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

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

Relationship Between TSH and Free T4 Levels 1,000 100 Elevated TSH 10 4.0 TSH (mLU/L) 100x TSH Reference Range 0.4 0.1 0.01 Relationship Between TSH Levels and Free T4. Spencer et al studied serum samples from 505 patients with various states of thyroid function to determine the relationship between TSH and free T4.1 The investigators found that there was a statistically significant (P<.001) inverse log-linear relationship between TSH and free T4 values. By giving patients a dose of T4, the investigators found that the degree of serum TSH suppression in any patient can be predicted from that patient’s TSH/T4 set-point (eg, the slope of the steady-state relationship), and the degree of serum T4 elevation achieved. Reference Spencer CA, et al. J Clin Endocrinol Metab. 1990;70:453-460. Undetectable TSH Hypo- Thyroid FT4 Reference Range Hyperthyroidid 0.7 ~2x 1.8 fT4 (ng/dL) Spencer ‘90

These dual insights of the log/linear TSH/free T4 relationship, together with the genetically determined FT4 setpoint, explain why TSH is the first abnormality to appear during the early phase of developing hypo- or hyperthyroidism, shown schematically here. Mild, often called “subclinical” hypo- or hyperthyroidism is a biochemical diagnosis characterized by a combination of a persistently abnormal TSH associated with normal range thyroid hormones levels usually without clinical symptoms. Subclinical conditions reflect the situation where the individual’s pituitary is sensing a small abnormality in free thyroxine relative to that individual’s FT4 setpoint not the FT4 population reference range which is of course constructed from multiple individuals with differing setpoints.

These dual insights of the log/linear TSH/free T4 relationship, together with the genetically determined FT4 setpoint, explain why TSH is the first abnormality to appear during the early phase of developing hypo- or hyperthyroidism, shown schematically here. Mild, often called “subclinical” hypo- or hyperthyroidism is a biochemical diagnosis characterized by a combination of a persistently abnormal TSH associated with normal range thyroid hormones levels usually without clinical symptoms. Subclinical conditions reflect the situation where the individual’s pituitary is sensing a small abnormality in free thyroxine relative to that individual’s FT4 setpoint not the FT4 population reference range which is of course constructed from multiple individuals with differing setpoints.

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

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

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 Hypothyroidism The 20-year Wickham Survey Follow-up Vanderpump ‘03 Courtesy of M. McDermott

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

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

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

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

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)

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

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 Prevalent CVD Incident CVD Mortality Overall RR Razvi ’08 Ochs ‘08 1.23* 1.27 1.20 1.09 1.18 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 Prevalent CVD Incident CVD Mortality Overall Razvi ’08 Ochs ‘08 1.23* 1.27 1.20 1.09 1.18 < age 65 Razvi ‘08 1.57* 1.68* 1.51* 1.37* 1.50* 1.01 1.02 0.85 1.12

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

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

Mood and Cognition in Subclinical Hypothyroidism 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 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)

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

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

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

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?

Indeed as shown in red, despite the strong association between TPOAb and overt hypothyroidism, TPOAb is not always detected even when TSH is unequivocally elevated. This likely reflects the fact that TPOAb antibodies are heterogeneous and current TPOAb measurements are only qualitative markers for thyroid autoimmunity and differ widely in sensitivity and specificity. In the NHANES study, the lowest prevalence of TPOAb was seen in TSH values between 0.1 and 1.5 mIU/L. A higher prevalence of TPOAb was seen in individuals with subclinical hyperthyroidism and TPOAb prevalence progressively increased as TSH rose towards the typical upper reference limit of 4.0, forming a continuum with subjects with subclinical and overt hypothyroidism. Since TPOAb is an imperfect marker for the presence of autoimmune thyroid dysfunction, it is likely that some TPOAb-negative individuals with occult thyroid dysfunction are ncluded in the normal cohort used for TSH reference range determinations and this is what skews the TSH upper reference limit from the expected gaussian limit of 2.5 to the typical upper limit of 4.0. Courtesy of C. Spencer

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 # of Subjects 0.28 2.5 3.5 5.0 TSH (mU/L) Theoretical (Gaussian) upper normal curve Actual upper normal curve Anti-TPO positive subjects removed

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 Disease free Reference 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 Effects on metabolism Strong correlation between TH and REE within normal range

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

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

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

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

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

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

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

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

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

Effects of Subclinical Hyperthyroidism on Bone -The SOF Study- Case-control study of Caucasian women > 65 years old followed for up to 6 years for fractures Increased risk of hip fracture if baseline TSH undetectable; increased risk of vertebral fracture if TSH low or undetectable * Bauer ‘01

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

Neurocognition in Subclinical Hyperthyroidism Mood: increased rates of depression, anxiety, hostility, irritability in some cross-sectional studies, but variable However, patients on L-T4 may report increased well-being when their TSH levels are suppressed (Carr ’88) Cognition: Very few studies Positive findings in attention/concentration, memory, executive function

Subclinical Hyperthyroidism 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)

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 REE increases 17% when TSH lowered from 10 to 0.1 mU/L (Al-Adsani ’97)

Case Report – Subclinical Hyperthyroid Patient Progression: Not relevant Symptoms: Suggestion of adverse effects Heart: Probably not a good idea Bone: Probably not a good idea Mood/cognition: ? Metabolism: ?

Subclinical Thyroid Disease - Some Practical Recommendations - Treat patients who have TSH levels greater than 10 mU/L with low doses of L-T4. Data for symptoms, QoL, lipid levels, cardiovascular disease, (mood, cognition) May not apply to elderly patients (? normal TSH range) Aim for a mid-normal TSH level (0.5 – 2.5 mU/L). (Emerging data on effects of variation in normal thyroid function) Don’t give in to the temptation to increase L-T4 doses if the TSH is already mid-normal. Data for adverse effects on heart, bone