Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association

Objectives

The purpose of these guidelines is to present an updated evidence-based framework for the diagnosis, treatment, and follow-up of patients with hypothyroidism.

Guidelines for CPGs

Current guidelines for CPGs in clinical medicine emphasize an evidence-based approach rather than simply expert opinion (6). Even though a purely evidence-based approach is not applicable to all actual clinical scenarios, we have incorporated this into these CPGs to provide objectivity.

Levels of scientific substantiation and recommendation grades (transparency)

All clinical data that are incorporated in these CPGs have been evaluated in terms of levels of scientific substantiation. The detailed methodology for assigning evidence levels (ELs) to the references used in these CPGs has been reported by Mechanick et al. (7), from which Table 2 is taken. The authors' EL ratings of the references are included in the References section. The four-step approach that the authors used to grade recommendations is summarized in Tables 3, 4, 5, and 6 of the 2010 Standardized Production of Clinical Practice Guidelines (5), from which Table 3 is taken. By explicitly providing numerical and semantic descriptors of the clinical evidence as well as relevant subjective factors and study flaws, the updated protocol has greater transparency than the 2008 AACE protocol described by Mechanick et al. (7).

In these guidelines, the grading system used for the recommendations does not reflect the instruction of the recommendation, but the strength of the recommendation. For example in some grading systems “should not” implies that there is substantial evidence to support a recommendation. However the grading method employed in this guideline enables authors to use this language even when the best evidence level available is “expert opinion.” Although different grading systems were employed, an effort was made to make these recommendations consistent with related portions of “Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists” (8,9), as well as the “Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum” (10).

The shortcomings of this evidence-based methodology in these CPGs are that many recommendations are based on weak scientific data (Level 3) or consensus opinion (Level 4), rather than strong scientific data (Levels 1 and 2). There are also the problems of (i) subjectivity on the part of the authors when weighing positive and negative, or epidemiologic versus experimental, data in order to arrive at an evidence-based recommendation grade or consensus opinion, (ii) subjectivity on the part of the authors when weighing subjective attributes, such as cost effectiveness and risk-to-benefit ratios, in order to arrive at an evidence-based recommendation grade or consensus opinion, (iii) potentially incomplete review of the literature by the authors despite extensive diligence, and (iv) bias in the available publications, which originate predominantly from experienced clinicians and large academic medical centers and may, therefore, not reflect the experience at large. The authors, through an a priori methodology and multiple levels of review, have tried to address these shortcomings by discussions with three experts (see Acknowledgments).

Summary of recommendation grades

The recommendations are evidence-based (Grades A, B, and C) or based on expert opinion because of a lack of conclusive clinical evidence (Grade D). The “best evidence” rating level (BEL), which corresponds to the best conclusive evidence found, accompanies the recommendation grade. Details regarding the mapping of clinical evidence ratings to these recommendation grades have already been provided [see Levels of scientific substantiation and recommendation grades (transparency)]. In this CPG, a substantial number of recommendations are upgraded or downgraded because the conclusions may not apply in other situations (non-generalizability). For example, what applies to an elderly population with established cardiac disease may not apply to a younger population without cardiac risk factors. Whenever expert opinions resulted in upgrading or downgrading a recommendation, it is explicitly stated after the recommendation.

Epidemiology

Hypothyroidism may be either subclinical or overt. Subclinical hypothyroidism is characterized by a serum TSH above the upper reference limit in combination with a normal free thyroxine (T₄). This designation is only applicable when thyroid function has been stable for weeks or more, the hypothalamic–pituitary–thyroid axis is normal, and there is no recent or ongoing severe illness. An elevated TSH, usually above 10 mIU/L, in combination with a subnormal free T₄ characterizes overt hypothyroidism.

The results of four studies are summarized in Table 4. The National Health and Nutrition Examination Survey (NHANES III) studied an unselected U.S. population over age 12 between 1988 and 1994, using the upper limit of normal for TSH as 4.5 mIU/mL (11). The prevalence of subclinical disease was 4.3% and of overt disease was 0.3%. The Colorado thyroid disease prevalence survey, in which self-selected individuals attending a health fair were tested and an upper normal TSH value of 5.0 mIU/L was used, reported a prevalence of 8.5% and 0.4% for subclinical and overt disease, respectively, in people not taking thyroid hormone (12). In the Framingham study, 5.9% of women and 2.3% of men over the age of 60 years had TSH values over 10 mIU/L, 39% of whom had subnormal T₄ levels (13). In the British Whickham survey 9.3% of women and 1.2% of men had serum TSH values over 10 mIU/L (14,15). The incidence of hypothyroidism in women was 3.5 per 1000 survivors per year and in men it was 0.6 per 1000 survivors per year. The risk of developing hypothyroidism in women with positive antibodies and elevated TSH was 4% per year versus 2%–3% per year in those with either alone (14,15). In men the relative risk rose even more in each category, but the rates remained well below those of women.

Primary and secondary etiologies of hypothyroidism

Environmental iodine deficiency is the most common cause of hypothyroidism on a worldwide basis (16). In areas of iodine sufficiency, such as the United States, the most common cause of hypothyroidism is chronic autoimmune thyroiditis (Hashimoto's thyroiditis). Autoimmune thyroid diseases (AITDs) have been estimated to be 5–10 times more common in women than in men. The ratio varies from series to series and is dependent on the definition of disease, whether it is clinically evident or not. In the Whickham survey (14), for example, 5% of women and 1% of men had both positive antibody tests and a serum TSH value >6. This form of AITD (i.e., Hashimoto's thyroiditis, chronic autoimmune thyroiditis) increases in frequency with age (11), and is more common in people with other autoimmune diseases and their families (17–25). Goiter may or may not be present.

AITDs are characterized pathologically by infiltration of the thyroid with sensitized T lymphocytes and serologically by circulating thyroid autoantibodies. Autoimmunity to the thyroid gland appears to be an inherited defect in immune surveillance, leading to abnormal regulation of immune responsiveness or alteration of presenting antigen in the thyroid (26,27).

One of the keys to diagnosing AITDs is determining the presence of elevated anti-thyroid antibody titers which include anti-thyroglobulin antibodies (TgAb), anti–microsomal/thyroid peroxidase antibodies (TPOAb), and TSH receptor antibodies (TSHRAb). Many patients with chronic autoimmune thyroiditis are biochemically euthyroid. However, approximately 75% have elevated anti-thyroid antibody titers. Once present, these antibodies generally persist, with spontaneous disappearance occurring infrequently. Among the disease-free population in the NHANES survey, tests for TgAb were positive in 10.4% and TPOAb in 11.3%. These antibodies were more common in women than men and increased with age. Only positive TPOAb tests were significantly associated with hypothyroidism (11). The presence of elevated TPOAb titers in patients with subclinical hypothyroidism helps to predict progression to overt hypothyroidism—4.3% per year with TPOAb vs. 2.6% per year without elevated TPOAb titers (14,28). The higher risk of developing overt hypothyroidism in TPOAb-positive patients is the reason that several professional societies and many clinical endocrinologists endorse measurement of TPOAbs in those with subclinical hypothyroidism.

In patients with a diffuse, firm goiter, TPOAb should be measured to identify autoimmune thyroiditis. Since nonimmunologically mediated multinodular goiter is rarely associated with destruction of functioning tissue and progression to hypothyroidism (29), it is important to identify those patients with the nodular variant of autoimmune thyroiditis in whom these risks are significant. In some cases, particularly in those with thyroid nodules, fine-needle aspiration (FNA) biopsy helps confirm the diagnosis and to exclude malignancy. Also, in patients with documented hypothyroidism, measurement of TPOAb identifies the cause.

In the presence of other autoimmune disease such as type 1 diabetes (20,21) or Addison's disease (17,18), chromosomal disorders such as Down's (30) or Turner's syndrome (31), and therapy with drugs such as lithium (32–34), interferon alpha (35,36), and amiodarone (37) or excess iodine ingestion (e.g., kelp) (38–40), TPOAb measurement may provide prognostic information on the risk of developing hypothyroidism.

TSHRAb may act as a TSH agonist or antagonist (41). Thyroid stimulating immunoglobulin (TSI) and/or thyrotropin binding inhibitory immunoglobulin (TBII) levels, employing sensitive assays, should be measured in euthyroid or L-thyroxine–treated hypothyroid pregnant women with a history of Graves' disease because they are predictors of fetal and neonatal thyrotoxicosis (42). Since the risk for thyrotoxicosis correlates with the magnitude of elevation of TSI, and since TSI levels tend to fall during the second trimester, TSI measurements are most informative when done in the early third trimester. The argument for measurement earlier in pregnancy is also based, in part, on determining whether establishing a surveillance program for ongoing fetal and subsequent neonatal thyroid dysfunction is necessary (43).

Hypothyroidism may occur as a result of radioiodine or surgical treatment for hyperthyroidism, thyroid cancer, or benign nodular thyroid disease and after external beam radiation for non–thyroid-related head and neck malignancies, including lymphoma. A relatively new pharmacologic cause of iatrogenic hypothyroidism is the tyrosine kinase inhibitors, most notably sunitinib (44,45), which may induce hypothyroidism through reduction of glandular vascularity and induction of type 3 deiodinase activity.

Central hypothyroidism occurs when there is insufficient production of bioactive TSH (46,47) due to pituitary or hypothalamic tumors (including craniopharyngiomas), inflammatory (lymphocytic or granulomatous hypophysitis) or infiltrative diseases, hemorrhagic necrosis (Sheehan's syndrome), or surgical and radiation treatment for pituitary or hypothalamic disease. In central hypothyroidism, serum TSH may be mildly elevated, but assessment of serum free T₄ is usually low, differentiating it from subclinical primary hypothyroidism.

Consumptive hypothyroidism is a rare condition that may occur in patients with hemangiomata and other tumors in which type 3 iodothyronine deiodinase is expressed, resulting in accelerated degradation of T₄ and triiodothyronine (T₃) (48,49).

Disorders associated with hypothyroidism

The most common form of thyroid failure has an autoimmune etiology. Not surprisingly, there is also an increased frequency of other autoimmune disorders in this population such as type 1 diabetes, pernicious anemia, primary adrenal failure (Addison's disease), myasthenia gravis, celiac disease, rheumatoid arthritis, systemic lupus erythematosis (17–25), and rarely thyroid lymphoma (50).

Distinct genetic syndromes with multiple autoimmune endocrinopathies have been described, with some overlapping clinical features. The presence of two of the three major characteristics is required to diagnose the syndrome of multiple autoimmune endocrinopathies (MAEs). The defining major characteristics for type 1 MAE and type 2 MAE are as follows:

• Type 1 MAE: Hypoparathyroidism, Addison's disease, and mucocutaneous candidiasis caused by mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE protein (51). Autoimmune thyroiditis is present in about 10%–15% (52).

When adrenal insufficiency is present, the diagnosis of subclinical hypothyroidism should be deferred until after glucocorticoid therapy has been instituted because TSH levels may be elevated in the presence of untreated adrenal insufficiency and may normalize with glucocorticoid therapy (54,55) (see L-thyroxine treatment of hypothyroidism).

Signs and symptoms of hypothyroidism

The well-known signs and symptoms of hypothyroidism tend to be more subtle than those of hyperthyroidism. Dry skin, cold sensitivity, fatigue, muscle cramps, voice changes, and constipation are among the most common. Less commonly appreciated and typically associated with severe hypothyroidism are carpal tunnel syndrome, sleep apnea, pituitary hyperplasia that can occur with or without hyperprolactinemia and galactorrhea, and hyponatremia that can occur within several weeks of the onset of profound hypothyroidism. Although, for example, in the case of some symptoms such as voice changes subjective (12,56) and objective (57) measures differ. Several rating scales (56,58,59) have been used to assess the presence and, in some cases, the severity of hypothyroidism, but have low sensitivity and specificity. While the exercise of calculating clinical scores has been largely superseded by sensitive thyroid function tests, it is useful to have objective clinical measures to gauge the severity of hypothyroidism. Early as well as recent studies strongly correlate the degree of hypothyroidism with ankle reflex relaxation time, a measure rarely used in current clinical practice today (60).

Normalization of a variety of clinical and metabolic end points including resting heart rate, serum cholesterol, anxiety level, sleep pattern, and menstrual cycle abnormalities including menometrorrhagia are further confirmatory findings that patients have been restored to a euthyroid state (61–65). Normalization of elevated serum creatine kinase or other muscle (66) or hepatic enzymes following treatment of hypothyroidism (67) are additional, less well-appreciated and also nonspecific therapeutic endpoints.

Measurement of T₄ and T₃

T₄ is bound to specific binding proteins in serum. These are T₄-binding globulin (TBG) and, to a lesser extent, transthyretin or T₄-binding prealbumin and albumin. Since approximately 99.97% of T₄ is protein-bound, levels of serum total T₄ will be affected by factors that alter binding independent of thyroid disease (Table 5) (68,69). Accordingly, methods for assessing (including estimating and measuring) serum free T₄, which is the metabolically available moiety (70), have been developed, and assessment of serum free T₄ has now largely replaced measurement of serum total T₄ as a measure of thyroid status. These methods include the serum free T₄ index, which is derived as the product of total T₄ and a thyroid hormone binding ratio, and the direct immunoassay of free T₄ after ultrafiltration or equilibrium dialysis of serum or after addition of anti-T₄ antibody to serum (71).

A subnormal assessment of serum free T₄ serves to establish a diagnosis of hypothyroidism, whether primary, in which serum TSH is elevated, or central, in which serum TSH is normal or low (46,47). An assessment of serum free T₄ (Table 6) is the primary test for detecting hypothyroidism in antithyroid drug–treated or surgical or radioiodine-ablated patients with previous hyperthyroidism in whom serum TSH may remain low for many weeks to months.

In monitoring patients with hypothyroidism on L-thyroxine replacement, blood for assessment of serum free T₄ should be collected before dosing because the level will be transiently increased by up to 20% after L-thyroxine administration (72). In one small study of athyreotic patients, serum total T₄ levels increased above baseline by 1 hour and peaked at 2.5 hours, while serum free T₄ levels peaked at 3.5 hours and remained higher than baseline for 9 hours (72).

In pregnancy, measurement of serum total T₄ is recommended over direct immunoassay of serum free T₄. Because of alterations in serum proteins in pregnancy, direct immunoassay of free T₄ may yield lower values based on reference ranges established with normal nonpregnant sera. Moreover, many patients will have values below the nonpregnant reference range in the third trimester, including values obtained with equilibrium dialysis (73). Finally, method-specific and trimester-specific reference ranges for direct immunoassay of free T₄ have not been generally established. By contrast, total T₄ increases during the first trimester and the reference range is ∼1.5-fold that of the nonpregnant range throughout pregnancy (73,74).

As is the case with T₄, T₃ is also bound to serum proteins, principally TBG, but to a lesser extent than T₄, ∼99.7%. Methods for assessing free T₃ concentration by direct immunoassay have been developed and are in current use (71). However, serum T₃ measurement, whether total or free, has limited utility in hypothyroidism because levels are often normal due to hyperstimulation of the remaining functioning thyroid tissue by elevated TSH and to up-regulation of type 2 iodothyronine deiodinase (75). Moreover, levels of T₃ are low in the absence of thyroid disease in patients with severe illness because of reduced peripheral conversion of T₄ to T₃ and increased inactivation of thyroid hormone (76,77).

Pitfalls encountered when interpreting serum TSH levels

Measurement of serum TSH is the primary screening test for thyroid dysfunction, for evaluation of thyroid hormone replacement in patients with primary hypothyroidism, and for assessment of suppressive therapy in patients with follicular cell–derived thyroid cancer. TSH levels vary diurnally by up to approximately 50% of mean values (78), with more recent reports indicating up to 40% variation on specimens performed serially during the same time of day (79). Values tend to be lowest in the late afternoon and highest around the hour of sleep. In light of this, variations of serum TSH values within the normal range of up to 40%–50% do not necessarily reflect a change in thyroid status.

TSH secretion is exquisitely sensitive to both minor increases and decreases in serum free T₄, and abnormal TSH levels occur during developing hypothyroidism and hyperthyroidism before free T₄ abnormalities are detectable (80). According to NHANES III (11), a disease-free population, which excludes those who self-reported thyroid disease or goiter or who were taking thyroid medications, the upper normal of serum TSH levels is 4.5 mIU/L. A “reference population” taken from the disease-free population composed of those who were not pregnant, did not have laboratory evidence of hyperthyroidism or hypothyroidism, did not have detectable TgAb or TPOAb, and were not taking estrogens, androgens, or lithium had an upper normal TSH value of 4.12 mIU/L. This was further supported by the Hanford Thyroid Disease Study, which analyzed a cohort without evidence of thyroid disease, were seronegative for thyroid autoantibodies, were not on thyroid medications, and had normal thyroid ultrasound examinations (which did not disclose nodularity or evidence of thyroiditis) (81). This upper normal value, however, may not apply to iodine insufficient regions even after becoming iodine sufficient for 20 years (82,83).

More recently (84) the NHANES III reference population was further analyzed and normal ranges based on age, U.S. Office of Management of Budget “Race and Ethnicity” categories, and sex were determined. These indicated the 97.5th percentile TSH values as low as 3.24 for African Americans between the ages of 30 and 39 years and as high as 7.84 for Mexican Americans ≥80 years of age. For every 10-year age increase after 30–39 years, the 97.5th percentile of serum TSH increases by 0.3 mIU/L. Body weight, anti-thyroid antibody status, and urinary iodine had no significant impact on these ranges.

The National Academy of Clinical Biochemists, however, indicated that 95% of individuals without evidence of thyroid disease have TSH concentrations below 2.5 mIU/L (85), and it has been suggested that the upper limit of the TSH reference range be lowered to 2.5 mIU/L (86). While many patients with TSH concentrations in this range do not develop hypothyroidism, those patients with AITD are much more likely to develop hypothyroidism, either subclinical or overt (87) (see Therapeutic endpoints in the treatment of hypothyroidism for further discussion).

In individuals without serologic evidence of AITD, TSH values above 3.0 mIU/L occur with increasing frequency with age, with elderly (>80 years of age) individuals having a 23.9% prevalence of TSH values between 2.5 and 4.5 mIU/L, and a 12% prevalence of TSH concentrations above 4.5 mIU/L (88). Thus, very mild TSH elevations in older individuals may not reflect subclinical thyroid dysfunction, but rather be a normal manifestation of aging. The caveat is that while the normal TSH reference range—particularly for some subpopulations—may need to be narrowed (85,86), the normal reference range may widen with increasing age (84). Thus, not all patients who have mild TSH elevations are hypothyroid and therefore would not require thyroid hormone therapy.

There are other pitfalls in the interpretation of the serum TSH because abnormal levels are observed in various nonthyroidal states. Serum TSH may be suppressed in hospitalized patients with acute illness, and levels below 0.1 mIU/L in combination with subnormal free T₄ estimates may be seen in critically ill patients, especially in those receiving dopamine infusions (89) or pharmacologic doses of glucocorticoids (90). In addition, TSH levels may increase to levels above normal, but generally below 20 mIU/L during the recovery phase from nonthyroidal illness (91). Thus, there are limitations to TSH measurements in hospitalized patients and, therefore, they should be only performed if there is an index of suspicion for thyroid dysfunction (76).

Serum TSH typically falls, but infrequently to below 0.1 mU/L, during the first trimester of pregnancy due to the thyroid stimulatory effects of human chorionic gonadotropin and returns to normal in the second trimester (10) (see Table 7).

TSH secretion may be inhibited by administration of subcutaneous octreotide, which does not cause persistent central hypothyroidism (92), and by oral bexarotene, which almost always does (93). In addition, patients with anorexia nervosa may have low TSH levels in combination with low levels of free T₄ (94), mimicking what may be seen in critically ill patients and in patients with central hypothyroidism due to pituitary and hypothalamic disorders.

Patients with nonfunctioning pituitary adenomas, with central hypothyroidism, may have mildly elevated serum TSH levels, generally not above 6 or 7 mIU/L, due to secretion of bioinactive isoforms of TSH (47). TSH levels may also be elevated in association with elevated serum thyroid hormone levels in patients with resistance to thyroid hormone (95). Heterophilic or interfering antibodies, including human antianimal (most commonly mouse) antibodies, rheumatoid factor, and autoimmune anti-TSH antibodies may cause falsely elevated serum TSH values (96). Lastly, adrenal insufficiency, as previously noted in Disorders associated with hypothyroidism, may be associated with TSH elevations that are reversed with glucocorticoid replacement (54,55).

Other diagnostic tests for hypothyroidism

Prior to the advent of routine validated chemical measurements of serum thyroid hormones and TSH, tests that correlated with thyroid status, but not sufficiently specific to diagnose hypothyroidism, were used to diagnose hypothyroidism and to gauge the response to thyroid hormone therapy. The following are previous notable and more recent examples:

• Basal metabolic rate was the “gold standard” for diagnosis. Extremely high and low values correlate well with marked hyperthyroidism and hypothyroidism, respectively, but are affected by many unrelated, diverse conditions, such as fever, pregnancy, cancer, acromegaly, hypogonadism, and starvation (97,98).

Screening and aggressive case finding for hypothyroidism

Criteria for population screening include:

• A condition that is prevalent and an important health problem

Despite this seemingly straightforward guidance, expert panels have disagreed about TSH screening of the general population (Table 8). The ATA recommends screening in all adults beginning at age 35 years and every 5 years thereafter (103). AACE recommends routine TSH measurement in older patients—age not specified—especially women (2). The American Academy of Family Physicians recommends routine screening in asymptomatic patients older than age 60 years (104), and the American College of Physicians recommends case finding in women older than 50 years (105). In contrast, a consensus panel (106), the Royal College of Physicians of London (107), and the U.S. Preventive Services Task Force (108) do not recommend routine screening for thyroid disease in adults. For recommendations in pregnancy, see Recommendations 20.1.1 and 20.1.2.

While there is no consensus about population screening for hypothyroidism there is compelling evidence to support case finding for hypothyroidism in:

• Those with autoimmune disease, such as type 1 diabetes (20,21)

When to treat hypothyroidism

Although there is general agreement that patients with primary hypothyroidism with TSH levels above 10 mIU/L should be treated (106,115–117), which patients with TSH levels of 4.5–10 mIU/L will benefit is less certain (118,119). A substantial number of studies have been done on patients with TSH levels between 2.5 and 4.5, indicating beneficial response in atherosclerosis risk factors such as atherogenic lipids (120–123), impaired endothelial function (124,125), and intima media thickness (126). This topic is further discussed in the section Cardiac benefit from treating subclinical hypothyroidism. However, there are virtually no clinical outcome data to support treating patients with subclinical hypothyroidism with TSH levels between 2.5 and 4.5 mIU/L. The possible exception to this statement is pregnancy because the rate of pregnancy loss, including spontaneous miscarriage before 20 weeks gestation and stillbirth after 20 weeks, have been reported to be increased in anti-thyroid antibody–negative women with TSH values between 2.5 and 5.0 (127).

L-thyroxine treatment of hypothyroidism

Since the generation of biologically active T₃ by the peripheral conversion of T₄ to T₃ was documented in 1970 (128), L-thyroxine monotherapy has become the mainstay of treating hypothyroidism, replacing desiccated thyroid and other forms of L-thyroxine and L-triiodothyronine combination therapy. Although a similar quality of life (129) and circulating T₃ levels (130) have been reported in patients treated with L-thyroxine compared with individuals without thyroid disease, other studies have not shown levels of satisfaction comparable to euthyroid controls (131). A number of studies, following a 1999 report citing the benefit of L-thyroxine and L-triiodothyronine combination therapy (132), have re-addressed the benefits of synthetic L-thyroxine and L-triiodothyronine combination therapy but have largely failed to confirm an advantage of this approach to improve cognitive or mood outcomes in hypothyroid individuals treated with L-thyroxine alone (133,134).

Yet several matters remain uncertain. What should the ratios of L-thyroxine and L-triiodothyronine replacement be (133)? What is the pharmacodynamic equivalence of L-thyroxine and L-triiodothyronine (135)? It was previously believed to be 1:4, but a recent small study indicated that it was approximately 1:3 (135). Why do some patients prefer combination therapy to L-thyroxine monotherapy (133)? Some insight into the latter question may be gained from a large-scale study of L-thyroxine and L-triiodothyronine combination therapy in which different responses were observed in patients with different genetic subtypes of type 2 deiodinase (136), despite a prior, smaller negative study (137). It is not known if those who responded positively to L-thyroxine and L-triiodothyronine combination therapy will have long-term benefit and whether genotyping patients with hypothyroidism who are clinically and biochemically euthyroid will ultimately reliably identify patients with hypothyroidism who are most likely to benefit from combination therapy.

Treatment of hypothyroidism is best accomplished using synthetic L-thyroxine sodium preparations. Because of the uniqueness of the various tablet formulations and a recently introduced preparation of liquid-containing capsules with the inactive ingredients gelatin, glycerin, and water, and because of uncertainty about the sensitivity of current bioequivalence assessment procedures to assure true interchangability among the tablets, current recommendations encourage the use of a consistent L-thyroxine preparation for individual patients to minimize variability from refill to refill (138,139).

Some reports have indicated an apparent increased dosage requirement for L-thyroxine in some patients with diminished gastric acid secretion (140,141). This has led to in vitro work showing significant differences in dissolution among L-thyroxine preparations (142), profiles of which appear to be dependent on the pH of the solution in which the preparations were dissolved. The liquicap preparation (Tirosint^®) (143) dissolution profile was the least affected by changes in pH (142). The clinical significance of these findings remains unclear. In more recent, though short-term studies, the use of histamine H2 receptor blockers and proton pump inhibitors does not appear to influence clinical measures in L-thyroxine tablet–treated patients (144).

Desiccated thyroid has not been systematically studied (see Dietary supplements and nutraceuticals in the treatment of hypothyroidism). Absorption studies indicate that the bioavailability of T₃ in desiccated thyroid is comparable to that of orally administered synthetic L-triiodothyronine (145). Therefore, the most commonly used form of desiccated thyroid, known as Armour^® Thyroid, which is of porcine origin, may be viewed as a L-thyroxine and L-triiodothyronine combination with a ratio of approximately 4:1 by weight (145). The content of thyroid hormone and the ratio of T₄ to T₃ may vary in desiccated thyroid preparations depending on the brand employed and whether it is of porcine or bovine origin.

The daily dosage of L-thyroxine is dependent on age, sex, and body size (146–151). Ideal body weight is best used for clinical dose calculations because lean body mass is the best predictor of daily requirements (152,153). A recent study, however, which did not subclassify patients on the basis of their initial degree of hypothyroidism, found that while the L-thyroxine dose per ideal body weight or degree of overweight differed by sex—with females having a higher dose requirement than men—it did not confirm that age was an independent predictor of dosage (154).

With little residual thyroid function, replacement therapy requires approximately 1.6 μg/kg of L-thyroxine daily (155,156). Patients who are athyreotic (after total thyroidectomy and/or radioiodine therapy) (157) and those with central hypothyroidism may require higher doses (158), while patients with subclinical hypothyroidism (159–162) or after treatment for Graves' disease (163) may require less. Young healthy adults may be started on full replacement dosage, which is also preferred after planned (in preparation for thyroid cancer imaging and therapy) or short-term inadvertent lapses in therapy. Starting with full replacement versus low dosages leads to more rapid normalization of serum TSH but similar time to symptom resolution (164). However, patients with subclinical hypothyroidism do not require full replacement doses (159). Doses of 25–75 μg daily are usually sufficient for achieving euthyroid levels (160), with larger doses usually required for those presenting with higher TSH values (161). One randomized control trial assigned L-thyroxine doses on the basis of the initial serum TSH values as follows: 25 μg for TSH 4.0–8.0 mIU/L, 50 μg for TSH 8–12 mIU/L, and 75 μg for TSH>12 mIU/L. After 2 months only minimal further adjustments were required to achieve euthyroidism (162).

One recent study demonstrated that L-thyroxine absorption within 30 minutes of breakfast is not as effective as when it is taken 4 hours after the last meal (165). Another study showed that taking it 60 minutes before breakfast on an empty stomach was better than taking it within 2 hours of the last meal of the day, which in turn was better than taking it within 20 minutes of breakfast (166). However, these two studies do not establish which of the two methods, L-thyroxine taken with water 60 minutes before breakfast or at bedtime 4 hours after the last meal on an empty stomach, is superior. Although L-thyroxine is better absorbed when taken 60 minutes before a meal compared to 30 minutes before a meal, compliance may be enhanced by instructing patients to consistently take it with water between 30 and 60 minutes prior to eating breakfast.

L-thyroxine should be stored per product insert at 20°C–25°C, (range, 15°C–30°C) or 68°F–77°F (range, 59°F–86°F) and protected from light and moisture. It should not be taken with substances or medications (see Table 10) that interfere with its absorption or metabolism. Because approximately 70% of an orally administered dose of L-thyroxine is absorbed (167–169), individuals unable to ingest L-thyroxine should initially receive 70% or less of their usual dose intravenously. Crushed L-thyroxine suspended in water should be given to patients receiving enteral feeding through nasogastric and other tubes. For optimal absorption feeding should be interrupted with doses given as long as possible after feeding and at least 1 hour before resuming feeding. Administering intravenous L-thyroxine solution, which is not universally available, should be considered when feeding may not be interrupted.

Dose adjustments are guided by serum TSH determinations 4–8 weeks (156,170) following initiation of therapy, dosage adjustments, or change in the L-thyroxine preparation (139,171). While TSH levels may decline within a month of initiating therapy with doses of L-thyroxine such as 50 or 75 μg, making adjustments with smaller doses may require 8 weeks or longer before TSH levels begin to plateau (170,172). Increment changes of 12.5–25 μg/d are initially made, but even smaller changes may be necessary to achieve goal TSH levels.

In the case of central hypothyroidism, estimates of dosage based on 1.6 μg/kg L-thyroxine daily and assessment of free T₄, not TSH, should guide therapy. Determinations are best done prior to taking thyroid hormone. The goal of therapy is generally to attain values above the mean for assays being employed, in keeping with observations that mean values for estimates of free T₄ in patients who are treated with L-thyroxine tend to be higher than mean values observed in untreated controls (150,173–175).

Some clinical manifestations of hypothyroidism, such as chronic skin changes, may take up to 3–6 months to resolve after serum TSH has returned to normal (176).

Once an adequate replacement dosage has been determined most, but not all of us, are of the opinion that periodic follow-up evaluations with repeat TSH testing at 6-month and then 12-month intervals are appropriate (172). Some authors think that more frequent testing is advisable to ensure and monitor compliance with therapy.

Dosage adjustments may be necessary as underlying function wanes. In pregnancy thyroid hormone requirements are increased, then revert back to baseline after delivery (177). Dosage adjustments are also necessary, generally when medications influencing absorption, plasma binding, or metabolism are added or discontinued. When such medications are introduced or discontinued thyroid hormone levels should initially be checked within 4–8 weeks of doing so, and tests performed at least every 4–8 weeks until stable euthyroid indices have been documented while on the same dose of L-thyroxine. Decreases in L-thyroxine requirements occur as patients age (151) and following significant weight loss. Moreover, although elderly patients absorb L-thyroxine less efficiently they often require 20–-25% less per kilogram daily than younger patients, due to decreased lean body mass (152,153). Regardless of the degree of hypothyroidism, patients older than 50–60 years, without evidence of coronary heart disease (CHD) may be started on doses of 50 μg daily. Among those with known CHD, the usual starting dose is reduced to 12.5–25 μg/day. Clinical monitoring for the onset of anginal symptoms is essential (178). Anginal symptoms may limit the attainment of euthyroidism. However, optimal medical management of arteriosclerotic cardiovascular disease (ASCVD) should generally allow for sufficient treatment with L-thyroxine to both reduce the serum TSH and maintain the patient angina-free. Emergency coronary artery bypass grafting in patients with unstable angina or left main coronary artery occlusion may be safely performed while the patient is still moderately to severely hypothyroid (179,180) but elective cases should be performed after the patient has become euthyroid.

The exacerbation of adrenal insufficiency was first described in cases of central hypothyroidism over 70 years ago (181). Although it rarely occurs, those with adrenal insufficiency, either primary or central, or at risk for it, should be treated with clinically appropriate doses of hydrocortisone until adrenal insufficiency is ruled out (182,183). In the absence of central hypothyroidism, elevated TSH levels may be seen in conjunction with normal T₄ levels, making it initially indistinguishable from subclinical hypothyroidism. However, when due to adrenal insufficiency elevated TSH levels fall with glucorticoid therapy alone (54,55).

Patients on high doses of L-thyroxine (>200 μg/d) with persistently or frequently elevated TSH levels may be noncompliant or have problems with L-thyroxine absorption (171). The former is much more common (184). Although daily dosing of L-thyroxine is ideal, missed doses should be made up when the omission is recognized, even on the same or subsequent days. In those with significant compliance problems, weekly dosing with L-thyroxine results in similar clinical safety, outcomes, and acceptable TSH values (185). Absorption is diminished by meals (165,166,168,186) and competing medications (see Table 10).

Steps should be taken to avoid overtreatment with L-thyroxine. This has been reported in 20% of those treated with thyroid hormone (12). The principal adverse consequences of subtle or frank overtreatment are cardiovascular (187–190), skeletal (191–194), and possibly affective disturbances (195–197). The elderly are particularly susceptible to atrial fibrillation, while postmenopausal women, who constitute a substantial portion of those on thyroid hormone, are prone to accelerated bone loss.

Therapeutic endpoints in the treatment of hypothyroidism

The most reliable therapeutic endpoint for the treatment of primary hypothyroidism is the serum TSH value. Confirmatory total T₄, free T₄, and T₃ levels do not have sufficient specificity to serve as therapeutic endpoints by themselves, nor do clinical criteria. Moreover, when serum TSH is within the normal range, free T₄ will also be in the normal range. On the other hand, T₃ levels may be in the lower reference range and occasionally mildly subnormal (150).

The normal range for TSH values, with an upper limit of 4.12 mIU/L is largely based on NHANES III (11) data, but it has not been universally accepted. Some have proposed that the upper normal should be either 2.5 or 3.0 mIU/L (86) for a number of reasons:

• The distribution of TSH values used to establish the normal reference range is skewed to the right by values between 3.1 and 4.12 mIU/L.

The counter arguments are that while many with TSH values between 2.5–3.0 and 4.12 mIU/L may have early hypothyroidism, many do not. Data to support treating patients in this range are lacking, with the exception of data in pregnancy (see Concurrent conditions of special significance in hypothyroid patients—Hypothyroidism during pregnancy). Though patients without thyroid disease have stable mean TSH values, measurements vary up to 50% above (78) and below the mean on a given day. Thus, if the upper normal of TSH were considered to be 2.5 mIU/L, patients with mean values just above the mean NHANES III value of 1.5 mIU/L would frequently be classified as hypothyroid when they are not (78,87). This would lead to more than 10 million additional diagnoses of hypothyroidism in the United States per year—without clear-cut benefit. The controversy has not only contributed to the debate about what TSH values should prompt treatment, but also what the target TSH should be for patients being treated for hypothyroidism. Data concerning clinical benefit are lacking to support targeting to reach low normal or subnormal TSH levels in the treatment of hypothyroidism (198,199). As a result, in patients who are not pregnant, the target range should be within the normal range. If upper and lower normal values for a third generation TSH assay are not available, the range used should be based on the NHANES III reference population range of 0.45–4.12. Although there are substantial normative data establishing what trimester specific normal ranges are for pregnancy (200–207) (see Table 7, TSH upper range of normal), there are no prospective trials establishing optimal target TSH ranges for patients with hypothyroidism who are pregnant and are being treated with L-thyroxine. The lower range of normal for serum TSH in pregnancy is generally 0.1–0.2 mIU/L lower than the normal range for those who are not pregnant (10).

The appropriate target TSH values treatment for treating patients with differentiated thyroid cancer, goiter, and nodular thyroid disease are beyond the scope of these guidelines.

When to consult an endocrinologist

Although most physicians can diagnose and treat hypothyroidism, consultation with an endocrinologist is recommended in the following situations:

• Children and infants

The basis for these recommendations stems from observations that cost-effective diagnostic evaluations and improved outcomes in the medical and surgical evaluation and management of thyroid disorders such as nodular thyroid disease and thyroid cancer are positively correlated with the volume of experience a surgeon has or whether or not the patient was evaluated by an endocrinologist (208–210). In addition, endocrinologists were more knowledgeable about thyroid disease and pregnancy than obstetrician-gynecologists, internists, and family physicians (211). Observational studies comparing care provided by endocrinologists with nonendocrinologists for congenital, pediatric, and central hypothyroidism as well the uncommon, challenging clinical situations just listed, which are regularly addressed by clinical endocrinologists, are lacking, and controlled studies would be unethical.

Concurrent conditions of special significance in hypothyroid patients

Dietary supplements and nutraceuticals in the treatment of hypothyroidism

The majority of dietary supplements (DS) fail to meet a level of scientific substantiation deemed necessary for the treatment of disease (268,269). In the case of hypothyroidism, this is the case for over-the-counter products marketed for “thyroid support” or as a “thyroid supplement” or to promote “thyroid health,” among others. The authors do not recommend the use of these or any unproven therapies (269).

DS are generally thought of as various vitamins, minerals, and other “natural” substances, such as proteins, herbs, and botanicals. The U.S. Food and Drug Administration (FDA) 1994 Dietary Supplement Health and Education Act expanded the definition of DS as follows (270):

Overlap of symptoms in euthyroid and hypothyroid persons

The symptoms of hypothyroidism are nonspecific and mimic symptoms that can be associated with variations in lifestyle, in the absence of disease, or those of many other conditions. This is well illustrated in the Colorado thyroid disease prevalence study (12). That study found that four or more symptoms of hypothyroidism were present in approximately 25% of those with overt hypothyroidism, 20% of those with subclinical hypothyroidism, and in 17% of euthyroid patients. Although the differences were statistically significant since 88% of the population studied was euthyroid, 9% had subclinical hypothyroidism, and only 0.4% were overtly hypothyroid, it is clear that there are many more euthyroid patients with symptoms suggestive of hypothyroidism than those who are subclinically or overtly hypothyroid.

A recent study compared symptoms in euthyroid patients who underwent surgery for benign thyroid disease. Those with Hashimoto's thyroiditis, the commonest cause of hypothyroidism in iodine sufficient regions, were more likely to complain of chronic fatigue, chronic irritability, chronic nervousness, and lower quality-of life than those without evidence of chronic thyroiditis (271). Nonetheless, the promulgation of claims that substances other than thyroid hormone may reverse these symptoms or influence thyroid status has contributed to the widespread use of alternative therapies for hypothyroidism.

Excess iodine intake and hypothyroidism

Iodine is used as a pharmaceutical in the management of hyperthyroidism and thyroid cancer (as radioiodine). Kelp supplements contain at least 150–250 μg of iodine per capsule compared with the recommended daily intake of iodine of 150 μg for adults who are not pregnant or nursing. In euthyroid patients, especially those with chronic thyroiditis, substantial kelp use may be associated with significant increases in TSH levels (38). No clinical data exist to support the preferential use of stable iodine, kelp, or other iodine-containing functional foods in the management of hypothyroidism in iodine-sufficient regions unless iodine deficiency is strongly suspected and confirmed.

Adverse metabolic effects of iodine supplementation are primarily reported in patients with organification defects (e.g., Hashimoto's thyroiditis) in which severe hypothyroidism ensues and is referred to as “iodide myxedema” (39,40). Even though pregnant women may be iodine deficient and require supplementation to achieve a total iodine intake of 200–300 μg/d, ingesting kelp or other seaweed-based products is not recommended owing to the variability in iodine content (16,272,273).

Desiccated thyroid

Animal-derived desiccated thyroid (see L-thyroxine treatment of hypothyroidism) contains T₄ and T₃. Since T₃ levels vary substantially throughout the day in those taking desiccated thyroid, T₃ levels cannot be easily monitored. Being viewed by some as a natural source of thyroid hormone has made it attractive to some patients who may not even have biochemically confirmed hypothyroidism and wish to lose weight or increase their sense of well-being (274). There are substantially more data on the use of synthetic L-thyroxine in the management of well-documented hypothyroidism, goiter, and thyroid cancer than for desiccated thyroid hormone. A PubMed computer search of the literature in January 2012 yielded 35 prospective randomized clinical trials (PRCTs) involving synthetic L-thyroxine published in 2007–2011, compared with no PRCTs involving desiccated thyroid extract for all years in the database. Thus, there are no controlled trials supporting the preferred use of desiccated thyroid hormone over synthetic L-thyroxine in the treatment of hypothyroidism or any other thyroid disease.

3,5,3′-Triiodothyroacetic acid

Another DS/N used for thyroid health is 3,5,3′-triiodothyroacetic acid (TRIAC; tiratricol), an active metabolite of T₃, which has been sold over the counter for weight loss. TRIAC appears to have enhanced hepatic and skeletal thyromimetic effects compared with L-thyroxine (275). The FDA scrutinized its use because of its lack of proven benefit as well as thyrotoxic and hypothyroid side effects (276–278). It is difficult to titrate or monitor clinically and biochemically. Its role in the treatment of hypothyroidism in syndromes of generalized resistance to thyroid hormone, particularly when L-thyroxine alone appears to be inadequate, remains uncertain (279,280). There are no data supporting its use in lieu of synthetic L-thyroxine in the treatment of hypothyroidism.

Thyroid-enhancing preparations

L-tyrosine has been touted as a treatment for hypothyroidism by virtue of its role in thyroid hormone synthesis. There are no preclinical or clinical studies demonstrating that L-tyrosine has thyromimetic properties. B vitamins, garlic, ginger, gingko, licorice, magnesium, manganese, meadowsweet, oats, pineapple, potassium, saw palmetto, and valerian are included in various commercially available “thyroid-enhancing preparations.” There are no preclinical or clinical studies demonstrating any thyromimetic properties of any of these DS/N. In a recent study (281), 9 out of 10 thyroid health supplements (marketed as “thyroid support”) studied contained clinically significant amounts of L-thyroxine (>91 μg/d) and/or L-triiodothyronine (>10 μg/day). Physicians should specifically engage patients regarding all forms of DS/N, specifically those marketed as thyroid support, and consider the possibility that any DS/N could be adulterated with L-thyroxine or L-triiodothyronine.

Thyromimetic preparations

Some DS/N with thyromimetic properties that have been studied but are of unproven clinical benefit include Asian ginseng (282), bladderwrack (283), capsaicin (284), echinacea (285), and forskolin (286).

Selenium

Selenium is an essential dietary mineral that is part of various selenoenzymes. These compounds are in many antioxidant, oxidation-reduction, and thyroid hormone deiodination pathways. It is not surprising that by virtue of these biochemical effects, selenium has been investigated as a modulator of autoimmune thyroid disease and thyroid hormone economy. In one study, selenium administration was found to reduce the risk for cancer, but in a follow-up study of the study cohort, there was an increased risk of diabetes (287). In a well-designed, European PRCT of 2143 euthyroid women, selenium administration (as 200 μg/d selenomethionine) was associated with a reduction in autoimmune thyroid disease, postpartum thyroiditis, and hypothyroidism (288). Since dietary selenium intake varies worldwide, these results may not be generalizable to all populations. In another PRCT involving 501 patients in the United Kingdom who were over age 60 years, varying doses of selenium (100, 200, or 300 μg/d) for 6 months were not associated with beneficial changes in T₄ to T₃ conversion (289). Most recently, a meta-analysis was performed of blinded PRCTs of patients with Hashimoto's thyroiditis receiving L-thyroxine therapy (290). The analysis found that selenium supplementation was associated with decreased anti-TPO titers and improved well-being or mood, but there were no significant changes in thyroid gland ultrasonographic morphology or L-thyroxine dosing. Taken together, what do these limited clinical data suggest? Selenium has notable theoretical potential for salutary effects on hypothyroidism and thyroid autoimmunity including Graves' eye disease (291), both as a preventive measure and as a treatment. However, there are simply not enough outcome data to suggest a role at the present time for routine selenium use to prevent or treat hypothyroidism in any population.

When should anti-thyroid antibodies be measured?

■ RECOMMENDATION 1

Anti-thyroid peroxidase antibody (TPOAb) measurements should be considered when evaluating patients with subclinical hypothyroidism.  Grade B, BEL 1

See: Epidemiology; Primary and secondary etiologies of hypothyroidism

Recommendation 1 was downgraded to B because the best evidence is only predictive in nature. If anti-thyroid antibodies are positive, hypothyroidism occurs at a rate of 4.3% per year versus 2.6% per year when anti-thyroid antibodies are negative. Therefore, the presence of positive TPOAb may or may not influence the decision to treat.

■ RECOMMENDATION 2

TPOAb measurement should be considered in order to identify autoimmune thyroiditis when nodular thyroid disease is suspected to be due to autoimmune thyroid disease.  Grade D, BEL 4

See: Primary and secondary etiologies of hypothyroidism

■ RECOMMENDATION 3

TPOAb measurement should be considered when evaluating patients with recurrent miscarriage, with or without infertility.  Grade A, BEL 2

See: Concurrent conditions of special significance—Infertility

Recommendation 3 was upgraded to A because of favorable risk–benefit potential.

■ RECOMMENDATION 4

Measurement of TSHRAbs using a sensitive assay should be considered in hypothyroid pregnant patients with a history of Graves' disease who were treated with radioactive iodine or thyroidectomy prior to pregnancy. This should be initially done either at 20–26 weeks of gestation or during the first trimester and if they are elevated again at 20–26 weeks of gestation.  Grade A, BEL 2

See: Primary and secondary etiologies of hypothyroidism

Recommendation 4 was upgraded to A because the correlation between a high titer of TSHRAb and the development of fetal or neonatal Graves' disease is strong.

What is the role of clinical scoring systems in the diagnosis of patients with hypothyroidism?

■ RECOMMENDATION 5

Clinical scoring systems should not be used to diagnose hypothyroidism.  Grade A, BEL 1

See: Signs and symptoms of hypothyroidism; Other diagnostic tests for hypothyroidism

What is the role of diagnostic tests apart from serum thyroid hormone levels and TSH in the evaluation of patients with hypothyroidism?

■ RECOMMENDATION 6

Tests such as clinical assessment of reflex relaxation time, cholesterol, and muscle enzymes should not be used to diagnose hypothyroidism.  Grade B, BEL 2

See: Signs and symptoms of hypothyroidism; Other diagnostic tests for hypothyroidism

What are the preferred thyroid hormone measurements in addition to TSH in the assessment of patients with hypothyroidism?

■ RECOMMENDATION 7

Apart from pregnancy, assessment of serum free T₄ should be done instead of total T₄ in the evaluation of hypothyroidism. An assessment of serum free T₄ includes a free T₄ index or free T₄ estimate and direct immunoassay of free T₄ without physical separation using anti-T₄ antibody.  Grade A, BEL 1

See: Measurement of T4 and T3 ; Table 6

■ RECOMMENDATION 8

Assessment of serum free T₄, in addition to TSH, should be considered when monitoring L-thyroxine therapy.  Grade B, BEL 1

See: Measurement of T4 and T3

Recommendation 8 was downgraded to B since it should only be used selectively.

■ RECOMMENDATION 9

In pregnancy, the measurement of total T₄ or a free T₄ index, in addition to TSH, should be done to assess thyroid status. Because of the wide variation in the results of different free T₄ assays, direct immunoassay measurement of free T₄ should only be employed when method-specific and trimester-specific reference ranges for serum free T₄ are available.  Grade B, BEL 2

See: Measurement of T4 and T3

■ RECOMMENDATION 10

Serum total T₃ or assessment of serum free T₃ should not be done to diagnose hypothyroidism.  Grade A, BEL 2

See: Measurement of T4 and T3

Recommendation 10 was upgraded to A because of many independent lines of evidence and expert opinion.

■ RECOMMENDATION 11

TSH measurements in hospitalized patients should be done only if there is an index of suspicion for thyroid dysfunction.  Grade A, BEL 2

See: Measurement of T4 and T3 ; Pitfalls encountered when interpreting serum TSH levels; Concurrent conditions of special significance in hypothyroid patients—Nonthyroidal illness

Recommendation 11 was upgraded to A because of cost considerations and potential for inappropriate intervention.

■ RECOMMENDATION 12

In patients with central hypothyroidism, assessment of free T₄ or free T₄ index, not TSH, should be done to diagnose and guide treatment of hypothyroidism.  Grade A, BEL 1

See: Measurement of T4 and T3 ; L-thyroxine treatment of hypothyroidism

When should TSH levels be measured in patients being treated for hypothyroidism?

■ RECOMMENDATION 13

Patients being treated for established hypothyroidism should have serum TSH measurements done at 4–8 weeks after initiating treatment or after a change in dose. Once an adequate replacement dose has been determined, periodic TSH measurements should be done after 6 months and then at 12-month intervals, or more frequently if the clinical situation dictates otherwise.  Grade B, BEL 2

See: L-thyroxine treatment of hypothyroidism

What should be considered the upper limit of the normal range of TSH values?

■ RECOMMENDATION 14.1

The reference range of a given laboratory should determine the upper limit of normal for a third generation TSH assay. The normal TSH reference range changes with age. If an age-based upper limit of normal for a third generation TSH assay is not available in an iodine sufficient area, an upper limit of normal of 4.12 should be considered.  Grade A, BEL 1

See: Pitfalls encountered when interpreting serum TSH levels; Therapeutic endpoints in the treatment of hypothyroidism; Table 7

■ RECOMMENDATION 14.2

In pregnancy, the upper limit of the normal range should be based on trimester-specific ranges for that laboratory. If trimester-specific reference ranges for TSH are not available in the laboratory, the following upper normal reference ranges are recommended: first trimester, 2.5 mIU/L; second trimester, 3.0 mIU/L; third trimester, 3.5 mIU/L.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patients—Hypothyroidism during pregnancy; Table 7

Which patients with TSH levels above a given laboratory's reference range should be considered for treatment with L-thyroxine?

■ RECOMMENDATION 15

Patients whose serum TSH levels exceed 10 mIU/L are at increased risk for heart failure and cardiovascular mortality, and should be considered for treatment with L-thyroxine.  Grade B, BEL 1

See: Areas for Future Research; When to treat hypothyroidism— Cardiac benefit from treating subclinical hypothyroidism

Recommendation 15 was downgraded to B because it is not generalizable and meta-analysis does not include prospective interventional studies.

■ RECOMMENDATION 16

Treatment based on individual factors for patients with TSH levels between the upper limit of a given laboratory's reference range and 10 mIU/L should be considered particularly if patients have symptoms suggestive of hypothyroidism, positive TPOAb or evidence of atherosclerotic cardiovascular disease, heart failure, or associated risk factors for these diseases.  Grade B, BEL 1

See: Epidemiology; Primary and secondary etiologies of hypothyroidism; Screening and aggressive case finding for hypothyroidism; When to treat hypothyroidism; Areas for Future Research— Cardiac benefit from treating subclinical hypothyroidism; Table 9

Recommendation 16 was downgraded to B because the evidence is not fully generalizable to the stated recommendation and there are no prospective, interventional studies.

In patients with hypothyroidism being treated with L-thyroxine, what should the target TSH ranges be?

■ RECOMMENDATION 17

In patients with hypothyroidism who are not pregnant, the target range should be the normal range of a third generation TSH assay. If an upper limit of normal for a third generation TSH assay is not available, in iodine-sufficient areas an upper limit of normal of 4.12 mIU/L should be considered and if a lower limit of normal is not available, 0.45 mIU/L should be considered.  Grade B, BEL 2

See: Pitfalls encountered when interpreting serum TSH levels; When to treat hypothyroidism; Therapeutic endpoints in the treatment of hypothyroidism; Table 7

In patients with hypothyroidism being treated with L-thyroxine who are pregnant, what should the target TSH ranges be?

■ RECOMMENDATION 18

In patients with hypothyroidism who are pregnant, the target range for TSH should be based on trimester-specific ranges for that laboratory. If trimester-specific reference ranges are not available in the laboratory, the following upper-normal reference ranges are recommended: first trimester, 2.5 mIU/L; second trimester, 3.0 mIU/L; and third trimester, 3.5 mIU/L.  Grade C, BEL 2

See: Pitfalls encountered when interpreting serum TSH levels; When to treat hypothyroidism; Therapeutic endpoints in the treatment of hypothyroidism; Concurrent conditions of special significance in hypothyroid patients— Hypothyroidism during pregnancy; Table 7

Recommendation 18 was downgraded to C due to lack of prospective studies establishing benefit.

Which patients with normal serum TSH levels should be considered for treatment with L-thyroxine?

■ RECOMMENDATION 19.1

Treatment with L-thyroxine should be considered in women of childbearing age with serum TSH levels between 2.5 mIU/L and the upper limit of normal for a given laboratory's reference range if they are in the first trimester of pregnancy or planning a pregnancy including assisted reproduction in the immediate future. Treatment with L-thyroxine should be considered in women in the second trimester of pregnancy with serum TSH levels between 3.0 mIU/L and the upper limit of normal for a given laboratory's reference range, and in women in the third trimester of pregnancy with serum TSH levels between 3.5 mIU/L and the upper limit of normal for a given laboratory's reference range.  Grade B, BEL 2

See: When to treat hypothyroidism; Concurrent conditions of special significance in hypothyroid patients— Hypothyroidism during pregnancy; Table 7

■ RECOMMENDATION 19.2

Treatment with L-thyroxine should be considered in women of childbearing age with normal serum TSH levels when they are pregnant or planning a pregnancy, including assisted reproduction in the immediate future, if they have or have had positive levels of serum TPOAb, particularly when there is a history of miscarriage or past history of hypothyroidism.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patients— Hypothyroidism during pregnancy; Table 7

■ RECOMMENDATION 19.3

Women of childbearing age who are pregnant or planning a pregnancy, including assisted reproduction in the immediate future, should be treated with L-thyroxine if they have or have had positive levels of serum TPOAb and their TSH is greater than 2.5 mIU/L.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patients— Hypothyroidism during pregnancy; Table 7

■ RECOMMENDATION 19.4

Women with positive levels of serum TPOAb or with a TSH greater than 2.5 mIU/L who are not being treated with L-thyroxine should be monitored every 4 weeks in the first 20 weeks of pregnancy for the development of hypothyroidism.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patients— Hypothyroidism during pregnancy; Table 7

Who, among patients who are pregnant, or planning pregnancy, or with other characteristics, should be screened for hypothyroidism?

■ RECOMMENDATION 20.1.1

Universal screening is not recommended for patients who are pregnant or are planning pregnancy, including assisted reproduction.  Grade B, BEL 1

See: Areas for Future Research— Screening for hypothyroidism in pregnancy

Recommendation 20.1.1 was downgraded to B because there are limitations to the evidence and therefore insufficient evidence for lack of benefit.

■ RECOMMENDATION 20.1.2

“Aggressive case finding,” rather than universal screening, should be considered for patients who are planning pregnancy.  Grade C, BEL 2

See: Areas for Future Research— Screening for hypothyroidism in pregnancy

Recommendation 20.1.2 was downgraded to C because even when a diagnosis of hypothyroidism is made, impact on outcomes has not been demonstrated.

■ RECOMMENDATION 20.2

Screening for hypothyroidism should be considered in patients over the age of 60.  Grade B, BEL 1

See: Epidemiology; Primary and secondary etiologies of hypothyroidism; Screening and aggressive case finding for hypothyroidism; Table 8

Recommendation 20.2 was downgraded to B because there is strong evidence that hypothyroidism is common in this group but insufficient evidence of benefit or cost effectiveness.

■ RECOMMENDATION 21

“Aggressive case finding” should be considered in those at increased risk for hypothyroidism.  Grade B, BEL 2

See: Epidemiology; Primary and secondary etiologies of hypothyroidism; Screening and aggressive case finding for hypothyroidism; Table 8

How should patients with hypothyroidism be treated and monitored?

■ RECOMMENDATION 22.1

Patients with hypothyroidism should be treated with L-thyroxine monotherapy.  Grade A, BEL 1

See: L-thyroxine treatment of hypothyroidism

■ RECOMMENDATION 22.2

The evidence does not support using L-thyroxine and L-triiodothyronine combinations to treat hypothyroidism.  Grade B, BEL 1

See: L-thyroxine treatment of hypothyroidism; Concurrent conditions of special significance in hypothyroid patients; Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Desiccated thyroid; Areas for Future Research— L-thyroxine/L-triiodothyronine combination therapy

Recommendation 22.2 was downgraded to Grade B because of still-unresolved issues raised by studies that report that some patients prefer and some patient subgroups may benefit from a combination of L-thyroxine and L-triiodothyronine.

■ RECOMMENDATION 22.3

L-thyroxine and L-triiodothyronine combinations should not be administered to pregnant women or those planning pregnancy.  Grade B, BEL 3

See: Concurrent conditions of special significance in hypothyroid patients— Hypothyroidism during pregnancy

Recommendation 22.3 was upgraded to B because of potential for harm.

■ RECOMMENDATION 22.4

There is no evidence to support using desiccated thyroid hormone in preference to L-thyroxine monotherapy in the treatment of hypothyroidism and therefore desiccated thyroid hormone should not be used for the treatment of hypothyroidism.  Grade D, BEL 4

See: L-thyroxine treatment of hypothyroidism; Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Desiccated thyroid

Recommendation 22.4 was a unanimous expert opinion.

■ RECOMMENDATION 22.5

3,5,3′-triiodothyroacetic acid (TRIAC; tiratricol) should not be used to treat primary and central hypothyroidism due to suggestions of harm in the literature.  Grade C, BEL 3

See: Dietary supplements and nutraceuticals in the treatment of hypothyroidism; 3,5,3′-Triiodothyroacetic acid

■ RECOMMENDATION 22.6

Patients resuming L-thyroxine therapy after interruption (less than 6 weeks) and without an intercurrent cardiac event or marked weight loss may resume their previously employed full replacement doses.  Grade D, BEL 4

See: L-thyroxine treatment of hypothyroidism

Recommendation 22.6 was a unanimous expert opinion.

■ RECOMMENDATION 22.7.1

When initiating therapy in young healthy adults with overt hypothyroidism, beginning treatment with full replacement doses should be considered.  Grade B, BEL 2

See: L-thyroxine treatment of hypothyroidism

■ RECOMMENDATION 22.7.2

When initiating therapy in patients older than 50–60 years with overt hypothyroidism, without evidence of coronary heart disease, an L-thyroxine dose of 50 μg daily should be considered.  Grade D, BEL 4

See: L-thyroxine treatment of hypothyroidism

Recommendation 22.7.2 was a unanimous expert opinion.

■ RECOMMENDATION 22.8

In patients with subclinical hypothyroidism, initial L-thyroxine dosing is generally lower than what is required in the treatment of overt hypothyroidism. A daily dose of 25–75 μg should be considered, depending on the degree of TSH elevation. Further adjustments should be guided by clinical response and follow-up laboratory determinations including TSH values.  Grade B, BEL 2

See: L-thyroxine treatment of hypothyroidism

■ RECOMMENDATION 22.9

Treatment with glucocorticoids in patients with combined adrenal insufficiency and hypothyroidism should precede treatment with L-thyroxine.  Grade B, BEL 2

See: Disorders associated with hypothyroidism; Pitfalls encountered when trying to interpret serum TSH levels; L-thyroxine treatment of hypothyroidism

■ RECOMMENDATION 23

L-thyroxine should be taken with water consistently 30–60 minutes before breakfast or at bedtime 4 hours after the last meal. It should be stored properly per product insert and not taken with substances or medications that interfere with its absorption.  Grade B, BEL 2

See: L-thyroxine treatment of hypothyroidism; Table 10

■ RECOMMENDATION 24

In patients with central hypothyroidism, assessments of serum free T₄ should guide therapy and targeted to exceed the midnormal range value for the assay being used.  Grade B, BEL 3

See: Primary and secondary etiologies of hypothyroidism; Measurement of T4 and T3 ; Pitfalls encountered when interpreting serum TSH levels; L-thyroxine treatment of hypothyroidism

Recommendation 24 was upgraded to B because more than 50% of patients with central hypothyroidism adequately treated with L-thyroxine have values in this range.

■ RECOMMENDATION 25.1

In patients with hypothyroidism being treated with L-thyroxine who are pregnant, serum TSH should be promptly measured after conception and L-thyroxine dosage adjusted, with a goal TSH of less than 2.5 mIU/L during the first trimester.  Grade B, BEL 2

See: Therapeutic endpoints in the treatment of hypothyroidism; Concurrent conditions of special significance in hypothyroid patients— Hypothyroidism during pregnancy; Table 7

■ RECOMMENDATION 25.2

In patients with hypothyroidism being treated with L-thyroxine who are pregnant, the goal TSH during the second trimester should be less than 3 mIU/L and during the third trimester should be less than 3.5 mIU/L.  Grade C, BEL 2

See: Therapeutic endpoints in the treatment of hypothyroidism; Concurrent conditions of special significance in hypothyroid patients— Hypothyroidism during pregnancy; Table 7.

Recommendation 25.2 was downgraded to C due to lack of prospective studies establishing benefit.

■ RECOMMENDATION 25.3

Maternal serum TSH (and total T₄) should be monitored every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation and L-thyroxine dosages adjusted as indicated.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patients— Hypothyroidism during pregnancy

■ RECOMMENDATION 26

In patients receiving L-thyroxine treatment for hypothyroidism, serum TSH should be remeasured within 4–8 weeks of initiation of treatment with drugs that decrease the bioavailability or alter the metabolic disposition of the L-thyroxine dose.  Grade A, BEL 1

See: L-thyroxine treatment of hypothyroidism; Areas for Future Research— Agents and conditions having an impact on L-thyroxine therapy and interpretation of thyroid tests; Tables 5 and 10.

■ RECOMMENDATION 27

Apart from pregnant patients being treated with L-thyroxine for hypothyroidism, the evidence does not support targeting specific TSH values within the normal reference range.  Grade B, BEL 2

See: Therapeutic endpoints in the treatment of hypothyroidism

When should endocrinologists be involved in the care of patients with hypothyroidism?

■ RECOMMENDATION 28

Physicians who are not endocrinologists, but who are familiar with the diagnosis and treatment of hypothyroidism should be able to care for most patients with primary hypothyroidism. However, patients with hypothyroidism who fall into the following categories should be seen in consultation with an endocrinologist. These categories are (i) children and infants, (ii) patients in whom it is difficult to render and maintain a euthyroid state, (iii) pregnancy, (iv) women planning conception, (v) cardiac disease, (vi) presence of goiter, nodule, or other structural changes in the thyroid gland, (vii) presence of other endocrine disease such as adrenal and pituitary disorders, (viii) unusual constellation of thyroid function test results, and (ix) unusual causes of hypothyroidism such as those induced by agents that interfere with absorption of L-thyroxine, impact thyroid gland hormone production or secretion, affect the hypothalamic–pituitary–thyroid axis (directly or indirectly), increase clearance, or peripherally impact metabolism.  Grade C, BEL 3

See: When to consult an endocrinologist; Table 10

Which patients should not be treated with thyroid hormone?

■ RECOMMENDATION 29

Thyroid hormones should not be used to treat symptoms suggestive of hypothyroidism without biochemical confirmation of the diagnosis.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patients—Patients with normal thyroid tests

■ RECOMMENDATION 30

Thyroid hormones should not be used to treat obesity in euthyroid patients.  Grade A, BEL 2

See: Concurrent conditions of special significance in hypothyroid patients—Obesity

Recommendation 30 was upgraded to Grade A because of potential harm.

■ RECOMMENDATION 31

There is insufficient evidence to support using thyroid hormones to treat depression in euthyroid patients.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patients—Depression

What is the role of iodine supplementation, dietary supplements, and nutraceuticals in the treatment of hypothyroidism?

■ RECOMMENDATION 32.1

Iodine supplementation, including kelp or other iodine-containing functional foods, should not be used in the management of hypothyroidism in iodine-sufficient areas.  Grade C, BEL 3

See: Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Excess iodine intake and hypothyroidism

■ RECOMMENDATION 32.2

Iodine supplementation in the form of kelp or other seaweed-based products should not be used to treat iodine deficiency in pregnant women.  Grade D, BEL 4

See: Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Excess iodine intake and hypothyroidism

Recommendation 32.2 was a unanimous expert opinion

■ RECOMMENDATION 33

Selenium should not be used to prevent or treat hypothyroidism.  Grade B, BEL 2

See: Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Selenium.

■ RECOMMENDATION 34

Patients taking dietary supplements and nutraceuticals for hypothyroidism should be advised that commercially available thyroid-enhancing products are not a remedy for hypothyroidism and should be counseled about the potential side effects of various preparations particularly those containing iodine or sympathomimetic amines as well as those marked as “thyroid support” since they could be adulterated with L-thyroxine or L-triiodothyronine.  Grade D, BEL 4

See: Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Thyroid enhancing preparations; Thyromimetic preparations

Recommendation 34 was a unanimous expert opinion.

Cardiac benefit from treating subclinical hypothyroidism

Overt hypothyroidism produces reversible changes in cardiovascular hemodynamics and in many of the modifiable cardiovascular risk factors for ASCVD and heart failure. Some prospective studies also indicate that treatment of subclinical hypothyroidism, including groups with minimally elevated TSH levels, results in improvement in surrogate markers for ASCVD such as atherogenic lipids (120–123) and carotid intima media thickness (126).

A meta-analysis of 10 longitudinal studies of subclinical hypothyroidism (119), which excluded patients with ASCVD at baseline, showed a relative risk of CHD of 1.2 when all studies were combined. When only higher quality studies were analyzed, the risk dropped to 1.02–1.08 depending on whether the study design allowed for adjudicated outcomes with or without knowledge of thyroid status. However, in studies with mean age younger than 65 years, the risk was 1.51 compared with 1.05 in studies with a mean age of 65 and over. Another meta-analysis, also done in 2008, of 15 studies with over 2500 participants with subclinical hypothyroidism, eight of which were also used in the aforementioned meta-analysis, showed elevated odds ratios for the incidence of ASCVD and cardiovascular all-cause mortality of 1.57 and 1.37 for those under 65 years, but not for those over 65 years (292).

A study from the Cleveland Clinic Preventive Cardiology Clinic of patients at high risk for ASCVD showed that those with TSH levels of 6.1–10 mIU/L as well as greater than 10 mIU/L who were under 65 years and not treated with thyroid hormone had higher all-cause mortality (118). Most recently a U.K. general practitioner database was analyzed to assess the impact of L-thyroxine treatment on fatal and nonfatal cardiac events in over 3000 individuals with subclinical hypothyroidism (TSH between 5.01 and 10 mIU/L) aged between 40 and 70 years and over 1500 individuals older than 70 years who were followed up for a median of ∼8 years. In the ∼50% of individuals between 40 and 70 years of age who were treated with L-thyroxine (87.4% women) the hazard ratio for ischemic heart disease events was reduced compared to the ∼50% of untreated individuals (82.5% women) (0.61, CI 0.49–0.92). This reduction was not evident in those older than 70 years, of whom 84.6% in the treatment group and 75.6% in the untreated group were women (293).

Yet other studies fail to show that an increased risk of cardiac disease in those with subclinical hypothyroidism is age dependent. The Cardiovascular Health Study followed 3000 patients 65 years or older with subclinical hypothyroidism who were initially free of heart failure. Those with TSH levels of 10 mIU/L or greater had an increased risk of heart failure (294). During the 20 years of follow-up in the Whickham Survey, an association was found between ASCVD and ASCVD-related mortality in those with subclinical hypothyroidism whose TSH values were between 6 and 15 mIU/L independent of age. When those treated with L-thyroxine were excluded, ASCVD-related morbidity and mortality were no longer evident (116). Additional large-scale studies in those with serum TSH values of 10 mIU/L or greater including a study of 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan demonstrated an increase in ASCVD that was independent of age (115) while a study of six prospective cohorts with over 2000 patients had an increased incidence of heart failure in those up to 80 years of age (117).

The absence of randomized prospective controlled trials leaves us with several unresolved key issues pertaining to subclinical hypothyroidism, including whether or not L-thyroxine treatment will prevent the development of ASCVD or decrease the frequency of hospital admissions for heart failure and whether age is a critical determinant of risk for cardiac morbidity. A prospective study to assess both of these parameters is currently being planned.

Cognitive benefit from treating subclinical hypothyroidism

Some reports on mood, cognitive, and other objective brain function studies in subclinical hypothyroidism demonstrate the presence and reversal of deficits after treatment with L-thyroxine (295). However, other studies have not (296,297).

L-thyroxine and L-triiodothyronine combination therapy

An important question is whether a recent study had sufficient data to warrant revisiting why some patients seem to feel better on L-thyroxine/L-triiodothyronine combinations and whether we can identify them and safely treat them (136) with this combination.

L-triiodothyronine monotherapy

A potential role for L-triiodothyronine monotherapy in lieu of L-thyroxine monotherapy was recently raised by a small randomized, double-blind crossover intervention study done comparing L-triiodothyronine monotherapy with L-thyroxine monotherapy in patients with hypothyroidism (298). Thrice daily dosing was employed for each. Comparable TSH levels were achieved. Mild weight loss and decreases in total cholesterol, LDL cholesterol, and apolipoprotein levels were seen without differences in cardiovascular function, insulin sensitivity, or quality of life with L-triiodothyronine monotherapy compared with L-thyroxine monotherapy. The small size and short duration of the study as well as thrice daily dosing presently precludes considering L-triiodothyronine monotherapy as an alternative to L-thyroxine monotherapy (298).

Thyroid hormone analogues

Thyroid hormone's effects are protean, affecting virtually every organ system. Efforts are underway to develop and study analogues that have selective beneficial effects on weight control, lipoproteins, and TSH suppression without inducing hypothyroidism or the most important negative consequences of hyperthyroidism on the heart and skeleton. Compounds studied to date include D-thyroxine (299), tiratricol (275), eprotiromone (KB 2115) (300,301), and diodothyropropionic acid (302). A recent prospective Phase II clinical trial of the thyroid hormone analogue eprotirome, designed to be a selective beta II receptor agonist, has been shown to lower both total cholesterol and Lp(a) without any change in thyroid hormone levels or untoward cardiovascular or bone effects (300). However, the development program for eprotirome has been discontinued due to adverse findings in preclinical studies. Further studies will be needed to confirm the benefit and lack of side effects of these agents.

Screening for hypothyroidism in pregnancy

It remains unclear if screening for hypothyroidism in pregnancy is beneficial. A consensus statement in 2004 (106) and clinical practice guidelines in 2007 (303) and 2011 (10) found insufficient data to support a 1999 (304) and restated 2005 recommendation (305) for universal screening for thyroid dysfunction during pregnancy, but rather recommended aggressive case finding.

Arguments for screening include the following:

• Limiting evaluation to women in high-risk groups misses 30% of pregnant women with overt or subclinical hypothyroidism (306).

However, questions remain about the utility of screening those at low risk for developing hypothyroidism (307) and whether screening and intervention earlier on in the first trimester (219) may be cost effective.

The Controlled Antenatal Thyroid Study in the United Kingdom and Italy examined the impact at 3 years of age of L-thyroxine treatment if free T₄ is below the 2.5th percentile or if TSH is above the 97.5th percentile (219). Analyses failed to demonstrate a benefit when screening was performed around the end of the first trimester. Whether earlier intervention, different cognitive testing, or the same testing performed at age greater than 3 years would yield different results is uncertain. “A Randomized Trial of Thyroxine Therapy for Subclinical Hypothyroidism or Hypothyroxinemia Diagnosed During Pregnancy”, done under the auspices of the National Institute of Child Health and Human Development, is presently studying the IQ at 5 years of age following a universal screening versus case finding program.

Agents and conditions having an impact on L-thyroxine therapy and interpretation of thyroid tests

Conditions such as pregnancy and malabsorption, drugs, diagnostic agents, dietary substances, and supplements can have an impact on thyroid hormone economy, which may or may not result in a change in thyroid status. For example, orally administered estrogens increase TBG levels. While this does not alter thyroid status in euthyroid individuals with normal thyroid reserve, it may do so when there is either marginal thyroid reserve or established hypothyroidism. Drugs may have multiple effects on thyroid hormone metabolism. Notable examples include glucocorticoids and amiodarone. In a number of cases, the mechanisms by which agents alter thyroid status are not known. The impact that an agent or condition has on thyroid status may require clinicians to increase monitoring, adjust dosages, or instruct patients to change how and when they take L-thyroxine.

Major determinants of whether or not drugs and other substances will have an impact on thyroid status include the following:

• Dosage

The principal mechanisms and reasons that conditions, drugs, and other substances have an impact on thyroid status are the following:

• Effects on thyroid hormone metabolism:

Table 10 lists agents and some conditions that affect thyroid status—particularly if they are commonly used—and are likely to do so or to have a profound impact on it. However, some very commonly used drugs such as sulfonylureas or sulfonamides or foodstuffs such as grapefruit juice that may only have a minor impact have been included. Because of their potential importance, some drugs, such as perchlorate, iopanoic acid, and ipodate, are also listed even though they are not generally available. On the other hand, some drugs that are rarely used have been omitted. Agents may appear more than once if there is more than one known mechanism of action. A comprehensive review of this subject and references for each drug or condition is beyond the scope of these guidelines. The interested reader is encouraged to consult other sources for more information (309–311).