Hypothyroidism

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Neurologic manifestations of myxoedema includeAtrophy of the optic nerveCTSCerebellar symptomsLoss of vibration sense in the legsHyperacusis and tinnitus

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Which of the following is not a common physical sign of hypothyroidism?Your Peers Chose:Ascites31%Bradycardia7%Slowed speech and movements6%Jaundice57%

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Physical signs of hypothyroidism include:Weight gainSlowed speech and movementsDry skinJaundicePallorCoarse, brittle, straw-like hairLoss of scalp hair, axillary hair, pubic hair, or a combinationDull facial expressionCoarse facial featuresPeriorbital puffinessMacroglossiaGoiter (simple or nodular)HoarsenessDecreased systolic blood pressure and increased diastolic blood pressureBradycardiaPericardial effusionAbdominal distention, ascites (uncommon)Hypothermia (only in severe hypothyroid states)Nonpitting edema (myxedema)Pitting edema of lower extremitiesHyporeflexia with delayed relaxation, ataxia, or bothFor more on the signs and symptoms of hypothyroidism, read here.Myxedema coma is a severe form of hypothyroidism that most commonly occurs in which of the following?Male patients with hypothyroidism and excessive weight gainFemale patients with galactorrhea and menstrual disturbances secondary to hypothyroidismPatients with hypothyroidism and decreased appetite, sleepiness, hair loss, and dry skinPatients with untreated hypothyroidism who are subjected to an external stress

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Which of the following is generally accepted as the most sensitive screening tool for primary hypothyroidism?Your Peers Chose:Free thyroxine (T4) assay30%Third-generation thyroid-stimulating hormone (TSH) assay64%Anti-thyroid peroxidase (anti-TPO) antibody assay3%Antithyroglobulin (anti-Tg) antibody assay3%

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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.

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In which of the following groups is screening for hypothyroidism recommended?Your Peers Chose:All adults older than 50 years on a routine basis24%Pregnant women, but not until the second trimester6%Asymptomatic adults older than 40 years6%Women older than 50 years who have one or more clinical features of the disease64%

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Screening recommendations from other groups are as follows:The American College of Physicians recommends screening all women older than 50 years who have one or more clinical features of diseaseThe American Academy of Family Physicians recommends screening asymptomatic patients older than 60 yearsThe American Association of Clinical Endocrinologists recommends TSH measurements in all women of childbearing age before pregnancy or during the first trimesterThe US Preventive Services Task Force concludes that the evidence is insufficient to recommend for or against routine screening for thyroid disease in adults (grade I recommendation)

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Which of the following is the initial treatment indicated in most cases of mild to moderate hypothyroidism?Your Peers Chose:Levothyroxine at a dose of 50-75 µg/day86%Levothyroxine at a dose of 4 µg per kilogram of lean body weight as an intravenous bolus, with 100 µg administered 24 hours later5%Desiccated thyroid at a dose of 15-30 mg orally per day4%Liothyronine at a dose of 25 µg orally per day5%

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The treatment goals for hypothyroidism are to reverse clinical progression and correct metabolic derangements, as evidenced by normal blood levels of TSH and 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.Thyroid hormone can be started at anticipated full replacement doses in individuals who are young and otherwise healthy. In elderly patients and those with known ischemic heart disease, treatment should begin with one fourth to one half the expected dose, and the dose 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

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Hypothyroidism is a common endocrine disorder resulting from deficiency of thyroid hormone. In the United States and other areas of adequate iodine intake, autoimmune thyroid disease (Hashimoto disease) is the most common cause of hypothyroidism; worldwide, iodine deficiency remains the foremost cause.The image below depicts the hypothalamic-pituitary-thyroid axis.The hypothalamic-pituitary-thyroid axis. Levels ofThe hypothalamic-pituitary-thyroid axis. Levels of circulating thyroid hormones are regulated by a complex feedback system involving the hypothalamus and pituitary gland.See 21 Hidden Clues to Diagnosing Nutritional Deficiencies, a Critical Images slideshow, to help identify clues to conditions associated with malnutrition.Signs and symptomsHypothyroidism commonly manifests as a slowing in physical and mental activity but may be asymptomatic. Symptoms and signs are often subtle and neither sensitive nor specific.The following are symptoms of hypothyroidism:Fatigue, loss of energy, lethargyWeight gainDecreased appetiteCold intoleranceDry skinHair lossSleepinessMuscle pain, joint pain, weakness in the extremitiesDepressionEmotional lability, mental impairmentForgetfulness, impaired memory, inability to concentrateConstipationMenstrual disturbances, impaired fertilityDecreased perspirationParesthesia and nerve entrapment syndromesBlurred visionDecreased hearingFullness in the throat, hoarsenessThe following are symptoms more specific to Hashimoto thyroiditis:Feeling of fullness in the throatPainless thyroid enlargementExhaustionTransient neck pain, sore throat, or bothPhysical signs of hypothyroidism include the following:Weight gainSlowed speech and movementsDry skinJaundicePallorCoarse, brittle, straw-like hairLoss of scalp hair, axillary hair, pubic hair, or a combinationDull facial expressionCoarse facial featuresPeriorbital puffinessMacroglossiaGoiter (simple or nodular)HoarsenessDecreased systolic blood pressure and increased diastolic blood pressureBradycardiaPericardial effusionAbdominal distention, ascites (uncommon)Hypothermia (only in severe hypothyroid states)Nonpitting edema (myxedema)Pitting edema of lower extremitiesHyporeflexia with delayed relaxation, ataxia, or bothMyxedema coma is a severe form of hypothyroidism that most commonly occurs in individuals with undiagnosed or untreated hypothyroidism who are subjected to an external stress. Features are as follows:Altered mental statusHypothermiaBradycardiaHypercarbiaHyponatremiaCardiomegaly, pericardial effusion, cardiogenic shock, and ascites may be presentSee Clinical Presentation for more detail.DiagnosisThird-generation thyroid-stimulating hormone (TSH) assays are generally the most sensitive screening tool for primary hypothyroidism. [1] If TSH levels are above the reference range, the next step is to measure free thyroxine (T4) or the free thyroxine index (FTI), which serves as a surrogate of the free hormone level. Routine measurement of triiodothyronine (T3) is not recommended.Results in patients with hypothyroidism are as follows:Elevated TSH with decreased T4 or FTIElevated TSH (usually 4.5-10.0 mIU/L) with normal free T4 or FTI is considered mild or subclinical hypothyroidismAbnormalities in the complete blood count and metabolic profile that may be found in patients with hypothyroidism include the following [2] :AnemiaDilutional hyponatremiaHyperlipidemiaReversible increases in creatinine Elevations in transaminases and creatinine kinaseNo universal screening recommendations exist for thyroid disease for adults.

The American Thyroid Association recommends screening at age 35 years and every 5 years thereafter, with closer attention to patients who are at high risk, such as the following [3] :Pregnant womenWomen older than 60 yearsPatients with type 1 diabetes or other autoimmune diseasePatients with a history of neck irradiationMonotherapy with levothyroxine (LT4) remains the treatment of choice for hypothyroidism.

Aspects of LT4 treatment are as follows:Otherwise young and healthy patients can be started on LT4 at anticipated full replacement dosesIn elderly patients and those with known ischemic heart disease, begin with one fourth to one half the expected dose and adjust the dose in small increments after no less than 4-6 weeksFor most cases of mild to moderate hypothyroidism, a starting LT4 dose of 50-75 µg daily will sufficeClinical benefits begin in 3-5 days and level off after 4-6 weeksAchieving a TSH level within the reference range may take several monthsLT4 dosing changes should be made every 6-8 weeks until the patient’s TSH is in target rangeAfter dose stabilization, patients can be monitored with annual clinical evaluations and TSH monitoring. Patients should be monitored for symptoms and signs of overtreatment, which include the following:TachycardiaPalpitationsAtrial fibrillationNervousnessTirednessHeadacheIncreased excitabilitySleeplessnessTremorsPossible anginaIn patients who continue to have symptoms (eg, weight gain, fatigue) despite normalization of their TSH level, consideration should be given to causes other than hypothyroidism. In some cases, however, the persistence of symptoms results from impaired conversion of T4 to T3 in the brain; these patients may benefit from combination LT4/liothyronine (LT3) therapy. [4]The updated guidelines on hypothyroidism issued by the American Thyroid Association in 2014 maintain the recommendation of levothyroxine as the preparation of choice for hypothyroidism, with the following considerations: [5, 6]If levothyroxine dose requirements are much higher than expected, consider evaluating for gastrointestinal disorders such as Helicobacter 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 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.Updated recommendations concerning

.Treatment of myxedema coma is as follows:Intravenous (IV) LT4 at a dose of 4 µg/kg of lean body weight, or approximately 200-250 µg, as a bolus in a single or divided dose, depending on the patient’s risk of cardiac diseaseAfter 24 hours, 100 µg LT4 IV, then 50 µg/day IVStress doses of IV glucocorticoidsSubsequent adjustment of the LT4 dose can be based on clinical and laboratory findingsSee Treatment and Medication for more detail.BackgroundHypothyroidism 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.PathophysiologyThe hypothalamic-pituitary-thyroid axis governs thyroid hormone secretion (see the image below).The hypothalamic-pituitary-thyroid axis. Levels ofThe 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 only small amounts of T3. The half-life of T4 is approximately 7-10 days. T4, a prohormone, is converted to T3, the active form of thyroid hormone, in the peripheral tissues by 5’-deiodination.Early in the disease process, compensatory mechanisms maintain T3 levels. Decreased production of T4 causes an increase in the secretion of TSH by the pituitary gland. TSH stimulates hypertrophy and hyperplasia of the thyroid gland and 5’-deiodinase activity, thereby increasing T3 production.Deficiency of thyroid hormone has a wide range of effects. Systemic effects are the result of either derangements in metabolic processes or direct effects by myxedematous infiltration (ie, accumulation of glucosaminoglycans in the tissues).The hypothyroid changes in the heart result in decreased contractility, cardiac enlargement, pericardial effusion, decreased pulse, and decreased cardiac output. A Swedish study, by Mourtzinis et al, found the rates of hypothyroidism and hyperthyroidism in patients with atrial fibrillation to be 5.9% and 2.3%, respectively, compared with 3.7% and 0.8%, respectively, in controls. [7]In the gastrointestinal (GI) tract, achlorhydria and prolonged intestinal transit time with gastric stasis can occur in hypothyroidism. Delayed puberty, anovulation, menstrual irregularities, and infertility are common. TSH screening should be a routine part of any investigation into menstrual irregularities or infertility.Decreased thyroid hormone effect can cause increased levels of total cholesterol and low-density lipoprotein (LDL) cholesterol and a possible change in high-density lipoprotein (HDL) cholesterol because of a change in metabolic clearance. In addition, hypothyroidism may result in an increase in insulin resistance.EtiologyIn 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 hypothyroidismTypes of primary hypothyroidism include the following:Chronic lymphocytic (autoimmune) thyroiditisPostpartum thyroiditisSubacute (

) thyroiditisDrug-induced hypothyroidismIatrogenic hypothyroidismChronic lymphocytic (autoimmune) thyroiditisThe 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 pp thyroiditisUp 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.

. [9]Subacute granulomatous thyroiditisAlso 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 hypothyroidismThe following medications reportedly have the potential to cause hypothyroidism:AmiodaroneInterferon alfaThalidomideLithiumStavudineOral tyrosine kinase inhibitors – Sunitinib, imatinib [10]Bexarotene [11]PerchlorateInterleukin (IL)-2EthionamideRifampinPhenytoinCarbamazepinePhenobarbitalAminoglutethimideSulfisoxazolep -Aminosalicylic acidIpilimumabUse 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.GeneticsGenome-wide association studies have suggested that a single-nucleotide polymorphism located near the FOXE1 gene is associated with risk of developing thyroid disease and that the strongest association is with hypothyroidism. Persons found to have GG at the described location had an odds ratio (OR) of 1.35 for development of hypothyroidism, whereas persons found to have AG at the location had an OR of 1.00, and persons found to have AA at the location had an OR of 0.74. [12]Approximately 10% of patients with congenital hypothyroidism have an error in thyroid hormone synthesis. [13] Mutations in the TPO gene appear to be the most common error of hormone synthesis, causing failure to produce adequate amounts of TPO. [14]Mutations in the TSHR and PAX8 genes are known to cause congenital hypothyroidism without goiter. [15, 16] Mutations in the TSHR gene can cause hypothyroidism due to insensitivity to TSH, though most cases are notable for a clinically euthyroid state despite abnormal laboratory test results (elevated TSH with normal serum thyroid hormone concentrations). Mutations in the PAX8 gene cause hypothyroidism due to dysgenesis or agenesis of the gland .Syndromic forms of hypothyroidism are also well described. Pendred syndrome is caused by a mutation in the SLC26A4 gene, which causes a defect in the organification of iodine (ie, incorporation into thyroid hormone), congenital sensorineural hearing loss, and, usually, an enlarged thyroid gland. It is inherited

in an autosomal recessive manner. [17]Autoimmune polyendocrinopathy type I is caused by a mutation in the AIRE gene and is characterized by the presence of Addison disease, hypoparathyroidism, and mucocutaneous candidiasis. A subset of patients with this disease also have a high prevalence of autoimmune thyroiditis and hypothyroidism and a novel mutation in the AIRE gene that is inherited in an autosomal dominant fashion. [18] Autoimmune polyendocrinopathy type 2 (Schmidt syndrome) is associated with adrenal insufficiency and hypothyroidism.Iodine deficiency or excessWorldwide, iodine deficiency is the most common cause of hypothyroidism. Excess iodine, as in radiocontrast dyes, amiodarone, health tonics (herbal and dietary supplements), and seaweed, can transiently inhibit iodide organification and thyroid hormone synthesis (the Wolff-Chiakoff effect). Most healthy individuals have a physiologic escape from this effect. In patients with iodine overload, the sodium-iodide symporter shuts down, and this allows intracellular iodine levels to drop and hormone secretion to resume.The Wolff-Chiakoff effect is short-lived because the sodium-iodide symporter is capable of rapidly downregulation. However, exposure to excess iodine can produce more profound and sustained hypothyroidism in individuals with abnormal thyroid glands (eg, from autoimmune thyroiditis, subtotal thyroidectomy, or prior radioiodine therapy). [19]Central hypothyroidismCentral hypothyroidism (secondary or tertiary) results when the hypothalamic-pituitary axis is damaged. The following potential causes should be considered [20, 21] :Pituitary adenomaTumors impinging on the hypothalamusLymphocytic hypophysitisSheehan syndromeHistory of brain or pituitary irradiationDrugs (eg, dopamine, prednisone, or opioids)Congenital nongoiterous hypothyroidism type 4TRH resistanceTRH deficiencyTumors in or around the pituitary cause impaired pituitary function by exerting pressure on normal pituitary cells and thereby affect the secretion of TRH, TSH, or both. Radiation, hypophysitis, and Sheehan syndrome cause death of these cells. Drugs such as dopamine and corticosteroids result in decreased TSH secretion.Congenital nongoiterous hypothyroidism type 4 is caused by a mutation in the TSHB gene and is inherited in an autosomal recessive pattern. Patients have hypothyroidism and a low TSH level that does not rise with administration of TRH. Many patients with this condition were the products of consanguineous unions. [22]TRH resistance is caused by a mutation in the TRHR gene and is inherited in an autosomal recessive manner. Patients with this condition have hypothyroidism and, unsurprisingly, have insensitivity to thyrotropin secretion. [23] That only a handful of cases of TRH resistance have been reported in the literature suggests that this is a rare condition.TRH deficiency is caused by mutation in the TRH gene and is inherited in an autosomal recessive manner. [24] The index case was a girl evaluated for short stature who was found to have an isolated deficiency of TRH. [25]EpidemiologyThe National Health and Nutrition Examination Survey (NHANES 1999-2002) of 4392 individuals reflecting the US population reported hypothyroidism (defined as TSH levels exceeding 4.5 mIU/L) in 3.7% of the population. [26] Hypothyroidism is more common in women with small body size at birth and low body mass index during childhood. [27]Iodine deficiency as a cause of hypothyroidism is more common in less-developed countries. Routine supplementation of salt, flour, and other food staples with iodine has decreased the rates of iodine deficiency.World Health Organization (WHO) data from 130 countries taken from January 1994 through December 2006 found inadequate iodine nutrition in 30.6% of the population. The WHO recommends urinary iodine concentrations between 100 and 199 μg/L in the general population and a range of 150-249 μg/L in pregnant women. In developed countries, death caused by hypothyroidism is uncommon.Age-related demographicsThe frequency of hypothyroidism, goiters, and thyroid nodules increases with age. Hypothyroidism is most prevalent in elderly populations, with 2-20% of older age groups having some form of hypothyroidism. The Framingham study found hypothyroidism (TSH > 10 mIU/L) in 5.9% of women and 2.4% of men older than 60 years. [28] In NHANES 1999-2002, the odds of having hypothyroidism were 5 times greater in persons aged 80 years and older than in individuals aged 12-49 years. [26]Sex-related demographicsCommunity 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 demographicsNHANES 1999-2002 reported that the prevalence of hypothyroidism (including the subclinical form) was higher in whites (5.1%) and Mexican Americans than in African Americans (1.7%). African Americans tend to have lower median TSH values. [26]PrognosisUndertreatment of hypothyroidism leads to disease progression, with gradual worsening of symptoms and further metabolic derangements. Ultimately, untreated hypothyroidism can cause profound coma or even death. Untreated hypothyroidism in infants can cause irreversible mental retardation.In most patients, fortunately, thyroid hormone treatment reverses the signs and symptoms of hypothyroidism. With treatment, other secondarily affected laboratory values (eg, circulating lipid levels and elevated prolactin levels) should improve.Using disease-specific (ThyPRO questionnaire) and generic (36-item Short Form Health Survey [SF-36]) measures of health-related quality of life (HRQL), Winther et al discovered that levothyroxine treatment resulted in improvement in some, but not all, aspects of HRQL in patients with hypothyroidism resulting from autoimmune thyroiditis. This included significant improvements in nine of 13 ThyPRO scales after 6 weeks of therapy. [29]A study by Chang et al suggested that subclinical and overt hypothyroidism are linked to reduced renal function, with subclinical hypothyroidism raising the risk of chronic kidney disease (estimated glomerular filtration rate of below 60 mL/min/1.73m2) by 2.03-fold, and overt hypothyroidism increasing the risk by 7.68-fold. The increased risk remained significant even after other potential risk factors for chronic kidney disease were taken into account. The study also indicated, however, that subclinical and overt hypothyroidism have a lesser effect on proteinuria risk. [30]A study by Sato et al suggested that in patients with heart failure, those with subclinical hypothyroidism have a worse prognosis, finding a significant increase in the rates of cardiac events and all-cause mortality in heart failure patients in the study with subclinical hypothyroidism compared with those who were euthyroid. [31]Patient EducationEmphasize proper compliance at each visit. Clearly discuss the lifelong nature of hypothyroidism, the need for lifelong levothyroxine therapy, the proper way to take medicine, and the need for TSH testing at least annually.Patients should take thyroid hormone as a single daily dose. Thyroid hormone is better absorbed in the small bowel; therefore, absorption can be affected by malabsorptive states, small bowel disease (eg, celiac sprue), and the patient’s age. Many drugs (eg, iron, calcium carbonate, calcium acetate aluminum hydroxide, sucralfate, raloxifene, and proton pump inhibitors) can interfere with absorption and therefore should not be taken within 2-4 hours of LT4 administration. [32]Estrogen/progestin oral contraceptives and pregnancy are associated with changes in thyroid-binding globulin. These changes may impact thyroid hormone dosing.

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T EssentialsHashimoto thyroiditis is part of the spectrum of autoimmune thyroid diseases (AITDs) and is characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune processes. This condition is the most common cause of hypothyroidism in the United States in individuals older than 6 years. [24]Signs and symptomsHypothyroidism typically has an insidious onset with subtle signs and symptoms that may progress to more advanced or even florid signs and symptoms over months to years. The presentation of patients with hypothyroidism may also be subclinical, diagnosed based on routine screening of thyroid function. Such patients may have nonspecific symptoms that are difficult to attribute to thyroid dysfunction. They frequently do not improve with thyroid hormone supplementation..Early nonspecific symptoms may include the following:FatigueConstipationDry skinWeight gainMore advanced/florid symptoms may include the following:Cold intoleranceVoice hoarseness and pressure symptoms in the neck from thyroid enlargementSlowed movement and loss of energyDecreased sweatingMild nerve deafnessPeripheral neuropathyGalactorrheaDepression, dementia, and other psychiatric disturbancesMemory lossJoint pains and muscle crampsHair lossMenstrual irregularitiesSleep apnea and daytime somnolenceSee Autoimmune Disorders: Making Sense of Nonspecific Symptoms, a Critical Images slideshow, to help identify several diseases that can cause a variety of nonspecific symptoms.See Clinical Presentation for more detail.DiagnosisPhysical findings are variable and depend on the extent of the hypothyroidism and other factors, such as age. Examination findings may include the following:Puffy face and periorbital edema typical of hypothyroid faciesCold, dry skin, which may be rough and scalyPeripheral edema of hands and feet, typically nonpittingThickened and brittle nails (may appear ridged)BradycardiaElevated blood pressure (typically diastolic hypertension)Diminished deep tendon reflexes and the classic prolonged relaxation phaseMacroglossiaSlow speechAtaxiaTestingLaboratory studies and potential results for patients with suspected Hashimoto thyroiditis include the following:Serum thyroid-stimulating hormone (TSH) levels: Sensitive test of thyroid function; levels are invariably raised in hypothyroidism due to Hashimoto thyroiditis and in primary hypothyroidism from any causeFree T4 levels: Needed to correctly interpret the TSH in some clinical settings; low total T4 or free T4 level in the presence of an elevated TSH level further confirms diagnosis of primary hypothyroidismT3 levels: Low T3 level and high reverse T3 level may aid in the diagnosis of nonthyroidal illnessThyroid autoantibodies: Presence of typically anti-TPO (anti-thyroid peroxidase) and anti-Tg (anti-thyroglobulin) antibodies delineates the cause of hypothyroidism as Hashimoto thyroiditis or its variant; however, 10-15% of patients with Hashimoto thyroiditis may be antibody negativeThe following tests are not necessary for the diagnosis of primary hypothyroidism but may be used to evaluate complications of hypothyroidism in some patients, as indicated:Complete blood count: Anemia in 30-40% of patients with hypothyroidismTotal and fractionated lipid profile: Possibly elevated total cholesterol, LDL, and triglyceride levels in hypothyroidismBasic metabolic panel: Decreased glomerular filtration rate, renal plasma flow, and renal free water clearance in hypothyroidism; may result in hyponatremiaCreatine kinase levels: Frequently elevated in severe hypothyroidismProlactin levels: May be elevated in primary hypothyroidismImaging testsFeatures of Hashimoto thyroiditis are usually identifiable on an ultrasonogram; however, a thyroid ultrasonogram is usually not necessary for diagnosing the condition. This imaging modality is useful for assessing thyroid size, echotexture, and, most importantly, whether thyroid nodules are present.Chest radiography and echocardiography are not usually performed and are not necessary in routine diagnosis or evaluation of hypothyroid patients.ProceduresHashimoto thyroiditis is a histologic diagnosis. Therefore, perform fine-needle aspiration of any dominant or suspicious thyroid nodules to exclude malignancy or the presence of a thyroid lymphoma in fast-growing goiters. [1]See Workup for more detail.ManagementPharmacotherapyThe treatment of choice for Hashimoto thyroiditis (or hypothyroidism from any cause) is thyroid hormone replacement. The drug of choice is individually tailored and titrated levothyroxine sodium administered orally, usually for life.SurgeryIndications for surgery include the following:A large goiter with obstructive symptoms, such as dysphagia, voice hoarseness, and stridor, caused by extrinsic obstruction of airflowPresence of a malignant nodule, as demonstrated by cytologic examinationPresence of a lymphoma diagnosed on fine-needle aspirationCosmetic reasons (eg, large, unsightly goiters)See Treatment and Medication for more detail.BackgroundHashimoto thyroiditis (or Hashimoto’s thyroiditis) is characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune processes. It is the most common cause of hypothyroidism in the United States after age 6 years. Hashimoto thyroiditis is part of the spectrum of autoimmune thyroid diseases (AITDs). [24] (See Etiology, Presentation, and Workup.)By strict criteria, Hashimoto thyroiditis is a histologic diagnosis first described by Hakaru Hashimoto, a Japanese surgeon working in Berlin, Germany. His report, published in 1912, was based on the examination of 4 postoperative cases. He is also credited with introducing the term struma lymphomatosa in reference to the syndrome.Other variants of AITD include the following conditions:Atrophic thyroiditisJuvenile thyroiditis [2]Postpartum thyroiditisSilent thyroiditisFocal thyroiditisEtiologyThe initiating process in Hashimoto thyroiditis is not well understood. [3, 4, 5, 6] The thyroid gland is typically goitrous but may be atrophic or normal in size. Antibodies binding to and blocking the thyroid-stimulating hormone (TSH) receptor, thyrotropin receptor blocking antibodies (TBII) have also been described and may contribute to impairment in thyroid function. The result is inadequate thyroid hormone production and secretion, although initially, preformed thyroxine (T4) and triiodothyronine (T3) may "leak" into the circulation from damaged cells.Patients with Hashimoto thyroiditis have antibodies to various thyroid antigens, the most frequently detected of which include anti-thyroid peroxidase (anti-TPO), antithyroglobulin (anti-Tg), and to a lesser extent, TSH receptor-blocking antibodies (TBII). Nevertheless, a small percentage of patients with Hashimoto thyroiditis (approximately 10-15%) may be serum antibody negative.Other antithyroid antibodies found in AITD (including Hashimoto thyroiditis) include thyroid-stimulating antibody and cytotoxic antibody.Hashimoto thyroiditis has a markedly higher clustering of other autoimmune diseases, including pernicious anemia, adrenal insufficiency, celiac disease, and type 1 diabetes mellitus. [7, 8] A study by Ruggeri et al of patients with Hashimoto thyroiditis indicated that the disease is associated with different nonthyroidal autoimmune diseases (NTADs) at different ages. Associated NTADs were significantly more prevalent in adults than children/adolescents in the study, and more adults than children/adolescents suffered from two or more associated NTADs, with the frequency of arthropathies and connective tissue diseases being greater in adults and the frequency of type 1 diabetes and celiac disease being higher in children/adolescents. [9]A study by Mazokopakis et al indicated that an association may exist between vitamin D deficiency and the development of Hashimoto thyroiditis. The study, which included 218 patients with Hashimoto thyroiditis, found serum 25-hydroxy vitamin D levels to be negatively correlated with anti-TPO levels in all patients, with the anti-TPO levels being significantly greater in the 186 patients who were vitamin D deficient. After receiving oral vitamin D3 supplementation of 1200-4000 IU daily for 4 months, serum anti-TPO levels in the vitamin D deficient patients were determined to be significantly reduced. [10, 27]In a study of 830 patients with Hashimoto thyroiditis, Tagami et al reported slight, but significant, increases in TSH serum levels and decreases in free T4 serum levels, with increasing patient age. In addition, TSH levels were positively correlated with levels of total cholesterol, triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and non-HDL, as well as with the ratio of LDL to HDL. Free T4 levels, on the other hand, were negatively correlated with these lipid parameters. [11]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 the disease. [12]EpidemiologyOccurrence in the United StatesHashimoto thyroiditis is the most common cause of hypothyroidism in the United States after age 6 years, with the incidence estimated to be 1.3% in a series of 5000 children aged 11-18 years. In adults, the incidence is estimated to be 3.5 per 1000 per year in women and 0.8 per 1000 per year in men. Incidence may be as high as 6% in the Appalachian region.In the Colorado Thyroid Disease Prevalence Study, involving 25,862 adults, the prevalence of elevated TSH in symptomatic and asymptomatic adults was 9.5%, with a greater percentage of those involved being women. The prevalence of hypothyroidism and of thyroid disease in general increases with age.International occurrenceWorldwide, the most common cause of hypothyroidism is iodine deficiency. However, Hashimoto thyroiditis remains the most common cause of spontaneous hypothyroidism in areas of adequate iodine intake. The annual incidence of Hashimoto thyroiditis worldwide is estimated to be 0.3-1.5 cases per 1000 persons. [13, 14, 27]Sex- and age-related demographicsThe incidence of Hashimoto thyroiditis is estimated to be 10-15 times higher in females. The most commonly affected age range in Hashimoto thyroiditis is 30-50 years, with the peak incidence in men occurring 10-15 years later. The overall incidence of hypothyroidism increases with age in men and women.PrognosisWith early diagnosis, timely institution of levothyroxine replacement therapy, informed patient follow-up care, and attention to other attendant complications, the prognosis in Hashimoto thyroiditis is excellent, with patients leading a normal life. Untreated myxedema coma has a poor prognosis and a high mortality rate.Morbidity related to Hashimoto thyroiditis typically results from failure to make the diagnosis of hypothyroidism or to institute L-thyroxine replacement therapy in adequate doses, or from failure on the part of the patient to take the replacement medication.The increased prevalence of lipid disorders in association with untreated hypothyroidism has the potential to increase morbidity from coronary artery disease.The risk for papillary thyroid carcinoma is increased in patients with Hashimoto thyroiditis. [15, 29, 30] These cancers are not clearly more aggressive than other papillary thyroid carcinomas. In fact, a study by Liang et al suggested that in patients with papillary thyroid carcinoma, those with concurrent Hashimoto thyroiditis have a better prognosis than do patients without it. Subjects with both papillary thyroid carcinoma and Hashimoto thyroiditis tended to have a smaller tumor size, a less advanced TNM stage, and a decreased lymph node metastasis rate. [25]A study by Kahaly et al indicated that a strong link exists between the presence of TSH receptor-stimulating antibodies (TSAbs) in patients with Hashimoto thyroiditis and the development of thyroid-associated orbitopathy (TAO). The study, which included 700 patients with Hashimoto thyroiditis, found higher serum levels of TSAbs in those with TAO than in those without this condition, while patients with active and severe TAO had higher TSAb levels than did patients with mild and inactive TAO. Healthy controls were negative for TSAbs. [16]Therapeutic complicationsComplications of overreplacement with levothyroxine sodium Include the following:Accelerated bone lossReduction in bone mineral densityOsteoporosisIncreased heart rateIncreased cardiac wall thicknessIncreased contractilityThe last three problems above increase the risk of cardiac arrhythmias (especially atrial fibrillation), particularly in the elderly population.Patient EducationPatients should know that thyroid replacement therapy in Hashimoto thyroiditis is, except in very rare cases, lifelong. Patients must be informed about the importance of compliance with their replacement therapy and must be instructed to report any symptoms suggestive of hyperthyroidism caused by overreplacement.Patients must be instructed to separate—by at least 4 hours—ingestion of levothyroxine from ingestion of cholestyramine, ferrous sulfate, sucralfate, calcium carbonate, aluminum hydroxide (and other antacids), and iron-containing multivitamins, all of which impair the absorption of levothyroxine.