Understanding Common Thyroid Disorders Douglas C. Bauer, MD UCSF Division of General Internal Medicine dbauer@psg.ucsf.edu No Disclosures 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 Page 1
Topics Covered • Rational use of thyroid tests • Subclinical thyroid disease • Other common thyroid problems • Screening and when to refer… Page 2
Thyroid Tests: sTSH • Excellent correlation with TRH stimulation (sTSH < 0.1) • Requires intact pituitary-hypothalamic axis; 4-6 weeks to equilibrate • Falsely low: B vitamin biotin, severe illness, corticosteroids, dopamine • Normal range 0.5-4.4 mU/L (non-pregnant); $58 TSH Levels and Age • TSH is higher in elderly: Normal or not? • NHANEs: >13,000 people 12 to 80+ years – Exclude anyone with known thyroid disease or drugs that could effect TSH • Upper 97.5 th Percentile < 60 around 4.0 mIU/L 60-69 up to 4.3 mIU/L 70-79 up to 5.9 mIU/L 80+ up to 7.5 mIU/L Surks, JCEM 2007 Page 3
Thyroid Tests: Free Thyroxine • Measures unbound hormone • Replacing “index” assays • Gold standard: Equilibrium dialysis • Other immunoassays: Improving • Normal range, 9-24 pmol/L (non- pregnant); $64 Are Both sTSH and Free T4 Necessary? • American Thyroid Association says “Yes” • Simultaneous ordering common • Among outpatients without CNS surgery: – If TSH normal, T4 and T3 will be normal – If TSH low or high, many will have normal T4 and T3… Bauer, Archives Intern Med 2003 Page 4
“High Value” Thyroid Testing Strategy In outpatients without suspicion of disrupted pituitary-thyroid axis: – When sTSH is normal, STOP testing – When sTSH is low, measure T4 (consider T3 if T4 is normal) – When sTSH is high, measure T4 (consider TPO antibodies) Subclinical Thyroid Disease • Subclinical hypothyroidism “Abnormally high sensitive TSH and normal thyroid hormone levels” • Subclinical hyperthyroidism “Abnormally low sensitive TSH and normal thyroid hormone levels” Page 5
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 6
Hypothyroidism: Etiology • Autoimmune (Hashimoto’s) • Iodine deficiency • Iatrogenic A. Radioiodine/ surgery B. Drugs (lithium, amiodarone) • Pituitary/ hypothalamic disease Page 7
Billewicz Index* Symptom/Sign Present Absent Bradykinesia +11 -3 Cold interance +4 -5 Coarse skin +7 -7 Pulse <75 +4 -4 Delayed AJ +15 -6 *hypothyroid if > 30 Overt Hypothyroidism in the Elderly • “Classic” features often missing • Neuropsychiatric complaints common: depression, weakness, memory loss • Other clues: hypercholesterolemia, elevated CK, pleural effusion Page 8
Subclinical 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% Subclinical Hypothyroidism: Symptoms ??? Multiple studies find “hypothyroid” symptoms are common among those with and without subclinical hypothyroidism Page 9
Subclinical Hypothyroidism: A Real Problem or Just a Lab Abnormality? • CV disease: – Increased risk of of CHD, heart failure in some older observational studies – Small trials show no effects on lipids, EF • Neuropsychiatric: – Increased fatigue 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 22 Page 10
Meta-Analysis: Subclinical Hypothyroidism and CV Events and Mortality • Individual level pooled data – 14 prospective cohorts (N=42,000 adults) • 6% had subclinical hypothyroidism • CHD and heart failure events: – Trend toward more events if TSH 7-10 – Two-fold increase if TSH>10 • Similar trends for CVD mortality… Rodondi, Jama 2010 Gencer, Circulation, 2012 The TRUST Study • Double blind RCT of 785 untreated adults >65 from 4 EU countries – 2 or more TSH between 5-20, normal T4 • 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 QOL and neuro- psychiatric outcomes Stott, NEJM 2017 Page 11
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 greater baseline symptoms • Effect on CVD: RR=0.9, CI 0.5-1.7 (so too small to reliably assess) Stott, NEJM 2017 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 CVD, but no trials that replacement helps… – Treat if goiter or considering pregnancy – Many treat if +TPO, or TSH>10 – “hypo symptoms” not improved with treatment (most common reason for Rx…) Page 12
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) – Bedtime dosing equivalent • Maintain TSH within the normal range – Some data that TSH=1.0-2.5 optimal – Wait 6 weeks after dose change • Yearly TSH (compliance, T4 clearance) Pregnancy and Thyroid Dysfunction • Normal TSH during pregnancy: 1 st 0.1-2.5; 2 nd 0.2- 3.5: 3 rd 0.3-3.0 • Thyroid replacement dose increases 30-50% (check monthly in first trimester) • Subclinical hypo (not hyper) associated with pregnancy loss and neurodevelopmental deficits – Maybe also be true for positive TPO • Treatment indications unclear – Large NIH trial neg negative. Yes if TPO positive? Chan, Clin Endo 2014; Casey NEJM March 2017 Page 13
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 >60 5.5 6.3% Bauer >55 5.8% Page 14
Crook’s Index* Symptom/Sign Present Absent Palpitation +2 0 Cold prefer. +5 0 Hyperkinetic +4 -2 Weight loss +3 0 Lid lag +1 0 *hyperthyroid if 10 or more Page 15
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 – Prospective cohort (N = 2000) – 3-fold increase if sTSH < 0.1 Swain, Jama 1994 Page 16
Subclinical Hyperthyroidism: Skeletal Effects • Florid hyperthyroidism causes fractures • Effect on BMD, bone loss controversial • Thyroid Studies Collaboration meta-analysis - 13 cohorts, 73k patients - TSH < 0.1 vs. normal - 2-fold increase in hip fracture, 60% higher risk of non-spine fracture • Little effect on BMD (higher bone turnover?) Blum, Jama 2015 Subclinical Hyperthyroidism: Natural History • Exogenous: Dose and GFR dependent • Endogenous: Few longitudinal data – 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) Vadiveloo, JCEM 2011 Page 17
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 12-18 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 Page 18
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