Disclosure of Financial Relationships I have no relationships with any entity Understanding Subclinical producing, marketing, re-selling, or distributing health care goods or services consumed by, or Thyroid Dysfunction used on, patients Douglas C. Bauer, MD UCSF Departments of Medicine, Epidemiology & Biostatistics San Francisco Coordinating Center Cases Topics Covered • Rational use of thyroid tests • 66 yr old female with 1 yr of fatigue and lassitude and no findings except • Subclinical thyroid dysfunction TSH=8.2, nl free T4, anti-TPO positive • When and who to screen • 54 yr old female with new atrial • Take home messages fibrillation and no other findings except TSH=0.04, normal free T4 Page 1
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, biotin, and dopamine • Normal range 0.5-4.4 mU/L (non-pregnant); $58 Normal TSH in NHANEs Thyroid Tests: Free Thyroxine • TSH skewed upwards in elderly: Normal or disease? • Measures unbound hormone • NHANEs: >13,000 people 12 to 80+ years – Exclude anyone with known thyroid disease or drugs • Has replaced “index” assays that could effect TSH – Median TSH 1.39 mIU/L • Gold standard: Equilibrium dialysis • Upper 97.5 th Percentile • Other immunoassays: Improving < 60 around 4.0 mIU/L • Normal range, 9-24 pmol/L (non- 60-69 up to 4.3 mIU/L pregnant); $64 70-79 up to 5.9 mIU/L 80+ up to 7.5 mIU/L Surks, JCEM 2007 Page 2
Are Both sTSH and Free T4 Necessary? Diagnostic Redundancy of sTSH and Free T4 • American Thyroid Association says “Yes” sTSH (mIU/L) • Others recommend sTSH first < 0.5 0.5 – 5 > 5.5 • Simultaneous ordering common in clinical practice < 9 4 16 49 • UCSF outpatient data (Bauer, Arch IM 2003) Free T4 – Results when both tests ordered on the 9 - 24 536 2024 309 same specimen (N=3143) (pmol/L) > 24 174 30 1 – Each test classified as low, normal or high Bauer, Archives Intern Med 2003 Thyroid Antibodies Subclinical (“Mild”) Thyroid Disease • Anti-thyroperoxidase, TPO (titer<100, $78) • Subclinical hypothyroidism “Abnormally high sensitive TSH and – Similar to “anti-microsomal” normal thyroid hormone levels” – Most sensitive thyroid autoantibody • Subclinical hyperthyroidism – Specificity a problem “Abnormally low sensitive TSH and normal thyroid hormone levels” • TSH receptor antibody (absent, $112) – Causes Grave’s disease – Rarely found in normal individuals Page 3
Thyroid Scans “High Value” Thyroid Testing Strategy • Technetium 99 ($450) In outpatients without suspicion of – Low radiation, quick disrupted pituitary-thyroid axis: – Useful for nodules in some circumstances – When sTSH is normal, STOP – Useful to determine cause of – When sTSH is low, measure T4 hyperthyroidism (consider T3 if T4 is normal) – When sTSH is high, measure T4 • High uptake: Grave’s, toxic nodule (consider TPO antibodies) • Low uptake: thyroiditis, thyroxine use Subclinical Hypothyroidism: Etiology Subclinical Hypothyroidism: Prevalence • Population based studies: • Autoimmune (Hashimoto’s) Author Age Men Women • Iodine deficiency Tunbridge >65 6.0% 10.9% • Iatrogenic Bagchi >55 1.8% 2.7% A. Radioiodine/ surgery Parle >60 2.9% 11.6% B. Drugs (lithium, amiodarone) Bauer >55 5.4% Page 4
Subclinical Hypothyroidism: A Real Problem or Just a Lab Abnormality? Subclinical Hypothyroidism: Symptoms • CV disease: – Increased risk of of CHD, heart failure in some older observational studies ??? – No randomized trials • Neuropsychiatric: – Increased fatigue and depression in some but not all observational studies Multiple studies find “hypothyroid” symptoms are – Inconsistent results in 4 small randomized common among those with and without subclinical hypothyroidism trials Thyroid Studies Collaboration, 2010-now Meta-Analysis: Prospective Studies of Subclinical Hypothyroidism and CHD Events and Mortality • Individual level data (N=42,000 adults) from 14 HUNT Study prospective cohorts • Birmingham Study • Whickham Survey • 6% had subclinical hypothyroidism • Cardiovascular Health Study - Leiden 85+ Study • After adjustment higher baseline TSH associated with • Health, Aging and Body Composition Study Pisa cohort greater CVD risk Nagasaki Adult – TSH = 4.5-6.9 RR = 1.1 (0.8, 1.4) Health Study – TSH = 7.0-9.9 RR = 1.1 (0.9, 1.4) p trend=0.004 – TSH > 10 RR = 2.0 (1.3, 3.2) Busselton Health Study • Results similar for CVD mortality… Rodondi, Jama 2010 20 Page 5
Meta-Analysis: Prospective Studies of Subclinical The TRUST Study Hypothyroidism and Heart Failure Outcomes • Double blind RCT of 785 adults >65 from • Individual level data (N=25,000 adults) from 6 4 EU countries prospective cohorts – 2 or more TSH between 5-20, normal T4 • 8% had subclinical hypothyroidism – Not currently treated • Higher baseline TSH associated with greater risk • Randomized to placebo or levothyroxine – TSH = 4.5-6.9 RR = 1.0 (0.8, 1.3) (50 mcg/d unless existing heart disease) – TSH = 7.0-9.9 RR = 1.7 (0.8, 3.2) p trend=0.05 – TSH > 10 RR = 1.9 (1.3, 2.7) • Titrated to normal TSH in T4 group, mock titration in placebo group • No data on ejection fraction… • 1-3 years of follow-up for QOL and neuro- psychiatric outcomes Gencer, Circulation 2012 Stott, NEJM 2017 Subclinical Hypothyroidism: TRUST Results Natural History and When to Treat • If persists >6 mo. spontaneous resolution rare • Baseline TSH=6.4, fell to 3.6 in treated group • Antibodies predict overt hypothyroidism • No effect on hypothyroid symptoms, tiredness or quality-of-life – 3-5%/yr if TPO pos, 1-3%/yr if TPO neg – Even among those with greater baseline • When to treat? Associated with CVD, but symptoms no trials that replacement helps… • Effect on CVD: RR=0.9, CI 0.5-1.7 (so too – Treat if goiter or considering pregnancy small to reliably assess) – Many treat if +TPO, or TSH>10 – “hypo symptoms” not improved with treatment (most common reason for Rx…) Stott, NEJM 2017 Page 6
Subclinical Hypothyroidism: Treatment Subclinical Hyperthyroidism: Etiology • Replace with levothyroxine (T4) • Iatrogenic – T3 + T4 benefit unproven – Over replacement (30-50% given rx) • Typical replacement dose 1.6 mcg/kg – Suppression of CA, goiters, and nodules – start lower (25-50 mcg/d), gradually • Autoimmune (Grave’s disease) increase if needed – Thyroid stimulating autoantibodies • Maintain TSH within the normal range • Autonomous nodule(s) – Some data that TSH=1.0-2.5 optimal – Usually T4, occasionally T3 – Wait 6 weeks after dose change • Monitor yearly (noncompliance, reduced T4 clearance) Subclinical Hyperthyroidism: Cardiac Effects Subclinical Hyperthyroidism: Prevalence • Population based studies: • Shortened systolic time intervals – Clinical significance uncertain Author Age Men Women Bagchi >55 1.8% 2.7% • Reduced exercise tolerance Falkenberg >60 1.9% • Increased incidence of atrial Parle >60 5.5 6.3% fibrillation Bauer >55 5.8% – Prospective cohort (N = 2000) – 3-fold increase if sTSH < 0.1 Swain, Jama 1994 Page 7
Subclinical Hyperthyroidism: Skeletal Effects Subclinical Hyperthyroidism: Natural History • Florid hyperthyroidism causes fractures • Exogenous: Dose and GFR dependent • Effect on BMD, bone loss controversial • Endogenous: Few longitudinal data • Thyroid Studies Collaboration meta-analysis – 2024 untreated individuals, 7 yr F/U - 13 cohorts, 73k patients – 1% developed overt hyperthyroidism - TSH < 0.1 vs. normal – TSH normalized in 17% after 2 yr, - 2-fold increase in hip fracture, 60% higher 36% after 7 years (particularly if TSH risk of non-spine fracture between 0.1 and 0.4) - Little effect on BMD • Mediated via accelerated bone turnover? Vadiveloo, JCEM 2011 Blum, Jama 2015 Subclinical Hyperthyroidism: Subclinical Hyperthyroidism: Treatment Who Should Be Treated? • Anti-thyroid drugs (PTU and methimazole) • Exogenous-subclinical – Remission: 30-50% after 12-18 mo if Grave’s – Dose reduction to normalize TSH unless contraindicated – Side effects: rash, fever, arthritis, cytopenias (all rare). Use PTU in 1 st trimester • Endogenous-subclinical – Repeat and follow if uncomplicated • Radioiodine – Consider treatment when TSH<0.1 in – Best treatment for hot nodules setting of atrial fibrillation or osteoporosis. – Remission: everyone No trials. – Side effects: transient thyroiditis (rare), hypothyroid (50%), fetal hypothyroidism Page 8
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