Page 1. Understanding Common Thyroid Disorders. Cases. Topics Covered

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1 Cases Understanding Common Thyroid Disorders Douglas C. Bauer, MD UCSF Division of General Internal Medicine No Disclosures 66 yr old female with 1 yr of fatigue and lassitude and no findings except TSH=8.2, nl free T4, anti-tpo positive 54 yr old female with new atrial fibrillation and no other findings except TSH=0.04, normal free T4 45 yr old female, enlarged thyroid with dominant nodule since 1999, FNA benign. On T4 suppression ever since, TSH=0.1 Topics Covered Rational use of thyroid tests Subclinical thyroid disease What can to wrong? Underactive Overactive Enlarged Screening for dysfunction and when to refer Page 1

2 Thyroid Tests: stsh Very sensitive to circulating thyroid hormone levels Excellent correlation with TRH stimulation (stsh < 0.1) Requires intact pituitary-hypothalamic axis; 4-6 weeks to equilibrate Falsely low: severe illness, corticosteroids, dopamine Normal range mu/l (non-pregnant); $58 Normal TSH in NHANEs TSH skewed upwards in elderly: Normal or disease? NHANEs: >13,000 people 12 to 80+ years (Surks, JCEM 2007) Exclude anyone with known thyroid disease or drugs that could effect TSH Median TSH 1.39 miu/l 97.5 th Percentile < 60 around 4.0 miu/l up to 4.3 miu/l up to 5.9 miu/l 80+ up to 7.5 miu/l Pregnancy discussed later Thyroid Tests: Free Thyroxine Measures unbound hormone Has replaced index assays Gold standard: Equilibrium dialysis Other immunoassays: Improving Normal range, 9-24 pmol/l (nonpregnant); $64 Are Both stsh and Free T4 Necessary? American Thyroid Association says Yes Others recommend stsh first Simultaneous ordering common in clinical practice UCSF outpatient data (Bauer, Arch IM 2003) Results when both tests ordered on the same specimen (N=3143) Each test classified as low, normal or high Page 2

3 Diagnostic Redundancy of stsh and Free T4 Subclinical Thyroid Disease Free T4 (pmol/l) stsh (miu/l) < > 5.5 < > Subclinical hypothyroidism Abnormally high sensitive TSH and normal thyroid hormone levels Subclinical hyperthyroidism Abnormally low sensitive TSH and normal thyroid hormone levels Thyroid Antibodies Anti-thyroperoxidase, TPO (titer<100, $78) Similar to anti-microsomal Most sensitive thyroid autoantibody Specificity a problem TSH receptor antibody (absent, $112) Causes Grave s disease Rarely found in normal individuals Thyroid Scans Technetium 99 ($450) Low radiation, quick Useful for nodules in some circumstances Useful to determine cause of hyperthyroidism High uptake: Grave s, toxic nodule Low uptake: thyroiditis, thyroxine use Page 3

4 Suggested Lab Testing Strategy When there is no suspicion of a disrupted pituitary-thyroid axis: If stsh is normal, STOP If stsh is low, measure T4 (consider T3 if T4 is normal) If stsh is high, measure T4, consider TPO antibodies Hypothyroidism: Etiology Autoimmune (Hashimoto s) Iodine deficiency Iatrogenic A. Radioiodine/ surgery B. Drugs (lithium, amiodarone) Pituitary/ hypothalamic disease Hypothyroidism: Prevalence Population based prevalence of elevated TSH: Author Age Men Women Tunbridge >65 6.0% 10.9% Bagchi >55 1.8% 2.7% Parle >60 2.9% 11.6% Bauer >55 5.4% Overt Hypothyroidism in the Elderly Classic features often missing Neuropsychiatric complaints common: depression, weakness, memory loss Other clues: hypercholesterolemia, elevated CK, pleural effusion Page 4

5 Subclinical Hypothyroidism: Clinical Outcomes CV: Increased risk of of CHD, heart failure in some but not all observational studies No randomized trials Neuropsychiatric: Increased fatigue, obesity and depression in some but not all observational studies Inconsistent results in 4 small randomized trials Thyroid Studies Collaboration HUNT Study Birmingham Study Whickham Survey Cardiovascular Health Study - Leiden 85+ Study Health, Aging and Body Composition Study Pisa cohort Nagasaki Adult Health Study Busselton Health Study 21 Meta-Analysis: Prospective Studies of Subclinical Hypothyroidism and CHD Outcomes - 14 studies, pool individual-level data (Rodondi, Jama 2010) - 42,000 individuals, 2,600 (6.3%) with subclinical hypothyroidism - 2,800 CHD events, 1,700 CHD deaths and 14,500 total deaths Events / Participants Multivariate* HR (95% CI) I 2 CHD events 2791 / (0.97, 1.56) 67% CHD mortality 1715 / (0.96, 1.34) 0% Total mortality 7770 / (0.95, 1.31) 67% * Adjusted for gender, age, systolic blood pressure, current and former smoking, total cholesterol, and prevalent diabetes at baseline 22 Panel A: TSH CHD events TSH mu/l TSH mu/l TSH mu/l CHD mortality TSH mu/l TSH mu/l TSH mu/l Total mortality TSH mu/l TSH mu/l TSH mu/l Risk of CHD Events, CHD Mortality and Total Mortality by TSH Category Subclinical hypothyroidism Euthyroidism Events / Participants Events / Participants 202 / / / / / / / / / / / / / / / / / / Hazard Ratio (95% CI) * HR adjusted for age and gender Sizes of data markers are proportional to the inverse of the variance of the hazard ratios (0.84, 1.35) 1.12 (0.88, 1.44) 2.00 (1.25, 3.20) Ptrend= (0.91, 1.34) 1.40 (0.96, 2.04) 1.64 (1.11, 2.42) Ptrend= (0.97, 1.17) 1.04 (0.82, 1.32) 1.13 (0.69, 1.86) Ptrend= Page 5

6 Meta-Analysis: Prospective Studies of Subclinical Hypothyroidism and Heart Failure Outcomes Individual level data (N=25,000 adults) from 6 prospective cohorts (Gencer, Circulation 2012) 8% had subclinical hypothyroidism Higher baseline TSH associated with greater risk TSH = RR = 1.0 (0.8, 1.3) TSH = RR = 1.7 (0.8, 3.2) TSH > 10 RR = 1.9 (1.3, 2.7) No data on ejection fraction The TRUST Study Double blind RCT of 785 adults >65 from 4 EU countries (Stott, NEJM 2017) 2 or more TSH between 5-20, normal T4 Not currently treated Randomized to placebo or levothyroxine (50 mcg/d unless existing heart disease) Titrated to normal TSH in T4 group, mock titration in placebo group 1-3 years of follow-up for neuropsychiatric and QOL outcomes TRUST Results Baseline TSH=6.4, fell to 3.6 in treated group No effect on hypothyroid symptoms, tiredness or quality-of-life, even among those with baseline symptoms No significan effect on CVD (RR=0.9, CI: ) but too small to reliably assess Subclinical Hypothyroidism: Natural History and When to Treat If persists >6 mo. spontaneous resolution rare Antibodies predict overt hypothyroidism 3-5%/yr if TPO pos, 1-3%/yr if TPO neg When to treat? Associated with worse CV outcomes, but no trials that T4 helps Treat if goiter or considering pregnancy Many treat if TPO pos, or TSH>10 If >65 symptoms not improved with T4 (most common reason for Rx ) Page 6

7 Hypothyroidism: Treatment Replace with levothyroxine (T4) T3 + T4 benefit unproven Typical replacement dose 1.6 mcg/kg >65 or CHD: start lower (25-50 mcg/d), gradually increase dose Maintain TSH within the normal range Some data that TSH= optimal Wait 6 weeks after dose change Monitor yearly (noncompliance, reduced T4 clearance) Pregnancy and Thyroid Dysfunction (New) Normal TSH during pregnancy: 1 st ; 2 nd : 3 rd Thyroid replacement dose increases 30-50% (check monthly in first trimester) Subclinical hypo (not hyper) associated with pregnancy loss and outcomes and neurodevelop deficits - Maybe also be true for positive TPO Treatment indications unclear, large NIH trial negative. Yes if TPO positive? Chan, Clin Endo 2014; Casey NEJM March 2017 Hyperthyroidism: Etiology Iatrogenic Over replacement (30-50% given rx) Suppression of CA, goiters, and nodules Autoimmune (Grave s disease) Thyroid stimulating autoantibodies Autonomous nodule(s) Usually T4, occasionally T3 TSH secreting tumors (rare) Hyperthyroidism: Prevalence Population based prevalence of suppressed TSH: Author age men women Bagchi >55 1.8% 2.7% Falkenberg >60 1.9% Parle > % Bauer >55 5.8% Page 7

8 Overt Hyperthyroidism in the Elderly Weight loss, palpitations, and nervousness less common Tachycardia, exophthalmos, tremor less common Atrial fibrillation more common 8-10% are asymptomatic Subclinical Hyperthyroidism: Cardiac Effects Shortened systolic time intervals Clinical significance uncertain Reduced exercise tolerance Increased incidence of atrial fibrillation (Swain, Jama 1994) Prospective cohort, N = fold increase if stsh < 0.1 Subclinical Hyperthyroidism: Skeletal Effects Florid hyperthyroidism causes fractures Effect on BMD, bone loss controversial Increased fracture risk (Wirth, Ann IM 2014) - Meta analysis of 7 cohorts, 50k patients - TSH < 0.1 vs. normal - 2-fold increase in hip fracture, 40% higher risk of non-spine fracture - Little effect on BMD Mediated via accelerated bone turnover? Subclinical Hyperthyroidism: Natural History Exogenous: Dose and GFR dependent Endogenous: Few longitudinal data (Vadiveloo, JCEM 2011) 2024 untreated individuals, 7 yr F/U 1% developed overt hyperthyroidism TSH normalized in 17% after 2 yr, 36% after 7 years (particularly if TSH between 0.1 and 0.4) Page 8

9 Hyperthyroidism: Who Should Be Treated? Exogenous (iatrogenic) Dose reduction unless contraindicated Endogenous-subclinical Repeat and follow if uncomplicated Consider treatment (as if overt) when TSH<0.1 in setting of atrial fibrillation or osteoporosis. No trials. Endogenous-overt Rule out thyroiditis. They get beta blocker Everyone else gets beta blocker and... Hyperthyroidism: Treatment Anti-thyroid drugs (PTU and methimazole) Remission: 30-50% after mo Side effects: rash, fever, arthritis, cytopenias (all rare). Use PTU in 1 st trimester Radioiodine Best treatment for hot nodules Remission: everyone Side effects: transient thyroiditis (rare), hypothyroid (50%), worsening exophthalmous (steroids prevent), fetal hypothyroidism Thyroid Nodules: Epidemiology and Evaluation Nodules are common (cancer is rare, but incidence is increasing in US) 90% women over age 60 have one or more thyroid nodules at autopsy Common on neck imaging for other reasons Risk factors for cancer: neck irritation, FH Evaluation: TSH, sono, +/- FNA 75% benign, 20% suspicious, 5% malignant Best centers: false negative 2% false positive 1% Thyroid Nodules: Treatment Cancer - Histology is important (papillary best) - Surgery +/- 131 I ablation - T4 suppression? If yes, TSH goal Benign nodules (Durante et al, Jama 2015) - 15% grow, 18% shrink spontaneously - T4 suppression has little effect - T4 doesn t prevent new nodules Page 9

10 Screening Cost-effectiveness Danese and Sawin, Jama 1995 Cost-utility analysis, stsh-based screening Modeled progression, symptoms and CAD Screening every 5 year from 35-65: $9,223 per QALY in women $22,595 per QALY in men Sensitivity analysis: cost of TSH key ($25) Screening for Subclinical Thyroid Disease American Collage of Physicians, 1998 reasonable to screen women older than 50 years of age for unsuspected but symptomatic thyroid disease. American Thyroid Association, 2000 all adults starting at age 35 and repeated every 5 years. US Preventive Task Force, 2015 the current evidence is insufficient to assess the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant asymptomatic adults. When to Refer to a Specialist? When Thyroid Tests are Confusing or Hypothyroidism Pregnant women Unstable CV disease Possible hypothalamic-pituitary etiology Hyperthyroidism Overt disease (particularly thyroid storm) Possible hypothalamic-pituitary etiology Nodules/Goiter Malignant or non-diagnostic FNA Surgery required Summary Take Home Points stsh is best test in most patients Subclinical thyroid disease is common and associated with morbidity Treatment of subclinical hypo does not improve symptoms in patients >65. Tx if TSH>10, but CV benefits unproven Treatment for subclinical hyper unclear. Consider if TSH<0.1 plus a fib or fractures Screening with stsh may be cost-effective (but is not recommended) Page 10

11 Cases 66 yr old female with 1 yr of fatigue and lassitude and no findings except TSH=8.2, nl free T4, anti-tpo positive 54 yr old female with new atrial fibrillation and no other findings except TSH=0.04, normal free T4 45 yr old female, enlarged thyroid with dominant nodule since 1999, FNA benign. On T4 suppression ever since, TSH=0.1 Key References Garber JR, et al. American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults. Endocr Pract Nov-Dec;18(6): Biondi B, Wartofsky L. Treatment with thyroid hormone. Endocr Rev Jun;35(3): Cooper DS, Biondi B. Subclinical thyroid disease. Lancet Mar 24;379(9821): Rugge JB et al. Screening and treatment of thyroid dysfunction: an evidence review for the US Preventive Services Task Force. Ann Intern Med Jan 6;162(1): Page 11