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. In tertiary hypothyroidism, inadequate secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus leads to insufficient release of TSH, which in turn causes inadequate thyroid stimulation. Worldwide, iodine deficiency remains the foremost cause of hypothyroidism. In the United States and other areas of adequate iodine intake, autoimmune thyroid disease (Hashimoto disease) is the most common cause. Hypothyroidism may also be drug-induced or otherwise iatrogenic. (See Etiology.) The patient’s presentation may vary from asymptomatic to myxedema coma with multisystem organ failure. Because nearly all metabolically active cells require thyroid hormone, deficiency of the hormone has a wide range of effects. Classic signs and symptoms, such as cold intolerance, puffiness, decreased sweating, and coarse skin, may not be present, especially in younger patients. (See Presentation.) Third-generation TSH assays are readily available and are generally the most sensitive screening tool for primary hypothyroidism. The generally accepted reference range for normal serum TSH is 0.40-4.2 mIU/L. If TSH levels are above the reference range, the next step would be to measure free thyroxine (T4). Subclinical hypothyroidism, also referred to as mild hypothyroidism, is defined as normal serum levels of free T4 and triiodothyronine (T3) with a slightly high serum TSH concentration. (See Workup.) For hypothyroidism, thyroid hormone is administered to supplement or replace endogenous production. In general, hypothyroidism can be adequately treated with a constant daily dose of levothyroxine (LT4). (See Treatment and Medication.) Congenital hypothyroidism, which affects 1 of every 4000 newborns, is due to congenital maldevelopment of the thyroid (see Pediatric Hypothyroidism). This disorder is included in the newborn screening panel in the United States and many other countries, and it is readily treatable once detected. Cretinism refers to severe hypothyroidism in an infant or child. This is classically the result of maternal iodine deficiency, and thankfully is increasingly rare.

The hypothalamic-pituitary-thyroid axis governs thyroid hormone secretion (see the image below). Although hypothalamic or pituitary disorders can affect thyroid function, localized disease of the thyroid gland that results in decreased thyroid hormone production is the most common cause of hypothyroidism. Under normal circumstances, the thyroid releases 100-125 nmol of T4 daily and only small amounts of T3. The half-life of T4 is approximately 7-10 days. T4, a prohormone, is converted to T3, the active form of thyroid hormone, in the peripheral tissues by 5’-deiodination. Early in the disease process, compensatory mechanisms maintain T3 levels. Decreased production of T4 causes an increase in the secretion of TSH by the pituitary gland. TSH stimulates hypertrophy and hyperplasia of the thyroid gland and 5’-deiodinase activity, thereby increasing T3 production. Deficiency of thyroid hormone has a wide range of effects. Systemic effects are the result of either derangements in metabolic processes or direct effects by myxedematous infiltration (ie, accumulation of glucosaminoglycans in the tissues). The hypothyroid changes in the heart result in decreased contractility, cardiac enlargement, pericardial effusion, decreased pulse, and decreased cardiac output. In the gastrointestinal (GI) tract, achlorhydria and prolonged intestinal transit time with gastric stasis can occur. 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.

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

Primary hypothyroidism

Types of primary hypothyroidism include the following:

• Chronic lymphocytic (autoimmune) thyroiditis
• Postpartum thyroiditis
• Subacute (granulomatous) thyroiditis
• Drug-induced hypothyroidism
• Iatrogenic 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. Postpartum thyroiditis Up to 10% of postpartum women may develop lymphocytic thyroiditis (postpartum thyroiditis) in the 2-12 months after delivery. The frequency may be as high as 25% in women with type 1 diabetes mellitus. Although a short course of treatment with levothyroxine (LT4) may be necessary, the condition is usually transient (2-4 months). However, patients with postpartum thyroiditis (anti-TPO–positive) are at increased risk of permanent hypothyroidism or recurrence of postpartum thyroiditis with future pregnancies. The hypothyroid state can be preceded by a short thyrotoxic state. High titers of anti-TPO antibodies during pregnancy have been reported to have high sensitive and specificity for postpartum autoimmune thyroid disease. In a 12-year longitudinal study, Stuckey et al found that hypothyroidism developed in 27 of 71 women (38%) who had a past history of postpartum thyroid dysfunction (PPTD). In comparison, only 14 of 338 women (4%) who had not had PPTD developed hypothyroidism. ^[7] Subacute granulomatous thyroiditis Also known as de Quervain disease, subacute granulomatous thyroiditis is a relatively uncommon disease that occurs most frequently in middle-aged women. Disease features include low grade fever, thyroid pain, dysphagia, and elevated erythrocyte sedimentation rate (ESR). The disease is usually self-limited and does not normally result in longstanding thyroid dysfunction. It is important to note that inflammatory conditions or viral syndromes may be associated with transient hyperthyroidism followed by transient hypothyroidism (ie, de Quervain or painful thyroiditis and subacute thyroiditis). Drug-induced and iatrogenic hypothyroidism The following medications reportedly have the potential to cause hypothyroidism:

• Amiodarone
• Interferon alfa
• Thalidomide
• Lithium
• Stavudine
• Oral tyrosine kinase inhibitors – Sunitinib, imatinib ^[8]
• Bexarotene ^[9]
• Perchlorate
• Interleukin (IL)-2
• Ethionamide
• Rifampin
• Phenytoin
• Carbamazepine
• Phenobarbital
• Aminoglutethimide
• Sulfisoxazole
• p -Aminosalicylic acid
• Ipilimumab

Use of radioactive iodine (I-131) for treatment of Graves disease generally results in permanent hypothyroidism within 3-6 months after therapy. The frequency of hypothyroidism after I-131 treatment is much lower in patients with toxic nodular goiters and those with autonomously functioning thyroid nodules. Patients treated with radioiodine should be monitored for clinical and biochemical evidence of hypothyroidism. External neck irradiation (for head and neck neoplasms, breast cancer, or Hodgkin disease) may result in hypothyroidism. Patients who have received these treatments require monitoring of thyroid function. Thyroidectomy of course results in hypothyroidism. Patients who undergo a thyroid lobectomy, with or without isthmectomy, have an approximately 15-30% chance of developing thyroid insufficiency.

Genetics

Genome-wide association studies have suggested that a single-nucleotide polymorphism located near the FOXE1 gene is associated with risk of developing thyroid disease and that the strongest association is with hypothyroidism. Persons found to have GG at the described location had an odds ratio (OR) of 1.35 for development of hypothyroidism, whereas persons found to have AG at the location had an OR of 1.00, and persons found to have AA at the location had an OR of 0.74. ^[10] Approximately 10% of patients with congenital hypothyroidism have an error in thyroid hormone synthesis. ^[11] Mutations in the TPO gene appear to be the most common error of hormone synthesis, causing failure to produce adequate amounts of TPO. ^[12] Mutations in the TSHR and PAX8 genes are known to cause congenital hypothyroidism without goiter. ^{[13, 14]} 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. ^[15] Autoimmune polyendocrinopathy type I is caused by a mutation in the AIREgene 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. ^[16] Autoimmune polyendocrinopathy type 2 (Schmidt syndrome) is associated with adrenal insufficiency and hypothyroidism.

Iodine deficiency or excess

Worldwide, iodine deficiency is the most common cause of hypothyroidism. Excess iodine, as in radiocontrast dyes, amiodarone, health tonics (herbal and dietary supplements), and seaweed, can transiently inhibit iodide organification and thyroid hormone synthesis (the Wolff-Chiakoff effect). Most healthy individuals have a physiologic escape from this effect. In patients with iodine overload, the sodium-iodide symporter shuts down, and this allows intracellular iodine levels to drop and hormone secretion to resume. The Wolff-Chiakoff effect is short-lived because the sodium-iodide symporter is capable of rapidly downregulation. However, exposure to excess iodine can produce more profound and sustained hypothyroidism in individuals with abnormal thyroid glands (eg, from autoimmune thyroiditis, subtotal thyroidectomy, or prior radioiodine therapy). ^[17]

Central hypothyroidism

Central hypothyroidism (secondary or tertiary) results when the hypothalamic-pituitary axis is damaged. The following potential causes should be considered ^{[18, 19]} :

• Pituitary adenoma
• Tumors impinging on the hypothalamus
• Lymphocytic hypophysitis
• Sheehan syndrome
• History of brain or pituitary irradiation
• Drugs (eg, dopamine, prednisone, or opioids)
• Congenital nongoiterous 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 nongoiterous hypothyroidism type 4 is caused by a mutation in the TSHB gene and is inherited in an autosomal recessive pattern. Patients have hypothyroidism and a low TSH level that does not rise with administration of TRH. Many patients with this condition were the products of consanguineous unions. ^[20] TRH resistance is caused by a mutation in the TRHR gene and is inherited in an autosomal recessive manner. Patients with this condition have hypothyroidism and, unsurprisingly, have insensitivity to thyrotropin secretion. ^[21] That only a handful of cases of TRH resistance have been reported in the literature suggests that this is a rare condition. TRH deficiency is caused by mutation in the TRH gene and is inherited in an autosomal recessive manner. ^[22] The index case was a girl evaluated for short stature who was found to have an isolated deficiency of TRH. ^[23]

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. ^[24]Hypothyroidism is more common in women with small body size at birth and low body mass index during childhood. ^[25] 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. ^[26] 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. ^[24]

Sex-related demographics

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

Race-related demographics

NHANES 1999-2002 reported that the prevalence of hypothyroidism (including the subclinical form) was higher in whites (5.1%) and Mexican Americans than in African Americans (1.7%). African Americans tend to have lower median TSH values. ^[24]

Undertreatment of hypothyroidism leads to disease progression, with gradual worsening of symptoms and further metabolic derangements. Ultimately, untreated hypothyroidism can cause profound coma or even death. Untreated hypothyroidism in infants can cause irreversible mental retardation. In most patients, fortunately, thyroid hormone treatment reverses the signs and symptoms of hypothyroidism. With treatment, other secondarily affected laboratory values (eg, circulating lipid levels and elevated prolactin levels) should improve. Using disease-specific (ThyPRO questionnaire) and generic (36-item Short Form Health Survey [SF-36]) measures of health-related quality of life (HRQL), Winther et al discovered that levothyroxine treatment resulted in improvement in some, but not all, aspects of HRQL in patients with hypothyroidism resulting from autoimmune thyroiditis. This included significant improvements in nine of 13 ThyPRO scales after 6 weeks of therapy. ^[27]

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. ^[28] 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.