What’s New in Subclinical Thyroid Disease

What’s New in Subclinical Thyroid Disease Mary H. Samuels, M.D. Oregon Health & Sciences University

“Subclinical” Thyroid Disease Subclinical Hypothyroidism: Subclinical Hyperthyroidism: Low to suppressed TSH Normal fT4, fT3 0.7% of population Does not increase with aging More common in women • Elevated TSH • Normal fT4, fT3 • 4% of population • Increases to 20% of older population • More common in women

Relationship Between TSH and Free T4 Levels 1,000 100 Elevated TSH 10 4.0 TSH ReferenceRange 100x TSH (mLU/L) 0.4 0.1 0.01 Undetectable TSH FT4 ReferenceRange Hypo-Thyroid Hyperthyroidid 0.7 ~2x 1.8 fT4 (ng/dL) Spencer ‘90

The Spectrum of Subclinical Thyroid Disease Subclinical Hypothyroidism “Euthyroid” Subjects Subclinical Hyperthyroidism

Subclinical Hypothyroidism- Prevalence - Mostly due to autoimmune thyroid disease

Case Report HPI: A 45 year old woman complains of fatigue, poor memory. PE: Unremarkable Labs: TSH = 8.2 mU/L free T4 = 1.1 ng/dL Is her subclinical hypothyroidism related to her complaints?

Possible Effects of Subclinical Hypothyroidism • Progression to overt hypothyroidism • Effects on symptoms and quality of life • Effects on lipid levels • Effects on the cardiovascular system • Effects on mood and cognition • Effects on metabolism

Incidence of Overt HypothyroidismThe 20-year Wickham Survey Follow-up Vanderpump ‘03 Courtesy of M. McDermott

Rate of TSH normalization as a function of baseline TSH % Spontaneous subclinical hypothyroidism in patients older than 55 years Diez ‘04

Symptoms and Quality of Life in Subclinical Hypothyroidism • Cross sectional studies are inconsistent, including two large, community-based studies (Bell ’07, Razvi ’05) • Six placebo-controlled L-T4 treatment studies tended to be negative • Outcomes included validated symptom scores and generic QoL measures

Lipid Levels in Subjects with Subclinical Hypothyroidism • Cross-sectional and treatment studies are inconsistent • Meta-analysis of 13 treatment studies to 2000 (Danese ’00) • Since 2000, 8 placebo-controlled randomized L-T4 treatment studies: 4 showed effect, 4 showed no effect Danese ‘00

Treatment of subclinical hypothyroidism more likely to reduce cholesterol levels if initial cholesterol is high Correlation between initial cholesterol and change in cholesterol with treatment of SCHypo (Danese ‘00)

Effects of Subclinical Hypothyroidism on the Cardiovascular System Cross-sectional studies: • Consistent decrements in LV systolic and diastolic function, even at minimal TSH elevations • Impaired cardiac performance with exercise • Increased SVR, impaired endothelium-dependent vasodilation • One study showed increased risk of CHF (Rodondi ‘05) • LV function improved in all studies (only 4 were double-blind, placebo-controlled) L-T4 treatment studies:

Subclinical Hypothyroidism and Cardiovascular Disease • Two recent large meta-analyses of 8-10 studies of the relationship between subclinical hypothyroidism and cardiovascular disease • Effects not large, confidence intervals overlap 1.0

Subclinical Hypothyroidism and Coronary Heart Disease

Hypothesis: CV risk of subclinical hypothyroidism depends on age (Biondi and Cooper ’08): Does Subclinical Hypothyroidism Protect the “Oldest Old?” Low TSH Normal TSH SCHypo Overt Hypo 558 subjects, aged 85 years at entry, followed for 4 years Gussekloo ‘04

Cognition: • Numerous cross-sectional and L-T4 treatment studies of cognition in SCHypo, but methods limited and results variable • Memory most commonly affected • Executive function poorly studied Mood and Cognition in Subclinical Hypothyroidism Mood: • Some cross-sectional studies suggest decrements in mood (depression, anxiety), while others do not • 2 randomized, placebo-controlled, blinded L-T4 treatment studies showed no improvement in depression or psychological distress scores (Kong ’02, Jorde ’06)

fMRI of Working Memory in Subclinical Hypothyroidism • 11 SCHypo subjects vs. 12 euthyroid controls • TSH = 14.7 vs. 1.7 mU/L • N-Back test (working memory/executive function) • fMRI with BOLD • 6 SCHypo subjects restudied 6 mo after L-T4 • TSH = 1.4 Zhu ‘06

fMRI of Working Memory in Subclinical Hypothyroidism • N-Back activated frontoparietal network in all subjects • SCHypo subjects had fewer frontoparietal areas of BOLD response (executive function areas) • Normalized after 6 mo of L-T4 Zhu ‘06

Subclinical Hypothyroidism and Dementia Women Men TSH 0-1.0 TSH 2-50 Baseline TSH levels vs. risk of developing Alzheimer’s Disease during mean follow-up of 13 years (Framingham study, Tan ’08)

Metabolic Effects of Subclinical Hypothyroidism • In healthy humans, thyroid function plays a major role in energy homeostasis • Thyroid hormone levels directly correlate with resting energy expenditure (REE) • T3 levels account for 20-25% of variation in REE • Small changes in thyroid hormone levels lead to large changes in energy metabolism (Al-Adsani ‘97) • REE decreases 17% when TSH increases from 0.1 to 10 mU/L

Case Report – Subclinical Hypothyroid Patient • Progression: 50% chance of overt hypothyroidism over 20 years, but recheck TSH first • Symptoms: Fatigue may improve with L-T4 • Lipids: Chol/LDL may improve with L-T4, especially if elevated at baseline • Heart: Mildly impaired, will improve with L- T4, but ? clinical significance • Mood/cognition: May improve, ? clinical significance • Metabolism: May improve, ? clinical significance

Case Report The 45 year old woman with a TSH of 8.2 mU/L starts taking L-T4. Three months later her memory is slightly better, but she still complains of fatigue. Her TSH is now 3.9 mU/L. Now do her symptoms have anything to do with her thyroid?

Courtesy of C. Spencer

Theoretical (Gaussian) upper normal curve # of Subjects Anti-TPO positive subjects removed Actual upper normal curve 0.28 2.5 3.5 5.0 TSH (mU/L) The True “Normal” TSH Range • The “normal” TSH range is skewed at the upper range, possibly by subjects with early autoimmune thyroid disease • In reference subjects ages 20-29 years, the normal TSH range is 0.40 – 3.56 mU/L (NHANES III, Hollowell ’02) • If TSH levels are normalized to a Gaussian distribution, the normal range is 0.40 – 2.5 mU/L • If this normal TSH range is adapted, 17% of the U.S. population (51 million people) will have “low-normal” thyroid function

Disease free Reference The True “Normal” TSH Range • Hypothesis: The upper normal TSH range is skewed because it includes subjects with occult thyroid disease, even without anti-thyroid antibodies (Spencer ’07) • Alternative hypothesis: Upper normal TSH range is skewed because normal TSH levels increase with healthy aging (Surks ’07) • Clinical correlations are sparse for these TSH levels NHANES III data

Possible Effects of Variations in Thyroid Function within the “Normal” TSH Range • Progression to overt hypothyroidism • Increases as TSH increases within normal range • Effects on symptoms and quality of life • No consistent effects • Effects on lipid levels • Direct correlations between TH levels and lipids, improvements when lower TSH within the normal range • Effects on the cardiovascular system • Studies inconsistent (? High-normal TSH protective in “oldest-old”) • Effects on bone • Inverse correlations between TH levels and BMD • Effects on mood and cognition • No consistent effects • Effects on metabolism • Strong correlation between TH and REE within normal range

Prevalence of Subclinical Hyperthyroidism Weighted sample of U.S. population 12 years or older “Total” pop = 17,353 “Disease free” = Excluding subjects with thyroid disease “Reference” = Disease free excluding pregnant, on certain meds, with overt thyroid disease, or with anti-thyroid antibodies NHANES III Hollowell ‘02

Case Report The 45 year old woman with a TSH of 3.9 mU/L has her L-T4 dose increased. She returns to clinic three months later. She states that she feels “great.” Her TSH is now 0.2 mU/L. Do her improved symptoms have anything to do with her thyroid now?

Possible Effects of Subclinical Hyperthyroidism • Progression to overt hyperthyroidism • Effects on symptoms and quality of life • Effects on the cardiovascular system • Effects on bone • Effects on mood and cognition • Effects on metabolism

Progression of Subclinical Hyperthyroidism • Progression rates to overt hyperthyroidism 1-5% per year • Depend on cause of hyperthyroidism, initial TSH (more common with undetectable vs. low TSH levels) • Also high normalization rates

Symptoms and Quality of Life in Subclinical Hyperthyroidism • A number of studies suggest increased hyperthyroid symptoms, decreased QoL in subclinical hyperthyroidism • A few studies suggest that lowering the L-T4 dose (in exogenous subclinical hyperthyroidism) or ATD (in endogenous subclinical hyperthyroidism) may improve QoL • Extremely small sample sizes

Effects of Subclinical Hyperthyroidism on the Cardiovascular System Cross-sectional studies: • Consistent deleterious effects on heart rate, exercise capacity, LV mass, bp, diastolic function, risk of atrial fibrillation • Unclear what TSH cut-off increases risk • Lowering L-T4 dose or adding beta blockers in exogenous subclinical hyperthyroidism probably reverses effects • Only 2 extremely small studies of treating endogenous subclinical hyperthyroidism: both reported improved HR and cardiac function L-T4 treatment studies:

Subclinical Hyperthyroidism and Coronary Heart Disease • Recent meta-analysis of 5 large population-based studies showed no increased risk of CVD or mortality with subclinical hyperthyroidism (Ochs ‘08), no differential effect of age

Effects of Subclinical Hyperthyroidism on Bone • TSH suppression from L-T4 therapy probably does not affect men or pre-menopausal women, may affect post-menopausal women • Similar effects of endogenous subclinical hyperthyroidism, but few studies

What’s New in Subclinical Thyroid Disease