Hypothyroidism

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. Cretinism refers to severe hypothyroidism in an infant or child. This is classically the result of maternal iodine deficiency, and thankfully is increasingly rare.

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

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

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. 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.[15]

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]

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).[16] Additionally, higher concordance rates are seen in autoimmune thyroid disease in monozygotic twins (29-55%) compared with dizygotic twins (0-7%).[17] Congenital causes of thyroid dysfunction are less common (see below).

Primary hypothyroidism

Types of primary hypothyroidism include the following:

·       Chronic lymphocytic (autoimmune) thyroiditis

·       Postpartum thyroiditis

·       Subacute (granulomatous) thyroiditis

·       Drug-induced hypothyroidism

·       Iatrogenic (postsurgical) hypothyroidism

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.[18]

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.[19, 20]

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.[21]

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.[22]

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.[23]

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.[24, 25]

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.[26]

Drug-induced and iatrogenic hypothyroidism

The following medications reportedly have the potential to cause hypothyroidism:

• Iodinated contrast
• Amiodarone
• Interferon alfa
• Thalidomide
• Lithium
• Stavudine
• Oral tyrosine kinase inhibitors – Sunitinib, imatinib ^[27]
• Bexarotene ^[28]
• Perchlorate
• Interleukin (IL)-2
• Ethionamide
• Rifampin
• Phenytoin
• Carbamazepine
• Phenobarbital
• Aminoglutethimide
• Sulfisoxazole
• p -Aminosalicylic acid
• Immune checkpoint inhibitors – Ipilimumab, pembrolizumab, nivolumab

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.

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 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.[29]

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.[24]

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.[30]

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.[31]

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 can 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).[32]

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.[30, 31]  

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.[33, 34]

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.[31]

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.[35]

Genetics

Genome-wide association studies have suggested that a single-nucleotide polymorphism located near the FOXE1 gene is associated with risk of developing thyroid disease and that the strongest association is with hypothyroidism. Persons found to have GG at the described location had an odds ratio (OR) of 1.35 for development of hypothyroidism, whereas persons found to have AG at the location had an OR of 1.00, and persons found to have AA at the location had an OR of 0.74.[36]

Approximately 10% of patients with congenital hypothyroidism have an error in thyroid hormone synthesis.[37] Mutations in the TPO gene appear to be the most common error of hormone synthesis, causing failure to produce adequate amounts of TPO.[38]

Mutations in the TSHR and PAX8 genes are known to cause congenital hypothyroidism without goiter.[39, 40] 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.[41]

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.[42] 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 downregulation. However, exposure to excess iodine can produce more profound and sustained hypothyroidism in individuals with abnormal thyroid glands (eg, from autoimmune thyroiditis, subtotal thyroidectomy, or prior radioiodine therapy).[43]

Central hypothyroidism

Central hypothyroidism (secondary or tertiary) results when the hypothalamic-pituitary axis is damaged. The following potential causes should be considered[44, 45] :

·       Pituitary adenoma

·       Tumors impinging on the hypothalamus

·       Lymphocytic hypophysitis

·       Sheehan syndrome

·       History of brain or pituitary irradiation

·       Drugs (eg, dopamine, prednisone, or opioids)

·       Congenital nongoitrous hypothyroidism type 4

·       TRH resistance

·       TRH deficiency

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.[46]

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.[47] .

TRH deficiency is caused by mutation in the TRH gene and is inherited in an autosomal recessive manner.[48] The index case was a girl evaluated for short stature who was found to have an isolated deficiency of TRH.[10]

The National Health and Nutrition Examination Survey (NHANES 1999-2002) of 4392 individuals reflecting the US population reported hypothyroidism (defined as TSH levels exceeding 4.5 mIU/L) in 3.7% of the population.[49] Hypothyroidism is more common in women with small body size at birth and low body mass index during childhood.[50]

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

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

Age-related demographics

The frequency of hypothyroidism, goiters, and thyroid nodules increases with age. Hypothyroidism is most prevalent in elderly populations, with 2-20% of older age groups having some form of hypothyroidism. The Framingham study found hypothyroidism (TSH > 10 mIU/L) in 5.9% of women and 2.4% of men older than 60 years.[51] In NHANES 1999-2002, the odds of having hypothyroidism were 5 times greater in persons aged 80 years and older than in individuals aged 12-49 years.[49]

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.

Race-related demographics

NHANES 1999-2002 reported that the prevalence of hypothyroidism (including the subclinical form) was higher in whites (5.1%) and Mexican Americans than in African Americans (1.7%). African Americans tend to have lower median TSH values.[49]

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, and in infants it can cause irreversible mental retardation.

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.[52]

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.[53]

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.[54]

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.[55]

Research indicates that hypothyroidism may be an independent risk factor for NAFLD. 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 NAFLD is potentially possible with such replacement.[56]

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.[57]

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.[58]

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.[59]

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.[60]  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 tablet form for replacement and suppressive therapy. For those without malabsorption, either form is sufficient.[61]

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.[62] 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.[63, 64]

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

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

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.[65]

In addition to impaired fertility, hypothyroidism in women can lead to heavy or irregular menstrual periods.[66]

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:

• Fatigue, loss of energy, lethargy
• Weight gain
• Decreased appetite
• Cold intolerance
• Dry skin
• Hair loss - With successful thyroid treatment, hypothyroidism-related hair loss is normally temporary, although regrowth takes several months, and the hair may not fully return ^[67]
• Sleepiness
• Muscle pain, joint pain, weakness in the extremities
• Depression
• Emotional lability, mental impairment
• Forgetfulness, impaired memory, inability to concentrate
• Constipation
• Menstrual disturbances, impaired fertility
• Decreased perspiration
• Paresthesias, nerve entrapment syndromes
• Blurred vision
• Decreased hearing
• Fullness in the throat, hoarseness

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.[68]

“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.[69]

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.[70]

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.[71, 72]

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

• Feeling of fullness in the throat
• Painless thyroid enlargement
• Exhaustion
• Transient neck pain, sore throat, or both

In hypothyroidism, facial changes include dulled expression, drooping eyelids, and puffiness of the eyes and face.[73]

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:

·       Weight gain

·       Slowed speech and movements

·       Dry skin (rarely, yellow hued from carotene)

·       Jaundice

·       Pallor

·       Coarse, brittle, straw-like hair

·       Loss of scalp hair, axillary hair, pubic hair, or a combination

·       Dull facial expression

·       Coarse facial features

·       Periorbital puffiness

·       Macroglossia

·       Goiter (simple or nodular)

·       Hoarseness

·       Decreased systolic blood pressure and increased diastolic blood pressure

·       Bradycardia

·       Pericardial effusion

·       Abdominal distention, ascites (uncommon)

·       Hypothermia (only in severe hypothyroid states)

·       Nonpitting edema (myxedema)

·       Pitting edema of lower extremities

·       Hyporeflexia with delayed relaxation, ataxia, or both

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.[74]

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.[75] Certain physiologic conditions, such as illness, psychiatric disorders, and significant physical stress (eg, running a marathon), exposure to extremes in temperature, negative energy balance), can produce marked variations in TSH levels.

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

The levels of these binding proteins can vary by hormonal status, inheritance, and in various disease states. Hence, free T4 assays, which measure unbound (ie, free) hormone, are 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 (triiodothyronine [T3] resin uptake, or thyroid hormone binding ratio [THBR]) or by measuring the TBG concentration. A free T4 index (FTI) serves as a surrogate of the free hormone level. The FTI is the product of T3 resin uptake and total T4 levels.

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

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

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

Assays for anti–thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg) antibodies may be helpful in determining the etiology of hypothyroidism or in predicting future hypothyroidism. However, once a patient has been found to be antibody positive, repeated antibody testing adds little to the clinical picture and thus is not recommended. Anti-TPO antibodies have been associated with increased risk of infertility and miscarriage; whether levothyroxine (LT4) treatment can lower this risk is controversial.[76, 77]

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

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

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

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

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

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

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.[78]  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.[79]

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] :

• Pregnant women
• Women older than 60 years
• Patients with type 1 diabetes or other autoimmune disease
• Patients with a history of neck irradiation

Screening recommendations from other groups

The American College of Physicians recommends screening all women older than 50 years who have 1 or more clinical features of disease.[80, 81]

The American Academy of Family Physicians recommends screening asymptomatic patients older than 60 years.[82]

The American Association of Clinical Endocrinologists recommends TSH measurements in all women of childbearing age before pregnancy or during the first trimester.[83]

The US Preventive Task Force concludes that the evidence is insufficient to recommend for or against routine screening for thyroid disease in adults (grade I recommendation).[84]

However, 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]

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

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

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:

·       Previous administration of radioiodine

·       Surgical removal

·       Metastasis

·       Lymphoma

·       Sarcoidosis

·       Tuberculosis

·       Amyloidosis

·       Cystinosis

·       Thalassemia

·       Riedel thyroiditis

·       Hemochromatosis

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:

• Tachycardia
• Palpitations
• Atrial fibrillation
• Nervousness
• Tiredness
• Headache
• Increased excitability
• Sleeplessness
• Tremors
• Possible angina

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] :

• If levothyroxine dose requirements are much higher than expected, consider evaluating for gastrointestinal disorders such as  H pylori –related gastritis, atrophic gastritis, or celiac disease; if such disorders are detected and effectively treated, re-evaluation of thyroid function and levothyroxine dosage is recommended
• Initiation or discontinuation of estrogen (or menopause) and androgens should be followed by reassessment of serum TSH at steady state, since such medications may alter levothyroxine requirement
• Serum TSH should be reassessed upon initiation of agents such as tyrosine kinase inhibitors that affect thyroxine metabolism and thyroxine or triiodothyronine deiodination
• Serum TSH monitoring is advisable when medications such as phenobarbital, phenytoin, carbamazepine, rifampin, and sertraline are started
• When deciding on a starting dose of levothyroxine, the patient’s weight, lean body mass, pregnancy status, etiology of hypothyroidism, degree of TSH elevation, age, and general clinical context, including the presence of cardiac disease, should be considered; the serum TSH goal appropriate for the clinical situation should also be considered
• Thyroid hormone therapy should be initiated as an initial full replacement or as partial replacement with gradual increments in the dose titrated upward using serum TSH as the goal
• Dose adjustments should be made upon significant changes in body weight, with aging, and with pregnancy; TSH assessment should be performed 4-6 weeks after any dosage change
• Reference ranges of serum TSH levels are higher in older populations (eg, >65 years), so higher serum TSH targets may be appropriate; per the American Thyroid Association (ATA), target serum TSH may be raised to 4-6 mIU/L in patients aged 70-80 years

A meta-analysis of randomized, controlled trials of T4-triiodothyronine (T3) combination therapy versus T4 monotherapy for treatment of clinical hypothyroidism found no difference in effectiveness between combination therapy and monotherapy with respect to side effects such as bodily pain, depression, fatigue, body weight, anxiety, quality of life, and total low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglyceride levels.[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 require aggressive management. Overreplacement or aggressive replacement with any thyroid hormone may precipitate tachyarrhythmias or, very rarely, thyroid storm and should be balanced against the need for urgent replacement. Risk is higher with T3 therapy.

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

The updated guidelines on hypothyroidism issued by the ATA in 2014 concerning hypothyroidism treatment in pregnant women are as follows[85, 86] :

• Pregnant women with overt hypothyroidism should receive levothyroxine replacement therapy with the dose titrated to achieve a TSH concentration within the trimester-specific reference range
• Serial serum TSH levels should be assessed every 4 weeks during the first half of pregnancy to adjust levothyroxine dosing to maintain TSH within the trimester-specific range
• Serum TSH should be reassessed during the second half of pregnancy
• In women already taking levothyroxine, two additional doses per week of the current levothyroxine dose, given as one extra dose twice weekly with several days’ separation, may be started as soon as pregnancy is confirmed

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:

• Preeclampsia
• Anemia
• Postpartum hemorrhage
• Cardiac ventricular dysfunction
• Increased risk of spontaneous abortion
• Low birth weight
• Impaired cognitive development in offspring ^[90]
• Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder ^[91]
• Fetal mortality

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 all pregnant and lactating women ingest a minimum of 250 mg iodine daily—optimally, in the form of potassium iodide, to ensure consistent delivery.[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 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.[77]

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] :

·       Subclinical hypothyroidism (TSH 4.2 mIU/L or less): 1.2 µg/kg/day

·       Subclinical hypothyroidism (TSH > 4.2-10 mIU/L): 1.42 µg/kg/day

·       Overt hypothyroidism: 2.33 µg/kg/day

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]

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 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]

Guidelines from the American Association of Clinical Endocrinologists (AACE) recommend treatment in patients with TSH levels higher than 10 mIU/L and in patients with TSH levels of 5-10 mIU/L in conjunction with goiter or positive anti-TPO antibodies; these patients have the highest rates of progression to overt hypothyroidism. An initial LT4 dosage of 50-75 µg/day can be used, which can be titrated every 6-8 weeks to achieve a target TSH of between 0.3 and 3 mIU/L.[83]

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, presence of anti-TPO antibodies, and cardiac risk factors. 

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

• Give 4 µg of LT4 per kilogram of lean body weight (approximately 200-250 µg) as an IV bolus in a single or divided dose, depending on the patient’s risk of cardiac disease and age
• 24 hours later, give 100 µg IV
• Subsequently, give 50 µg/day IV, along with stress doses of IV glucocorticoids
• Adjust the dosage on the basis of clinical and laboratory findings
• Provide antibiotic coverage for sepsis
• Avoid volume contraction

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

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

Advanced age, high-dose T4 therapy, and cardiac complications have the highest associations with mortality in myxedema coma (see Hypothyroidism and Myxedema Coma in Emergency Medicine).[115]

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

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

Subclinical hyperthyroidism is a more common complication of treatment with LT4, 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).[116]

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.[117] 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.[118] 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.[119]

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.

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

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[120] :

• Walnuts
• Soybean flour
• Cottonseed meal
• Iron supplements or iron-containing multivitamins
• Calcium supplements

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).

Indications for referral to an endocrinologist include any of the following[3] :

·       A nodular thyroid, suspicious thyroid nodules, or compressive symptoms (eg, dysphagia)

·       Pregnancy (or planned pregnancy)

·       Underlying cardiac disorders or other endocrine disorders

·       Age younger than 18 years

·       Secondary or tertiary hypothyroidism

·       Unusual constellation of thyroid function test results

·       Inability to maintain TSH in the target range

·       Unresponsiveness to treatment

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.

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.

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[121] :

·       The diagnosis of CeH should be considered in every patient in whom low serum concentrations of free thyroxine (T4) and low or normal thyroid-stimulating hormone (TSH) levels have been found on a screening examination

·       The diagnosis of CeH should be considered in neonates and children with clinical manifestations of congenital hypothyroidism but low or normal neonatal TSH screening results

·       Screening for CeH should be performed in all children with a familial history of CeH and/or manifestations of hypothalamic-pituitary defects or lesions, such as failure to thrive, developmental delay, growth hormone (GH) deficiency, and delayed or precocious puberty

·       CeH due to IGSF1 defect should be ruled out in adolescents or adult patients with macroorchidism

·       Screening for CeH should be carried out in all patients with a personal or familial history of hypothalamic-pituitary lesions or diseases, moderate to severe head trauma, stroke, previous cranial irradiation, hemochromatosis, or iron overload, particularly when hypothyroid manifestations are present

·       CeH screening should be performed in all patients with hypothyroid manifestations associated with clinical findings pointing to a hypothalamic-pituitary disease (eg, hyperprolactinemia, acromegalic features, diabetes insipidus, recurrent headaches, visual field defects) and in children with developmental delay; screening should also be carried out in newborns with hypotonia and/or prolonged jaundice and/or signs of congenital hypopituitarism (eg, micropenis with undescended testes)

·       The possibility of CeH development should be ruled out in patients with hypothalamic-pituitary disease after the commencement of recombinant human GH (rhGH) or estrogen replacement therapy

·       Patients should be evaluated for the presence of CeH via the assessment of serum free T4 and TSH levels

·       CeH diagnosis should be confirmed by the combined findings of serum free T4 concentrations below the lower limit of the normal range and inappropriately low/normal TSH concentrations on at least two separate determinations, as well as after exclusion of the following: nonthyroidal illness, isolated maternal hypothyroxinemia, levothyroxine (LT4) withdrawal syndrome, recovery from thyrotoxicosis, technical assay problems or interference, defects in T4-binding globulin, use of drugs that reduce TSH secretion, premature birth, Allan-Herndon-Dudley syndrome, THRA mutations, and TSHβ mutations

·       When causative mutations in candidate genes are found, genetic analyses should be extended to all first-degree relatives for (early) CeH diagnosis or to uncover carrier status

·       LT4 is recommended as first-line treatment for CeH

·       In CeH patients, replacement therapy with LT4 should commence only after evidence of conserved cortisol secretion has been obtained; if coexistent central adrenal insufficiency has not been ruled out, thyroid replacement must be started after steroid therapy in order to prevent the possible induction of an adrenal crisis

·       In congenital and severe forms of CeH (eg, TSHβ mutations), LT4 treatment should be started as soon as possible (optimally within 2 weeks after birth) at doses used also for primary congenital hypothyroidism (10-12 μg/kg body weight per day), in order to rapidly rescue serum free T4 levels to normal range and secure optimal neurodevelopment as quickly as possible

·       In patients with CeH, concomitant free T4 and TSH measurements should be used to check the adequacy of replacement therapy 6-8 weeks after the start of LT4 replacement, provided that blood is withdrawn before the morning replacement dose or at least 4 hours after LT4 administration; replacement therapy should be aimed at maintaining the free T4 level above the median value of the normal range

·       Once adequate thyroid replacement is achieved, pediatric patients with CeH should undergo monitoring of free T4 concentrations according to the age-related reference ranges, and follow-up should be conducted in the same way as in patients with primary hypothyroidism

·       Once adequate thyroid replacement is achieved, adult patients with CeH should undergo annual monitoring of free T4

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

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.

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

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

Liothyronine (Cytomel, Triostat)

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

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

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

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

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.