Clinical Practice Guidelines for Hypothyroidism in Adults ...

PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS 1207Disorders associated with hypothyroidismThe most common form of thyroid failure has an autoimmuneetiology. Not surprisingly, there is also an increasedfrequency of other autoimmune disorders in this populationsuch as type 1 diabetes, pernicious anemia, primary adrenalfailure (Addison’s disease), myasthenia gravis, celiac disease,rheumatoid arthritis, systemic lupus erythematosis (17–25),and rarely thyroid lymphoma (50).Distinct genetic syndromes with multiple autoimmuneendocrinopathies have been described, with some overlappingclinical features. The presence of two of the threemajor characteristics is required to diagnose the syndrome ofmultiple autoimmune endocrinopathies (MAEs). The definingmajor characteristics for type 1 MAE and type 2 MAE areas follows: Type 1 MAE: Hypoparathyroidism, Addison’s disease,and mucocutaneous candidiasis caused by mutations inthe autoimmune regulator gene (AIRE), resulting indefective AIRE protein (51). Autoimmune thyroiditis ispresent in about 10%–15% (52). Type 2 MAE: Addison’s disease, autoimmune thyroiditis,and type 1 diabetes known as Schmidt’s syndrome(53).When adrenal insufficiency is present, the diagnosis ofsubclinical hypothyroidism should be deferred until afterglucocorticoid therapy has been instituted because TSHlevels may be elevated in the presence of untreated adrenalinsufficiency and may normalize with glucocorticoid therapy(54,55) (see L-thyroxine treatment of hypothyroidism).Signs and symptoms of hypothyroidismThe well-known signs and symptoms of hypothyroidismtend to be more subtle than those of hyperthyroidism. Dry skin,cold sensitivity, fatigue, muscle cramps, voice changes, andconstipation are among the most common. Less commonlyappreciated and typically associated with severe hypothyroidismare carpal tunnel syndrome, sleep apnea, pituitaryhyperplasia that can occur with or without hyperprolactinemiaand galactorrhea, and hyponatremia that can occur withinseveral weeks of the onset of profound hypothyroidism. Although,for example, in the case of some symptoms such asvoice changes subjective (12,56) and objective (57) measuresdiffer. Several rating scales (56,58,59) have been used to assessthe presence and, in some cases, the severity of hypothyroidism,but have low sensitivity and specificity. While the exerciseof calculating clinical scores has been largely superseded bysensitive thyroid function tests, it is useful to have objectiveclinical measures to gauge the severity of hypothyroidism.Early as well as recent studies strongly correlate the degree ofhypothyroidism with ankle reflex relaxation time, a measurerarely used in current clinical practice today (60).Normalization of a variety of clinical and metabolic endpoints including resting heart rate, serum cholesterol, anxietylevel, sleep pattern, and menstrual cycle abnormalities includingmenometrorrhagia are further confirmatory findingsthat patients have been restored to a euthyroid state (61–65).Normalization of elevated serum creatine kinase or othermuscle (66) or hepatic enzymes following treatment ofhypothyroidism (67) are additional, less well-appreciated andalso nonspecific therapeutic endpoints.Measurement of T 4 and T 3T 4 is bound to specific binding proteins in serum. Theseare T 4 -binding globulin (TBG) and, to a lesser extent,transthyretin or T 4 -binding prealbumin and albumin. Sinceapproximately 99.97% of T 4 is protein-bound, levels ofserum total T 4 will be affected by factors that alter bindingindependent of thyroid disease (Table 5) (68,69). Accordingly,methods for assessing (including estimating andmeasuring) serum free T 4 , which is the metabolicallyavailable moiety (70), have been developed, and assessmentof serum free T 4 has now largely replaced measurement ofserum total T 4 as a measure of thyroid status. Thesemethods include the serum free T 4 index, which is derivedas the product of total T 4 and a thyroid hormone bindingratio, and the direct immunoassay of free T 4 after ultrafiltrationor equilibrium dialysis of serum or after addition ofanti-T 4 antibody to serum (71).A subnormal assessment of serum free T 4 serves to establisha diagnosis of hypothyroidism, whether primary, inwhich serum TSH is elevated, or central, in which serum TSHis normal or low (46,47). An assessment of serum free T 4(Table 6) is the primary test for detecting hypothyroidism inantithyroid drug–treated or surgical or radioiodine-ablatedpatients with previous hyperthyroidism in whom serum TSHmay remain low for many weeks to months.In monitoring patients with hypothyroidism on L-thyroxinereplacement, blood for assessment of serum free T 4 should becollected before dosing because the level will be transientlyincreased by up to 20% after L-thyroxine administration (72).In one small study of athyreotic patients, serum total T 4 levelsincreased above baseline by 1 hour and peaked at 2.5 hours,while serum free T 4 levels peaked at 3.5 hours and remainedhigher than baseline for 9 hours (72).In pregnancy, measurement of serum total T 4 is recommendedover direct immunoassay of serum free T 4 . Becauseof alterations in serum proteins in pregnancy, directimmunoassay of free T 4 may yield lower values based onreference ranges established with normal nonpregnant sera.Moreover, many patients will have values below the nonpregnantreference range in the third trimester, includingTable 5. Factors That Alter Thyroxineand Triiodothyronine Binding in SerumIncreased TBG Decreased TBG Binding inhibitorsInherited Inherited SalicylatesPregnancy Androgens FurosemideNeonatal state Anabolic steroids Free fatty acidsEstrogens Glucocorticoids PhenytoinHepatitis Severe illness CarbamazepinePorphyria Hepatic failure NSAIDs (variable,HeroinNephrosistransient)Methadone Nicotinic acid HeparinMitotane L-Asparaginase5-FluorouracilSERMS (e.g.,tamoxifen,raloxifene)PerphanazineTBG, T 4 -binding globulin; SERMS, selective estrogen receptormodulators; NSAIDs, nonsteroidal anti-inflammatory drugs.