Clinical Practice Guidelines for Hypothyroidism in Adults ...

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PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS 1205BestevidencelevelTable 3. Grade-Recommendation Protocol2010 AACE Protocol for Production of Clinical PracticeGuidelines—Step III: Grading of recommendations;How different evidence levels can be mappedto the same recommendation gradeSubjectivefactorimpactTwothirdsRecommendationconsensus Mapping a grade1 None Yes Direct A2 Positive Yes Adjust up A2 None Yes Direct B1 Negative Yes Adjust down B3 Positive Yes Adjust up B3 None Yes Direct C2 Negative Yes Adjust down C4 Positive Yes Adjust up C4 None Yes Direct D3 Negative Yes Adjust down D1,2,3,4 N/A No Adjust down DAdopted by the AACE and the ATA for the Hypothyroidism CPG.a Starting with the left column, best evidence levels (BELs),subjective factors, and consensus map to recommendation gradesin the right column. When subjective factors have little or no impact(‘‘none’’), then the BEL is directly mapped to recommendationgrades. When subjective factors have a strong impact, then recommendationgrades may be adjusted up (‘‘positive’’ impact) or down(‘‘negative’’ impact). If a two-thirds consensus cannot be reached,then the recommendation grade is D.Source: Mechanick et al., 2010 (5).N/A, not applicable (regardless of the presence or absence ofstrong subjective factors, the absence of a two-thirds consensusmandates a recommendation grade D).enables authors to use this language even when the best evidencelevel available is ‘‘expert opinion.’’ Although differentgrading systems were employed, an effort was made to makethese recommendations consistent with related portions of‘‘Hyperthyroidism and Other Causes of Thyrotoxicosis:Management Guidelines of the American Thyroid Associationand American Association of Clinical Endocrinologists’’(8,9), as well as the ‘‘Guidelines of the American ThyroidAssociation for the Diagnosis and Management of ThyroidDisease During Pregnancy and Postpartum’’ (10).The shortcomings of this evidence-based methodology inthese CPGs are that many recommendations are based onweak scientific data (Level 3) or consensus opinion (Level 4),rather than strong scientific data (Levels 1 and 2). There arealso the problems of (i) subjectivity on the part of the authorswhen weighing positive and negative, or epidemiologicversus experimental, data in order to arrive at an evidencebasedrecommendation grade or consensus opinion, (ii) subjectivityon the part of the authors when weighing subjectiveattributes, such as cost effectiveness and risk-to-benefit ratios,in order to arrive at an evidence-based recommendationgrade or consensus opinion, (iii) potentially incomplete reviewof the literature by the authors despite extensive diligence,and (iv) bias in the available publications, whichoriginate predominantly from experienced clinicians andlarge academic medical centers and may, therefore, not reflectthe experience at large. The authors, through an a priorimethodology and multiple levels of review, have tried toaddress these shortcomings by discussions with three experts(see Acknowledgments).Summary of recommendation gradesThe recommendations are evidence-based (Grades A, B, andC) or based on expert opinion because of a lack of conclusiveclinical evidence (Grade D). The ‘‘best evidence’’ rating level(BEL), which corresponds to the best conclusive evidencefound, accompanies the recommendation grade. Details regardingthe mapping of clinical evidence ratings to these recommendationgrades have already been provided [see Levels ofscientific substantiation and recommendation grades (transparency)].In this CPG, a substantial number of recommendations areupgraded or downgraded because the conclusions may notapply in other situations (non-generalizability). For example,what applies to an elderly population with established cardiacdisease may not apply to a younger population without cardiacrisk factors. Whenever expert opinions resulted in upgradingor downgrading a recommendation, it is explicitly stated afterthe recommendation.TOPICS RELATING TO HYPOTHYROIDISMEpidemiologyHypothyroidism may be either subclinical or overt. Subclinicalhypothyroidism is characterized by a serum TSHabove the upper reference limit in combination with a normalfree thyroxine (T 4 ). This designation is only applicable whenthyroid function has been stable for weeks or more, the hypothalamic–pituitary–thyroidaxis is normal, and there is norecent or ongoing severe illness. An elevated TSH, usuallyabove 10 mIU/L, in combination with a subnormal free T 4characterizes 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 age12 between 1988 and 1994, using the upper limit of normal forTable 4. Prevalence of HypothyroidismStudy Subclinical Overt TSH CommentNHANES III 4.3% 0.3% 4.5Colorado Thyroid Disease Prevalence 8.5% 0.4% 5.0 Not on thyroid hormoneFramingham 10.0 Over age 60 years: 5.9% women; 2.3% men; 39% ofwhom had subnormal T 4British Whickham 10.0 9.3% women; 1.2% menSources: Hollowell et al., 2002 (11); Canaris et al., 2000 (12); Sawin et al., 1985 (13); Vanderpump et al., 1995 (14); Vanderpump andTunbridge, 2002 (15).NHANES, National Health and Nutrition Examination Survey.
1206 GARBER ET AL.TSH as 4.5 mIU/mL (11). The prevalence of subclinical diseasewas 4.3% and of overt disease was 0.3%. The Coloradothyroid disease prevalence survey, in which self-selected individualsattending a health fair were tested and an uppernormal TSH value of 5.0 mIU/L was used, reported a prevalenceof 8.5% and 0.4% for subclinical and overt disease,respectively, in people not taking thyroid hormone (12). In theFramingham study, 5.9% of women and 2.3% of men over theage of 60 years had TSH values over 10 mIU/L, 39% of whomhad subnormal T 4 levels (13). In the British Whickham survey9.3% of women and 1.2% of men had serum TSH values over10 mIU/L (14,15). The incidence of hypothyroidism in womenwas 3.5 per 1000 survivors per year and in men it was 0.6 per1000 survivors per year. The risk of developing hypothyroidismin women with positive antibodies and elevated TSHwas 4% per year versus 2%–3% per year in those with eitheralone (14,15). In men the relative risk rose even more in eachcategory, but the rates remained well below those of women.Primary and secondary etiologiesof hypothyroidismEnvironmental iodine deficiency is the most commoncause of hypothyroidism on a worldwide basis (16). In areasof iodine sufficiency, such as the United States, the mostcommon cause of hypothyroidism is chronic autoimmunethyroiditis (Hashimoto’s thyroiditis). Autoimmune thyroiddiseases (AITDs) have been estimated to be 5–10 times morecommon in women than in men. The ratio varies from seriesto series and is dependent on the definition of disease,whether it is clinically evident or not. In the Whickhamsurvey (14), for example, 5% of women and 1% of men hadboth positive antibody tests and a serum TSH value > 6.This form of AITD (i.e., Hashimoto’s thyroiditis, chronicautoimmune thyroiditis) increases in frequency with age(11), and is more common in people with other autoimmunediseases and their families (17–25). Goiter may or may notbe present.AITDs are characterized pathologically by infiltration ofthe thyroid with sensitized T lymphocytes and serologicallyby circulating thyroid autoantibodies. Autoimmunity to thethyroid gland appears to be an inherited defect in immunesurveillance, leading to abnormal regulation of immune responsivenessor alteration of presenting antigen in the thyroid(26,27).One of the keys to diagnosing AITDs is determiningthe presence of elevated anti-thyroid antibody titerswhich include anti-thyroglobulin antibodies (TgAb), anti–microsomal/thyroid peroxidase antibodies (TPOAb), andTSH receptor antibodies (TSHRAb). Many patients withchronic autoimmune thyroiditis are biochemically euthyroid.However, approximately 75% have elevated anti-thyroidantibody titers. Once present, these antibodies generallypersist, with spontaneous disappearance occurring infrequently.Among the disease-free population in the NHANESsurvey, tests for TgAb were positive in 10.4% and TPOAb in11.3%. These antibodies were more common in women thanmen and increased with age. Only positive TPOAb tests weresignificantly associated with hypothyroidism (11). The presenceof elevated TPOAb titers in patients with subclinicalhypothyroidism helps to predict progression to overt hypothyroidism—4.3%per year with TPOAb vs. 2.6% per yearwithout elevated TPOAb titers (14,28). The higher risk ofdeveloping overt hypothyroidism in TPOAb-positive patientsis the reason that several professional societies and manyclinical endocrinologists endorse measurement of TPOAbs inthose with subclinical hypothyroidism.In patients with a diffuse, firm goiter, TPOAb should bemeasured to identify autoimmune thyroiditis. Since nonimmunologicallymediated multinodular goiter is rarely associatedwith destruction of functioning tissue andprogression to hypothyroidism (29), it is important to identifythose patients with the nodular variant of autoimmune thyroiditisin 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 excludemalignancy. Also, in patients with documentedhypothyroidism, measurement of TPOAb identifies the cause.In the presence of other autoimmune disease such astype 1 diabetes (20,21) or Addison’s disease (17,18), chromosomaldisorders such as Down’s (30) or Turner’s syndrome(31), and therapy with drugs such as lithium (32–34), interferonalpha (35,36), and amiodarone (37) or excess iodine ingestion(e.g., kelp) (38–40), TPOAb measurement may provide prognosticinformation on the risk of developing hypothyroidism.TSHRAb may act as a TSH agonist or antagonist (41).Thyroid stimulating immunoglobulin (TSI) and/or thyrotropinbinding inhibitory immunoglobulin (TBII) levels,employing sensitive assays, should be measured in euthyroidor L-thyroxine–treated hypothyroid pregnant womenwith a history of Graves’ disease because they are predictorsof fetal and neonatal thyrotoxicosis (42). Since the risk forthyrotoxicosis correlates with the magnitude of elevation ofTSI, and since TSI levels tend to fall during the second trimester,TSI measurements are most informative when donein the early third trimester. The argument for measurementearlier in pregnancy is also based, in part, on determiningwhether establishing a surveillance program for ongoingfetal and subsequent neonatal thyroid dysfunction isnecessary (43).Hypothyroidism may occur as a result of radioiodine orsurgical treatment for hyperthyroidism, thyroid cancer, orbenign nodular thyroid disease and after external beam radiationfor non–thyroid-related head and neck malignancies,including lymphoma. A relatively new pharmacologic causeof iatrogenic hypothyroidism is the tyrosine kinase inhibitors,most notably sunitinib (44,45), which may induce hypothyroidismthrough reduction of glandular vascularity and inductionof type 3 deiodinase activity.Central hypothyroidism occurs when there is insufficientproduction of bioactive TSH (46,47) due to pituitary or hypothalamictumors (including craniopharyngiomas), inflammatory(lymphocytic or granulomatous hypophysitis) orinfiltrative diseases, hemorrhagic necrosis (Sheehan’s syndrome),or surgical and radiation treatment for pituitary orhypothalamic disease. In central hypothyroidism, serum TSHmay be mildly elevated, but assessment of serum free T 4 isusually low, differentiating it from subclinical primary hypothyroidism.Consumptive hypothyroidism is a rare condition that mayoccur in patients with hemangiomata and other tumors inwhich type 3 iodothyronine deiodinase is expressed, resultingin accelerated degradation of T 4 and triiodothyronine (T 3 )(48,49).
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