thyroid dysfunction and the long-term risk of hypothyroidism: results from a 12-year follow-up study of women with and without postpartum thyroid dysfunction. Clin Endocrinol (Oxf). 2010 Sep. 73(3):389-95. [View Abstract]
  10. Wolter P, Dumez H, Schoffski P. Sunitinib and hypothyroidism. N Engl J Med. 2007 Apr 12. 356(15):1580; author reply 1580-1. [View Abstract]
  11. Smit JW, Stokkel MP, Pereira AM, Romijn JA, Visser TJ. Bexarotene-induced hypothyroidism: bexarotene stimulates the peripheral metabolism of thyroid hormones. J Clin Endocrinol Metab. 2007 Jul. 92(7):2496-9. [View Abstract]
  12. Denny JC, Crawford DC, Ritchie MD, et al. Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies. Am J Hum Genet. 2011 Oct 7. 89(4):529-42. [View Abstract]
  13. Vono-Toniolo J, Rivolta CM, Targovnik HM, Medeiros-Neto G, Kopp P. Naturally occurring mutations in the thyroglobulin gene. Thyroid. 2005 Sep. 15(9):1021-33. [View Abstract]
  14. Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. 2005 May. 42(5):379-89. [View Abstract]
  15. Paschke R, Ludgate M. The thyrotropin receptor in thyroid diseases. N Engl J Med. 1997 Dec 4. 337(23):1675-81. [View Abstract]
  16. Macchia PE, Lapi P, Krude H, et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet. 1998 May. 19(1):83-6. [View Abstract]
  17. Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. 1997 Dec. 17(4):411-22. [View Abstract]
  18. Cetani F, Barbesino G, Borsari S, et al. A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. J Clin Endocrinol Metab. 2001 Oct. 86(10):4747-52. [View Abstract]
  19. Woeber KA. Iodine and thyroid disease. Med Clin North Am. 1991 Jan. 75(1):169-78. [View Abstract]
  20. Yamada M, Mori M. Mechanisms related to the pathophysiology and management of central hypothyroidism. Nat Clin Pract Endocrinol Metab. 2008 Dec. 4(12):683-94. [View Abstract]
  21. Nebesio TD, McKenna MP, Nabhan ZM, Eugster EA. Newborn screening results in children with central hypothyroidism. J Pediatr. 2010 Jun. 156(6):990-3. [View Abstract]
  22. Doeker BM, Pfaffle RW, Pohlenz J, Andler W. Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin beta-subunit gene follows an autosomal recessive inheritance. J Clin Endocrinol Metab. 1998 May. 83(5):1762-5. [View Abstract]
  23. Bonomi M, Busnelli M, Beck-Peccoz P, et al. A family with complete resistance to thyrotropin-releasing hormone. N Engl J Med. 2009 Feb 12. 360(7):731-4. [View Abstract]
  24. Katakami H, Kato Y, Inada M, Imura H. Hypothalamic hypothyroidism due to isolated thyrotropin-releasing hormone (TRH) deficiency. J Endocrinol Invest. 1984 Jun. 7(3):231-3. [View Abstract]
  25. Niimi H, Inomata H, Sasaki N, Nakajima H. Congenital isolated thyrotrophin releasing hormone deficiency. Arch Dis Child. 1982 Nov. 57(11):877-8. [View Abstract]
  26. Aoki Y, Belin RM, Clickner R, et al. Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002). Thyroid. 2007 Dec. 17 (12):1211-23. [View Abstract]
  27. Kajantie E, Phillips DI, Osmond C, Barker DJ, Forsen T, Eriksson JG. Spontaneous hypothyroidism in adult women is predicted by small body size at birth and during childhood. J Clin Endocrinol Metab. 2006 Dec. 91(12):4953-6. [View Abstract]
  28. Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P. The aging thyroid. Thyroid deficiency in the Framingham Study. Arch Intern Med. 1985 Aug. 145(8):1386-8. [View Abstract]
  29. Winther KH, Cramon P, Watt T, et al. Disease-Specific as Well as Generic Quality of Life Is Widely Impacted in Autoimmune Hypothyroidism and Improves during the First Six Months of Levothyroxine Therapy. PLoS One. 2016 Jun 3. 11(6):e0156925. [View Abstract]
  30. Chang YC, Chang CH, Yeh YC, Chuang LM, Tu YK. Subclinical and overt hypothyroidism is associated with reduced glomerular filtration rate and proteinuria: a large cross-sectional population study. Sci Rep. 2018 Feb 1. 8 (1):2031. [View Abstract]
  31. Sato Y, Yoshihisa A, Kimishima Y, et al. Subclinical Hypothyroidism Is Associated With Adverse Prognosis in Heart Failure Patients. Can J Cardiol. 2018 Jan. 34 (1):80-7. [View Abstract]
  32. Zamfirescu I, Carlson HE. Absorption of levothyroxine when coadministered with various calcium formulations. Thyroid. 2011 May. 21(5):483-6. [View Abstract]
  33. Piantanida E, Gallo D, Veronesi G, et al. Masked hypertension in newly diagnosed hypothyroidism: a pilot study. J Endocrinol Invest. 2016 May 19. [View Abstract]
  34. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002 Feb. 87(2):489-99. [View Abstract]
  35. Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab. 2006 Jul. 91(7):2587-91. [View Abstract]
  36. Liu Y. Clinical significance of thyroid uptake on F18-fluorodeoxyglucose positron emission tomography. Ann Nucl Med. 2009 Jan. 23(1):17-23. [View Abstract]
  37. Clinical guideline, part 1. Screening for thyroid disease. American College of Physicians. Ann Intern Med. 1998 Jul 15. 129(2):141-3. [View Abstract]
  38. Helfand M, Redfern CC. Clinical guideline, part 2. Screening for thyroid disease: an update. American College of Physicians. Ann Intern Med. 1998 Jul 15. 129(2):144-58. [View Abstract]
  39. American Academy of Family Physicians. Summary of Policy Recommendations for Periodic Health Examinations. Reprint no. 510. Leawood, KS: American Academy of Family Physicians; 2002.
  40. [Guideline] Baskin HJ, Cobin RH, Duick DS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002 Nov-Dec. 8(6):457-69. [View Abstract]
  41. Screening for thyroid disease: recommendation statement. Ann Intern Med. 2004 Jan 20. 140(2):125-7. [View Abstract]
  42. Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2006 Jul. 91(7):2592-9. [View Abstract]
  43. Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One. 2011. 6(8):e22552. [View Abstract]
  44. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999 Aug 19. 341(8):549-55. [View Abstract]
  45. Blatt AJ, Nakamoto JM, Kaufman HW. National status of testing for hypothyroidism during pregnancy and postpartum. J Clin Endocrinol Metab. 2012 Mar. 97(3):777-84. [View Abstract]
  46. [Guideline] Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011 Oct. 21(10):1081-125. [View Abstract]
  47. LeBeau SO, Mandel SJ. Thyroid disorders during pregnancy. Endocrinol Metab Clin North Am. 2006 Mar. 35(1):117-36, vii. [View Abstract]
  48. Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab. 2006 Jul. 91(7):2587-91. [View Abstract]
  49. Velkeniers B, Van Meerhaeghe A, Poppe K, Unuane D, Tournaye H, Haentjens P. Levothyroxine treatment and pregnancy outcome in women with subclinical hypothyroidism undergoing assisted reproduction technologies: systematic review and meta-analysis of RCTs. Hum Reprod Update. 2013 May-Jun. 19(3):251-8. [View Abstract]
  50. Busko M. Optimal levothyroxine doses for hypothyroidism in pregnancy. Medscape Medical News from WebMD. December 9, 2013. Available at http://www.medscape.com/viewarticle/817459. Accessed: January 5, 2014.
  51. Abalovich M, Vazquez A, Alcaraz G, et al. Adequate levothyroxine doses for the treatment of hypothyroidism newly discovered during pregnancy. Thyroid. 2013 Nov. 23(11):1479-83. [View Abstract]
  52. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012 Mar 24. 379(9821):1142-54. [View Abstract]
  53. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004 Jan 14. 291(2):228-38. [View Abstract]
  54. [Guideline] De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012 Aug. 97(8):2543-65. [View Abstract]
  55. Gyamfi C, Wapner RJ, D'Alton ME. Thyroid dysfunction in pregnancy: the basic science and clinical evidence surrounding the controversy in management. Obstet Gynecol. 2009 Mar. 113(3):702-7. [View Abstract]
  56. Rosario PW, Bessa B, Valadao MM, Purisch S. Natural history of mild subclinical hypothyroidism: prognostic value of ultrasound. Thyroid. 2009 Jan. 19(1):9-12. [View Abstract]
  57. Ito M, Arishima T, Kudo T, et al. Effect of levo-thyroxine replacement on non-high-density lipoprotein cholesterol in hypothyroid patients. J Clin Endocrinol Metab. 2007 Feb. 92(2):608-11. [View Abstract]
  58. Peleg RK, Efrati S, Benbassat C, Fygenzo M, Golik A. The effect of levothyroxine on arterial stiffness and lipid profile in patients with subclinical hypothyroidism. Thyroid. 2008 Aug. 18(8):825-30. [View Abstract]
  59. Cinemre H, Bilir C, Gokosmanoglu F, Bahcebasi T. Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study. J Clin Endocrinol Metab. 2009 Jan. 94(1):151-6. [View Abstract]
  60. Abreu I, Lau E, Sousa-Pinto B, Carvalho D. Subclinical hypothyroidism: to treat or not to treat! A systematic review with meta-analysis on lipid profile. Endocr Connect. 2017 Mar 1. [View Abstract]
  61. Wartofsky L. Myxedema coma. Endocrinol Metab Clin North Am. 2006 Dec. 35(4):687-98, vii-viii. [View Abstract]
  62. Turner MR, Camacho X, Fischer HD, et al. Levothyroxine dose and risk of fractures in older adults: nested case-control study. BMJ. 2011 Apr 28. 342:d2238. [View Abstract]
  63. [Guideline] Persani L, Brabant G, Dattani M, et al. 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018 Oct. 7 (5):225-37. [View Abstract]
  64. Busko M. Subclinical hypothyroidism in pregnancy usually transient. Medscape Medical News from WebMD. December 20, 2013. Available at http://www.medscape.com/viewarticle/818195. Accessed: December 30, 2013.
  65. Shields BM, Knight BA, Hill AV, Hattersley AT, Vaidya B. Five-year follow-up for women with subclinical hypothyroidism in pregnancy. J Clin Endocrinol Metab. 2013 Dec. 98(12):E1941-5. [View Abstract]

The hypothalamic-pituitary-thyroid axis. Levels of circulating thyroid hormones are regulated by a complex feedback system involving the hypothalamus and pituitary gland.

The hypothalamic-pituitary-thyroid axis. Levels of circulating thyroid hormones are regulated by a complex feedback system involving the hypothalamus and pituitary gland.

The hypothalamic-pituitary-thyroid axis. Levels of circulating thyroid hormones are regulated by a complex feedback system involving the hypothalamus and pituitary gland.