Hypothyroidism

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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.



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

ICD-10 codes

These include the following:

Signs and symptoms of hypothyroidism

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 of hypothyroidism

Third-generation thyroid-stimulating hormone (TSH) assays are generally the most sensitive screening tool for primary hypothyroidism.[3] 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.

Biotin, a popular health supplement, may interfere with immunoassays of many hormones, resulting in values that are falsely elevated or suppressed, including for thyroid levels. To avoid misleading test results, the American Thyroid Association recommends cessation of biotin consumption at least 2 days prior to thyroid testing.[4]

Results in patients with hypothyroidism are as follows:

Abnormalities in the complete blood count (CBC) and metabolic profile that may be found in patients with hypothyroidism include the following[5] :

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[7] :

The American College of Obstetricians and Gynecologists (ACOG) does not recommend universal screening for thyroid disease in pregnant women. However, those who are at increased risk warrant screening. These include pregnant women with a personal or family history of thyroid disease, type 1 diabetes, or symptoms suggestive of thyroid disease. There is no proven benefit in screening pregnant women with a mildly enlarged thyroid gland, whereas those with a significant goiter or distinct thyroid nodules require screening.[8]

See Workup for more detail.

Management of hypothyroidism

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).

Significant controversy persists regarding the treatment of patients with mild hypothyroidism.[9] Reviews by the US Preventive Services Task Force[10] and an independent expert panel[11] found inconclusive evidence to recommend aggressive treatment of patients with TSH levels of 4.5-10 mIU/L.

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

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. This generally occurs in the presence of other pituitary hormone deficiencies. 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. However, this is rare.

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.)

Some, but not all, studies have indicated that low vitamin D levels can be linked to autoimmune thyroid diseases, such as Hashimoto thyroiditis and Graves disease. However, intervention studies have not to date demonstrated a benefit of supplementation. No association has been found between vitamin D levels and thyroid cancer. This remains an area of investigation.[12]

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. (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. As with clinical hypothyroidism, Hashimoto thyroiditis is the most common cause of subclinical hypothyroidism in the United States.[13, 14]  (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.[15] 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 small amounts of T3. The ratio of T4:T3 production varies between about 14:1 and 4:1, depending on iodine sufficiency and TSH stimulation. The half-life of T4 is approximately 7-10 days, whereas the half-life of T3 is about 24 hours. T4, a prohormone, is converted via the action of deiodinases to T3, the active form of thyroid hormone.

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 glycosaminoglycans in the tissues).

The hypothyroid changes in the heart result in decreased contractility, cardiac enlargement, pericardial effusion, decreased pulse, and decreased cardiac output.  

In the gastrointestinal (GI) tract, achlorhydria and prolonged intestinal transit time with gastric stasis can occur in hypothyroidism. Metabolic dysfunction–associated steatotic liver disease (MASLD; formerly known as non-alcoholic fatty liver disease [NAFLD]) may also be significantly associated with hypothyroidism, as shown in a meta-analysis of 44,140 individuals with diagnosed hypothyroidism.[16]

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.

A study by Wopereis et al looked at the increased risk for anemia arising in hypothyroidism, reporting that for overt hypothyroidism, the pooled hazard ratio (HR) for anemia development was 1.38, while for subclinical hypothyroidism, it was 1.18. Although it is not clear how hypothyroidism leads to anemia, there is evidence that reduced thyroid function may interfere with the production of healthy erythrocytes. The possibility exists that T3, T4, and TSH are directly involved in erythropoiesis.[6]

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. There is commonly a genetic predisposition for autoimmune thyroid disease occurring in 20-30% of the siblings of affected patients, with a greater prevalence seen in circulating thyroid antibodies (~50% of siblings of affected patients).[17] Additionally, higher concordance rates are seen in autoimmune thyroid disease in monozygotic twins (29-55%) compared with dizygotic twins (0-7%).[18] Congenital causes of thyroid dysfunction are less common (see below).

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.[19]

The relationship between Hashimoto thyroiditis and thyroid cancer is under debate. The cellular changes of Hashimoto thyroiditis are often found surrounding thyroid cancers that have been removed, but it is not known whether the thyroid inflammation characterizing Hashimoto thyroiditis gives rise to the cancer or vice versa. A literature review by Lee et al indicated that pathologically confirmed Hashimoto thyroiditis has been identified in cases of papillary thyroid carcinoma more frequently than in benign thyroid disorders or other carcinomas, the occurrence rates being 2.8 and 2.4 times greater, respectively.[20, 21]

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 frequently transient (2-4 months). Nonetheless, after initiation, hypothyroidism developing from postpartum thyroiditis can last as long as a year before resolving on its own, and patients with postpartum thyroiditis (anti-TPO–positive) are at increased risk for permanent hypothyroidism or recurrence of postpartum thyroiditis with future pregnancies.[22]

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 sensitivity 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.[23]

Subacute granulomatous thyroiditis

Also known as de Quervain, or painful, thyroiditis, subacute granulomatous thyroiditis is a relatively uncommon disease that occurs most frequently in women (5:1) and is rare in the elderly. 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 thyroiditis and subacute thyroiditis).

There have been several studies demonstrating an association between coronavirus disease 2019 (COVID-19) and the development of subacute thyroiditis.[24]

Riedel thyroiditis

This disease, characterized by dense fibrosis of the thyroid gland, typically occurs between the ages of 30-60 years and is more prevalent in women (3-4:1). It presents with a rock hard, fixed, and painless goiter. Symptoms are typically related to compressive effects on surrounding structures or hypoparathyroidism due to extension of the fibrosis.

The disease has been linked to immunoglobulin G4 (IgG4) and is associated with a systemic fibrotic process. Most patients initially present with euthyroidism but later develop hypothyroidism as normal thyroid tissue is replaced. ESR levels are often normal, but high concentrations of anti-TPO antibodies are frequently present (~67% of patients). Open biopsy provides definitive diagnosis, and treatment is often surgical, although some studies have shown that early treatment with glucocorticoids, methotrexate, or tamoxifen may be beneficial.[25, 26]

Systemic lupus erythematosus

Between 15% and 19% of patients with systemic lupus erythematosus (SLE) have primary hypothyroidism, with hypothyroidism being the most common thyroid disease in patients with SLE. Although all age groups of individuals with SLE have a greater frequency of hypothyroidism, this is especially true in patients under age 20 years, the odds ratio (OR) being 8.38. In addition, the tendency to develop clinical or subclinical hypothyroidism is greater in female patients with SLE than in males.[27]

Drug-induced and iatrogenic hypothyroidism

The following medications reportedly have the potential to cause hypothyroidism:

Several of these medications, such as the anticonvulsants, are cytochrome P450 hepatic enzyme inducers and may unmask a latent hypothyroid state due to their impact on thyroid hormone economy or binding.

The use of radioactive iodine (I-131) for the 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) of over 40 Gy commonly results in hypothyroidism. Patients who have received these treatments require monitoring of thyroid function. A study by Shimizu et al found that out of 162 patients with high-risk head and neck cancer who underwent postoperative chemoradiotherapy, 16.7% developed hypothyroidism within two years of the treatment.[30]

A literature review by Rooney et al reported the estimated incidence of head and neck radiation therapy–associated hypothyroidism—as per the most recent evidence used in the analysis, with “high-quality thyroid function evaluation and long-term follow up”—to be 40-50%. The investigators indicated that female sex and a reduced normal thyroid volume were associated with an increased risk for such radiation treatment–related hypothyroidism.[31]

Thyroidectomy results in hypothyroidism, although this depends on the extent of resection and the underlying disease. Patients who undergo a thyroid lobectomy, with or without isthmectomy, have an approximately 15-30% chance of developing thyroid insufficiency.

Amiodarone-induced thyroid dysfunction can manifest as thyrotoxicosis or hypothyroidism, with the latter being more common in iodine-sufficient populations such as that of the United States (~20% of patients treated with amiodarone). There may also be an association with underlying autoimmune thyroid disease, as a higher prevalence of amiodarone-induced hypothyroidism is seen in patients with preexisting thyroid autoantibodies. The mechanism of action is due in part to an excess of iodine release during the metabolism of amiodarone (with each 200 mg tablet containing 75 mg of iodine), as well as apoptosis of thyroid cells through an iodine-independent mechanism.[32]

The 24-hour uptake of I-123 is typically low, and findings on color flow Doppler ultrasonography are variable. Due to the long half-life of amiodarone (approximately 100 days), recovery of thyroid function is prolonged. Treatment of amiodarone-induced thyroid dysfunction includes supplementation with levothyroxine, typically at higher replacement doses due to decreased 5’-deiodinase activity in peripheral tissues, an effect mediated by amiodarone.[25]

Immune checkpoint inhibitors (ICIs) enhance T-cell activity via inhibition of the negative inhibitory effects of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1). A variety of immune-related adverse effects have been associated with ICIs, with hypophysitis and thyroid dysfunction being the primary endocrine-related outcomes. The exact etiology of immune-related adverse thyroid effects is unknown, and while most cases are mild and self-limited, progression to permanent hypothyroidism can occur. Some cases suggest an underlying destructive thyroiditis that presents with an initial thyrotoxic phase (similar to tyrosine kinase inhibitor [TKI]–related thyroid dysfunction) and is followed by hypothyroidism. However, overt primary hypothyroidism as the initial event is also seen, with an incidence between 10-60%, and is typically irreversible.[33]

The reported incidence of hypophysitis associated with CTLA-4 inhibitor therapy is 0.4-17.0%; it is reported to occur more frequently in males and presents with central hypothyroidism and central hypoadrenalism.[34]

Primary thyroid dysfunction occurs with CTLA-4 and PD-1/PD-L1 inhibitors and can present more commonly as subclinical or overt hypothyroidism, transient thyrotoxicosis, or painless thyroiditis. Rarely, Graves disease and euthyroid orbitopathy occur. The incidence and severity of thyroid dysfunction increases with combination CTLA-4 and PD-1 inhibitor therapy (6% incidence with ipilimumab alone vs 22% with a combination of ipilimumab and nivolumab, in a study reported by Ryder et al).[35]

Screening for thyroid dysfunction using TSH and free T4 levels is recommended before treatment initiation, at 4-6 weekly intervals, and should be repeated before each treatment cycle. For confirmed primary and central hypothyroidism, levothyroxine therapy is started, but hypocortisolism should be ruled out prior to treating central hypothyroidism. If cortisol is low, glucocorticoid therapy is initiated at least 3-5 days prior to thyroid hormone replacement to prevent an acute adrenal crisis. Subclinical hypothyroidism often resolves without treatment.[33, 34]  

Tyrosine kinase inhibitors (TKIs) cause iatrogenic hypothyroidism via several different mechanisms, due to differences in their spectrum of targeted kinases. This in turn leads to varying rates of thyroid dysfunction. Destructive thyroiditis, postulated to be the primary process leading to thyroid dysfunction, causes an initial transient thyrotoxic phase that is followed by overt hypothyroidism. The anti-angiogenic effects of TKIs are mediated via anti-vascular endothelial growth factor receptor (anti-VEGFR) and platelet-derived growth factor receptor (PDGFR) signaling, which leads to decreased vascularization of the thyroid parenchyma, resulting in cellular hypoxia. In turn, thyroid hormone synthesis is also decreased by way of this process. If treatment is prolonged, permanent hypothyroidism can ensue.

TKIs may also play an inhibitory role in the secretion of TRH from the hypothalamus, via reduced nitric oxide production, leading to decreased TSH release. Independent of the thyroid gland, as seen in patient status post thyroidectomy, TKIs (particularly imatinib) increase levothyroxine requirements by increasing the activity of type 3 deiodinase and causing decreased tissue availability of T3.[36, 37]

Of the TKIs, sunitinib is the one most likely to cause new-onset hypothyroidism, with the disease occurring in 14-70% of patients who take the drug. The risk rises with prolonged therapy and an increased number of treatment cycles. It can reportedly take as little as 4 weeks and as long as 92 weeks for hypothyroidism to develop with sunitinib therapy. Of interest, iatrogenic hypothyroidism resulting from TKI use has been associated with prolonged survival rates of unknown etiology.[34]

TSH screening is recommended at TKI initiation, then monthly for the first 6 months. Thereafter, TSH can be checked every 2-3 months (or sooner if new symptoms or clinical signs of thyroid disease occur). In patients with established hypothyroidism, TSH should be checked every month for the first 3 months, and then every 3 months thereafter. If levothyroxine is prescribed during the course of treatment, a trial withdrawal can be considered at the conclusion of TKI treatment.[38]

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 the nucleic acids 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.[39]

Approximately 10% of patients with congenital hypothyroidism have an error in thyroid hormone synthesis.[40] Mutations in the TPO gene appear to be the most common error of hormone synthesis, causing failure to produce adequate amounts of TPO.[41]

Mutations in the TSHR and PAX8 genes are known to cause congenital hypothyroidism without goiter.[42, 43] 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.[44]

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.[45] 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-Chaikoff effect). Most healthy individuals have a physiologic escape from this effect after 10-14 days. 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-Chaikoff effect is short-lived because the sodium-iodide symporter is capable of rapid down-regulation. 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).[46]

Central hypothyroidism

Central hypothyroidism (secondary or tertiary) results when the hypothalamic-pituitary axis is damaged. The following potential causes should be considered[47, 48] :

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 nongoitrous 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.[49]

TRH resistance is a rare condition caused by a mutation in the TRHR gene and is inherited in an autosomal recessive manner. Patients with this condition have hypothyroidism and insensitivity to thyrotropin secretion.[50] .

TRH deficiency is caused by mutation in the TRH gene and is inherited in an autosomal recessive manner.[51] The index case was a girl evaluated for short stature who was found to have an isolated deficiency of TRH.[10]

Epidemiology

A retrospective study by Wyne et al using a medical/pharmacy claims database reported a steady increase in hypothyroidism in the United States, with the prevalence rising from 9.5% in 2012 to 11.7% in 2019.[52]

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, but even so, an estimated 35-45% of the world’s population is affected by iodine deficiency.[53]

According to a report released in 2024 by the World Health Organization (WHO) and the Iodine Global Network, the growing consumption of plant-based foods in the WHO European region (made up of over 50 countries) as a substitution for important sources of iodine, such as milk, dairy, and fish, is contributing to the problem of insufficient iodine intake.[54]

Age-related demographics

The frequency of hypothyroidism, goiters, and thyroid nodules increases with age. The previously mentioned study by Wyne et al reported that between 2012 and 2019, hyperthyroidism maintained a consistent prevalence in persons aged less than 50 years, while in persons aged 50-59 years, the prevalence grew from 10.4% to 11.2%, and in individuals aged 60 years or older, from 16.2% to 17.8%.[52]

Sex-related demographics

Community studies use slightly different criteria for determining hypothyroidism; therefore, female-to-male ratios vary. Generally, the prevalence of thyroid disease is reportedly 2-8 times higher in females.

However, using the National Health and Nutrition Examination Survey (NHANES) from the 2009-2010 and 2011-2012 survey cycles, the above-mentioned report by Wyne and colleagues found 51.5% of persons in the United States with hypothyroidism to be female.[52]

Race-related demographics

Using the NHANES from the 2009-2010 and 2011-2012 survey cycles, the aforementioned study by Wyne and colleagues found 65.6% of persons in the United States with hypothyroidism to be non-Hispanic White.[52]

Prognosis

Undertreatment of hypothyroidism leads to disease progression, with gradual worsening of symptoms and further metabolic derangements. Ultimately, untreated hypothyroidism can result in profound coma or even death.

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

Thyroid hormone therapy 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.[55]

Nonetheless, a study by Sohn et al found that in individuals with hypothyroidism (defined in this study as overt hypothyroidism in patients undergoing long-term levothyroxine treatment), there was significantly higher all-cause mortality than in persons without hypothyroidism, with the adjusted hazard ratio (HR) being 1.14. Over a mean 6-year follow-up, the death rate for patients with hypothyroidism was 5.2%, compared with 3.9% for the controls.[56]

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.[57]

Similarly, a prospective observational study by Tsuda et al indicated that in patients with chronic kidney disease, subclinical hypothyroidism is an independent risk factor for poor outcome. The report found, for example, that in chronic kidney disease patients with subclinical hypothyroidism, the hazard ratio for a composite endpoint of doubling of serum creatinine, end-stage renal disease, or death was 1.61, compared with euthyroid patients.[58]

Research indicates that hypothyroidism may be an independent risk factor for MASLD. A study by Almomani et al did not find that thyroid hormone replacement reduced the risk by a statistically significant amount, although other reports have suggested that prevention or reversal of MASLD is potentially possible with such replacement.[59]

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.[60]

In a meta-analysis by Tsai et al, overt hypothyroidism was significantly associated with increased all-cause mortality, but not cardiovascular mortality, among the elderly.[61]

A study by Thvilum et al indicated that hypothyroidism increases the risk of dementia, with the risk rising by 12% for every 6 months of elevated TSH.[62]

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.[63]  Continuous tube feedings interfere with thyroid hormone absorption; the tube feedings should be interrupted for at least 30-60 minutes before and after hormone administration.

For patients with malabsorption issues, such as those with celiac disease, Helicobacter pylori infection, lactose intolerance, inflammatory bowel disease, atrophic gastritis, or status post bariatric surgery, liquid LT4 formulations may be more efficient than the tablet form for replacement and suppressive therapy. For those without malabsorption, either form is sufficient.[64]

The effects of using softgel LT4 may also prove beneficial in malabsorptive states, and its effects have been found to be consistent with the liquid formulation.[65] For both liquid and softgel LT4 formulations, cost is often a limiting factor for use.

Although it has generally been recommended that thyroid hormone be administered in the morning before breakfast, studies of bedtime dosing have demonstrated acceptable absorption if the hormone is taken 3 or more hours after the evening meal.[66, 67]

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

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.

It has not yet been established whether hypothyroidism has a direct biochemical link to insomnia, although research has suggested that untreated subclinical hypothyroidism may be associated with poor sleep quality. It is also possible that the symptoms of an underactive thyroid, including muscle and joint pain, cold intolerance, and increased anxiety, may adversely affect sleep.[68]

In addition to impaired fertility, hypothyroidism in women can lead to heavy or irregular menstrual periods.[69]

Myxedema coma is a severe form of hypothyroidism that results in an altered mental status, hypothermia, bradycardia, hypercapnia, 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:

Approximately one third of individuals with hypothyroidism suffer from headache. However, the actual association between hypothyroidism and headache is uncertain, with there being evidence of a possible bidirectional relationship between the two, particularly in the case of migraine.[71]

“Brain fog,” characterized by lack of energy, forgetfulness, and fatigue, is another symptom of hypothyroidism. In one survey, 905 out of 5282 people (17.1%) reported suffering from symptoms of brain fog not long after being diagnosed with hypothyroidism.[72]

A study by Tricarico et al suggested that patients with hypothyroidism undergoing hormone replacement therapy (HRT) have a greater likelihood for recurrence of benign paroxysmal positional vertigo, particularly individuals who have Hashimoto thyroiditis and positive thyroid antibodies. The investigators indicated that this may signal a connection between autoimmunity and recurrent vertigo.[73]

Research indicates that hypothyroidism is linked to sexual dysfunction in males, including erectile dysfunction, delayed ejaculation, and hypoactive sexual desire (HSD). It is also suggested that sexual dysfunction in males results from the hypothyroid state itself rather than from the antibodies that lead to hypothyroidism.[74, 75]

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

Physical Examination

In hypothyroidism, facial changes include dulled expression, drooping eyelids, and puffiness of the eyes and face.[76]

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.[77]

Laboratory Studies

Third-generation thyroid-stimulating hormone (TSH) assays are readily available and are generally the most sensitive screening tool for primary hypothyroidism.[3] 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.[78] 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, and the remainder bound loosely to albumin.

The levels of these binding proteins can vary by hormonal status and inheritance and in various disease states. Hence, free T4 assays, which measure unbound (ie, free) hormone, are the accepted standard. 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 labor intensive. Free thyroid hormone levels can be estimated by calculating the percentage of available thyroid hormone-binding sites (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. Anti-TPO antibodies have been associated with increased risk of infertility and miscarriage; whether levothyroxine (LT4) treatment can lower this risk is controversial.[79, 80]

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 CBC and metabolic profile may show abnormalities in patients with hypothyroidism. These include anemia, dilutional hyponatremia, hyperlipidemia, and reversible increases in serum creatinine.[5] Elevations in transaminases and creatinine kinase have also been found.

Primary hypothyroidism causes an elevation of TRH, which can produce 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.[81]  A study by Chen et al found the risk of thyroid malignancy to be 63.6% in lesions with focal uptake, while most instances of diffuse uptake were associated with chronic thyroiditis.[82]

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[7] :

Screening recommendations from other groups

The US Preventive Services Task Force (USPSTF) concludes that there is not sufficient evidence to gauge how the benefits of screening asymptomatic, nonpregnant adults for thyroid dysfunction balance against the harms.[83] Although this statement was made in 2015, the USPSTF reported that a May 2024 literature scan found “a lack of new evidence to support an updated systematic review on the topic at this time.”[84]

The American College of Obstetricians and Gynecologists (ACOG) does not recommend universal screening for thyroid disease in pregnant women. However, those who are at increased risk warrant screening. This includes pregnant women with a personal or family history of thyroid disease, type 1 diabetes, or symptoms suggestive of thyroid disease. There is no proven benefit in screening pregnant women with a mildly enlarged thyroid gland, whereas those with a significant goiter or distinct thyroid nodules require screening.[8]

Fine-Needle Aspiration Biopsy

Thyroid nodules are often found incidentally during physical examination or on chest radiography, computed tomography (CT) scanning, 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 ultrasonographic 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 (1.6 μg/kg/day). Pregnant women will require doses about 25% higher. 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 4-6 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[85, 86] :

A meta-analysis of randomized, controlled trials of T4-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 LDL and HDL cholesterol and triglyceride levels.[87]

A study of athyreotic patients found a high heterogeneity in these patients’ ability to produce T3 when treated with levothyroxine. Approximately 20% of these athyreotic patients did not maintain normal free T4 or free T3 values despite a normal TSH.[88] 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 rare 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.[89]

Most patients with hypothyroidism can be treated in an ambulatory care setting. Patients who require long-term, continuous tube feeding may need 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 need 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[85, 86] :

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 recommended by ACOG (2020) 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.[92]  A literature review by Dong and Stagnaro-Green found that the pooled prevalence rate for overt hypothyroidism in pregnancy was 0.50% (with the 97.5th percentile used as an upper limit for TSH).[93]

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 25% 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 “[i]n most regions, including the United States, women who are planning pregnancy or currently pregnant, should supplement their diet with a daily oral supplement that contains 150 μg of iodine in the form of potassium iodide.” According to the guidelines, the optimal time to start such supplementation is 3 months prior to a planned pregnancy.[94]

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.[95]

Autoimmune thyroid disease without overt hypothyroidism has been associated with adverse pregnancy outcomes, as has subclinical hypothyroidism. In a meta-analysis of 19 prospective cohort studies (47,045 women), the risk of preterm birth was higher in association with subclinical hypothyroidism, isolated hypothyroxinemia (decreased free T4 concentration with normal TSH concentration), and thyroid peroxidase (TPO) antibody positivity.[96] Additionally, 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.[97] Interestingly, treatment with LT4 prior to conception did not significantly alter the rates of live births, pregnancy loss, preterm birth, or neonatal outcomes in a study of 952 euthyroid women with positive anti-TPO antibodies.[80]

In a meta-analysis of three studies involving 220 women with subclinical hypothyroidism or thyroid autoimmunity who were undergoing procedures with assisted reproduction technologies, Velkeniers et al concluded that treatment with LT4 should be recommended to improve pregnancy outcomes.[98] 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 or subclinical hypothyroidism. At this time, treatment recommendations for the periconception period in women with subclinical hypothyroidism, hypothyroxinemia, or thyroid autoimmunity remain inconclusive.

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)[99, 100] :

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.

Due to the decreased thyroid hormone demand following delivery, prepregnancy doses of LT4 should be resumed in women with subclinical hypothyroidism. A serum TSH level should be obtained at week 6 post delivery.[101]

Subclinical Hypothyroidism

Significant controversy persists regarding the treatment of patients with mild hypothyroidism.[9] Reviews by the US Preventive Services Task Force[10] and an independent expert panel[11] found inconclusive evidence to recommend aggressive treatment of patients with TSH levels of 4.5-10 mIU/L.

Some have argued that treatment of these patients improves symptoms, prevents progression to overt hypothyroidism, and may have cardioprotective benefits. However a randomized, controlled trial with 95 participants found that treatment with LT4 did not lead to significant improvement of the left ventricular ejection fraction after 52 weeks in patients with subclinical hypothyroidism and acute myocardial infarction.[102]

In pregnant women with subclinical hypothyroidism (using a TSH cutoff of ≥4.0 mIU/L) and negative anti-TPO antibodies, LT4 therapy may reduce the risk for preterm delivery.[103] The Endocrine Society recommends T4 replacement in pregnant women with subclinical hypothyroidism,[104]  but ACOG does not recommend it as a routine measure.[105]

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).[106]

In nonpregnant patients, following subclinical hypothyroidism and treating the patients 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[107] and to decrease arterial stiffness and systolic blood pressure.[108] In patients with concomitant subclinical hypothyroidism and iron deficiency anemia, iron supplementation may be ineffective if LT4 is not given.[109]

A literature review by Abreu et al suggested that LT4 therapy can hinder the development of coronary artery disease in subclinical hypothyroidism. Evaluating randomized, placebo-controlled trials, the investigators reported that patients receiving LT4 experienced significant reductions in serum TSH and in total and low-density lipoprotein cholesterol compared with patients receiving placebo.[110]

In older adults (≥65 years) with subclinical hypothyroidism, treatment guidelines remain inconclusive. Generally, treatment is not recommended if TSH is between 4.5-6.9 mIU/L, given the low risk for progression to overt hypothyroidism and the more relaxed TSH targets in the elderly favored by some guidelines.[111]

The TRUST trial, a randomized, controlled study of LT4 therapy for subclinical hypothyroidism in older adults, randomized 737 men and women aged 65 years or older to treatment with LT4 versus placebo. Results showed no benefit in primary outcomes of hypothyroid symptoms and fatigue score after 12 months of therapy. There were also no significant benefits noted with regard to the secondary outcomes of quality of life, handgrip strength, cognitive function, blood pressure, weight, body mass index (BMI), waist circumference, carotid intima medial thickness (CIMT), and carotid plaque thickness.[112] In a substudy of the TRUST trial, participants treated with LT4 for 18 months did not have any significant differences in carotid atherosclerosis and CIMT compared with the placebo group.[113] In a nested study within the TRUST trial, no significant difference was seen in systolic or diastolic heart function in LT4-treated participants compared with placebo.[114]

In general, for patients older than 70 years with TSH of 10 mIU/L or greater, treatment should be based on individual patient factors, including hypothyroid symptoms, the presence of anti-TPO antibodies, and cardiac risk factors. 

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.[115]  A study by Chen et al using the National (Nationwide) Inpatient Sample (2016-2018) found the overall mortality rate for adult patients with myxedema coma to be 6.8%, compared with 0.7% for patients with hypothyroidism but without myxedema coma. Myxedema coma had an independent association with in-hospital mortality, the adjusted odds ratio (OR) being 9.92. Older age, public insurance, and unhoused status were all associated with myxedema coma, while admissions for patients with myxedema coma were more frequent in winter (see Hypothyroidism and Myxedema Coma).[116]

Complications of Treatment

Thyroid hormone replacement can precipitate adrenal crisis 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, and caution should be used in initiating full replacement doses of LT4 in the elderly. In a study by Sawin et al, 2007 elderly patients (aged ≥60 years) without a prior history of atrial fibrillation were followed over a 10-year period to assess the frequency of this arrhythmia according to TSH levels. The investigators found that the risk of atrial fibrillation was three times higher in the cohort with low TSH levels (≤0.1 mIU/L), with a 10-year cumulative incidence of 28% for atrial fibrillation, compared with 11% in those with normal TSH levels (>0.4-5.0 mIU/L).[117]

The relationship of overtreatment to osteoporosis and fracture is best studied in the elderly and in postmenopausal women. A large population-based, nested case-control study demonstrated a two- to three-fold increase in fractures in LT4 users older than 70 years; the increase was dose-related.[118] An observational cohort study that evaluated the association between serum TSH level and risk for cardiovascular disease, dysrhythmias, and fractures in patients on T4-replacement therapy showed an increased risk for all three outcomes with an elevated (>4.0 mIU/L) or suppressed (≤0.03 mIU/L) TSH level. Interestingly, patients with a low (0.04-0.4 mIU/L), but not suppressed, TSH level did not have an increased risk for these outcomes.[119] Nonetheless, these studies support careful dose titration and avoidance of TSH oversuppression, especially in elderly patients.

Overall, patients at risk for osteoporosis (eg, women who are estrogen-deficient and the elderly) and individuals receiving a long-term suppressive dose of LT4 (eg, patients with differentiated thyroid cancer) should be closely monitored. A meta-analysis of 385 premenopausal women and 409 postmenopausal women, all on suppressive LT4 therapy, revealed that the treatment was associated with a significant detrimental effect on bone mass of the hip and spine in the postmenopausal group.[120]

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 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.

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.

Although there is no evidence that avoiding certain foods will aid thyroid function, some foods can discourage the absorption of thyroid hormone replacement medication and so should not be consumed at the same time as the medication. These include the following[121] :

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[3] :

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[122] :

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 (Ermeza, Euthyrox, L Thyroxine)

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, Liothyronine T3, Thyroid Hormone)

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 (Adthyza, Armour Thyroid, Nature-Throid (DSC))

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, and how might biotin interfere with screening?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, and is there a link between vitamin D levels and autoimmune thyroid disease?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, FACP, Professor, Department of Internal Medicine, Director, Division of Endocrinology, Diabetes and Metabolism, Associate Dean for Educational Programs, Vice-Chair of Medicine for Education, Edward Randall III Chair in Internal Medicine, Program Director, Endocrinology, Diabetes and Metabolism Fellowship Program, University of Texas Health Science Center at Houston, McGovern Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

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

Disclosure: Nothing to disclose.

Sapna Naik, MD, Assistant Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, UTHealth, University of Texas Health Science Center at Houston, McGovern Medical School; Attending Physician, Department of Gastroenterology, Memorial Hermann Hospital – Texas Medical Center, and Lyndon B Johnson General Hospital

Disclosure: Nothing to disclose.

Chief Editor

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

Disclosure: Nothing to disclose.

Additional Contributors

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

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. ICD10Data.com. Other hypothyroidism E03. Available at https://www.icd10data.com/ICD10CM/Codes/E00-E89/E00-E07/E03-. Accessed: May 24, 2022.
  2. ICD10Data.com. 2022 ICD-10-CM Diagnosis Code E03.9. Available at https://www.icd10data.com/ICD10CM/Codes/E00-E89/E00-E07/E03-/E03.9. Accessed: May 24, 2022.
  3. 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]
  4. Li D, Radulescu A, Shrestha RT, et al. Association of Biotin Ingestion With Performance of Hormone and Nonhormone Assays in Healthy Adults. JAMA. 2017 Sep 26. 318 (12):1150-60. [View Abstract]
  5. den Hollander JG, Wulkan RW, Mantel MJ, Berghout A. Correlation between severity of thyroid dysfunction and renal function. Clin Endocrinol (Oxf). 2005 Apr. 62 (4):423-7. [View Abstract]
  6. Wopereis DM, Du Puy RS, van Heemst D, et al. The Relation Between Thyroid Function and Anemia: A Pooled Analysis of Individual Participant Data. J Clin Endocrinol Metab. 2018 Oct 1. 103 (10):3658-67. [View Abstract]
  7. 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]
  8. Thyroid Disease in Pregnancy: ACOG Practice Bulletin, Number 223. Obstet Gynecol. 2020 Jun. 135 (6):e261-74. [View Abstract]
  9. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012 Mar 24. 379 (9821):1142-54. [View Abstract]
  10. 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]
  11. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004 Jan 14. 291 (2):228-38. [View Abstract]
  12. Kim D. The Role of Vitamin D in Thyroid Diseases. Int J Mol Sci. 2017 Sep 12. 18 (9):[View Abstract]
  13. Gosi SKY, Kaur J, Garla VV. Subclinical Hypothyroidism. StatPearls. 2024 Feb 15. [View Abstract]
  14. Livingston EH. Subclinical Hypothyroidism. JAMA Patient Page. Available at https://jamanetwork.com/journals/jama/fullarticle/2737684. July 9, 2019; Accessed: May 23, 2022.
  15. Danner E, Jaaskelainen J, Niuro L, et al. Comorbidity in Congenital Hypothyroidism-A Nationwide, Population-based Cohort Study. J Clin Endocrinol Metab. 2023 Nov 17. 108 (12):e1695-e1701. [View Abstract]
  16. Mantovani A, Nascimbeni F, Lonardo A, et al. Association Between Primary Hypothyroidism and Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Thyroid. 2018 Oct. 28 (10):1270-84. [View Abstract]
  17. Tomer Y, Davies TF. Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function. Endocr Rev. 2003 Oct. 24 (5):694-717. [View Abstract]
  18. Brix TH, Hegedus L. Twin studies as a model for exploring the aetiology of autoimmune thyroid disease. Clin Endocrinol (Oxf). 2012 Apr. 76 (4):457-64. [View Abstract]
  19. Bothra N, Shah N, Goroshi M, Jadhav S, Padalkar S, Thakkar H, et al. Hashimoto's thyroiditis: relative recurrence risk ratio and implications for screening of first-degree relatives. Clin Endocrinol (Oxf). 2017 Aug. 87 (2):201-206. [View Abstract]
  20. Sabra M. Thyroid cancer: Is there a relationship between thyroid cancer and Hashimoto’s thyroiditis?. Clin Thyroidology Public. 6(7):6.
  21. Lee JH, Kim Y, Choi JW, Kim YS. The association between papillary thyroid carcinoma and histologically proven Hashimoto's thyroiditis: a meta-analysis. Eur J Endocrinol. 2013 Mar. 168 (3):343-9. [View Abstract]
  22. Cleveland Clinic. Postpartum Thyroiditis. Available at https://my.clevelandclinic.org/health/diseases/15294-postpartum-thyroiditis. Reviewed October 23, 2020; Accessed: May 23, 2022.
  23. 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]
  24. Muller I, Cannavaro D, Dazzi D, et al. SARS-CoV-2-related atypical thyroiditis. Lancet Diabetes Endocrinol. 2020 Sep. 8 (9):739-41. [View Abstract]
  25. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med. 2003 Jun 26. 348 (26):2646-55. [View Abstract]
  26. Zala A, Berhane T, Juhlin CC, Calissendorff J, Falhammar H. Riedel Thyroiditis. J Clin Endocrinol Metab. 2020 Sep 1. 105 (9):[View Abstract]
  27. Klionsky Y, Antonelli M. Thyroid Disease in Lupus: An Updated Review. ACR Open Rheumatol. 2020 Feb. 2 (2):74-8. [View Abstract]
  28. Wolter P, Dumez H, Schöffski P. Sunitinib and hypothyroidism. N Engl J Med. 2007 Apr 12. 356 (15):1580; author reply 1580-1. [View Abstract]
  29. 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]
  30. Shimizu H, Kodaira T, Kiyota N, et al. Incidence and risk factors associated with the development of hypothyroidism after postoperative chemoradiotherapy for head and neck cancer patients with high-risk features: Supplementary analysis of JCOG1008. Oral Oncol. 2024 Oct. 157:106976. [View Abstract]
  31. Rooney MK, Andring LM, Corrigan KL, et al. Hypothyroidism following Radiotherapy for Head and Neck Cancer: A Systematic Review of the Literature and Opportunities to Improve the Therapeutic Ratio. Cancers (Basel). 2023 Aug 29. 15 (17):[View Abstract]
  32. Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG. Iodine-Induced hypothyroidism. Thyroid. 2001 May. 11 (5):501-10. [View Abstract]
  33. Muir CA, Menzies AM, Clifton-Bligh R, Tsang VHM. Thyroid Toxicity Following Immune Checkpoint Inhibitor Treatment in Advanced Cancer. Thyroid. 2020 Oct. 30 (10):1458-69. [View Abstract]
  34. Bhattacharya S, Goyal A, Kaur P, Singh R, Kalra S. Anticancer Drug-induced Thyroid Dysfunction. Eur Endocrinol. 2020 Apr. 16 (1):32-39. [View Abstract]
  35. Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer. 2014 Apr. 21 (2):371-81. [View Abstract]
  36. Jannin A, Penel N, Ladsous M, Vantyghem MC, Do Cao C. Tyrosine kinase inhibitors and immune checkpoint inhibitors-induced thyroid disorders. Crit Rev Oncol Hematol. 2019 Sep. 141:23-35. [View Abstract]
  37. Makita N, Iiri T. Tyrosine kinase inhibitor-induced thyroid disorders: a review and hypothesis. Thyroid. 2013 Feb. 23 (2):151-9. [View Abstract]
  38. Drui D, Illouz F, Do Cao C, Caron P. Expert opinion on thyroid complications of new anti-cancer therapies: Tyrosine kinase inhibitors. Ann Endocrinol (Paris). 2018 Oct. 79 (5):569-73. [View Abstract]
  39. Denny JC, Crawford DC, Ritchie MD, Bielinski SJ, Basford MA, 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]
  40. 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]
  41. Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. 2005 May. 42 (5):379-89. [View Abstract]
  42. Paschke R, Ludgate M. The thyrotropin receptor in thyroid diseases. N Engl J Med. 1997 Dec 4. 337 (23):1675-81. [View Abstract]
  43. Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet. 1998 May. 19 (1):83-6. [View Abstract]
  44. Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, 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]
  45. Cetani F, Barbesino G, Borsari S, Pardi E, Cianferotti L, Pinchera A, 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]
  46. Woeber KA. Iodine and thyroid disease. Med Clin North Am. 1991 Jan. 75 (1):169-78. [View Abstract]
  47. 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]
  48. Nebesio TD, McKenna MP, Nabhan ZM, Eugster EA. Newborn screening results in children with central hypothyroidism. J Pediatr. 2010 Jun. 156 (6):990-993. [View Abstract]
  49. Doeker BM, Pfäffle 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]
  50. Bonomi M, Busnelli M, Beck-Peccoz P, Costanzo D, Antonica F, Dolci C, et al. A family with complete resistance to thyrotropin-releasing hormone. N Engl J Med. 2009 Feb 12. 360 (7):731-4. [View Abstract]
  51. 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]
  52. Wyne KL, Nair L, Schneiderman CP, et al. Hypothyroidism Prevalence in the United States: A Retrospective Study Combining National Health and Nutrition Examination Survey and Claims Data, 2009-2019. J Endocr Soc. 2022 Nov 17. 7 (1):bvac172. [View Abstract]
  53. Hatch-McChesney A, Lieberman HR. Iodine and Iodine Deficiency: A Comprehensive Review of a Re-Emerging Issue. Nutrients. 2022 Aug 24. 14 (17):[View Abstract]
  54. World Health Organization, Iodine Global Network. Prevention and control of iodine deficiency in the WHO European Region: adapting to changes in diet and lifestyle. Available at https://www.who.int/europe/publications/i/item/9789289061193. 2024; Accessed: October 3, 2024.
  55. Winther KH, Cramon P, Watt T, Bjorner JB, Ekholm O, Feldt-Rasmussen U, 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. 11 (6):e0156925. [View Abstract]
  56. Sohn SY, Seo GH, Chung JH. Risk of All-Cause Mortality in Levothyroxine-Treated Hypothyroid Patients: A Nationwide Korean Cohort Study. Front Endocrinol (Lausanne). 2021. 12:680647. [View Abstract]
  57. 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]
  58. Tsuda S, Nakayama M, Matsukuma Y, Yoshitomi R, Haruyama N, Fukui A, et al. Subclinical hypothyroidism is independently associated with poor renal outcomes in patients with chronic kidney disease. Endocrine. 2021 Jan 20. 341(8):549-55. [View Abstract]
  59. Almomani A, Hitawala AA, Kumar P, et al. Prevalence of hypothyroidism and effect of thyroid hormone replacement therapy in patients with non-alcoholic fatty liver disease: A population-based study. World J Hepatol. 2022 Mar 27. 14 (3):551-8. [View Abstract]
  60. Sato Y, Yoshihisa A, Kimishima Y, Kiko T, Watanabe S, Kanno Y, et al. Subclinical Hypothyroidism Is Associated With Adverse Prognosis in Heart Failure Patients. Can J Cardiol. 2018 Jan. 34 (1):80-87. [View Abstract]
  61. Tsai TY, Tu YK, Munir KM, et al. Association of Hypothyroidism and Mortality in the Elderly Population: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2020 Jun 1. 105 (6):[View Abstract]
  62. Thvilum M, Brandt F, Lillevang-Johansen M, Folkestad L, Brix TH, Hegedüs L. Increased risk of dementia in hypothyroidism: A Danish nationwide register-based study. Clin Endocrinol (Oxf). 2021 Jun. 94 (6):1017-24. [View Abstract]
  63. Zamfirescu I, Carlson HE. Absorption of levothyroxine when coadministered with various calcium formulations. Thyroid. 2011 May. 21 (5):483-6. [View Abstract]
  64. Laurent I, Tang S, Astere M, et al. Liquid L-thyroxine versus tablet L-thyroxine in patients on L- thyroxine replacement or suppressive therapy: a meta-analysis. Endocrine. 2018 Jul. 61 (1):28-35. [View Abstract]
  65. Virili C, Trimboli P, Romanelli F, Centanni M. Liquid and softgel levothyroxine use in clinical practice: state of the art. Endocrine. 2016 Oct. 54 (1):3-14. [View Abstract]
  66. Skelin M, Lucijanic T, Liberati-Cizmek AM, et al. Effect of timing of levothyroxine administration on the treatment of hypothyroidism: a three-period crossover randomized study. Endocrine. 2018 Nov. 62 (2):432-9. [View Abstract]
  67. Pang X, Pu T, Xu L, Sun R. Effect of l-thyroxine administration before breakfast vs at bedtime on hypothyroidism: A meta-analysis. Clin Endocrinol (Oxf). 2020 May. 92 (5):475-81. [View Abstract]
  68. Green ME, Bernet V, Cheung J. Thyroid Dysfunction and Sleep Disorders. Front Endocrinol (Lausanne). 2021. 12:725829. [View Abstract]
  69. MedlinePlus. Hypothyroidism. Available at https://medlineplus.gov/hypothyroidism.html. Updated June 16, 2021; Accessed: May 23, 2022.
  70. British Thyroid Foundation. Hair loss and thyroid disorders. BTF. Available at https://www.btf-thyroid.org/hair-loss-and-thyroid-disorders. Accessed: May 23, 2022.
  71. Spanou I, Bougea A, Liakakis G, et al. Relationship of Migraine and Tension-Type Headache With Hypothyroidism: A Literature Review. Headache. 2019 Sep. 59 (8):1174-86. [View Abstract]
  72. Monostra M. Fatigue common with ‘brain fog’ among adults with hypothyroidism. Healio. Available at https://www.healio.com/news/endocrinology/20210528/fatigue-common-with-brain-fog-among-adults-with-hypothyroidism. May 29, 2021; Accessed: May 24, 2022.
  73. Tricarico L, Di Cesare T, Galli J, Fetoni AR, Paludetti G, Picciotti PM. Benign paroxysmal positional vertigo: is hypothyroidism a risk factor for recurrence?. Acta Otorhinolaryngol Ital. 2022 Feb 7. [View Abstract]
  74. Carani C, Isidori AM, Granata A, et al. Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients. J Clin Endocrinol Metab. 2005 Dec. 90 (12):6472-9. [View Abstract]
  75. Bates JN, Kohn TP, Pastuszak AW. Effect of Thyroid Hormone Derangements on Sexual Function in Men and Women. Sex Med Rev. 2020 Apr. 8 (2):217-30. [View Abstract]
  76. Hershman JM. Hypothyroidism. Merck Manual: Consumer Version. Available at https://www.merckmanuals.com/home/hormonal-and-metabolic-disorders/thyroid-gland-disorders/hypothyroidism. Reviewed/revised February 2024; Accessed: October 4, 2024.
  77. Piantanida E, Gallo D, Veronesi G, Pariani N, Masiello E, Premoli P, et al. Masked hypertension in newly diagnosed hypothyroidism: a pilot study. J Endocrinol Invest. 2016 Oct. 39 (10):1131-8. [View Abstract]
  78. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, 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]
  79. [Guideline] 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]
  80. Dhillon-Smith RK, Middleton LJ, Sunner KK, et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. N Engl J Med. 2019 Apr 4. 380 (14):1316-25. [View Abstract]
  81. Liu Y. Clinical significance of thyroid uptake on F18-fluorodeoxyglucose positron emission tomography. Ann Nucl Med. 2009 Jan. 23 (1):17-23. [View Abstract]
  82. Chen W, Parsons M, Torigian DA, Zhuang H, Alavi A. Evaluation of thyroid FDG uptake incidentally identified on FDG-PET/CT imaging. Nucl Med Commun. 2009 Mar. 30 (3):240-4. [View Abstract]
  83. [Guideline] LeFevre ML, U.S. Preventive Services Task Force. Screening for thyroid dysfunction: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015 May 5. 162 (9):641-50. [View Abstract]
  84. [Guideline] US Preventive Services Task Force. Thyroid Dysfunction: Screening. USPSTF. Available at https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/thyroid-dysfunction-screening. March 24, 2015; Accessed: October 3, 2024.
  85. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, 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]
  86. 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.
  87. 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]
  88. [Guideline] 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]
  89. [Guideline] McDermott MT. Does combination T4 and T3 therapy make sense?. Endocr Pract. 2012 Sep-Oct. 18 (5):750-7. [View Abstract]
  90. Finken MJ, van Eijsden M, Loomans EM, Vrijkotte TG, Rotteveel J. Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring. J Clin Endocrinol Metab. 2013 Apr. 98 (4):1417-26. [View Abstract]
  91. Ge GM, Leung MTY, Man KKC, et al. Maternal Thyroid Dysfunction During Pregnancy and the Risk of Adverse Outcomes in the Offspring: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2020 Dec 1. 105 (12):[View Abstract]
  92. 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]
  93. Dong AC, Stagnaro-Green A. Differences in Diagnostic Criteria Mask the True Prevalence of Thyroid Disease in Pregnancy: A Systematic Review and Meta-Analysis. Thyroid. 2019 Feb. 29 (2):278-89. [View Abstract]
  94. [Guideline] Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar. 27 (3):315-89. [View Abstract]
  95. LeBeau SO, Mandel SJ. Thyroid disorders during pregnancy. Endocrinol Metab Clin North Am. 2006 Mar. 35 (1):117-36, vii. [View Abstract]
  96. Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth., Korevaar TIM, Derakhshan A, et al. Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis. JAMA. 2019 Aug 20. 322 (7):632-41. [View Abstract]
  97. 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]
  98. 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]
  99. 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.
  100. Abalovich M, Vázquez A, Alcaraz G, Kitaigrodsky A, Szuman G, Calabrese C, et al. Adequate levothyroxine doses for the treatment of hypothyroidism newly discovered during pregnancy. Thyroid. 2013 Nov. 23 (11):1479-83. [View Abstract]
  101. Shan Z, Teng W. Thyroid hormone therapy of hypothyroidism in pregnancy. Endocrine. 2019 Oct. 66 (1):35-42. [View Abstract]
  102. Jabbar A, Ingoe L, Junejo S, et al. Effect of Levothyroxine on Left Ventricular Ejection Fraction in Patients With Subclinical Hypothyroidism and Acute Myocardial Infarction: A Randomized Clinical Trial. JAMA. 2020 Jul 21. 324 (3):249-58. [View Abstract]
  103. Nazarpour S, Ramezani Tehrani F, et al. Effects of Levothyroxine on Pregnant Women With Subclinical Hypothyroidism, Negative for Thyroid Peroxidase Antibodies. J Clin Endocrinol Metab. 2018 Mar 1. 103 (3):926-35. [View Abstract]
  104. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, 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]
  105. 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):702-707. [View Abstract]
  106. Rosário PW, Bessa B, Valadão MM, Purisch S. Natural history of mild subclinical hypothyroidism: prognostic value of ultrasound. Thyroid. 2009 Jan. 19 (1):9-12. [View Abstract]
  107. Ito M, Arishima T, Kudo T, Nishihara E, Ohye H, Kubota S, 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]
  108. 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]
  109. 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]
  110. Abreu IM, Lau E, de Sousa Pinto B, Carvalho D. Subclinical hypothyroidism: to treat or not to treat, that is the question! A systematic review with meta-analysis on lipid profile. Endocr Connect. 2017 Apr. 6 (3):188-199. [View Abstract]
  111. Biondi B, Cappola AR, Cooper DS. Subclinical Hypothyroidism: A Review. JAMA. 2019 Jul 9. 322 (2):153-60. [View Abstract]
  112. Stott DJ, Rodondi N, Kearney PM, et al. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med. 2017 Jun 29. 376 (26):2534-44. [View Abstract]
  113. Blum MR, Gencer B, Adam L, et al. Impact of Thyroid Hormone Therapy on Atherosclerosis in the Elderly With Subclinical Hypothyroidism: A Randomized Trial. J Clin Endocrinol Metab. 2018 Aug 1. 103 (8):2988-97. [View Abstract]
  114. Gencer B, Moutzouri E, Blum MR, et al. The Impact of Levothyroxine on Cardiac Function in Older Adults With Mild Subclinical Hypothyroidism: A Randomized Clinical Trial. Am J Med. 2020 Jul. 133 (7):848-56.e5. [View Abstract]
  115. Wartofsky L. Myxedema coma. Endocrinol Metab Clin North Am. 2006 Dec. 35 (4):687-98, vii-viii. [View Abstract]
  116. Chen DH, Hurtado CR, Chang P, Zakher M, Angell TE. Clinical Features and Outcomes of Myxedema Coma in Patients Hospitalized for Hypothyroidism: Analysis of the United States National Inpatient Sample. Thyroid. 2024 Apr. 34 (4):419-28. [View Abstract]
  117. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994 Nov 10. 331 (19):1249-52. [View Abstract]
  118. Turner MR, Camacho X, Fischer HD, Austin PC, Anderson GM, Rochon PA, et al. Levothyroxine dose and risk of fractures in older adults: nested case-control study. BMJ. 2011 Apr 28. 342:d2238. [View Abstract]
  119. Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab. 2010 Jan. 95 (1):186-93. [View Abstract]
  120. Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY. Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab. 1996 Dec. 81 (12):4278-89. [View Abstract]
  121. Mayo Clinic. Hypothyroidism diet: Can certain foods increase thyroid function?. Available at https://www.mayoclinic.org/diseases-conditions/hypothyroidism/expert-answers/hypothyroidism-diet/faq-20058554. June 1, 2021; Accessed: May 23, 2022.
  122. [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]

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.