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ORIGINAL

E n d o c r i n e

ARTICLE
C a r e

Subclinical Hypothyroidism and Survival: The Effects
of Heart Failure and Race
Connie M. Rhee, Gary C. Curhan, Erik K. Alexander, Ishir Bhan, and
Steven M. Brunelli
Renal Division (C.M.R., G.C.C., S.M.B.), Department of Medicine; Channing Division of Network
Medicine (G.C.C.), Department of Medicine; Division of Endocrinology, Diabetes, and Hypertension
(E.K.A.), Department of Medicine; and Division of Pharmacoepidemiology and Pharmacoeconomics
(S.M.B.), Department of Medicine, Brigham and Women’s Hospital; Harvard Medical School (C.M.R.,
G.C.C., E.K.A., I.B., S.M.B.); Department of Epidemiology (G.C.C.), Harvard School of Public Health,
Boston, Massachusetts 02115; Renal Division (I.B.), Department of Medicine, Massachusetts General Hospital,
Boston, Massachusetts 02114; and DaVita Clinical Research (S.M.B.), Minneapolis, Minnesota 55404

Context: Studies examining the association between subclinical hypothyroidism and mortality
have yielded conflicting results. Emerging data suggest these associations may depend upon underlying congestive heart failure (CHF) and/or race, but this has not been empirically determined.
Objective: Our objective was to examine the association between subclinical hypothyroidism and
hypothyroidism overall with mortality according to pre-existing CHF and race.
Design and Participants: We examined the associations of subclinical hypothyroidism (TSH higher
than assay upper limit of normal; total T4 within reference) and hypothyroidism overall (TSH higher
than assay upper limit of normal; total T4 below lower limit of normal or within reference) with
all-cause mortality among Third National Health and Nutrition Examination Survey participants
stratified by CHF and race using multivariable Cox models. To confirm whether differences between strata were statistically significant, we tested for interaction on the basis of CHF (separately)
and race by likelihood ratio testing.
Results: There were 14 130 (95.0%) euthyroid controls and 749 (5.0%) participants with hypothyroidism, 691 (4.6%) of whom had subclinical disease. Subclinical hypothyroidism vs euthyroidism
was associated with greater mortality in those with CHF but not in those without: adjusted hazard
ratios (HRs) (95% confidence intervals [CIs]) ⫽ 1.44 (1.01–2.06) and 0.97 (0.85–1.11), respectively (P
interaction ⫽ .03). Similar findings were observed for hypothyroidism overall. Hypothyroidism
overall vs euthyroidism was associated with greater mortality in Black participants (HR ⫽ 1.44 [95%
CI ⫽ 1.03–2.03]) but not in non-Blacks (HR ⫽ 0.95 [95% CI ⫽ 0.83–1.08]) (P interaction ⫽ .03).
Conclusion: Among participants with CHF, subclinical hypothyroidism and hypothyroidism overall
are associated with greater death risk. Additional studies are needed to confirm findings and
explore possible mechanisms for the differential hypothyroidism-mortality association across race.
(J Clin Endocrinol Metab 98: 2326 –2336, 2013)

H

ypothyroidism is a highly prevalent condition (⬎9.5
million people in the United States) (1) with pervasive effects on virtually every organ system (ie, hemato-

logic, neuropsychiatric, reproductive, and cardiovascular)
(2). Most hypothyroidism is subclinical disease (1), and
there is considerable controversy as to whether subclinical

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2013 by The Endocrine Society
Received January 3, 2013. Accepted April 4, 2013.
First Published Online May 29, 2013

Abbreviations: ACE, angiotensin-converting enzyme; ACR, albumin to creatinine ratio;
aHR, adjusted hazard ratio; BMI, body mass index; CHD, coronary heart disease; CHF,
congestive heart failure; CI, confidence interval; eGFR, estimated glomerular filtration rate;
LLN, lower limit of normal; MI, myocardial infarction; NDI, National Death Index; NHANES
III, Third National Health and Nutrition Examination Survey; TT4; total T4 ULN, upper limit
of normal.

2326

jcem.endojournals.org

J Clin Endocrinol Metab, June 2013, 98(6):2326 –2336

doi: 10.1210/jc.2013-1039

we excluded participants with secondary hypothyroidism (TSH ⬍ lower limit of normal [LLN] and TT4 ⬍ LLN) (30) due to sparse representation (n ⫽ 2). Notably. we excluded participants with primary hyperthyroidism (TSH ⬍ LLN. patients at high risk for or who had recent cardiac events) have observed that subclinical hypothyroidism is associated with greater all-cause and cardiovascular mortality (9.6 mIU/L and 4. Serum creatinine measurements were calibrated to the Cleveland Clinic laboratory by subtracting 0. 12). 16). 14. systemic vascular resistance. and all participants gave their informed written consent before participation.S. adult population from the Third National Health and Nutrition Examination Survey (NHANES III) with detailed laboratory data and extended follow-up over which to observe outcomes. multistage. and Mexican-American participants were oversampled to enable precise estimation within these subgroups (29). Given that the comparison of interest was between primary hypothyroidism (subclinical and overall) vs euthyroidism with mortality within strata of CHF and race. perhaps owing to a different physiological set point (28). There have been conflicting results in regard to the differential association between subclinical hypothyroidism and outcomes across racial groups in the aforementioned meta-analyses.org 2327 amine whether the association between 1) subclinical hypothyroidism and 2) hypothyroidism overall with mortality is modified by concomitant CHF and race using a large. likely due to the heterogeneity of patient populations within and across studies (4 –17).S. stratified. In subclinical hypothyroidism. this has not been observed in lower-risk groups (5– 8. or allcause mortality (18. total T4 (TT4). it is plausible that the hypothalamic-pituitarythyroid axis may be intrinsically different in Blacks vs nonBlacks. elderly. who had baseline serum TSH. and medications were assessed. creatinine.doi: 10. respectively (32). 11. comorbid conditions.23 . TT4. 19). CHD mortality. and missing data on CHF status (n ⫽ 18). Within the NHANES III. Black. From these. California). It is plausible that subpopulations with CHF may be predisposed to cardiac morbidity and mortality associated with subclinical hypothyroidism. blood and urine samples were collected for measurement of serum TSH. Indianapolis. and TT4 was measured with an RIA (Roche Molecular Biochemicals. The survey employed a complex. Previous studies evaluating the associations between subclinical hypothyroidism and mortality have yielded conflicting results. Given hypothyroidism’s impact on cardiac contractility.5 to 13. and urine albumin and creatinine (details below). Microalbuminuria and macroalbuminuria were defined as an albumin to creatinine ratio (ACR) of 30 to 299 mg/g and ⱖ300 mg/g. In a previous metaanalysis. Given the low representation of Blacks. Whereas there appeared to be greater risk of coronary heart disease (CHD) events in Whites compared with Blacks (18). Subjects and Methods Source cohort We conducted a retrospective cohort study using data from the NHANES III. modification by race was not observed for CHF events. the association between subclinical hypothyroidism and mortality did not differ among patients with and without underlying cardiovascular disease (18). Emerging data suggest these associations may be dependent upon underlying cardiovascular risk. At the time of enrollment. pre-existing congestive heart failure (CHF) was observed to modify the association between subclinical hypothyroidism and CHF events (19). Indiana).2013-1039 hypothyroidism negatively impacts survival (3. 31). We included NHANES III participants ages ⱖ18 years old at enrollment. clustered sampling design in which children. TSH) is considered the most sensitive and specific biochemical metric of thyroid function (23). The normal reference ranges for TSH and TT4 were 0. and creatinine measurements and had available follow-up data (n ⫽ 15 467). participants’ self-reported sociodemographics.2 ␮g/dL. We conducted the following study to ex- jcem. n ⫽ 560). and atherosclerosis (20. a survey executed by the National Center for Health Statistics (NCHS) from 1998 to 1994 to provide national estimates of the health and nutritional status of U. and spot urine and serum creatinine were measured by the Jaffe rate reaction (31). 21). race and comorbidity status (including CHF) were self-identified by participants. Whereas studies in populations with high underlying cardiovascular risk (eg. The final analytical cohort contained 14 879 participants. it has been speculated that subclinical hypothyroidism might predispose to death from cardiac causes. Therefore. respectively (1. whereas in a subsequent meta-analysis. analyses may have been underpowered to detect interaction by race. We hypothesized that the association between subclinical hypothyroidism and mortality differs according to CHF and race. 4). electrophysiologic irritability. 24 –27). children and adults. n ⫽ 8) (30). San Juan Capistrano. The current study was deemed exempt by the Partners Healthcare Institutional Review Board. Thyrotropin (commonly referred to as thyroid stimulating hormone. Laboratory measures TSH was measured with a chemiluminescence immunometric assay (Nichols Institute Diagnostics. Spot urine albumin was measured by solid-phase fluorescent immunoassay. secondary hyperthyroidism (TSH ⬎ upper limit of normal 关ULN兴 and TT4 ⬎ ULN. race was not missing for any patients.1210/jc. previous studies have also shown that median TSH levels are lower in Blacks than among persons of other races (1. owing to underlying distortions in ventricular architecture that confer heightened susceptibility to hypothyroid-related perturbations (22). nationally representative sample of the U. The NHANES III study protocol was approved by the NCHS Institutional Review Board. serum TSH is elevated in the context of normal thyroxine (T4) levels.endojournals.39 to 4.

Statistical significance of effect modification was assessed by likelihood ratio testing comparing models with and without the corresponding 2-way factorby-exposure cross-product terms (eg.9 for males. 39).411 for males. and had a lower prevalence of smoking (Table 1). hypertension. diabetes. Cause-of-death information was available for 98. 1]⫺1. 98(6):2326 –2336 myocardial infarction (MI). because it has been shown to provide superior coverage of deaths compared with other sources (37). respectively. Scr is serum creatinine.8% of the source cohort.73 m2). ␣ ⫽ ⫺0. In the latter analyses. and ␹2 tests as dictated by data type. body mass index (BMI). Stratum-specific estimates were estimated within subgroups defined by race. gemfibrozil.329 for females and ⫺0.993Age ⫻ 1. previous stroke. The primary outcome of interest was all-cause mortality. ␬ ⫽ 0.05 was considered statistically significant. and long-acting nitrates) and 2) participants on baseline thyroid supplementation (n ⫽ 260) and thyroid-suppressive therapy (n ⫽ 3) were excluded. Sensitivity analyses were also conducted in which 1) multivariable Cox models were additionally adjusted for cardiovascular medications (amiodarone. among the latter.018 [if female] ⫻ 1. a significant association between subclinical hypothyroidism and hypothyroidism overall with allcause mortality was not observed: adjusted hazard ratios (aHRs) ⫽ 1. in this report. pre-existing CHF.endojournals. hypertension.18) and 1. statins. and pre-existing atherosclerotic disease (previous MI or stroke). higher BMI. 30 –299. sex. Mortality data were available through December 31. female.02 (95% CI. The NDI is a central computerized index of annually updated death record information compiled from data submitted by state vital statistics offices to the NCHS. Baseline characteristics between exposure groups were compared using 2-sample t tests. College Station. and other race/ethnicity). Analogous methods were used to estimate associations between exposure and mortality in all analyses. Wilcoxon rank sum tests. and unadjusted Cox proportional hazards models. dihydropyridine and nondihydropyridine calcium channel blockers. this cutoff was selected based on the TSH threshold at which treatment of subclinical hypothyroidism is often recommended based on published guidelines (36). and participants with TSH within the reference range were considered euthyroid. log-rank testing. Injuries. 0. In the overall cohort. and eGFR (categorized as ⬍60 or ⱖ60 mL/min/1. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR ⫽ 141 ⫻ min[Scr/␬. The NDI is considered the gold standard for death ascertainment for epidemiologic research. June 2013. overt is below LLN) (30). CHF. Participants were considered at risk the day after baseline TSH and TT4 measurements until death or end of follow-up. 14 130 (95. Mexican-American. we sought to examine how mortality was associated with hypothyroidism overall and with subclinical hypothyroidism. active smoking status. previous Subclinical hypothyroidism and mortality according to pre-existing CHF Within the overall cohort. In the former analyses. and exogenous thyroid hormone use.2328 Rhee et al Subclinical Hypothyroidism and Survival mg/dL as previously described (33). Compared with euthyroidism.org) (38.15). Median time at risk was 14. Exposure ascertainment In co-primary analyses. 1]␣ ⫻ max[Scr/␬. 691 had subclinical hypothyroidism (representing 4.7 for females and 0. and Causes of Death codes. Secondary analyses considered death from cardiovascular causes. Texas). Analyses were performed using Stata MP version 10. CHF ⫻ subclinical hypothyroidism). and were ascertained through linkage of NHANES III to death certificate data from the National Death Index (NDI).3 years. Multivariable Cox proportional hazards models were adjusted for potential confounders of the exposure-mortality association based on published data that included age. An interaction P value of ⬍. angiotensin-converting enzyme 关ACE兴 inhibitors. Unadjusted associations between exposure and mortality were estimated using Kaplan-Meier plots. hypercholesterolemia.159 [if Black].1 (StataCorp.209 ⫻ 0.04 (with 95% confidence interval [CI] of 0. this was ascribed on the basis of International Statistical Classification of Diseases. participants with TSH higher than ULN were considered hypothyroid. respectively. published on The Endocrine Society’s Journals Online web site at http://jcem. Outcome ascertainment J Clin Endocrinol Metab.6% of the total cohort and 92.0%) of whom had hypothyroidism overall. participants contributed a total of 199 299 patient-years of at-risk time during which 3337 all-cause deaths (1477 cardiovascular deaths) were observed. 2006. Results Statistical analyses Cohort description The overall study cohort consisted of 14 879 participants. Similar patterns of association were observed when comparing patients with hypothyroidism overall with euthyroidism (Table 1) and when comparing subclinical hypothyroidism as defined by TSH levels with euthyroidism (Supplemental Table 2). micro. secondary analyses were also conducted in which subclinical and overt hypothyroidism were defined by severity of TSH derangement (subclinical is ⱕ10 mIU/L. previous stroke. Given that TT4 levels may not be concordant with unbound. diabetes. thiazide and loop diuretics. pre-existing CHF. hypercholesterolemia. participants with subclinical hypothyroidism tended to be older. ACR (categorized as ⬍30. biologically active free T4 levels (35). categories of race/ethnicity (non-Hispanic Black and non-Hispanic White referred to as Black and White.90 –1. The proportional hazards assumption was confirmed graphically and through Schoenfeld residual testing. min indicates the minimum of Scr/␬ or 1. overt is ⬎10 mIU/L). previous MI. .and macroalbuminuria. niacin. had higher prevalence of low eGFR. digoxin. hypothyroid participants were parsed into subclinical and overt disease on the basis of their TT4 levels (subclinical is within reference range.91–1.0%) of whom were euthyroid and 749 (5. or ⱖ300 mg/g or missing). and White.3% of participants with hypothyroidism overall). ␤-blockers. 10th revision codes (Supplemental Table 1. and max indicates the maximum of Scr/␬ or 1) (34).

6 0.4 73.001 Previous stroke.0 P ⬍ . % Yes No Don’t know/blank 2.2 37.2 1.001 5.5–24.doi: 10.001 Hypercholesterolemia.2 94.1 P ⫽ . % Yes No 2.1 4. % Yes No Don’t know/blank 25.4 3.0 5.72 4. jcem.1 57.4 97.2 ⫾ 19.9 P ⬍ .001 26.1 27.001 10.0 88. % ⬍18.6 4.8 92.1 P ⫽ .5 33.5 P ⬍ . % 26.001 64.4 0.6 64.001 57. mIU/L Median IQR Min--Max Age.9 1.4% P ⬍ .3 ⫾ 19.4 Race.4 89.4 P ⬍ .1% eGFR (mL/min/1.4 27. y 1.01 15.8 89.3% P ⬍ .7% 0.0 36.7 95.1 3.8 3.6 27.8 P ⬍ .5 33.7 11.0 50.001 6.001 93.001 40.001 Diabetes.4% 2. % White Black Mexican-American Other Hypothyroid Overall (n ⴝ 749) Subclinical Hypothyroid (n ⴝ 691) 6.73m2).2 38.2 2.9 9.9 97.001 77.2 (Continued ) .5 P ⬍ .9 14.9 35.5 1.4 P ⬍ .5 94.8% 2.60 45.4% 79.8 0.2 BMI (kg/m2).5 18.0 P ⬍ .002 15.6% 18.4 64. % Yes No Don’t know/blank 3.0 35.1 Active smoking.3 1.3– 8.9 P ⬍ .30 –9.9 2.001 2.5 36.8 0.00 –2.001 CHF.8 P ⬍ .30 5. % Yes No Don’t know/blank 16.9 92.49 1. % ⱖ60 30 –59 ⬍30 11.001 Previous MI.3 0.0% P ⬍ .9% 5.6 36. % ⬍30 30 –299 ⱖ300 Missing 87.001 7.1 P ⬍ .1210/jc. % Yes No Don’t know/blank 7.2 Female sex.001 63.5 5.5 0. % 52.001 35.0% P ⬍ .6 33.1 78.3 34.001 80.2013-1039 Table 1.39 – 4.endojournals.6 35.1 28.5 11.6 89.1 0.3 P ⬍ .001 ACR (mg/g).001 8.0 59.001 Hypertension.1 8.0 0.1 7.3 27.9 25–29.2% 17.9 5.6 P ⬍ .9 0.2 P ⬍ .1 P ⬍ .2 P ⬍ .5 92.4 1.4 13.10 0.80 4.7 1.65– 83.1 P ⬍ .65–382 59.2 P ⬍ .org 2329 Comparison of Baseline Characteristics Between Thyroid Functional Status Categorizationsa Euthyroid (n ⴝ 14 130) TSH.4 ⫾ 19.

84 –1. Thyroid functional status was categorized as euthyroid (TSH within reference range).95 [95% CI. hypothyroidism overall was significantly associated with greater all-cause mortality compared with euthyroidism in those with CHF (aHR ⫽ 1. a Data are presented as mean ⫾ SD or proportions unless otherwise indicated.3 Hypothyroid Overall (n ⴝ 749) 16. however. 1.03). 0. pre-existing CHF modified the association between subclinical hypothyroidism (P interaction ⫽ .85–1.005 9.001 10. results were qualitatively similar (Table 2). results were qualitatively similar (Table 2). results were qualitatively similar (Table 2). 0.9 P ⫽ . After exclusion of participants using baseline thyroid medications.001 Subclinical Hypothyroid (n ⴝ 691) 16.44 [95% CI.97 [95% CI. or ␹2 test.83–1.98 [95% CI.84 –1.03) and hypothyroidism overall (P interaction ⫽ .4 P ⬍ . subclinical hypothyroidism defined by TSH levels trended toward greater allcause mortality only among Black participants (aHR ⫽ 1.6 8.7 P ⬍ . Subclinical hypothyroidism and mortality considering both pre-existing CHF and race The concurrent effects of race and CHF on the association between subclinical hypothyroidism and hypothy- .01) with all-cause mortality. maximum.77 [95% CI.05–2. 1.96 –2. in stratified analyses.001 Abbreviations: IQR.85–1. results were qualitatively similar (Table 2). 0. 98(6):2326 –2336 Table 1.3 8. Significance testing was performed separately for hypothyroid overall vs euthyroid and subclinical hypothyroid vs euthyroid by 2-sample t test. tests of interaction for race were statistically significant (P interaction ⫽ .7 3. Similarly. the association between subclinical hypothyroidism with mortality in participants with preexisting CHF was even more potent (Table 2).11]) (Figure 1A). A similar pattern of results was observed in secondary analyses of subclinical hypothyroidism defined by TSH levels only. 0. the association between hypothyroidism overall with mortality in Black participants was even more potent (Table 2). and subclinical hypothyroid (TSH higher than ULN and TT4 within reference range). however. 0.07) did not reach statistical significance (Figure 2A).06]) but not in those without CHF (aHR ⫽ 0. Supplemental Figure 2).64]) but not in those without CHF (aHR ⫽ 0.09]) (Figure 1B). but not in those of other races (aHR ⫽ 0.3 1. Max.17) but not in other races (HR ⫽ 0. 1. In sensitivity analyses adjusted for cardiovascular medications.03) but not in those who were non-Black (aHR ⫽ 0.8 4. After exclusion of participants using baseline thyroid medications. Hypothyroidism overall was significantly associated with greater all-cause mortality compared with euthyroidism in Black participants (aHR ⫽ 1.005) (Table 2). After exclusion of participants using baseline thyroid medications. In sensitivity analyses adjusted for cardiovascular medications.01–2. Continued Euthyroid (n ⴝ 14 130) 30 –34.01.96 [95% CI. Subclinical hypothyroidism was significantly associated with greater all-cause mortality compared with euthyroidism in those with CHF (aHR ⫽ 1. hypothyroid overall (TSH higher than ULN).08) (Figure 2B). In stratified analyses. 1. Similarly. Supplemental Figure 1). estimates and tests for interaction did not reach statistical significance (P interaction ⫽ . In sensitivity analyses adjusted for cardiovascular medications. results were qualitatively similar. subclinical hypothyroidism was associated with greater all-cause mortality compared with euthyroidism in Black participants (HR 1.1 5.97 [95% CI.12]) (P interaction ⫽ .14]). After exclusion of participants using baseline thyroid medications. 0.83–1.95 [95% CI. In sensitivity analyses adjusted for cardiovascular medications. June 2013. interquartile range.9 35–39.44 [95% CI. Hypothyroidism overall and mortality according to race Race modified the association between hypothyroidism overall with all-cause mortality (P interaction ⫽ .05]) but not in those without CHF (aHR ⫽ 0. Wilcoxon rank sum test. tests of interaction for race were statistically significant (P interaction ⫽ .48 [95% CI.03) (Table 2). tests of interaction (P interaction ⫽ . 0.9 ⱖ40 Exogenous thyroid hormone use. associations between subclinical hypothyroidism and hypothyroidism overall with mortality in participants with pre-existing CHF were even more potent (Table 2).08.47 [95% CI.05–2.03–2.51 [95% CI.1 4. minimum. % 16. Subclinical hypothyroidism was significantly associated with greater all-cause mortality compared with euthyroidism in those with CHF (aHR ⫽ 1. Min.19 –2. 1. In the primary analyses.2330 Rhee et al Subclinical Hypothyroidism and Survival J Clin Endocrinol Metab. In sensitivity analyses adjusted for cardiovascular medications. After exclusion of participants using baseline thyroid medications.9 P ⬍ .10]).28]).

previous MI. 0. sex. however.2). Additionally. When cardiovascular mortality was considered (Table 4).93 [95% CI. Figure 1. Subclinical hypothyroidism and mortality according to pre-existing atherosclerotic disease In stratified analyses. Subclinical hypothyroidism and hypothyroidism overall were each associated with greater all-cause mortality in those with CHF. Similarly. hypertension.66] and 0. race/ethnicity.7).endojournals. In contrast. Similarly.00) among non-Blacks (P interaction ⫽ . BMI. race modified the association between hypothyroidism overall and all-cause mortality. Similarly.2). however.S. we observed that pre-existing CHF was an important modifier of the association between subclinical hypothyroidism and hypothyroidism overall with mortality. Among participants without CHF.00 –1.55 (1. stratified by preexisting CHF status. adults. Discussion roidism overall with all-cause mortality were considered (Table 3).06 –2. race modified the association between subclinical hypothyroidism and mortality. hypercholesterolemia.75–1. race modified the association between subclinical hypothyroidism and mortality among participants without CHF (P interaction ⫽ . race modified the association between hypothyroidism overall with mortality.43 (0.68 (0. respectively).4).1210/jc.08). aHR (95% CI) was 2.34 [95% CI.61) among Blacks and 1.82–1. Analyses were adjusted for age. In this large. 1. aHR (95% CI) was 1.36 (0.002). 1. tests of interaction did not reach statistical significance (P interaction ⫽ . 0. 0. but not in those without.005).9). among participants with CHF.96 –2. Comparison of the association between subclinical hypothyroidism (TSH higher than ULN. Among participants without CHF. we observed that sub- . TT4 within reference range) (A) and hypothyroidism overall (TSH higher than ULN) (B) vs euthyroidism (TSH within reference range) with all-cause mortality.27) among Blacks and 0.73–1.14]).02) among non-Blacks (P interaction ⫽ .30 [95% CI. however.92–2.2013-1039 jcem.13].84 – 8.04 –1. hypothyroidism overall was associated with greater all-cause mortality compared with euthyroidism in participants with atherosclerotic disease but not in those without (aHR ⫽ 1.doi: 10.03) among non-Blacks (P interaction ⫽ . These findings were robust across multiple secondary analyses as well as sensitivity analyses that adjusted for cardiovascular medications and excluded participants on baseline thyroid medications.77–1.01) but not among participants with CHF (P interaction ⬎ 0. diabetes. smoking.91 [95% CI. and eGFR (specification for each as per Table 1).004) but not among participants with CHF (P interaction ⫽ .32 [95% CI. ACR. nationally representative sample of U.74]) but not in those without (aHR ⫽ 0.96 [95% CI. When race and CHF were considered concurrently. tests of interaction did not reach statistical significance (P interaction ⫽ . previous stroke. 1.75] and 0.02–1. race modified the association between subclinical hypothyroidism and mortality: aHR (95% CI) was 1.87 (0.14) among Blacks and 0. among participants with CHF. subclinical hypothyroidism was associated greater all-cause mortality compared with euthyroidism in participants with atherosclerotic disease (aHR ⫽ 1.03). Subclinical hypothyroidism defined by TSH levels was also associated with greater all-cause mortality compared with euthyroidism in participants with atherosclerotic disease but not in those without (aHR ⫽ 1. race modified the association between hypothyroidism overall and mortality among participants without CHF (P interaction ⫽ . tests of interaction did not reach statistical significance (P interaction ⫽ . hypothyroidism overall was associated with greater all-cause mortality in Blacks but not in other races.81–1.08]).89 (0.org 2331 hypothyroidism overall was associated with elevated risk that did not differ according to race (P interaction ⫽ . Statistical significance of effect modification was assessed by likelihood ratio testing.

Previous data have suggested that subclinical hypothyroidism is associated with ischemic heart disease (13).05–2.44 (1.08) .09) .15) .85–1.50 (1. smoking.2332 Rhee et al Subclinical Hypothyroidism and Survival J Clin Endocrinol Metab.01–2.879 1.02–2.80 (1.84 –1.83–1.08 Hypothyroidism overall vs euthyroidism Overall cohort 14 879 Pre-existing CHF Yes 470 No 14 409 P for interaction Race Black 4061 Non-Black 10 818 P for interaction Exclusion of Thyroid Medication Usec 1. There has been ongoing debate as to whether subclinical hypothyroidism.03 1. CHF.97 (0.03 1.06) 1.20) 1. niacin.72) No 14 409 0.91–1. sex.10) P for interaction .83–1.05 (0.77 (1. The second. 10 –17).95 (0. hypercholesterolemia. ACR.23) Non-Black 10 818 0.99) 0.01 1.005 1.04 (0.98 (0.84 –1.95 (0.08 .09) .97 (0. and gemfibrozil).47 (1.00 (0.02 (0.53 (1. and the study did not consider survival as an outcome.08) .85–1.409 0.06 (0. The first. or both.44 (0.91–1.03 1. 12).16) .19 –2.03 .01 1.07 Subclinical hypothyroidism (TSH-based definition) vs euthyroidism Overall cohort 14.20) 0.19 –2. Adjusted for all covariates in multivariable-adjusted model as well as amiodarone.82 (1.83–1. considered to be a milder form of hypothyroidism.93–1.24) 1.15) 1.10) 0.11) 0. adversely impacts survival (3.96 (0.54 (1.97 (0. Two meta-analyses have sought to examine this issue more systematically.18) 1.22–2.01 .12) 0. hypertension.12) .47 (1. There is plausible reason to suspect that subclinical hypothyroidism is causally associated with greater mortality risk. 14.20) Pre-existing CHF Yes 470 1.97 (0.94 –2.12) No 14.05–2. Studies in patients of average underlying cardiovascular risk have tended to be negative (5– 8.85–1. Stratified Analyses of the Association Between Subclinical Hypothyroidism and Hypothyroidism Overall With All-Cause Mortality HR (95% CI) n Multivariable Adjusteda Multivariable ⴙ Cardiovascular Medication Adjustedb Subclinical hypothyroidism (TSH/TT4-based definition) vs euthyroidism Overall cohort 14 879 1.72) 1.89 –1.25) 1. previous MI.04 (0.47 (1.84 –1. 16). The directionality of the association was similar to that seen in this study.03) 0.88 –1.94 –1. however.97 (0.35) 1.95 (0. adjusted for all covariates in multivariable-adjusted model. previous studies that directly examined the associations of subclinical hypothyroidism with all-cause and cardiovascular mortality have yielded mixed results (4 – 8.05) 0.12) Non-Black 10 818 0. calcium channel blockers (dihydropyridine and nondihydropyridine).23) 1.87–1.12) P for interaction .17) .07 (0.85–1. 4). Nonetheless.01 (0.95 (0.02–2.06 –2.17) .37) 0.85–1. examined for but did not detect a differential association of subclinical hypothyroidism with CHD events and mortality among patients who did and did not have any form of pre-existing cardiovascular . CHF (14). by Gencer et al (19).04 Race Black 4061 1. previous stroke.06 –2.96 –2. thiazide and loop diuretics.91–1.02 Race Black 4061 1. June 2013. pre-existing CHF (omitted from models stratified on CHF). digoxin. clinical hypothyroidism and hypothyroidism overall were associated with greater mortality in the context of Black race. antihyperlipidemics (statins.66 (1.03 1.01 a Adjusted for age. by Rodondi et al (18). and cardiac conduction abnormalities (41) that may predispose to malignant ventricular arrhythmias.86 –1.99 (0.91–1.96 (0.02–2. 11. interaction tests did not reach statistical significance.14) 0. ACE inhibitors. whereas those in patients at high cardiovascular risk have tended to be positive (9.93–1.00 (0.01 1. 98(6):2326 –2336 Table 2.20) 1.16) 1.14) .02 (0. b c Participants on baseline thyroid supplementation and suppressive therapy excluded.00 (0.51 (1.90 –1. race (omitted from models stratified on race).28) 1.08 (0.41 (0.03 1. BMI.11) 0.84 –1.12) P for interaction .90 –1.15) 1.05 (0.15–2.97 (0. and longacting nitrates.99 –2. ␤-blockers.07 .18) Pre-existing CHF Yes 470 1. and eGFR.53 (0.17) 1.03–2.49 (1.86 –1.99 –1.07–2.44 (1. accelerated coronary atherogenesis (40).13) P for interaction . diabetes.64) 1.48 (0. indicated that subclinical hypothyroidism was associated with a greater risk of heart failure events among patients with pre-existing CHF but not among those without.83–1.

but not those with other forms of cardiovascular disease. However. cardiac contractility. In the overall cohort. sex.org 2333 tween either subclinical hypothyroidism or hypothyroidism overall with mortality. when CHF is subsumed into a broader category of heart disease. Therefore. thyroid functional disease categorizations were based on one-time measure- . and robustness of findings across analytical strategies. including its large sample size. To our knowledge. and psychosocial factors that may explain differential racial susceptibility. cardiac contractility. ours is the first study to observe that CHF modifies the association between subclinical hypothyroidism and hypothyroidism overall with all-cause mortality among nonhospitalized patients. This is also the first study to observe that Blacks have a greater mortality risk related to hypothyroidism compared with other races. in stratified analyses. several limitations of our study bear mention. disease. Our study has several strengths. Two of the aforementioned meta-analyses comparing the association between subclinical hypothyroidism and outcomes across racial groups have shown conflicting results (18. However. effect modification by heart failure is diluted and not observed. hypercholesterolemia.doi: 10. diabetes. comprehensive availability of thyroid functional test data. BMI. ventricular remodeling. Given that most NHANES III participants did not have pre-existing CHF. Analyses were adjusted for age. it is plausible that participants with pre-existing CHF may have a lower reserve with which to tolerate the acute hemodynamic. TT4 within reference range) (A) and hypothyroidism overall (TSH higher than ULN) (B) vs euthyroidism (TSH within reference range) with all-cause mortality. analyses of the population as a whole may have been dominated by effects among those without CHF. The larger representation of Blacks in our cohort compared with previous studies may have provided greater power to detect interaction by race. epidemiologic studies have shown that Blacks have a lower median TSH and distribution compared with Whites (24 –27). large representation of Black participants. and vascular tone.endojournals. In contrast. Given the compensatory alterations in neurohormonal activation. neither meta-analysis observed effect modification by race for CHF events or mortality (18. with subsequent implications on mortality. smoking. definitions of hypothyroidism using standard TSH reference ranges indicate that Blacks have a lower prevalence of hypothyroidism. Comparison of the association between subclinical hypothyroidism (TSH higher than ULN. previous MI. socioeconomic. ventricular remodeling. ACR. pre-existing CHF. and eGFR (specification for each as per Table 1).2013-1039 Figure 2. which was consistent across multiple sensitivity analyses. and vascular tone required to maintain cardiac output in structural heart disease (22). 42). hypertension. 19). Additional studies are needed to confirm this finding and to explore potential genetic. and electrophysiologic changes associated with subclinical hypothyroidism. It is possible that the pooled (nonstratified) analysis masked important subgroup effects. One possibility is that subclinical hypothyroidism poses unique risk among patients with CHF. we observed that hypothyroidism was associated with greater mortality among Blacks but not among non-Blacks. It has been suggested that there may be misclassification of thyroid functional disease among Blacks on this basis and that race-based reference ranges should be considered (28. stratified by race (Black vs non-Black). biologic. For reasons not yet fully elucidated. First. thus. previous stroke. Rodondi et al (18) found that subclinical hypothyroidism was associated with increased CHD events in Whites but not among Blacks. 19). both were associated with greater death risk in those with CHF but not in those without. extended follow-up period. other types of which do not interact with subclinical hypothyroidism. Statistical significance of effect modification was assessed by likelihood ratio testing. volume.1210/jc. we did not observe significant associations be- jcem. possibly related to consequent alterations in neurohormonal activation.

92–2.5 mIU/L when measured monthly over a 1-year period) (43.001 P interaction for race .14 –3.03–2.2334 Rhee et al Subclinical Hypothyroidism and Survival J Clin Endocrinol Metab. Lastly. not shown).50) 1.23) ⬎. For Black with CHF present. as with all observational studies.4 2. population. as well as hypothyroidism overall.004 P Interaction for CHF .86 (0.40) .S. estimates are adjusted for age.01 P Interaction for CHF . n ⫽ 113. TSH deviated from its normal set point on the basis of nonthyroidal illness. eGFR.02) 0. we cannot exclude the possibility that. hypercholesterolemia.23– 6.14) .68) 1. hypertension.53 (0. Black with CHF absent.25 (0. sex. direct thyroid hormone measurements in NHANES III used TT4 levels in lieu of free T4 levels.001 . and Non-Black with CHF absent. CHF status was self-identified as opposed to using objective measurements (ie.50 (1.27) . BMI.44) 0. echocardi- ography).06 (1. and Non-Black with CHF absent. previous stroke. diabetes.87–2.06 –2.01 Hypothyroidism Overall HR (95% CI) CHF present CHF Absent 1.70 –1. diabetes. Most commonly. Non-Black with CHF present. and ACR by Cox proportional hazards regression.07) .77–1. additional studies are needed to confirm findings. estimates are adjusted for age. Associations Between Subclinical Hypothyroidism and Hypothyroidism Overall With All-Cause Mortality Within Strata Defined by CHF Status and Racea Subclinical Hypothyroidism (TSH/TT4-Based Definition) HR (95% CI) CHF Present Hypothyroidism Overall P Interaction for CHF CHF Absent Black 2.4 1. we cannot exclude the possibility of residual confounding.75–1.89 (0. and environmental determinants of hypothyroidism and its associated complications across racial/ethnic groups. However. n ⫽ 113. are associated with a greater risk of mortality in subpopulations with pre-existing CHF and of Black race.43 (0.18) 0. variation of 0. which may have identified a subset with more severe disease. n ⫽ 357. resultant bias should therefore favor patients with higher TSH levels and would render conservative the observed association between hypothyroidism and death.03 Non-Black 1.03) ⬍. in some patients studied here. In conclusion.68) 1. hypertension. . 44). Table 4.68 (0. Non-Black with CHF present. June 2013.7 . It is also possible that self-report of CHF status may have resulted in misclassification of disease.87 (0. previous MI. Third. TSH falls in response to systemic illness. Second. we employed two definitions of subclinical hypothyroidism (based on concurrent TSH/TT4 levels vs TSH levels only) that yielded essentially the same findings.61 (0. n ⫽ 3948.61) 1. active smoking status.03 (0.9 1.58 – 4. 98(6):2326 –2336 Table 3.03 . Nonetheless. These findings bear particular relevance given the high prevalence of hypothyroidism and CHF and the racial/ethnic diversity of the U. and to examine the differential therapeutic effectiveness and safety of thyroid hormone supplementation for subclinical hypothyroidism and hypothyroidism overall vis-à-vis effects on survival according to race/ethnicity and underlying cardiovascular risk. we cannot exclude the possibility that there was misclassification bias in the opposite direction. not shown).09 . our findings demonstrated that subclinical hypothyroidism.01 a Reference for each cell is euthyroidism (HR ⫽ 1. sex. hypercholesterolemia. active smoking status. BMI. n ⫽ 10 461.05 .005 a Reference for each cell is euthyroidism (HR ⫽ 1.84 – 8.00) . Black with CHF absent.87 (0. n ⫽ 10 461.06) . previous MI. At this stage.55 (1. eGFR.36 (0. biologic. In healthy ambulatory patients.20 –3.35–11. For Black with CHF present. to elaborate underlying genetic. TSH is typically maintained in a narrow range over time (ie. because TSH was not measured longitudinally.002 HR (95% CI) CHF Present P Interaction for CHF CHF Absent 1.96 –2.70 –1. with the former measurements subject to thyroid functional status misclassification on the basis of differential levels of thyroid-binding globulin or differential T4 protein binding (35). such that participants with other types of cardiovascular disease (ie. ments of TSH with or without TT4 and were therefore subject to misclassification. and ACR by Cox proportional hazards regression.51) 0.39 (0.98 (1. atherosclerosis) may have identified themselves as having CHF.98 –2. previous stroke. n ⫽ 3948. n ⫽ 357. Associations Between Subclinical Hypothyroidism and Hypothyroidism Overall With Cardiovascular Mortality Within Strata Defined by CHF Status and Racea Subclinical Hypothyroidism (TSH/TT4-Based Definition) HR (95% CI) Black Non-Black P interaction for race CHF Present CHF Absent 2. Thus.

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