1. SUBCLINICAL HYPERTHYROIDISM Won Bae Kim, M.D., Ph.D. Department of Internal Medicine Asan Medical Center University of Ulsan College of Medicine Seoul, Korea

2. Subclinical hyperthyroidism (SH) Definition Patient having normal free thyroxine (FT4) and total triiodothyronine (T3) levels in conjunction with a thyrotropin (TSH) level persistently below the normal range in the absence of factors known to suppress TSH √ Factors known to suppress TSH - Medications : corticosteroids and dopamine - Hypothalamic or pituitary hypo-function - Non-thyroidal illness

3. Prevalence of SH Varies with the TSH cut-off, iodine intake Endogenous : 0.5-6.3% Exogenous (on T4) : 14-23.5% NHANES III: 3.2% (<0.4 mU/L) 0.7% (<0.1 mU/L)

4. Prevalence of SH JCEM 87:489, 2002

5. Prevalence of SH : Increase with aging NHANES III, JCEM 87:489, 2002

6. Etiology of SH Exogenous - Overzealous thyroid hormone replacement Tx. - Thyroid hormone suppressive Tx. Endogenous - Thyroid gland autonomy √ autonomously functioning adenoma √ toxic multi-nodular goiter - Graves’ disease

7. Etiology of SH (in iodine rich area) Etiology of SH (in iodine rich area) Kasagi K, J Endocrinol Invest 20:183, 1997 Of 186 patients with suppressed TSH √ Undergoing Tx. for hyper- / hypothyroidism 150 √ Graves’ disease (mild) 16 √ Remission after Tx. of Graves’ disease 12 √ Subacute - or painless thyroiditis 4 √ Autonomous nodular goiter 4

8. Natural course of SH Source No. of pts F/UOutcome Sweden comm.402 yr 30% Hyperthyroid 23% Borderline 10% Normal Great Britain66> 1 yr 2 % Hyperthyroid 39% Borderline 59% Normal Framingham334 yr88% Normal Scotland15> 4 mo 27% Hyperthyroid 47% Normal ※ No data on long-term F/U study

9. Natural course of SH : A retrospective study (Endogenous SH) No treatment Change in clinical status between non-nodular and nodular patients, median follow-up period of 3.2 years (Poola R, WMJ 110:277, 2011)

10. Natural course of SH : A retrospective study (Endogenous SH) Time of follow-up without developing overt hyperthyroidism in patients classified according to 4 risk factors (Diez JJ, Am J Med Sci 337:225, 2009) √ Retrospective study √ in Spain √ 75 pts (68 F / 7 M) √ 62 ± 14 yrs √ Ex : Graves = 4 Nodular ds = 68 Unknown = 3

11. Natural course of SH : A retrospective study (Endogenous SH) Non-adjusted and adjusted hazard ratios (with 95% CI) for the development of overt hyperthyroidism (Cox models) in several variables √ Retrospective study √ in Spain √ 75 pts (68 F / 7 M) √ 62 ± 14 yrs √ Ex : Graves = 4 Nodular ds = 68 Unknown = 3 Diez JJ, Am J Med Sci 337:225, 2009

12. Clinical consequences of SH Cardiovascular effects √ arrhythmia (AF, tachycardia..) √ reducing exercise capacity ? √ increasing LV mass ? Coronary heart disease mortality Bone & mineral metabolism √ decrease in BMD √ increased fracture risk ? Symptoms & quality of life ? Mood and cognitive function ?

13. Clinical consequences of SH : A source of controversies The definitions of subclinical hyperthyroidism and the follow up of patients vary between studies and might explain some of the differences. Vadiveloo T, JCEM 87:489, 2011

14. Clinical consequences of SH : TEARS Objective : to investigate the long-term outcomes for patients with endogenous subclinical hyperthyroidism (SH) Design : Population record-linkage technology was used retrospectively to identify patients with SH and hospital admissions from January 1, 1993, to December 31, 2009. Patients : All Tayside residents over 18 yr old with at least two serum TSH measurements below the reference range for at least 4 months apart and normal free T4/total T4 and normal total T3 concentrations at baseline were included as potential cases. Using a unique patient identifier, data linkage enabled a cohort of SH cases to be identified from biochemistry, prescription, admission, and radioactive iodine treatment records matched to five comparators from the general population. Outcome measure : The association between endogenous SH and cardiovascular disease, fracture, dysrhythmia, dementia, and cancer was assessed. Vadiveloo T, JCEM 87:489, 2011

15. Clinical consequences of SH : TEARS Vadiveloo T, JCEM 87:489, 2011

16. Clinical consequences of SH : TEARS Vadiveloo T, JCEM 87:489, 2011

17. Clinical consequences of SH : TEARS Vadiveloo T, JCEM 87:489, 2011

18. There was an association between subclinical hyperthyroidism and increased risk of cardiovascular disease and dysrhythmia, and possibly fracture and dementia, but not with cancer. After excluding patients who developed hyperthyroidism and those who reverted to normal during the follow-up period, subclinical hyperthyroidism was still associated with an increased risk of cardiovascular disease and dysrhythmia, and possibly dementia, but not with osteoporotic fracture or cancer. For fracture and dementia, when the patients were divided into two groups based on their TSH measurement, there was no dose- response effect, suggesting that the association is less likely to be causal. Clinical consequences of SH : TEARS Vadiveloo T, JCEM 87:489, 2011

19. Clinical consequences of SH : Thyroid Study Collaboration Objective : to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts from 1950 to 2011 Design : A meta-analysis Patients : Individual data on 52,674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22,437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Endogenous subclinical hyperthyroidism was defined as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels. Collet TH, Arch Intern Med 172:799, 2012

20. Clinical consequences of SH : Thyroid Study Collaboration Collet TH, Arch Intern Med 172:799, 2012

21. Clinical consequences of SH : Thyroid Study Collaboration Collet TH, Arch Intern Med 172:799, 2012

22. In this analysis of all available prospective cohorts, endogenous subclinical hyperthyroidism was associated with an increased risk of total mortality, CHD mortality, and incident AF. Coronary heart disease mortality and incident AF (but not other outcomes) were significantly greater in participants with thyrotropin levels lower than 0.10 mIU/L than those with thyrotropin levels between 0.10 and 0.44 mIU/L (for both, p value for trend < 0.03). Risks did not differ significantly by age, sex, or preexisting CVD and were similar after further adjustment for cardiovascular risk factors. Clinical consequences of SH : Thyroid Study Collaboration Collet TH, Arch Intern Med 172:799, 2012

23. Clinical consequences of SH Cardiovascular effects √ arrhythmia (AF, tachycardia..) √ reducing exercise capacity ? √ increasing LV mass ? Coronary heart disease mortality Bone & mineral metabolism √ decrease in BMD √ increased fracture risk ? Symptoms & quality of life ? Mood and cognitive function ?

24. Treatment of patients with SH Few data are available to guide clinical decisions regarding the treatment of SH. Quality of evidence on the benefits of treatment Clinical conditionTSH 0.1-0.45TSH < 0.1 Progression to overt hypothyroidismNone Adverse cardiac event except AFNone Atrial fibrillation (AF)None Cardiac dysfunction?Insufficient Hyperthyroid and Neuropsychiatric SxNoneInsufficient Reduced BMDNoneFair FracturesNone Surks MI, JAMA 291:228, 2004

25. Treatment of patients with SH Review of guidelines promulgated by various professional groups OrganizationGuideline American Thyroid Assoc. (ATA, 1995)No opinion American Assoc. of Clinical Endocrinologists (AACE, 2002) Periodic assessment to determine individual therapeutic options Royal College of Physician (1995) No agreement on benefits of detedting / treating SH American College of Physician (1998) No agreement on benefits of detedting / treating SH ATA, AACE, Endocrine Society Consensus Conference (2004) Treat older individuals or patients with risks (cardiac, postmenopausal) if TSH < 0.1 (Category B) (Category E for TSH > 0.1 U/L) Cooper DS, JCEM 92:3, 2007

26. Subclinical hyperthyroidism Postmenopausal or >60yr, or history of heart disease, osteoporosis, or symptoms Premenopausal or <60yr or no history of heart disease, osteoporosis, or symptoms TSH <0.1mU/L Radioiodine uptake and scan, BMD (women) -> Therapy TSH 0.1-0.4mU/L Consider radioiodine uptake and scan, BMD (women) -> Consider therapy TSH <0.1mU/L Radioiodine uptake and scan, BMD (women) ->Therapy optional TSH 0.1-0.4mU/L Consider radioiodine uptake and scan -> No therapy Cooper DS, JCEM 92:3, 2007 Algorithm for Treatment of SH