What is hypothyroidism?

Hypothyroidism (underactivity of the thyroid gland) occurs when the thyroid gland produces less than the normal amount of thyroid hormone. The result is the slowing down of many bodily functions. Although hypothyroidism may be temporary, it usually is a permanent condition. Of the nearly 25 million people suffering from a thyroid condition, most have hypothyroidism. What are the features of hypothyroidism? In its earliest stage, hypothyroidism may cause few symptoms, since the body has the ability to partially compensate for a failing thyroid gland by increasing the stimulation to it, much like pressing down on the accelerator when climbing a hill to keep the car going the same speed. As thyroid hormone production decreases and the bodys metabolism slows, a variety of features may result. Pervasive fatigue Drowsiness Forgetfulness Difficulty with learning Dry, brittle hair and nails Dry, itchy skin Puffy face Constipation Sore muscles Weight gain and fluid retention Heavy and/or irregular menstrual flow Increased frequency of miscarriages Increased sensitivity to many medications What are the major causes of hypothyroidism? AU TO IMMU N E THY RO I D I T I S (Hashimotos thyroiditisseparate brochure available) The bodys immune system may produce a reaction in the thyroid gland that results in hypothyroidism and, most often, a goiter (enlargement of the thyroid). Other autoimmune diseases may be associated with this disorder, and additional family members may also be affected. R A D I OA C T I V E I O D I N E T R E ATME N T Hypothyroidism frequently develops as a desired therapeutic goal after the use of radioactive iodine treatment for hyperthyroidism. THY RO I D O P E R AT I O N Hypothyroidism may be related to surgery on the thyroid gland, especially if most of the thyroid has been removed. ME D I C AT I O N S Lithium, high doses of iodine, and amiodarone (Cordarone, Pacerone) can cause hypothyroidism.

S U B A C U T E THY RO I D I T I S This condition may follow a viral infection and is characterized by painful thyroid gland enlargement and inflammation, which results in the release of large amounts of thyroid hormone into the blood. Fortunately, this condition usually resolves spontaneously. The thyroid usually heals itself over several months, but often not before a temporary period of hypothyroidism occurs. P O S T PA RT UM THY RO I D I T I S Five percent to ten percent of women develop mild to moderate hyperthyroidism within several months of giving birth. Hyperthyroidism in this condition usually lasts for approximately one to two months. It is often followed by several months of hypothyroidism, but most women will eventually recover normal thyroid function. In some cases, however, the thyroid gland does not heal, so the hypothyroidism becomes permanent and requires lifelong thyroid hormone replacement. This condition may occur again with subsequent pregnancies. S I L E N T THY RO I D I T I S Transient (temporary) hyperthyroidism can be caused by silent thyroiditis, a condition which appears to be the same as postpartum thyroiditis but not related to pregnancy. It is not accompanied by a painful thyroid gland. CONGENITAL HYPOTHYROIDISM An infant may be born with an inadequate amount of thyroid tissue or an enzyme defect that does not allow normal thyroid hormone production. If this condition is not treated promptly, physical stunting and/or mental damage (cretinism) may develop. P I T U I TA RY HY P OTHY RO I D I SM TSH is produced by the pituitary gland, which is located behind the nose at the base of the brain. Any destructive disease of the pituitary gland may cause damage to the cells that secrete Thyroid-Stimulating Hormone hypothyroidism YOUR THYROID A KEY TO GOOD HEALTH Powe r of P r e v e n t ion (TSH), which stimulates the thyroid to produce normal amounts of thyroid hormone. This is a very rare cause of hypothyroidism. How is hypothyroidism diagnosed? Characteristic symptoms and physical signs, which can be detected by a physician, can signal hypothyroidism. However, the condition may develop so slowly that many patients do not realize that their body has changed, so it is critically important to perform diagnostic laboratory

tests to confirm the diagnosis and to determine the cause of hypothyroidism. T SH ( THY RO I D - S T IMU L AT I N G HO RMO N E O R THY ROT RO P I N ) TEST An increased TSH level in the blood is the most accurate indicator of primary (nonpituitary) hypothyroidism. Production of this pituitary hormone is increased when the thyroid gland even slightly underproduces thyroid hormone. OTHE R T E S T S Estimates of free thyroxine - the active thyroid hormone in the blood. It is important to note that there is a range of free thyroxine levels in the blood of normal people, similar to the range for height, and that a value of free thyroxine that is within normal limits for the general population may not be appropriate for a particular individual. Thyroid autoantibodies - indicates the likelihood of auto-immune thyroiditis being the cause of hypothyroidism. A primary care physician may make the diagnosis of hypothyroidism, but assistance is often needed from an endocrinologist, a physician who is a specialist in thyroid diseases. How is hypothyroidism treated? Hypothyroidism is generally treated with a single daily dose of levothyroxine, given as a tablet. An experienced physician can prescribe the correct form and dosage to return the thyroid balance to normal. Older patients who may have underlying heart disease are usually started at a low dose and gradually increased while younger healthy patients can be started on full replacement doses at once. Thyroid hormone acts very slowly in some parts of the body, so it may take several months after treatment for some features to improve. Since most cases of hypothyroidism are permanent and often progressive, it is usually necessary to treat this condition throughout ones lifetime. Periodic monitoring of TSH levels and clinical status are necessary to ensure that the proper dose is being given, since medication doses may have to be adjusted from time to time. Optimal adjustment of thyroid hormone dosage is critical, since the body is very sensitive to even small changes in thyroid hormone levels. Levothyroxine tablets come in 12 different strengths, and it is essential to take them in a consistent manner every day. A dose of thyroid hormone that is too low may fail to prevent enlargement of the thyroid gland, allow symptoms of hypothyroidism to persist, and be associated with increased serum cholesterol levels,

which may increase the risk for atherosclerosis and heart disease. A dose that is too high can cause symptoms of hyperthyroidism, create excessive strain on the heart, and lead to an increased risk of developing osteoporosis. It is extremely important that women planning to become pregnant are kept well adjusted, since hypothyroidism can affect the development of the baby. During pregnancy, thyroid hormone replacement requirements often change, so more frequent monitoring is necessary. Various medications and supplements (particularly iron) may affect the absorption of thyroid hormone; therefore, the levels may need more frequent monitoring during illness or change in medication. Thyroid hormone is critical for normal brain development in babies. Infants requiring thyroid hormone therapy should NOT be treated with purchased liquid suspensions, since the active hormone may deteriorate once dissolved and the baby could receive less thyroid hormone than necessary. Instead, infants with hypothyroidism should receive their thyroid hormone by crushing a single tablet daily of the correct dose and suspending it in one teaspoon of liquid and administering it properly. Appropriate management of hypothyroidism requires continued care by a physician experienced in the treatment of this condition.

Supplement to The Journal of Family Practice June 2006 S1 Thyroid dysfunction is the one of the most commonly encountered endocrine abnormalities in primary care, with mild hypothyroidism occurring in about 4% to 10% of the US population and in up to 18% of those over age 60; for women in this age group, the prevalence of hypothyroidism may be as high as 20%.1,2 Primary hypothyroidism is a graded disorder, with a wide spectrum of severity between mild and overt disease.3 Because hypothyroidism is associated with several other comorbid disorders and many vague symptoms, the diagnostic workup may include screening tools for a variety of other diseases, such as depression and anxiety, to rule these out as a primary diagnosis. Although hypothyroidism has significant clinical consequences, it is also readily treatable. As in diagnosis, nuances in treatment can present important clinical challenges. This supplement focuses on the clinical consequences and diagnosis of hypothyroidism, including identification of special populations. It also discusses management of hypothyroidism and use of thyroid hormone replacement therapy, particularly levothyroxine (synthetic T4) (Levo-T, Levolet, Levothroid, Levoxyl, Novothyrox, Synthroid,

Practice recommendations Clinical Update Copyright 2006 Dowden Health Media and the Primary Care Education Consortium www.jfponline.com June 2006 Hypothyroidism is a commonly encountered endocrine disorder with serious clinical consequences, but it is readily treatable. (SOR: A) Screening of thyroid function is clearly indicated in persons with signs/symptoms of hypothyroidism. Other possible groups include those with subclinical hypothyroidism, diabetes mellitus, previous thyroid surgery or neck irradiation, the elderly, and others. (SOR: C) Underdosing thyroid replacement puts patients at risk for clinical sequelae of continued hypothyroidism, such as hypercholesterolemia or depression. (SOR: A) Ovedosing thyroid replacement puts patients at risk for clinical sequelae of hyperthyroidism, such as osteoporosis or atrial fibrillation. (SOR: A) Although the FDA has recognized bioequivalent levothyroxine products, the current standards potentially allow for significant differences in the bioavailability of products rated as bioequivalent. (SOR: B) Managing the Challenges of Hypothyroidism Jeffrey R. Garber, MD, FACE James V. Hennessey, MD, FACP Joseph A. Lieberman III, MD, MPH Charlene M. Morris, PA-C, MPAS Robert L. Talbert, PharmD Disclosures: Dr Garber reports that he is a consultant to King Pharmaceuticals and Abbott Laboratories. Dr Hennessey reports that he has received grant or research support from Novartis and Abbott Laboratories, serves as a consultant to Abbott Laboratories, and participates on the speakers bureau for Aventis. Dr Lieberman reports that he serves as a consultant to Abbott Laboratories, Ortho McNeil, Pfizer Inc, Sanofi, and Takeda, and that he serves on the speakers bureau for Takeda. Ms Morris reports that she is a consultant to Abbott Laboratories and is on the speakers bureau for Eli Lilly and Boehringer Ingelheim. Dr Talbert reports that he serves as a consultant to Abbott Laboratories. Jeffrey R. Garber, MD, FACE Chief of Endocrinology Harvard Vanguard Medical Associates Boston, MA James V. Hennessey, MD, FACP Associate Professor of Medicine Brown University School of Medicine Associate Physician, Rhode Island Hospital

Hallet Center for Diabetes and Endocrinology The CORO Center, Providence, RI Joseph A. Lieberman III, MD, MPH Professor of Family Medicine Jefferson Medical College Philadelphia, PA Charlene M. Morris, PA-C, MPAS Staff Physician Assistant Halyburton Hospital Cherry Point, NC Robert L. Talbert, PharmD Professor of Pharmacy Medicine and Pharmacology University of Texas Health Science Center San Antonio, TX This supplement to THE JOURNAL OF FAMILY PRACTICE is supported by a grant from Abbott Laboratories. It was developed by the Primary Care Education Consortium and the Texas Academy of Family Physicians and has been edited and peer-reviewed by THE JOURNAL OF FAMILY PRACTICE. FAMILY PRACTICE THE JOURNAL OF Supplement to S2 June 2006 Supplement to The Journal of Family Practice Unithroid, and generics) and briefly addresses hyperthyroidism resulting from overtreatment of hypothyroidism. Central hypothyroidism, caused by pituitary-based deficiencies of thyrotropin-stimulating hormone or thyrotropinreleasing hormone, will not be discussed. BACKGROUND The pituitary hormone thyrotropin (thyroid-stimulating hormone [TSH]) is responsible for maintaining normal thyroid morphology and for providing the primary stimulus for synthesis and secretion of the thyroid hormones thyroxine (T4) and triiodothyronine (T3).4 An inverse relationship exists between TSH levels and circulating T4 and T3, where high TSH levels typically indicate hypothyroidism and too little thyroid secretion. Thyroid hormone has many critical roles for both homeostasis and growth and development; therefore, an imbalance of thyroid hormone may severely impact patient functioning. The most common cause of permanent hypothyroidism in North America is a chronic autoimmune condition, Hashimotos thyroiditis.5 High titers of antithyroid peroxidase autoantibodies may be present in up to 95% of those with Hashimotos thyroiditis and are helpful in diagnosis.6 Other permanent causes of hypothyroidism include thyroidectomy, radioactive iodine therapy, head or neck irradiation, and congenital

defects. Hypothyroidism may temporarily arise from an inflammation of the thyroid gland, from some medications, or from too much or too little iodine.6 SCREENING Screening in asymptomatic patients is controversial even among expert groups (TABLE 1). The American Academy of Family Physicians recommends routine screening for persons beginning at age 60 years, while some groups recommend beginning screening at an earlier age. Thyroid function tests are clearly indicated for patients who have signs and symptoms indicative of hypothyroidism and are also appropriate for those with subclinical hypothyroidism, since they are at increased risk for progression to overt hypothyroidism; patients with diabetes, previous thyroid surgery or neck radiation, premature gray hair, or pernicious anemia; and the elderly, especially women and those with dementia. Women in the second trimester of pregnancy should be screened for antimicrosomal antibodies since at least 5% of women develop postpartum thyroiditis, 25% of whom develop chronic hypothyroidism requiring lifelong therapy.7 Additionally, any patient with an unexplained laboratory abnormality (eg, hypercholesterolemia, hyponatremia, anemia, hypercalcemia, elevated creatine phosphokinase) likely warrants a serum TSH test. The incremental cost of adding a TSH determination to quintennial cholesterol screening starting at age 35 years has been estimated to be $9200 per quality-adjusted life year for women and $22,600 for men; these figures are comparable to those for screening for breast cancer and hypertension.7 Routine thyroid function screening is not recommended for patients who are hospitalized with acute illness but have no evidence of thyroid dysfunction, since these patients have a high frequency of transient thyroid function abnormalities.7 DIAGNOSIS Signs and symptoms. The presentation and clinical manifestation of hypothyroidism vary widely. Classic clinical signs of hypothyroidism are often subtle and insidious in onset and include fatigue, cold skin, and a general slowing of activity5 (TABLE 2). In addition, comorbid disorders or serum abnormalities are often present and may make accurate diagnosis more difficult. One of the most common is hypercholesterolemia, but others include carpal tunnel-like symptoms of tingling in the hands, menstrual changes, infertility, or arthritis-like aches in and around the joints.6 Patients with subclinical hypothyroidism may be asymptomatic or have nonspecific signs and symptoms such as Managing the Challenges of Hypothyroidism Professional association Summary of TSH screening recommendation American Thyroid Association Age 35 years and every 5 years thereafter (2000)

American Association of Clinical Endocrinologists Older, especially women (2002), pregnancy (1999) American College of Physicians Women >50 years with 1 or more symptoms possibly caused by thyroid disease (1998) US Preventive Services Task Force Insufficient evidence for or against adult routine screening American Academy of Family Physicians Routine screening for patients >60 years (2002) Recommendations for thyroid testing among professional organizations TABLE 1 Supplement to The Journal of Family Practice June 2006 S3 FAMILY PRACTICE THE JOURNAL OF depression, cognitive dysfunction, and weight gain. Use of available screening tools for depression and anxiety may help narrow the diagnosis or identify other underlying causes of the symptoms. Other symptoms may also include abnormalities in cardiac, gastrointestinal, or reproductive function.5,8 The effects of subclinical disease on the cardiovascular system and mental health and its impact during pregnancy are less established than for overt hypothyroidism. Thyroid physical exam. The normal isthmus is several millimeters thick, with a felt-like consistency. Extending from the isthmus upward and either left or right of midline, a pyramidal lobe may be palpable in the presence of generalized thyroid enlargement as seen in Hashimotos thyroiditis or Graves disease and may be mistaken for an isthmus nodule or a pretracheal, delphian lymph node. The physician should examine the patients thyroid lobes for size, texture, consistency, and the presence of nodules or tenderness. The right lobe may be somewhat larger than the left, and each is expected to be about 4 to 5 cm long and 2 to 3 cm wide, approximately the size of the distal phalanx of the patients thumb. The volume of the thyroid gland varies directly with body size, gender, and, to a lesser degree, age. The consistency of normal thyroid tissue is described as rubbery. A spectrum of increasing firmness of thyroid tissue has been described, ranging from the softness associated with Graves disease to the firmness of colloid goiter and early Hashimotos thyroiditis. The physician should note the size, location, and consistency of nodular lesions palpated in the course of the thyroid exam. When an apparent solitary nodule is palpated, multiple occult nodules are likely to be present in about half of patients. Only about 6% of nodules <0.5 cm in diameter are palpable, while about half of the nodules >2 cm are reliably detected by experienced examiners. Pain in the thyroid may indicate the presence of thyroiditis. TSH values. An appropriate laboratory evaluation is critical

to establish the diagnosis and etiology of hypothyroidism, and to do so most cost-effectively.5 The sensitive TSH assay has become the single best screening test for hypothyroidism (and hyperthyroidism),5 but establishment of a single TSH reference range to diagnose and monitor thyroid disease continues to be controversial. In the NHANES III study, serum TSH levels fell in the range of 0.45 to 4.12 mU/L,1 while The National Academy of Clinical Biochemistry proposed a normal TSH range of 0.4 to 4.0 mU/L;9 other organizations propose 0.3 to 3.0 mU/L. Complicating matters, each laboratory may use a different TSH reference range. For the purposes of this supplement, a normal TSH is considered to be 0.45 to 4.12 mU/L; although physicians should be aware that there is some flexibility in interpretation. Other assays. Free-T4 level testing is important to determine thyroid gland function and, in conjunction with TSH testing, the cause of the hypothyroidism. A high TSH level and low free-T4 level indicate primary hypothyroidism, while a low TSH level and low free-T4 level indicate secondary hypothyroidism. A high TSH level and normal free-T4 level indicate subclinical hypothyroidism.6 Free-T3 level testing is not useful in diagnosing hypothyroidism. Measurement of antithyroid antibodies is useful for determining if the etiology of primary hypothyroidism is an Fatigue Slow speech Depression Weight gain Dry skin, yellow skin Cold intolerance Hair loss or coarse hair Hoarse voice Constipation Fluid retention Decreased concentration, forgetfulness, and other evidence of intellectual impairment Facial puffiness Macroglossia Reflex delay in the relaxation phase Ataxia Irregular or heavy menses and infertility Myalgias Hyperlipidemia Bradycardia and hypothermia Myxedema or nonpitting edema Anemia Signs and symptoms of hypothyroidism TABLE 2 S4 June 2006 Supplement to The Journal of Family Practice

autoimmune disorder. Antithyroid peroxidase antibodies are especially helpful in predicting progress from subclinical to overt hypothyroidism10 and in screening for preclinical hypothyroidism in children whose parents both have autoimmune thyroid disease.11 Referral. Although most primary care physicians can diagnose and treat hypothyroidism, referral to an endocrinologist may be warranted for children and adolescents, patients unresponsive to therapy, pregnant or postpartum women, severly ill and cardiac patients, those taking amiodarone or phenytoin, patients with sodium levels <130 mEq/L, and in the presence of goiter, nodule, or other structural changes in the thyroid gland or other endocrine disease.5,6 TREATMENT Symptomatic individuals with lesser degrees of subclinical hypothyroidism may benefit from thyroid replacement, but this has not been proved. The American Association of Clinical Endocrinologists suggests treatment for patients with a TSH level 10 mU/mL, as well as close follow-up of patients with subclinical hypothyroidism to monitor for conversion to overt hypothyroidism.2,5 Treatment goals for patients with hypothyroidism are to Restore normal thyroid hormone concentrations in the tissue Provide symptomatic relief Prevent neurologic deficits in newborns and children Reverse the biochemical abnormalities of hypothyroidism. Product types available for thyroid replacement therapy include synthetic and natural combinations of T3 (liothyronine) and T4 (levothyroxine), and desiccated natural thyroid, with levothyroxine alone considered the drug of choice for thyroid replacement therapy. Liothyronine (Cytomel) produces fluctuating levels of T3, has a shorter elimination half-life than T4, and often requires twice-daily dosing. Liothyronine is 4 times more potent than levothyroxine and may, therefore, cause palpitations and other cardiac side effects. Additionally, liothyronine produces high T3 but low T4 levels, which is the opposite of a normal physiologic condition and is potentially hazardous to fetal welfare during pregnancy. In general, combining levothyroxine with liothyronine has not been definitively shown to provide superior results to levothyroxine alone;12-14 however, there may be an occasional patient who benefits from combined therapy.15 Desiccated thyroid is derived from thyroids of slaughtered pigs (Armour Thyroid, Thyrolar) or cows, and may contain a variable T3:T4 ratio that also may provide a higher ratio of T3 than physiologically required. The T3 in desiccated thyroid is available shortly after ingestion.

Levothyroxine (synthetic T4) is the drug of choice for thyroid replacement therapy because it is dosed once daily, produces reliable results, is chemically stable, has a long elimination half-life (~7 days), and is relatively inexpensive. About 85% of the T4 dose is converted to T3 in vivo, at an expected consistent rate. The US Food and Drug Administration (FDA) recently approved generic levothyroxine preparations based on standardized bioequivalency testing. However, professional endocrine organizations have argued that the method by which products are determined to be bioequivalent allows too much variability in tablet strength to ensure consistent levothyroxine dosing across products and puts patients at risk for over- or undertreatment of their thyroid disorder. How to start replacement therapy. Physicians must tailor treatment and management of hypothyroidism to individual patients.5 Individualized doses are important because even small changes in the administered dose of levothyroxine can shift a patient from a euthyroid to a hyperthyroid or hypothyroid state. A small study comparing fixed-dose to individually titrated levothyroxine in hypothyroid patients showed that fixed-dose levothyroxine therapy can cause hyperthyroid symptoms, modifications in myocardial structure, and altered cardiopulmonary function, primarily during physical activity.16 However, careful adjustment of the levothyroxine dose reversed and almost completely normalized cardiopulmonary function parameters in study participants. An initial levothyroxine dosage may range from 12.5 g to a full replacement dose (average of 1.6 g/kg) based on age, weight, presence of associated disorders, cardiac status of the patient, and severity and duration of hypothyroidism.5,6 Titration with 12.5 to 25 g/day should occur slowly every 6 to 8 weeks until the TSH level reaches about 0.3 to 3.0 mU/mL; smaller levothyroxine doses should be used as the TSH nears the desired range.5 An even more gradual dosing schedule should be instituted for patients who have congestive heart failure, angina, or anxiety. In older adults, dosage should be titrated carefully in increments of 12.5 g to 25 g until the TSH normalizes. The higher the pretreatment TSH level, the longer the expected titration period. After a patients TSH level has normalized, the maintenance dosage should be continued with an annual or semiannual TSH test or when the patient demonstrates a change Managing the Challenges of Hypothyroidism Even small changes in the dose of levothyroxine can shift a patient from a euthyroid to a hyperthyroid or hypothyroid state. Supplement to The Journal of Family Practice June 2006 S5

FAMILY PRACTICE THE JOURNAL OF in symptoms.5 Requirements may change with patient age, severe illness, and pregnancy. If a patient shows no appreciable benefit after 3 months, the need for treatment should be reassessed and referral to an endocrinologist considered. Thyroid overreplacement. Some evidence indicates that up to 20% of patients receiving levothyroxine are overtreated. 2 This may result in overt or subclinical hyperthyroidism, which may cause cardiac hypertrophy, atrial fibrillation, and accelerated bone turnover.17,18 The risk of atrial fibrillation is increased up to 3-fold in elderly patients who receive thyroid overreplacement with a TSH <0.1 mU/mL compared with patients who are euthyroid.19 Hyperthyroidism is considered a risk factor for osteoporosis, which may be compounded in the postmenopausal population.5 One meta-analysis demonstrated a clear relationship between hyperthyroidism and decreased bone mineral density, with normalization of bone mineral density upon normalization of the thyroid state.17 However, timely identification and correction can prevent the cardiac and bone problems of thyroid overreplacement. In patients suspected of exposure to higherthanneeded doses of thyroid hormone, a T4 test more accurately assesses thyroid status since it may take weeks or months for the TSH to reach steady state.5 Hypothyroidism is often accompanied by weight gain, so it is no surprise that treatment of hypothyroidism often results in weight loss. One study showed that small changes in the levothyroxine dose can have a significant impact on the resting energy expenditure.20 However, it is not advisable to increase the levothyroxine dose beyond that necessary to achieve a euthyroid state. Although additional weight loss may occur, it is likely to be short-lived, since it is thought that the body will adapt by increasing appetite and decreasing physical activity, thereby negating effects on the metabolic rate.6 Interacting conditions and drugs. Dosing requirements may be affected by malabsorptive states or drug interactions. Many medications are known to cause druginduced hypothyroidism or hyperthyroidism5 (TABLE 3). Other medications may alter thyroid function tests without inducing thyroid dysfunction; for example, estrogen, even at low doses, increases serum levels of thyroxinebinding globulin. Therefore, euthyroid patients receiving any form of estrogen generally show elevated total T3 and T4 values, while serum TSH, free T3, and free T4 levels remain unchanged. BIOEQUIVALENCE AND ITS

CLINICAL IMPORTANCE Twelve strengths of levothyroxine are available (25 g, 50 g, 75 g, 88 g, 100 g, 112 g, 125 g, 137 g, 150 g, 175 g, 200 g, 300 g), with some strengths differing by as little as 9% to 12.5%. The wide range of tablet strengths is offered to accommodate once-daily dosing of a variety of individual patient requirements and to avoid both over- and underreplacement. As is the case with warfarin, phenytoin, and digoxin, to name a few, levothyroxine is a drug with a narrow therapeutic index (NTI) since the difference between subtherapeutic and toxic blood levels is small. In fact, Carr and colleagues showed that a 25-g increase in dose was generally sufficient to make a clinically and biochemically euthyroid patient subclinically hyperthyroid.21 The converse was observed for a 25-g decrease in dose. Several professional organizations have proposed that the FDA reassess its bioequivalence standards for NTI drugs because these standards may classify 2 generic brands of an NTI drug as bioequivalent, yet produce therapeutically different results. In determining if 2 drugs are bioequivalent (rated as A or AB), the FDA compares the pharmacokinetics of the drugs, specifically, differences in the area under the timeconcentration curve (AUC) and the maximum drug concentration (Cmax). For drug A to be rated as bioequivalent to drug R (the reference standard), both the mean and the standard deviation (90% confidence interval [CI]) of the AUC and the Cmax of drug A must fall between 80% and 125% of the reference standard R. For levothyroxine, this approach is problematic. First, bioequivalence studies are conducted in healthy subjects and assess surrogate endpoints (AUC and Cmax) that have not been shown to correlate with thyroid function. Also, the FDA has not identified a single reference levothyroxine standard against which other levothyroxine products must be compared; rather, the FDA recognizes multiple levothyroxine reference standards yielding 3 distinct groups of levothyroxine products with an AB rating.22 Consequently, it can be difficult to remember which products are FIGURE Drug A Reference Drug B Drug R Pharmacokinetic reference range 125% 100% 80% FDA bioequivalence standard for levothyroxine S6 June 2006 Supplement to The Journal of Family Practice

bioequivalent. Finally, 2 levothyroxine products within the same group can be rated as bioequivalent, yet differ significantly in the amount of drug delivered. As shown in the FIGURE, drug A is classified as bioequivalent to drug R since the mean and the 90% CI of drug A fall within the 80% to 125% range;22 this is similar for drug B. Note, however, that the mean for drug A is approximately 90%, while the mean for drug B is 115%. Should a patient stabilized on drug B be switched to drug A, that patient would receive 78% of the previous levothyroxine dose (90% 115%) when taking drug A than when taking drug B. This is analogous to taking a patient stabilized on a daily dose of 112 g and decreasing the dose by 2 tablet strengths to 88 g. This patients thyroid classification would likely change to hypothyroidism, as shown by Carr and colleagues21 and illustrated by the following published case study23 (TABLE 4). A patient stabilized on one levothyroxine product was changed to the same dose of another levothyroxine product. Three months later, she exhibited signs and symptoms of hypothyroidism. She was switched back to her original levothyroxine product and subsequently became euthyroid. Using current standards, bioequivalent levothyroxine products used interchangeably may put patients at risk of hypothyroidism or hyperthyroidism. It is, therefore, essential that patients remain on the same levothyroxine product. Pharmacists can substitute levothyroxine products classified by the FDA as bioequivalent without physician consultation. In fact, substitution to a generic drug is legally required in some states. Physicians should ensure that patients receive and remain on the same levothyroxine product.24 Steps physicians may take to manage levothyroxine product substitution include the following:24 Restrict substitution by writing on the prescription: Do not substitute, Dispense as written, or whatever is necessary in your state. Alert patients that their levothyroxine brand may be switched at the pharmacy, and encourage them to ask to remain on the same brand at every pharmacy refill. Make sure patients understand the need to have their TSH levels retested and dosing readjusted every time their levothyroxine brand is switched. Obtain serum TSH levels 8 to 12 weeks after dose or brand changes. If TSH levels deviate from the therapeutic goal range, consider brand substitution as a possible explanation. SPECIAL SUBGROUPS Older adults. Thyroid dysfunction occurs frequently in the elderly population, yet often goes unnoticed.25 Because older adults are at increased risk of many other

co-presenting disorders, including depression, dry skin, Managing the Challenges of Hypothyroidism Other drugs Amiodarone Antacids containing aluminum hydroxide Calcium Carbamazepine Cholestyramine Conditions Hypothyroidism can cause higher serum digoxin levels and increased sensitivity to anesthetic and sedative agents. Higher phenytoin levels have been reported with hypothyroidism. Treatment with thyroid hormone may affect the INR of patients being treated with warfarin. Higher estrogen levels (higher estrogen levels and other factors in pregnancy usually lead to a significant increase in T4 dose requirement, while estrogen replacement may lead to an increase in dose requirement). Requirement for insulin or antidiabetic agents may be reduced in hypothyroid patients and subsequently increase after initiation of thyroid replacement. Magnitude and relative importance are likely to be patient-specific. Ferrous sulfate Furosemide Glucocorticoids Methadone Phenobarbital Phenytoin Rifampin Salicylates Sertraline Soy Sucralfate Tamoxifen Interactions with levothyroxine TABLE 3 Supplement to The Journal of Family Practice June 2006 S7 FAMILY PRACTICE THE JOURNAL OF and cardiac abnormalities, overt hypothyroidism should always be a diagnostic consideration. However physicians do not have clear guidance on how to treat subclinical hypothyroidism in elderly patients. A study from the Netherlands demonstrated that people over 85 years of age with high levels of TSH may have a prolonged life span. Interestingly, this population did not experience adverse effects of hypothyroidism.25 Therefore, the clinical benefit of treating subclinical hypothyroidism in individuals older than 85 may be limited.

Depressed patients. A high incidence of comorbidity exists between depression and both clinical and subclinical hypothyroidism.26 A small study of 31 subjects highlighted that the lifetime frequency of depression was significantly higher in those who met the criteria for subclinical hypothyroidism (56%) than in those who did not (20%).27 The authors speculated that subclinical hypothyroidism might lower the threshold for the development of depression in response to other factors. Accordingly, the American Association of Clinical Endocrinologists and the American College of Endocrinology recommend that overt or subclinical hypothyroidism should be considered in every person with depression.5 Case reports and small studies also have indicated that thyroid replacement in depressed patients may improve the signs and symptoms of depression when used alone or as adjunctive therapy.28,29 Patients with hypercholesterolemia. Elevated cholesterol levels are often present in patients with hypothyroidism. In overt hypothyroidism, adequate thyroid substitution therapy can often reverse hypercholesterolemia. 30,31 One analysis demonstrated that adequate thyroid replacement and subsequent normalization of TSH significantly reduced an abnormally high serum total cholesterol level.31 However, in patients with subclinical hypothyroidism and hypercholesterolemia, the benefits may be more modest, with one retrospective analysis observing a 6% reduction in total cholesterol with thyroid replacement therapy. Presently, the total cholesterol threshold above which screening for hypothyroidism is cost-effective is unknown. Pregnant and postpartum patients. Hypothyroidism during pregnancy and the postpartum period may present significant risk to the mother, fetus, and neonate due to possible unrecognized thyroid pathology.32 One large retrospective study showed that pregnancies in women with subclinical hypothyroidism were 3 times more likely to be complicated by placental abruption and preterm delivery.33 Also, women with pre-existing hypothyroidism frequently require increased doses of levothyroxine, particularly during the first trimester of pregnancy, to maintain serum TSH in the low-normal range and serum free T4 in the high-normal range.5,34 Consequently, primary care physicians should consider referral to an endocrinologist for such patients. Transient thyroiditis occurs postpartum in 5% to 8% of women in the general population and in up to 25% of women with type 1 diabetes mellitus.35 Most of these women return to a euthyroid state within 1 year, but about 25% develop permanent primary hypothyroidism.35 The risk increases with previous postpartum hypothyroidism, diabetes mellitus, or a family history of autoimmune thyroid

disease. Postpartum thyroiditis is an autoimmune thyroid disorder, characterized by elevated levels of antithyroid antibodies, that may or may not cause symptoms. Thyroperoxidase antibody and TSH testing are used in its diagnosis. Free-T4 levels are used adjunctively to confirm that patients are either hypothyroid or hyperthyroid. ENCOURAGING PATIENT ADHERENCE Patient nonadherence is thought to be the principal reason for lack of expected response to therapy or high TSH levels, despite high doses of levothyroxine. An elevated serum thyrotropin concentration with serum free thyroxine at the upper end of the normal range suggests improved adherence immediately before testing due to a lag in the thyrotropin response.36 Physicians may increase patients adherence to treatment for hypothyroidism if, during the initial treatment and as needed throughout therapy, they educate and engage their patients in dialogue: Explain the risks associated with hypothyroidism and hyperthyroidism. Inform patients that clinic visits will become less frequent once a euthyroid state has been established. Alert patients to the need to take levothyroxine on an empty stomach. 37-year-old woman with a history of hypothyroidism for 18 years was being treated with levothyroxine preparation A 200 g/d and doing well with no symptoms. Her physician changed her therapy to levothyroxine preparation B 200 g/d. After 3 months, she reported feeling puffy. Her thyroid function test results were: TSH 15.15 mU/L (0.5 to 6.5 mU/L) T4 83.7 nmol/L (58 to 154 nmol/L) She was switched back to levothyroxine preparation A 200 g/d. One year later her thyroid function test results were: TSH 4.9 mU/L T4 117.1 nmol/L Case study TABLE 4 S8 June 2006 Supplement to The Journal of Family Practice Describe interactions of thyroid replacement therapy with drugs such as iron, calcium, and multivitamins and explain how to manage those interactions. Encourage patients to ask questions and seek answers. Provide advice on how and where to obtain reliable information.

CONCLUSION Although hypothyroidism is a readily treatable disease, challenges remain regarding diagnosis, screening, and treatment. Among the diagnostic challenges is the absence of a universally accepted reference range. Familiarity with the normal range for the local laboratory is essential. Hypothyroidism is typically treated with levothyroxine, which is slowly titrated to achieve a normal TSH level. Overdosing is to be avoided as this puts patients at risk for clinical sequelae of hyperthyroidism, such as osteoporosis or atrial fibrillation. Although the FDA has established groups of bioequivalent levothyroxine products, the wide range of these standards and the therapeutic substitution possible can subject patients to potential clinically important differences in the amount of levothyroxine actually taken. Therefore, switching the patient from one levothyroxine product to another at any point during therapy is discouraged. Primary care physicians can help their patients with hypothyroidism manage their disease through education and ongoing dialogue. REFERENCES 1. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489-499. 2. Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. J Clin Endocrinol Metab. 2005;90:581-585. 3. Meier C, Trittibach P, Guglielmetti M, Staub JJ, Muller B. Serum thyroid stimulating hormone in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: cross sectional survey. BMJ. 2003;326:311-312. 4. Spencer CA.Clinical utility of sensitive TSH assays. Thyroid Today. 1986;9:1-8. 5. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8:457-469. 6. Garber JR, White SS. The Harvard Medical School Guide to Overcoming Thyroid Problems. New York, NY: McGraw-Hill; 2005. 7. Sherman SI. The laboratory approach to thyroid disorders. In: Cooper DS, ed. Medical Management of Thyroid Disease. New York, NY: Marcel Dekker; 2001:1-32. 8. Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med. 2002;137:904-914. 9. National Academy of Clinical Biochemistry web site. LPMG: Laboratory support for the diagnosis and monitoring of thyroid disease. C. Thyrotropin/Thyroid stimulating hormone (TSH). Available at: http://www.nacb.org/lmpg/ thyroid_LMPG_PDF.stm. Accessed March 24, 2006. 10. McDermott MT, Ridgway EC. Diagnosis and treatment of hypothyroidism. In: Cooper DS, ed. Medical Management of Thyroid Disease. New York, NY: Marcel Dekker; 2001:135-186.

11. Foley TP. Pediatric thyroid disorders. In: Cooper DS, ed. Medical Management of Thyroid Disease. New York, NY: Marcel Dekker; 2001:313-344. 12. Escobar-Morreale HF, Botella-Carretero JI, Escobar del Ray F, Morreale de Escobar G. Review: Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab. 2005;90:4946-4954. 13. Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, Galan JM, Barrios V, Sancho J. Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med. 2005;142:412-424. 14. Siegmund W, Spieker K, Weike AI, et al. Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf). 2004;60:750-757. 15. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340:424-429. 16. Mercuro G, Panzuto MG, Bina A, et al. Cardiac function, physical exercise capacity, and quality of life during long-term thyrotropin-suppressive therapy with levothyroxine: effect of individual dose tailoring. J Clin Endocrinol Metab. 2000;85:159-164. 17. Vestergaard P, Mosekilde L. Hyperthyroidism, bone mineral, and fracture riska meta-analysis. Thyroid. 2003;13:585-593. 18. Burman KD. How serious are the risks of thyroid hormone over-replacement? Thyroid Today. 1995;18:1-9. 19. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994;331:1249-1252. 20. al Adsani H, Hoffer LJ, Silva JE. Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J Clin Endocrinol Metab. 1997;82:1118-1125. 21. Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol (Oxf). 1988;28:325-333. 22. US Food and Drug Administration web site. Approved drug products with therapeutic equivalence evaluations. 26th edition. Available at: http://www.fda.gov/ cder/ob/docs/preface/ecpreface.htm#Therapeutic%20EquivalenceRelated%20Terms. Accessed March 24, 2006. 23. Copeland PM. Two cases of therapeutic failure associated with levothyroxine brand interchange. Ann Pharmacother. 1995;29:482-485. 24. The American Thyroid Association web site. ATA, TES, and AACE express disappointment and concern for the health of millions of thyroid patients after FDA announces decision to approve generic substitutes for levothyroxine products. Available at: www.thyroid.org/professionals/advocacy/04_06_24_fda.html. Accessed March 24, 2006. 25. Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004;292:2591-2599. 26. Rack SK, Makela EH. Hypothyroidism and depression: a therapeutic challenge. Ann Pharmacother. 2000;34:1142-1145.

27. Haggerty JJ Jr, Stern RA, Mason GA, Beckwith J, Morey CE, Prange AJ Jr. Subclinical hypothyroidism: a modifiable risk factor for depression? Am J Psychiatry. 1993;150:508-510. 28. Gulseren S, Gulseren L, Hekimsoy Z, Cetinay P, Ozen C, Tokatlioglu B. Depression, anxiety, health-related quality of life, and disability in patients with overt and subclinical thyroid dysfunction. Arch Med Res. 2006;37:133-139. 29. Altshuler LL, Bauer M, Frye MA, et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry. 2001;158:1617-1622. 30. Tanis BC, Westendorp GJ, Smelt HM. Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocrinol (Oxf). 1996;44:643-649. 31. Danese MD, Ladenson PW, Meinert CL, Powe NR. Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab. 2000;85:29933001. 32. Mestman JH, Goodwin TM, Montoro MM. Thyroid disorders of pregnancy. Endocrinol Metab Clin North Am. 1995;24:41-71. 33. Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol. 2005;105:239-245. 34. Mandel SJ, Larsen PR, Seely EW, Brent GA. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med. 1990;323:91-96. 35. Stagnaro-Green A. Postpartum thyroiditis. Best Pract Res Clin Endocrinol Metab. 2004;18(2):303-316. 36. The CE Solution web site. Current solutions for the treatment of thyroid disorder. Available at: http://www.thecesolution.com/ce/lessons/Abbott_ThyroidTreatment_ 081505/Abbott%20Thyroid%20Treatment%20(2).pdf. Accessed April 7, 2006. Managing the Challenges of Hypothyroidism HYPOTHYROIDISM Hypothyroidism results from undersecretion of thyroid hormone from the thyroid gland. In the United States, the most common cause of primary hypothyroidism is chronic autoimmune thyroiditis (Hashimotos disease). Other causes are surgical removal of the thyroid gland, thyroid gland ablation with radioactive iodine, external irradiation, a biosynthetic defect in iodine organification, replacement of the thyroid gland by tumor (lymphoma), and drugs such as lithium or interferon. Secondary causes of hypothyroidism include pituitary and hypothalamic disease. Patients should undergo assessment for the cause of their hypothyroidism. Clinical Features The symptoms are generally related to the duration and severity of hypothyroidism, the rapidity with which hypothyroidism occurs, and the psychologic characteristics of the patient. The signs and symptoms of hypothyroidism can include one or more of the following: Fatigue

 Weight gain from fluid retention Dry skin and cold intolerance Yellow skin Coarseness or loss of hair Hoarseness Goiter Reflex delay, relaxation phase Ataxia Constipation Memory and mental impairment Decreased concentration Depression Irregular or heavy menses and infertility Myalgias Hyperlipidemia Bradycardia and hypothermia Myxedema fluid infiltration of tissues Although most physicians can diagnose and treat hypothyroidism, in certain situations a clinical endocrinologist experienced in the spectrum of thyroid disease would be most likely to recognize the more subtle manifestations of hypothyroidism and most skilled in the physical examination of the thyroid gland. Consultation with an endocrinologist is recommended in the following situations: Patients of age 18 years or less Patients unresponsive to therapy Pregnant patients Cardiac patients Presence of goiter, nodule, or other structural changes in the thyroid gland Presence of other endocrine disease Not all patients with chronic thyroiditis have hypothyroidism, and if it is present, it may not persist. Rarely, patients with chronic thyroiditis have a change from a hypothyroid to a nonsuppressible euthyroid state or even to a hyperthyroid state because of the development of stimulating TSH receptor autoantibodies (TSI or TRAb) of Graves disease. If such patients had been receiving levothyroxine treatment, downward dose adjustments or even cessation of levothyroxine therapy might be required. Therefore, adequate follow-up evaluations are imperative. The patient should be informed that this treatment adjustment may be necessary. When a patient has a goiter, a complete assessment, including a comprehensive history and physical examination and appropriate laboratory evaluation, should be performed. Patients with chronic thyroiditis have a high incidence of other associated autoimmune diseases such as vitiligo, rheumatoid arthritis, Addisons disease, diabetes mellitus, and pernicious anemia (2,28).

Diagnosis Laboratory Evaluation Appropriate laboratory evaluation is critical to establish the diagnosis and cause of hypothyroidism in the most AACE Thyroid Guidelines, Endocr Pract. 2002;8(No. 6) 463 cost-effective way. The most valuable test is a sensitive measurement of TSH level. A TSH assay should always be used as the primary test to establish the diagnosis of primary hypothyroidism. Additional tests may include the following: Free T4 estimate Thyroid autoantibodiesanti-thyroid peroxidase and antithyroglobulin autoantibodies Thyroid scan, ultrasonography, or both (if necessary to evaluate suspicious structural thyroid abnormalities) Differential Diagnosis A patient with chronic thyroiditis may have an atrophic or an enlarged thyroid gland, or it may be of normal size. Thyroid autoantibodies are positive in 95% of patients with autoimmune thyroiditis (Hashimotos thyroiditis), and high titers are of considerable value in making this specific diagnosis. Thyroid nodules are not uncommon with chronic thyroiditis and are associated with a small risk (5%) of thyroid cancer. Sudden enlargement of the thyroid gland in a patient with chronic thyroiditis should raise concern about thyroid lymphoma. Patients with chronic thyroiditis may have normal results of thyroid function tests, including the sensitive TSH. Patients with associated subclinical hypothyroidism have a high TSH level in conjunction with normal free thyroid hormone (T4 and T3) estimates. Patients with clinical or overt hypothyroidism exhibit reduced free T4 estimates and increased TSH levels (28,29). Treatment and Management Chronic Thyroiditis and Clinical Hypothyroidism The treatment and management of chronic thyroiditis and clinical hypothyroidism must be tailored to the individual patient. Many clinical endocrinologists treat the goiter of chronic thyroiditis with levothyroxine, even in patients with a normal level of TSH, and all physicians will treat clinical hypothyroidism with levothyroxine replacement therapy. The management of subclinical hypothyroidism is addressed in the subsequent section. AACE advocates the use of a high-quality brand preparation of levothyroxine. Bioequivalence of levothyroxine preparations is based on total T4 measurement and not TSH levels; therefore, bioequivalence is not the same as therapeutic equivalence. Furthermore, various brands of levothyroxine are not compared against a levothyroxine standard. Preferably, the patient should receive the same

brand of levothyroxine throughout treatment. In general, desiccated thyroid hormone, combinations of thyroid hormones, or triiodothyronine should not be used as replacement therapy. The mean replacement dosage of levothyroxine is 1.6 g/kg of body weight per day, although the appropriate dosage may vary among patients. The appropriate pace of treatment depends on the duration and severity of the hypothyroidism and on the presence of other associated medical disorders. The initial levothyroxine dosage may range from 12.5 g daily to a full replacement dose based on the age, weight, and cardiac status of the patient and the severity and duration of the hypothyroidism. Importantly, patients should undergo reassessment and therapy should be titrated after an interval of at least 6 weeks following any change in levothyroxine brand or dose. The serum TSH level is most important, and a free T4 estimate may be included in the assessment as well. Once the TSH level is in the normal range, the frequency of visits can be decreased. Although each patients care must be individualized, a follow-up visit in 6 months and then annually is a common schedule. During followup assessments, an appropriate interim history should be recorded, and physical examination should be performed in conjunction with pertinent laboratory tests. Involving the patient in the levothyroxine treatment by explaining the thyroid disease and potential consequences should result in improved adherence to recommendations. Thyroid hormone absorption can be affected by malabsorptive states and patient age. In addition, commercially available levothyroxine products may not be bioequivalent. Because levothyroxine has a narrow therapeutic range, small differences in absorption can result in subclinical or clinical hypothyroidism or hyperthyroidism. Drug interactions also present a problem. Certain drugs such as cholestyramine, ferrous sulfate, sucralfate, calcium, and some antacids containing aluminum hydroxide interfere with levothyroxine absorption. Other drugs such as anticonvulsants affect thyroid hormone binding, whereas others such as rifampin and sertraline hydrochloride may accelerate levothyroxine metabolism and necessitate a higher replacement dose. The physician must make the appropriate adjustments in levothyroxine dosage in the face of absorption variability and drug interactions. Inappropriate levothyroxine replacement can result in increased costs because of the need for additional patient visits and laboratory tests (28,30-35). Recent studies have shown a resurgence of interest in the possible benefits of treatment of hypothyroidism with combinations of T4 and T3 or with natural thyroid preparations. The small-scale study that seems to have sparked

this interest treated patients for only 5 weeks, focused on mood changes, used a T4 plus T3 combination that differs substantially from that found in natural thyroid products, may have found benefit in only a subset of patients, and has not been replicated (36,37). Insufficient evidence is available to know which patients with hypothyroidism, if any, would be better treated with a combination of T4 plus T3 rather than with T4 alone. Subclinical Hypothyroidism Subclinical hypothyroidism refers to mildly increased serum TSH levels in the setting of normal free T4 and T3 estimates. Although subclinical hypothyroidism may represent early thyroid failure, it may occur in the presence or absence of symptoms. It is a common disorder, the prevalence ranging from 1 to 10% of the adult population with increasing frequency in women, in patients with advanced age, and in those with greater dietary iodine intake. Usually, subclinical hypothyroidism is asympto464 AACE Thyroid Guidelines, Endocr Pract. 2002;8(No. 6) matic and is discovered on routine, screening TSH determination. The most common cause of subclinical hypothyroidism is autoimmune thyroiditis (Hashimotos disease). Progression to overt hypothyroidism is reported to vary from 3 to 20%, the risks being greater in those patients with goiter or thyroid antibodies (or both) (16,18). Although subclinical hypothyroidism is often asymptomatic, potential risks associated with the condition include progression to overt hypothyroidism, cardiovascular effects, hyperlipidemia, and neuropsychiatric effects (16,19). Recent studies have suggested that treatment of subclinical hypothyroidism will reduce cardiovascular risk factors, improve the lipid profile, and minimize neurobehavioral abnormalities (19,20). Some of these data, however, were derived from studies that included patients with TSH levels well above 10 IU/mL; for patients with mildly increased TSH levels (5 to 10 IU/mL), the data are controversial. Treatment of subclinical hypothyroidism remains controversial, and recent arguments for and against treatment have been proposed (19,21). We believe that treatment is indicated in patients with TSH levels >10 IU/mL or in patients with TSH levels between 5 and 10 IU/mL in conjunction with goiter or positive anti-thyroid peroxidase antibodies (or both). These patients have the highest rates of progression to overt hypothyroidism. An initial dosage of levothyroxine of 25 to 50 g/day can be used, the serum TSH level should be measured in 6 to 8 weeks, and the levothyroxine dose should be adjusted as necessary. The target TSH level should be between 0.3 and 3.0 IU/mL. Once a stable TSH level is achieved, annual

examination is appropriate. Hypothyroidism During Pregnancy Untreated overt hypothyroidism during pregnancy may increase the incidence of maternal hypertension, preeclampsia, anemia, postpartum hemorrhage, cardiac ventricular dysfunction, spontaneous abortion, fetal death or stillbirth, low birth weight, and, possibly, abnormal brain development (38). Evidence from a populationbased study suggests that even mild, asymptomatic, untreated maternal hypothyroidism during pregnancy may have an adverse effect on cognitive function of the offspring and that this outcome can be prevented by thyroid hormone replacement therapy (39). Mildly increased serum TSH levels during pregnancy might also increase the risk of fetal death, but whether treatment prevents this complication is not yet known. In most of these women, thyroid antibodies developa finding that seems to be a risk factor for spontaneous abortion independent of thyroid hormone and TSH levels (38,40). Because levothyroxine therapy is safe during pregnancy, thyroid hormone replacement treatment seems advisable for all pregnant women with hypothyroidism, even if it is mild. As a further recommendation, TSH measurement should be routine before pregnancy or during first trimester screening for thyroid dysfunction. When a woman with hypothyroidism or underlying chronic thyroiditis becomes pregnant, the thyroid function may changeit can improve in some mild cases or deteriorate in others. In general, the dosage of thyroid hormone should be increased in patients with moderate to severe hypothyroidism. These patients should undergo assessment of their serum TSH level every 6 weeks during pregnancy to ensure that the requirement for levothyroxine has not changed (41-43). Hypothyroidism and Concurrent Conditions Diabetes Mellitus In approximately 10% of patients with type 1 diabetes mellitus, chronic thyroiditis will develop during their lifetime, which may include the insidious onset of subclinical hypothyroidism. Of importance, patients with diabetes should be examined for the development of a goiter. Sensitive TSH measurements should be obtained at regular intervals in patients with diabetes, especially if a goiter develops or if evidence is found of other autoimmune disorders. In addition, postpartum thyroiditis will develop in up to 25% of women with type 1 diabetes (44,45). Infertility Some patients with infertility and menstrual irregularities have underlying chronic thyroiditis in conjunction with subclinical or clinical hypothyroidism. Typically,

these patients seek medical attention because of infertility or a previous miscarriage, rather than hypothyroidism. Chronic thyroiditis can be identified by a careful, comprehensive history, physical examination, and appropriate laboratory evaluation. In some patients with high TSH levels, levothyroxine replacement therapy may normalize the menstrual cycle and restore normal fertility (2,28,46). Depression The diagnosis of subclinical or clinical hypothyroidism must be considered in every patient with depression. In fact, a small proportion of all patients with depression have primary hypothyroidismeither overt or subclinical. Moreover, all patients receiving lithium therapy require periodic thyroid evaluation because lithium may induce goiter and hypothyroidism. The diagnosis of chronic thyroiditis or subclinical or clinical hypothyroidism is based on a high serum TSH level and positive thyroid autoantibodies. Appropriate levothyroxine replacement therapy should be instituted. Occasionally in psychiatric practice, some patients who have depression are treated not only with antidepressants but also with thyroid hormone replacement, even though they have normal thyroid function. No firm evidence has shown that thyroid hormone treatment alone does anything to alleviate depression in such patients (28,33). Euthyroid Sick Syndrome The evaluation of thyroid function in chronically ill patients may be confusing. Many medications, such as AACE Thyroid Guidelines, Endocr Pract. 2002;8(No. 6) 465 corticosteroids and dopamine, may interfere with the results of thyroid function tests. In addition, when a patient is ill or starving, the body tends to compensate by decreasing metabolic rates, which may result in a low free T4 or T3 estimate and a normal or low TSH level. If the TSH value is less than 10 IU/mL, treatment should ideally be deferred until the patients medical condition has resolved. Assessment of the patient by a clinical endocrinologist is appropriate before initiation of levothyroxine treatment. CONCLUSION These guidelines established by AACE present several approaches to the assessment and treatment of patients with hyperthyroidism and hypothyroidism. They highlight the complexity of thyroid diseases and describe diagnostic and therapeutic strategies in various settings. These guidelines are not intended to be a comprehensive outline of therapeutic options. Subclinical thyroid disease often remains undiagnosed. Through sound judgment, timely intervention, initiation of appropriate treatment, and patient involvement, an optimal level of care is attainable.

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