Reversible morbidity markers in subclinical hypothyroidism.

http://informahealthcare.com/pgm ISSN: 0032-5481 (print), 1941-9260 (electronic) Postgrad Med, 2015; Early Online: 78– 2015 Informa UK, Ltd. DOI: 10.1080/00325481.2015.998158

REVIEW

Reversible morbidity markers in subclinical hypothyroidism James V. Hennessey1 & Ramon Espaillat2

Postgraduate Medicine Downloaded from informahealthcare.com by University of California San Francisco on 03/20/15 For personal use only.

1 2

Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA, USA, and AbbVie, Inc., North Chicago, IL, USA

Abstract

Keywords:

Importance. Subclinical hypothyroidism (SCH) is a common clinical entity with a putative role in a wide range of disorders. The impact of SCH on mortality and markers of morbidity has been demonstrated, but studies have shown inconsistent results. Evidence regarding the effect of levothyroxine treatment on reversing morbidity markers is emerging, but the value of treatment is still unclear. Objective. The objectives of this review were to assess recent, high-quality studies evaluating the role of SCH in cardiovascular health, cognition, mood, pregnancy, anemia, and renal disease; to examine the effects of levothyroxine on reducing mortality or reversing markers of morbidity in these conditions; and to consider how new research insights may help guide clinical practice. Evidence review. A PubMed search was conducted (using ‘subclinical hypothyroidism’ [Title/Abstract] AND morbidity [MeSH Subheading] as search criteria) and was restricted to human studies published in the English language between 1990 and 2013. Subsequent searches of retrieved articles yielded further studies, which were included based on quality. Emphasis was given to large observational studies, well-conducted meta-analyses, and randomized controlled trials. Findings. The difficulty of diagnosing SCH, particularly in the elderly, may underlie many of the conflicting results seen in the literature. Increased understanding of the at-risk patient population will result in better selection of study subjects and, likely, unequivocal results. Regardless of the current confusion, emerging evidence suggests that certain markers of morbidity are reversed by levothyroxine therapy across the disorders examined here. Conclusion and relevance. Future large, well-controlled studies will not only clarify the role of SCH but also help identify patients for whom levothyroxine treatment will provide the most benefit.

cardiovascular morbidity, cognitive function, levothyroxine therapy, morbidity, subclinical hypothyroidism

Introduction Hypothyroidism exists in both overt and subclinical forms and is a common clinical entity. Overt hypothyroidism, which has a prevalence of 0.3% to 0.4% in the USA, is categorized by elevated serum thyrotropin (thyroid-stimulating hormone [TSH]) coupled with a subnormal level of free thyroxine (FT4) [1]. The common signs and symptoms of overt hypothyroidism are well characterized, as are the benefits of levothyroxine treatment [1]. Subclinical hypothyroidism (SCH) is defined as a serum TSH level above the reference limit with a normal FT4 level, according to guidelines issued in 2012 by the American Association of Clinical Endocrinologists and the American Thyroid Association [1]. Diagnostic accuracy in distinguishing among euthyroidism, SCH, and overt hypothyroidism requires stable thyroid function (i.e., reproducible TSH levels over weeks or months), a normal hypothalamic-pituitarythyroid axis, and no recent or current severe illness [1]. Additionally, it has been suggested that current immunoassay Correspondence: James V. Hennessey, MD, FACP, Associate Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, GZ6, Boston, MA 02215-5400, USA Tel: +1 617 667 9344. Fax: +1 617 667 7060. E-mail: [email protected]

History Received 6 October 2014 Accepted 10 December 2014 Published online 26 December 2014

platforms for the measurement of FT4 may not be as accurate or specific as newly developed mass spectrometry methods, and the latter may be more appropriate for patients with certain conditions (i.e., pregnancy or kidney disease) [2-9]. SCH was identified in 4.3% of participants in the National Health and Nutrition Examination Survey (NHANES III) and 9.0% of participants in a statewide health fair in Colorado and is more prevalent than overt hypothyroidism [10,11]. Because it is associated with few or none of the signs and symptoms of overt hypothyroidism, SCH is essentially a laboratory diagnosis, and the merits of treating SCH remain a matter of debate [12]. There is growing evidence, however, that SCH may be associated with negative clinical consequences. Further, certain markers of morbidity associated with SCH may be reversed by therapy. Studies reporting the relationship of SCH with selected morbidity markers were identified through a PubMed search using ‘subclinical hypothyroidism’ [Title/ Abstract] AND morbidity [MeSH Subheading] as search criteria and restricted to human studies published in the English language between 1990 and 2013. The retrieved articles generated subsequent searches; studies were selected for inclusion based on quality; data from large observational studies, well-conducted meta-analyses, and randomized controlled trials were emphasized.

DOI: 10.1080/00325481.2015.998158


Considerations based on TSH levels in patient subpopulations Reference ranges for TSH must be considered for any identified association of SCH with morbidity markers. NHANES III defined overt hypothyroidism as TSH > 4.5 mIU/l with T4 < 57.9 nmol/l (< 4.5 mg/dl), and SCH as TSH > 4.5 mIU/l with T4 ‡ 57.9 nmol/l but < 169.9 nmol/l (4.5–13.2 mg/dl) [11]. It was observed, however, that TSH levels in the reference population (‡ 12 years of age and free of thyroid disease and its risk factors [n = 13,344]) differed depending on age, sex, and race or ethnicity [11]. The NHANES III data have been reanalyzed and appropriate reference limits have been developed for patient-specific populations to limit misclassification of thyroid function. Specifically, increasing age was associated with a significantly increased upper limit of TSH; additionally, black individuals had a significantly lower upper-limit TSH value compared with white individuals [13]. Because TSH levels increase with age, older patients with mild elevations may be misdiagnosed with SCH [14]. Indeed, using an upper limit of 4.5 mIU/l may result in misdiagnosis of up to 15% of patients who are ‡ 70 years of age [15]. Conversely, there is potential for underdiagnosis of SCH in younger patients. Additional research on younger individuals in assessments of SCH, using TSH level > 4.5 mIU/l as the benchmark for inclusion, may allow clearer observation of the effects of more marked hypothyroidism on measured outcomes, reveal adverse influences of SCH on physiology, and provide more distinct evidence for a positive impact of therapy. A further consideration is the accuracy of the SCH diagnosis based on one measurement. Test results may be misleading if thyroid function is not stable, if the hypothalamic-pituitarythyroid axis is disturbed, or if the patient has or is recovering from a serious illness [1,16]. Because TSH elevations may be transitory, a single measurement is insufficiently diagnostic, particularly for mild TSH elevations. Results from the population-based, longitudinal Cardiovascular Health Study indicated that 35% of patients aged ‡ 65 years with a single baseline measure reverted to euthyroidism, and those with milder TSH elevations were more likely to become euthyroid [17]. Other studies using a single baseline thyroid assessment have seen reversion to normal in 52% and 62% of patients with untreated SCH after follow up of 3 to 5 years [18,19]. Although anti-microsomal/anti-thyroid peroxidase antibodies (TPOAbs) in patients with elevated TSH levels significantly increase the likelihood of persistent SCH [20], few studies have tested for TPOAb. Because of these issues, many studies may have inadvertently included euthyroid patients, thereby confounding the effects of SCH on outcomes. In addition, the analysis of the results of some studies of levothyroxine intervention may be complicated by the possibility that investigators may have induced TSH suppression in some patients by inadvertently overdosing their patients with levothyroxine.

Cardiovascular health A relationship has long been recognized between overt hypothyroidism and negative effects on cardiovascular health, including bradycardia, impaired systolic function, impaired

Morbidity markers in SCH

79

left ventricular (LV) diastolic filling, increased systemic vascular resistance, diastolic hypertension, increased arterial stiffness, and endothelial dysfunction [21]. Further, overt hypothyroidism has been linked to increased mortality [22]. There is conflicting evidence, however, about whether SCH affects cardiovascular morbidity and mortality [23-28]. A well-conducted meta-analysis of 12 observational studies in unselected community dwelling subjects (euthyroid, n = 24,868; SCH, n = 2399) examined the effects of SCH on the prevalence and incidence of ischemic heart disease (IHD) and cardiovascular mortality [29]. A modest association was noted with SCH in the overall population; however, grouping subjects by age (< 65 vs ‡ 65 years) revealed a highly significant relationship between SCH and prevalent IHD in younger (but not older) subjects (odds ratio [OR] = 1.57; 95% CI: 1.19–2.06; P = 0.001; Figure 1; see Table I, for synopses of this and other studies regarding cardiovascular health) [29]. A retrospective analysis of the UK General Practitioner Research Database suggests that levothyroxine treatment for SCH can reduce the risk of IHD events, but only in younger patients. This analysis grouped patients with SCH by age (40–70 years, n = 3093; > 70 years, n = 1642). Patients with a first-ever increased TSH (5.01–10.00 mIU/l) and normal serum FT4 (both based on a single measurement) and no history of IHD or cerebrovascular disease were included. In younger patients, the adjusted risk of fatal and nonfatal IHD events was lower in those treated with levothyroxine (hazard ratio [HR] = 0.61; 95% CI: 0.39–0.95), whereas older patients did not appear to benefit from treatment [30]. A meta-analysis of patient-level data from six prospective studies (euthyroid, n = 22,674; SCH, n = 2068), adjusted for age and gender, noted that the risk of heart failure (HF) events became elevated with increasing TSH level. A significant increase in risk, compared with euthyroidism, was noted in individuals with SCH when TSH levels were 10.0 to 19.9 mIU/l (HR = 1.86; 95% CI: 1.27–2.72) [31]. An association between SCH and mortality was also investigated in NHANES III. In participants with preexisting congestive heart failure, the presence of SCH was associated with an increased risk of all-cause mortality versus euthyroidism (multivariable-adjusted HR = 1.44; 95% CI: 1.01–2.06; P = 0.01) [26]. In contrast, a large retrospective cohort study recently found that subjects with SCH had a lower risk of allcause mortality versus euthyroid subjects (adjusted incidence rate ratio [IRR] = 0.92; 95% CI: 0.87–0.97), despite having an elevated risk of myocardial infarction (IRR = 1.13; 95% CI: 1.01–1.27) [32]. No association was observed between SCH and major adverse cardiovascular events (IRR = 0.99; 95% CI: 0.94–1.06), HF (IRR = 1.03; 95% CI: 0.94–1.12), or stroke (IRR = 0.94; 95% CI: 0.86–1.03) [32]. Several small randomized studies have evaluated whether levothyroxine therapy reverses markers of cardiovascular morbidity in individuals with SCH (see Table II, for synopses of studies that have assessed effects of levothyroxine on cardiovascular parameters). Monzani et al. randomized 20 patients with SCH to receive levothyroxine (n = 10) or placebo (n = 10) for 6 months [33]. Only treated patients achieved normalized TSH levels and significant improvements in LV

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J. V. Hennessey & R. Espaillat

Postgrad Med, 2015; Early Online: 78–

IHD prevalence (random) 95% CI

IHD prevalence (random) 95% CI

Age < 65 years 2.30 (1.28, 4.13) 2.50 (1.13, 5.53) 1.03 (0.73, 1.45) 1.46 (0.77, 2.75) 1.40 (0.96, 2.03) 1.27 (0.30, 5.39) 2.20 (1.20, 4.01) 1.57 (1.19, 2.06)

Subtotal (95% CI) Test for heterogeneity: Chi2 = 9.86, df = 6 (P = 0.13), I2 = 39.1% Test for overall effect: Z = 3.20 (P = 0.001)


Age ≥ 65 years 1.08 (0.85, 1.37) 0.99 (0.63, 1.56) 1.01 (0.79, 1.29) 0.41 (0.05, 3.46) 0.82 (0.50, 1.34) 1.01 (0.87, 1.18)

Subtotal (95% CI) Test for heterogeneity: Chi2 = 1.68, df = 4 (P = 0.79), I2 = 0% Test for overall effect: Z = 0.13 (P = 0.90) Total (95% CI) Test for heterogeneity: Chi2 = 19.97, df = 11 (P = 0.05), I2 = 44.9% Test for overall effect: Z = 2.20 (P = 0.03) 0.2

0.5

1.23 (1.02, 1.48)

1

High in euthyroidism

2

5

High in SCH

Figure 1. Prevalence of IHD in SCH and euthyroid subjects is shown. Data are from a meta-analysis of 12 cross-sectional studies. Group 1 studies included participants aged < 65 years, whereas group 2 studies included participants aged ‡ 65 years. Prevalence of IHD was significantly increased in younger patients. Adapted with permission from Razvi et al. 2008 [29]. Abbreviations: CI = Confidence interval; IHD = Ischemic heart disease; SCH = Subclinical hypothyroidism.

function and myocardium textural parameters. A similar study found that levothyroxine improved endothelium-dependent vasodilation in individuals with SCH [34]. In another study, LV function and mechanics, evaluated using two- and threedimensional echocardiography and speckle tracking imaging, were significantly worse in women with untreated SCH (n = 54; aged £ 50 years), compared with normal matched controls (n = 40) [35]. In patients with SCH, significantly improved LV function was noted in those treated with levothyroxine, whereas LV mechanics improved but did not normalize within the 1-year follow-up period, even though patients attained euthyroid status [35]. These early changes in cardiac function and mechanics suggest that SCH may have a subtle role in cardiovascular health and that certain markers of cardiac morbidity can be reversed with levothyroxine treatment. Dyslipidemia Overt hypothyroidism is associated with dyslipidemic changes that can be improved with levothyroxine therapy [36,37]. Results of studies examining the relationship between SCH and lipid profiles show clear associations between TSH, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in patients with TSH > 10 mIU/l [38]. A large, cross-sectional, population-based study from Norway (the HUNT study) demonstrated that levels of TC, LDL-C, non–high-density lipoprotein cholesterol, and triglycerides exhibited a linear positive

relationship across the range of TSH values, even those within the normal range [39]. The effect of levothyroxine on lipid profiles and vascular reactivity in patients with SCH has been evaluated in various studies (Table II). A meta-analysis and several controlled studies found that levothyroxine treatment improved dyslipidemia, the waist-to-hip ratio, and brachial artery flow-mediated dilatation (a marker of vascular endothelial function) [40-44]. Two research groups observed improvements in TC, LDL-C, and carotid artery intima-media thickness (a marker of early atherosclerotic change) with levothyroxine treatment [45,46]. Although it remains unclear whether treating SCH with levothyroxine prevents clinically relevant atherosclerotic heart disease, it is noteworthy that the Third Report of the National Cholesterol Education Program (Adult Treatment Panel III) recommends, “[a]ny person who presents with elevated LDL cholesterol or other form of hyperlipidemia must undergo evaluation to rule out secondary dyslipidemia” and identifies hypothyroidism as a major cause of secondary dyslipidemia [47]. The accumulated evidence suggests that SCH negatively affects cardiovascular health, but inconsistent findings have caused some confusion regarding this relationship. As noted earlier, careful diagnosis of SCH is required to avoid underestimating the impact of SCH. Most of the evidence for a connection has been noted in patients aged £ 65 years [29], those with TSH levels > 10 mIU/l [23,27,31,38], and in patients with concomitant heart disease [26]. Preliminary data

3/10 studies repeated thyroid function tests

1

1

1

1

Second test at 6 months

TSH cut-off values = 4.0–6.0 mIU/l

TSH > ULN, which ranged from 2.8– 6.0 mIU/l depending on the study

TSH = 6.0–15.0 mIU/l and normal FT4 TSH ‡ 4.5 to < 20 mIU/l, normal FT4

TSH = 4.5–19.9 mIU/l and normal FT4

TSH ‡ 4.5 mIU/l and normal FT4 levels

Meta-analysis of prospective observational studies

Meta-analysis of 15 population-based studies

Observational

Meta-analysis of individual patient data from 11 prospective observational studies

Meta-analysis of individual patient data from prospective observational studies

Post-hoc evaluation of the randomized, controlled, prospective study of pravastatin in the elderly at risk

Ochs et al., 2008 [24]

Razvi et al., 2008 [29]

Razvi et al., 2010 [25]

Rodondi et al., 2010 [27]

Gencer et al., 2012 [31]

Nanchen et al., 2012 [23]

1

Morbidity and mortality Observational TSH > 4 mIU/l, normal FT4

Number of tests

Walsh et al., 2005 [28]

Tests and criteria

Study description

SCH diagnosis

Author, year

Table I. Relationships between SCH and cardiovascular health.

Aged 70–82 years History of vascular disease or with known CVD risk factors SCH: n = 199 Euthyroid: n = 5046

SCH: n = 2068 Euthyroid: n = 22,674

CHD All-cause mortality CVD mortality

Community-living subjects without significant comorbidities Mean age in 8/10 included studies: > 65 years SCH: n = 1491 Euthyroid: n = 12,530 Community-dwelling subjects Depending on the measure, SCH: n ranged from 954 to 2399 Euthyroid: n ranged from 8673 to 24,868 SCH: n = 97, mean age = 50 years Euthyroid: n = 2279, mean age = 45 years SCH: n = 3450 Euthyroid: n = 51,837

Fatal/nonfatal CHD events Fatal/nonfatal CVD events SCH stratified by TSH 4.5– 10 mIU/l and > 10 mIU/l

HF events

CHD events (fatal and nonfatal) CHD mortality All-cause

Incident IHD IHD mortality

Incident, prevalent IHD IHD mortality

CHD events (fatal and nonfatal) CVD mortality

Markers

SCH: n = 39; mean age = 51 years Euthyroid: n = 1906; mean age = 49 years

Patients

Significantly increased rate of HF when TSH ‡ 10 mIU/l Significantly increased risk of CVD events in patients with TSH ‡ 10 mIU/l and not receiving pravastatin

Significant association between SCH and incident IHD, but not allcause or IHD mortality Significantly higher risk of CHD events and CHD mortality among subjects with SCH and TSH ‡ 10 mIU/l Stratified analysis by TSH level found a positive relationship when TSH = 10.0–19.9 mIU/l

SCH associated with prevalent and incident IHD and IHD mortality, but only in subjects £ 65 years

SCH associated with: increased prevalence of CHD in those with TSH ‡ 10.0 mIU/l Increased risk of CHD events (irrespective of TSH level) Suggestion of modestly increased risk of CHD, all-cause and CVD mortality

Findings


Increased risk at high TSH level persisted after controlling for preexisting HF, AF, and CVD risk factors PROSPER study. Given population age, potential inclusion of euthyroid patients in the SCH group

Mean age in four studies ‡ 68 years

Reanalysis of the Whickham Survey cohort

Mean age of SCH subjects in 9/15 studies was ‡ 65 years

Standard TSH cut-offs for studies conducted in elderly patients may have included euthyroid subjects Few studies confirmed persistent SCH

Busselton Health Study

Comments

DOI: 10.1080/00325481.2015.998158

Morbidity markers in SCH 81

Observational

Observational

Rhee et al., 2013 [26]

Selmer et al., 2014 [32]

Tadic et al., 2014 [35]

Taddei et al., 2003 [34]

1

1

1

TSH = 5.01–10 mIU/l, normal FT4

TSH > ULN but £ 10 mIU/l TSH > 5.0 mIU/l, normal FT4, normal total T4

Open-label study of levothyroxine treatment

TSH > 5 mIU/l, normal FT3 and FT4; etiology of SCH was chronic autoimmune thyroiditis diagnosed by increased TPOAb and/or antithyroglobulin auto-Ab+ and diffuse hypoechogenicity by thyroid ultrasound NR

NR

NR

Number of tests

Tests and criteria

SCH diagnosis

Myocardial function and mechanics Randomized, controlled, TSH > 3.6 mIU/l and normal FT4; only patients 1-year study of with stable elevated levothyroxine serum TSH and normal FT4 levels for ‡ 1 year before enrollment Open-label study of levTSH > 3.6 mIU/l othyroxine treatment for ‡ 6 months All had Hashimoto’s thyroiditis and were TPOAb+ and anti-thyroglobulin Ab+

Case record review of levothyroxinetreated/untreated patients from the UK GPRD

Razvi et al., 2012 [30]

Monzani et al., 2001 [33]

Study description

Author, year

Table I. (Continued)

SCH: n = 54 female patients; mean age = 41 years Euthyroid: n = 40

Lipid parameters Vascular parameters: FBF; NO contribution to endotheliumdependent vasodilatation; endotheliumindependent vasodilatation; MFVRs LV structure, function and deformation via 2DE and 3DE speckle tracking imaging

Myocardial function and structure: EchoDoppler parameters CVI

All-cause mortality MACE Other events (MI, HF, stroke)

SCH: n = 11,560 Euthyroid: n = 540,710

Levothyroxine: n = 10 Placebo: n = 10 Note: all patients had Hashimoto’s thyroiditis Age-matched controls: n = 20 SCH: n = 14, mean age = 40 years Euthyroid: n = 28; mean age = ~ 39 years

All-cause mortality

IHD events (fatal and nonfatal) All-cause mortality Mortality due to circulatory disease, IHD, cancer, CVA, AF

Markers

SCH: n = 691 Euthyroid: n = 14,130

Aged ‡ 40 years with incident SCH Stratified by age; 40–70 years: n = 3093 and > 70 years: n = 1642

Patients

Compared to euthyroidism, LV deformation and function are significantly different in patients with SCH

At BL, SCH patients had small but significant functional and textural myocardial impairments compared with control patients Impaired endothelial vasodilation was seen in SCH versus euthyroid patients at BL

40- to 70-year-old group, untreated: IHD events in 6.6%; allcause mortality in 6.4% > 70-year-old group, untreated: IHD events in 10.7%; all-cause mortality in 40.5% SCH is associated with increased all-cause mortality in those with preexisting CHF SCH (overall and grade 1): overall lower mortality risk SCH (overall and grade 2): increased risk of MI No other associations seen

Findings


Patients with SCH at BL were evaluated after achieving 1 year of stable euthyroidism induced by levothyroxine

9 patients with SCH at BL were evaluated after 6 months of stable euthyroidism induced by levothyroxine

SCH subclassification: Grade 1: TSH 5–10 mIU/l Grade 2: TSH > 10 mIU/l

NHANES III

Effects of levothyroxine treatment on end points in Table II

Comments

82 J. V. Hennessey & R. Espaillat Postgrad Med, 2015; Early Online: 78–

Observational HUNT study

1-year, open-label study of levothyroxine

Asvold et al., 2007 [39]

Kim et al., 2009 [46]

TSH > 5.5 mIU/l and normal FT4

TSH > 3.6 mIU/l for ‡ 6 months; TPOAb+ and anti-thyroglobulin auto-Ab+ Etiology was Hashimoto’s thyroiditis in 48/49 subjects TSH > 3.6 mIU/l for ‡ 6 months, n = 36 with Hashimoto’s thyroiditis TPOAb+ and antithyroglobulin auto-Ab+ n = 9 diagnosed with SCH after radioiodine therapy for toxic adenoma or multinodular toxic goiter TSH = 4.1–9.9 mIU/l and FT4 ‡ 8.0 pmol/l

Tests and criteria

‡ 2 positive tests measured at least 2 months apart

1

NR

NR

Number of tests

SCH diagnosis

SCH associated with significantly higher TC, LDL-C, ApoB, mean and maximal cIMT versus normal controls

Positive linear association between increasing TSH (including those outside the reference range) and TC, LDL-C, non-HDL-C and TG; no clear association with HDL-C SCH versus euthyroidism: modest elevations in TC, LDL-C, nonHDL-C, and TG TC, LDL-C, and cIMT significantly higher than euthyroid controls at BL BL HDL-C and TG levels similar to euthyroid controls

Serum lipids cIMT

Serum lipids

Serum lipids cIMT

Mean age = 37 years Levothyroxine: n = 23 Placebo: n = 22 Normal controls: n = 32

Stratified by TSH (mIU/l) < 0.10: n = 128 0.1–0.49: n = 569 0.5–3.5: n = 27,727 3.6–9.9: n = 2007 ‡ 10.0: n = 225 SCH: n = 1247

SCH: n = 28 Mean age = 36 years All TPOAb+

SCH associated with significantly higher BL TC, LDL-C, ApoB, and Lp(a) than controls

Findings

Serum lipids

Markers

Aged 18–50 years Randomized to levothyroxine: n = 24 or placebo: n = 25 Normal controls: n = 33

Patients

cIMT predicts atherosclerotic CVD

A normal reference range established for this study population: TSH = 0.50–3.5 mIU/l


Comments

Abbreviations: Ab = Antibody; AF = Atrial fibrillation; Apo = Apolipoprotein; BL = Baseline; CHD = Coronary heart disease; CHF = Congestive heart failure; cIMT = Carotid artery intima-media thickness; CVA = Cerebrovascular disease; CVD = Cardiovascular disease; CVI = Cyclic variation index; DE = Dimensional echocardiography; FBF = Forearm blood flow; FT3 = Free triiodothyronine; FT4 = Free thyroxine; GPRD = General Practitioner Research Database; HDL-C = High-density lipoprotein cholesterol; HF = Heart failure; IHD = Ischemic heart disease; LDL-C = Low-density lipoprotein cholesterol; Lp = Lipoprotein; LV = Left ventricular; MACE = Major adverse cardiovascular events (cardiovascular death, nonfatal MI, and nonfatal stroke); MFVR = Minimal forearm vascular resistance; MI = Myocardial infarction; NHANES III = Third National Health and Nutrition Examination Survey; NO = Nitric oxide; NR = Not reported; SCH = Subclinical hypothyroidism; TC = Total cholesterol; TG = Triglycerides; TPOAb = Anti-thyroid peroxidase antibody; TSH = Thyroid-stimulating hormone; ULN = Upper limit of normal.

Randomized, controlled study of levothyroxine

Lipids Randomized, controlled

Study description


Caraccio et al., 2002 [42]

Author, year

Table I. (Continued)


DOI: 10.1080/00325481.2015.998158


Randomized, controlled, 48-week study of levothyroxine

Lipids Meta-analysis of levothyroxine treatment studies

Open-label study of levothyroxine treatment Measured before and after treatment; number of measurements not reported 2 TSH tests

TSH > 5.0 mIU/l, and exaggerated TSH response (> 35 mIU/l after oral TRH stimulation), and normal FT4

Mean ages ranged from 32 to 71 years across studies Depending on the measure, total numbers ranged from 168 to 247 Female patients, mean age = 59 years, randomized to: Levothyroxine: n = 31 Placebo: n = 32

100 patients, mean age = 54 years 50 randomized to levothyroxine or placebo per study period SCH: n = 54 female patients; mean age = 41 years Euthyroid: n = 40

‡ 2; at least 3 months apart

NR

Levothyroxine: n = 10 Placebo: n = 10 Note: all patients had Hashimoto’s thyroiditis

Aged ‡ 40 years with incident SCH Stratified by age; 40–70 years: n = 3093 and > 70 years: n = 1642

SCH: n = 97, mean age = 50 years Euthyroid: n = 2279, mean age = 45 years

Patients

NR

TSH > ULN but < 20 mIU/l

TSH > 5 mIU/l, normal FT3 and FT4

Myocardial function and mechanics TSH > 3.6 mIU/l and Randomized, normal FT4, controlled, 1-year FT4 for ‡ 1 year; only study of patients with stable elelevothyroxine vated serum TSH and normal FT4 levels for ‡ 1 year before enrollment TSH > 4 mIU/l and norRandomized, mal FT4 controlled, 12-week crossover

1

1

Number of tests

Serum lipids

Serum lipids

LV structure, function, and deformation via 2DE and 3DE speckle tracking imaging

Brachial artery FMD Serum lipids Weight, waist-to-hip ratio

Myocardial function and structure: EchoDoppler parameters CVI

IHD events (fatal and nonfatal) All-cause mortality Mortality due to circulatory disease, IHD, cancer, CVA, AF

Incident IHD IHD mortality

Markers

Levothyroxine treatment associated with small but significant decreases in TC and LDL-C No change in HDL-C or TG TC, LDL-C, and ApoB were significantly reduced versus BL with levothyroxine, but there were no significant between-group differences seen with/without treatment HDL-C, TG, ApoA1, and Lp(a) were unchanged

LV mechanics improved but were not completely restored with levothyroxine

Significant improvements versus placebo in TC, LDL-C, waist-tohip ratio, and FMD

Normalization of impaired diastolic and systolic functions and altered myocardial texture achieved with levothyroxine

When stratified by treatment, all-cause mortality was lower in SCH patients receiving levothyroxine In patients aged 40– 70 years, incident IHD events (fatal and nonfatal) and all-cause mortality were lower with levothyroxine No significant associations found with levothyroxine treatment in patients aged > 70 years

Findings

Greater treatment effects seen in women with higher BL levels of TSH (> 12 mIU/l), TC, and LDL-C

Included 13 studies of various design and small patient numbers (median = 15, range: 7–33)

Patients with SCH evaluated after achieving 1 year of stable euthyroidism

FMD is a marker of vascular endothelial function

Reanalysis of the Whickham Survey cohort

Comments


Meier et al., 2001 [41]

Danese et al., 2000 [40]

Tadic et al., 2014 [35]

Razvi et al., 2007 [44]


TSH = 5.01–10 mIU/l, normal FT4

Razvi et al., 2012 [30]

Case record review of levothyroxinetreated/-untreated patients from the UK GPRD

Morbidity and mortality Observational TSH = 6.0–15.0 mIU/l and normal FT4

Razvi et al., 2010 [25]

Tests and criteria

Study description

Author, year

SCH diagnosis

Table II. Effects of levothyroxine treatment on cardiovascular parameters in patients with SCH.


84 Postgrad Med, 2015; Early Online: 78–

Randomized, controlled

Open-label study of levothyroxine treatment



1-year open-label study of levothyroxine

Caraccio et al., 2002 [42]

Taddei et al., 2003 [34]


Teixeira et al., 2008 [43]

Kim et al., 2009 [46]

TSH > 5.5 mIU/l and normal FT4

TSH > 3.6 mIU/l for ‡ 6 months n = 36 with Hashimoto’s thyroiditis; TPOAb+ and antithyroglobulin Ab+; n = 9 diagnosed with SCH after radioiodine therapy for toxic adenoma or multinodular toxic goiter TSH > 4 mIU/l, normal FT4 Serum lipids

Mean age = 37 years Levothyroxine: n = 23 Placebo: n = 22

Levothyroxine: n = 35; mean age = 49 years Placebo: n = 25; mean age = 48 years SCH: n = 28 Mean age = 36 years All TPOAb+

NR

2 assessments; ‡ 6 weeks apart ‡ 2 positive tests measured at least 2 months apart

Serum lipids cIMT

Lipid parameters Vascular parameters: FBF; NO contribution to endotheliumdependent vasodilatation; endotheliumindependent vasodilatation; MFVRs Serum lipids cIMT

NR

SCH: n = 14, mean age = 40 years Euthyroid: n = 28; mean age = ~ 39 years

Markers Serum lipids

NR

TSH > 3.6 mIU/l for ‡ 6 months, TPOAb+ and antithyroglobulin Ab+ Etiology was Hashimoto’s thyroiditis in 48/49 subjects TSH > 3.6 mIU/l for ‡ 6 months All had Hashimoto’s thyroiditis and were TPOAb+ and antithyroglobulin Ab+

Patients Aged 18–50 years Randomized to levothyroxine: n = 24 or placebo: n = 25

Number of tests

SCH diagnosis Tests and criteria

Levothyroxine treatment associated with significantly lower TC and LDL-C TC, LDL-C, and cIMT: significant improvements with levothyroxine BL HDL-C and TG levels did not change with levothyroxine

Significant decreases in treated versus untreated patients in TC, LDL-C, and cIMT

Slight but significant decreases in TC and LDL-C with levothyroxine Endothelial vasodilation improved with levothyroxine

Levothyroxine associated with significantly decreased TC and LDLC, but no change in Lp(a)

Findings


Patients evaluated after achieving 6 months of stable euthyroidism

Assessments at BL and 6 months after normalization of TSH with levothyroxine cIMT predicts atherosclerotic CVD

9 patients with SCH evaluated after 6 months of stable euthyroidism

Levothyroxine-treated patients evaluated after 6 months of stable euthyroidism

Comments

Abbreviations: Ab = Antibody; AF = Atrial fibrillation; Apo = Apolipoprotein; BL = Baseline; cIMT = Carotid artery intima-media thickness; CVA = Cerebrovascular disease; CVD = Cardiovascular disease; CVI = Cyclic variation index; DE = Dimensional echocardiography; FBF = Forearm blood flow; FMD = Flow-mediated dilatation; FT3 = Free triiodothyronine; FT4 = Free thyroxine; GPRD = General Practitioner Research Database; HDL-C = High-density lipoprotein cholesterol; IHD = Ischemic heart disease; LDL-C = Low-density lipoprotein cholesterol; Lp = Lipoprotein; LV = Left ventricular; MFVR = Minimal forearm vascular resistance; NO = Nitric oxide; NR = Not reported; SCH = Subclinical hypothyroidism; TC = Total cholesterol; TG = Triglycerides; TPOAb = Anti-thyroid peroxidase antibody; TRH = Thyrotropin-releasing hormone; TSH = Thyroid-stimulating hormone; ULN = Upper limit of normal.

Study description

Author, year

Table II. (Continued)


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suggest that levothyroxine may reverse cardiovascular morbidity markers; however, large, randomized, controlled studies are needed to confirm the benefits and risks of treatment.


Cognition and mood Limited data are available on the relationship of SCH with cognition and mood in adults, children, adolescents, and the elderly. In adults, assessments of cognition in relation to SCH have included functional magnetic resonance imaging (fMRI). Visual-spatial and verbal memory were significantly impaired at baseline in a study of adults with overt hypothyroidism (n = 21) and SCH (n = 17), compared with control subjects (n = 19); 3 months of levothyroxine treatment significantly improved impairment in patients with SCH, but not overt hypothyroidism [48]. Patients with SCH (n = 11) had worse performance than euthyroid controls (n = 12) in a working memory test (the N-back test); fMRI conducted simultaneously revealed that brain regions involved in executive performance were affected [49]. N-back test scores and brain activation normalized following 6 months of levothyroxine treatment. A second fMRI study also found that brain areas involved in executive function were less active during the N-back test in subjects with SCH, compared with euthyroid subjects [50]. Brain activation levels normalized in patients with SCH following levothyroxine treatment. Cognition in children and adolescents with (n = 17) and without (n = 17) SCH was significantly different in a crosssectional study that used the Wechsler Intelligence Scale for Children-Revised digit span, which assesses immediate auditory recall, freedom from distraction, attention, concentration, and mental control; several aspects of the Stroop test, which measures selective attention, cognitive flexibility, and processing speed, were also significantly different [51]. Interestingly, subjects with SCH from the NHANES III youth sample (22 of 1327 adolescents) had better scores on reading and block design tests than euthyroid participants, even after adjustment (P < 0.05 for both) [52]. Thus far, efforts to identify cognitive impairment in elderly patients with SCH have been unsuccessful and the cognitive benefits of levothyroxine treatment remain unproven [53]. A randomized, double-blind, placebo-controlled trial in 94 subjects with SCH aged ‡ 65 years (mean age, 74 years) failed to find evidence of cognitive benefit with 1 year of levothyroxine treatment [54]. However, this study had several important limitations, including only a single assessment of TSH, a diagnosis of SCH with a TSH level > 5.5 mIU/l, and a lack of cognitive dysfunction in the population at baseline. Additionally, 16% of subjects who received levothyroxine with the intention of normalizing TSH continued to be hypothyroid at 12 months, whereas 50% of control SCH subjects had normalized TSH without intervention by study end. These observations call into question the diagnosis of SCH in study participants and suggest that any effects of intervention would be difficult to detect [54]. In addition to cognition, researchers have assessed psychiatric function in patients with SCH, based on the longstanding literature describing associations between overt


hypothyroidism and mood symptoms [55]. Bauer et al. used positron-emission tomography with [18F] fluorodeoxyglucose to assess changes in brain glucose metabolism in four patients with overt hypothyroidism and nine patients with SCH, before and after 3 months of levothyroxine treatment [56]. Results were compared against those from 10 healthy age-matched controls. Clinician- and self-reported assessments indicated that patients with hypothyroidism had significant depressive and somatic symptoms at baseline. Untreated patients with SCH had significantly less brain activity than controls in multiple brain regions; however, brain activity was normalized with levothyroxine therapy. Notably, TSH level, lower brain activity, and depressive and somatic symptoms were correlated; symptoms improved, and brain activity levels were restored, with levothyroxine therapy [56]. Jorde et al. evaluated cognition, mood, and hypothyroid symptoms in subjects with confirmed elevations of TSH (3.5–10 mIU/l) [57]. These authors reported on a doubleblind, placebo-controlled, 1-year evaluation of levothyroxine treatment. However, after an initial exclusion of subjects with hypothyroid symptoms from the SCH pool, baseline assessments found few or no significant differences between the asymptomatic subjects with SCH (n = 89; mean age: > 62 years, none > 80 years) and euthyroid subjects (n = 154) who were not similarly prescreened for the presence of symptoms. Post-treatment assessment in SCH patients randomized to levothyroxine (n = 36) or placebo (n = 33) found no changes in any parameter in either group [57]. Cognition, mood, hypothyroid symptoms, and health status were assessed in a double-blind, randomized crossover study in female patients with overt hypothyroidism (n = 19) receiving lower doses of levothyroxine for 12 weeks to experimentally induce SCH. During the SCH period, subjects had marginally worse hypothyroid, mood, and fatigue symptoms; significant differences were observed only for cognitive tests of working memory [58]. In summary, decrements in certain domains of cognition in subjects with SCH (i.e., working memory) have been demonstrated, and some deficits appear to be reversible with levothyroxine treatment. However, further study is needed to determine the effects of SCH on cognition in elderly patients and the potential benefits of levothyroxine. Mood symptoms also may be worse in individuals with true SCH, although the relationship between SCH and depressive symptoms requires further elucidation, and the benefit of levothyroxine therapy remains to be substantiated [59]. Future studies may attend to some of the limitations described above.

Effects of maternal SCH on pregnancy outcomes and offspring Thyroid dysfunction is common in pregnancy. It is well appreciated that overt hypothyroidism has serious negative consequences for both mother and child, but the effects of SCH during pregnancy and the benefits of levothyroxine treatment are just now becoming better understood [60]. The rate of spontaneous pregnancy loss was significantly higher in women with SCH (TSH ‡ 2.5–£ 5.0 mIU/l) in the first trimester (n = 642) than in euthyroid (TSH < 2.5 mIU/l)



DOI: 10.1080/00325481.2015.998158

women (n = 3481; 6.1% vs 3.6%; P = 0.006); the OR for miscarriage was significantly increased with each 1-point increase in TSH level (OR = 1.157; 95% CI: 1.002–1.336; P = 0.047) [61]. Other studies have suggested that SCH is associated with an increased risk of severe preeclampsia, placental abruption, and preterm birth [62,63]. Several studies have assessed the effect of levothyroxine treatment on pregnancy outcome. A prospective study examined levothyroxine treatment in euthyroid women with thyroid autoimmunity, determined by the presence of TPOAb [64]; such women are predisposed to develop SCH or overt hypothyroidism during pregnancy. Pregnancy outcomes were compared among levothyroxine-treated TPOAb+ women (n = 57), untreated TPOAb+ women (n = 58), and an untreated TPOAb group (n = 869) that served as a normal control. TSH values during pregnancy were significantly higher in untreated TPOAb+ women, as were rates of miscarriage (13.8% vs 3.5% and 2.4% in the levothyroxine-treated and normal groups, respectively) and premature delivery (22.4% vs 7.0% and 8.2% in the levothyroxine-treated and normal groups, respectively) [64]. Levothyroxine treatment in infertile women who were undergoing in vitro fertilization in a prospective, randomized trial was associated with significantly better outcomes for number of grade I or grade II embryos and rates of embryo implantation, miscarriage, and live birth compared with outcomes in untreated women; however, there was no significant between-group difference in the rate of pregnancy per cycle [65]. The effects of overt maternal hypothyroidism on the neurocognitive development of offspring are well recognized [53,66,67]. In contrast, some but not all studies have noted the negative effects of maternal SCH on cognitive function in their children [66,68]. One study found significantly lower mean intelligence and motor scores (P = 0.008 and P < 0.001, respectively) in children whose mothers had SCH (TSH > 4.21 mIU/l, normal FT4 and total T4, and TPOAb ) during pregnancy (n = 18) compared with normal controls (n = 36) [69]. A much larger study (n = 5131) found that symptoms of attention deficit hyperactivity disorder were significantly more common at 8 years of age in girls, although not boys, for every natural log increase in maternal TSH level during pregnancy (adjusted OR = 1.39; 95% CI: 1.07–1.80) [70]. A large, randomized, controlled study assessed the effects of levothyroxine treatment on cognition in the offspring of women diagnosed with reduced thyroid function early in pregnancy [71]. Cognition at 3 years was similar in children of treated (n = 390) and untreated (n = 404) mothers, suggesting that levothyroxine treatment had no benefit. However, treatment may have begun too late in gestation (median of 13 weeks, 3 days) to influence brain development [71]. Accumulating evidence suggests that SCH is associated with adverse pregnancy outcomes; well-controlled studies are needed to determine whether levothyroxine treatment can mitigate the effects of SCH during pregnancy.

Iron-deficiency anemia The hematopoietic system is among the many affected by hypothyroidism, with anemia being a frequent finding in this

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setting (Table III). One study found that anemia was significantly more common among patients with overt hypothyroidism or SCH compared with healthy individuals (P £ 0.021), but was similarly prevalent between the populations of patients with overt hypothyroidism and SCH (P = 0.568) [72]. In patients with SCH and iron-deficiency anemia, levothyroxine in combination with iron was effective in overcoming resistance to iron alone and increased red blood cell, hematocrit, and iron levels, and transferrin saturation (Table III) [73,74]. As a clinical caveat, it should be noted that the simultaneous ingestion of supplemental iron will diminish levothyroxine absorption significantly. Although the package inserts may differ for the different products and formulations, levothyroxine is best ingested fasting, with water only, 60 minutes prior to breakfast. Iron supplementation should be taken with a meal ingested at a different time of day.

Renal disease Relatively little is known about the link between chronic kidney disease (CKD) and hypothyroidism. The NHANES III dataset demonstrated that the prevalence of hypothyroidism increased as kidney function decreased, from 5.4% of patients with estimated glomerular filtration rate (eGFR) ‡ 90 mL/ min/1.73 m2 to > 20% with an eGFR of < 60 mL/min/ 1.73 m2. Although the hypothyroid group included individuals with overt hypothyroidism and SCH, the association between CKD and SCH may also be significant because 56% of the hypothyroid population had SCH (Table III) [75]. A retrospective study demonstrated that hypothyroidism in patients with advanced CKD was associated with a higher risk of mortality compared with euthyroidism; patients with adequately treated hypothyroidism did not have an increased risk of death [76]. Another retrospective study demonstrated the positive effects of levothyroxine treatment in patients with SCH and stage II to stage IV CKD. At 12 months, eGFR was lower in untreated versus treated patients (P = 0.04), and kidney function deteriorated faster in the untreated versus the treated group (P = 0.04). Levothyroxine treatment independently predicted better renal outcome (Table III) [77]. These intriguing results must be confirmed in larger randomized, controlled studies. However, preliminary findings suggest that levothyroxine may reverse markers of CKD morbidity.

Future research needs There is a large body of evidence that suggests that SCH has a negative effect in a wide range of conditions, and that levothyroxine treatment may reverse markers of morbidity. However, much of this evidence is derived from uncontrolled or smaller studies not powered to provide definitive results. Controlled studies with appropriate TSH inclusion criteria and long-term follow up are needed to better understand the risks of SCH and the benefits of levothyroxine treatment on associated morbidities. Recent clinical guidelines have highlighted two areas of particular interest: the cardiac and cognitive benefits of treating SCH [1].

Tests and criteria

All-cause mortality Hypothyroid: n = 350 (SCH: n = 238) Euthyroid: n = 2365

Included patients had ‡ 1 TSH measurement; first value after ESRD diagnosis was considered for SCH diagnosis

TSH levels: Low-normal: 0.4–2.9 mIU/l High-normal: ‡ 3 mIU/l and £ ULN SCH: > ULN and £ 10.0 mIU/l Overt hypothyroidism: > 10.0 mIU/l

Retrospective cohort study in patients with ESRD

Rhee et al., 2013 [76]

eGFR

Levothyroxine-treated: n = 180 No levothyroxine: n = 129

Repeated within 3 months to confirm the diagnosis

TSH > 4.94 mIU/l, normal FT4

Retrospective study in patients with stage II–IV CKD

Shin et al., 2012 [77]

eGFR

Hypothyroidism: n = 1162 No hypothyroidism: n = 13,461

Hypothyroidism prevalence higher with decreasing kidney function: 5.4% at eGFR ‡ 90 ml/min/1.73 m2 > 20% at eGFR < 60 ml/min/1.73 m2, Lower eGFR (< 60 ml/min/1.73 m2) a significant predictor of hypothyroidism At 12 months: eGFR significantly lower in untreated patients Overall rate of decline in eGFR greater in untreated patients With mean follow up of 35 months: Incidence of ESRD higher in untreated patients Levothyroxine significantly reduced risk of ESRD (by 85%) Risk of all-cause mortality higher in patients with SCH (HR = 1.37 [1.10–1.69]; P = 0.004), but not overt hypothyroidism Patients with hypothyroidism who received levothyroxine and attained euthyroid status (n = 323) did not have increased mortality

Between-group comparisons revealed statistically significant increases in hemoglobin and ferritin levels with oral iron + levothyroxine versus either treatment alone

Prevalence of anemia significantly higher in patients with overt hypothyroidism (43%) and SCH (39%) versus euthyroidism (26%) Anemia of chronic diseases significantly higher in overt hypothyroidism (31%) and SCH (24%) versus euthyroidism (15.5%) Addition of levothyroxine to oral iron treatment in patients with SCH significantly improved serum iron and blood count measures versus oral iron therapy alone

Findings


Abbreviations: BL = Baseline; CKD = Chronic kidney disease; eGFR = estimated glomerular filtration rate; ESRD = End stage renal disease; FT3 = Free triiodothyronine; FT4 = Free thyroxine; Hb = Hemoglobin; Hct = Hematocrit; HR = Hazard ratio; NHANES III = Third National Health and Nutrition Examination Survey; NR = Not reported; PBO = Placebo; SCH = Subclinical hypothyroidism; TIBC = Total iron binding capacity; TSH = Thyroid-stimulating hormone; ULN = Upper limit of normal.

Oral iron + PBO: n = 20 Levothyroxine + PBO: n = 20 Oral iron + levothyroxine: n = 20

SCH and overt hypothyroidism = TSH > 4.5 mIU/l or treatment with thyroid medication SCH = TSH > 4.5 mIU/l, total T4 ‡ 4.5 mg/dl

NR

TSH = 4.5–10 mIU/l, normal FT4 and FT3 Assessed at BL

Randomized, double-blind, controlled, 3-month study in patients with irondeficiency anemia CKD Observational (NHANES III)

Ravanbod et al., 2013 [73]

Lo et al., 2005 [75]

Measured at BL and 3–4 weeks after the end of treatment to rule out transient SCH

TSH > 4.2 mIU/l, normal FT4

Randomized, double-blind, controlled, 3-month study in patients with irondeficiency anemia

Hb RBC Hct Fe Transferrin saturation Ferritin TIBC Hb Ferritin

Markers

Oral iron: n = 25 Oral iron + levothyroxine: n = 25

Patients Anemia and subtypes: Iron-deficiency anemia Folic acid-deficiency anemia Vitamin B12 Anemia of chronic disease

NR

Number of tests Overt hypothyroidism: n = 100 SCH: n = 100 Euthyroid: n = 200

Iron-deficiency anemia Cross-sectional SCH: elevated TSH, normal FT4 and FT3 Overt hypothyroidism: elevated TSH, low FT4 and/or FT3 Euthyroid: TSH = 0.27–4.2 mIU/L; FT4 = 0.70–1.48 ng/dl; FT3 = 3.1– 6.8 pmol/l

Study description

Cinemre et al., 2009 [74]

Erdogan et al., 2012 [72]

Author, year

SCH diagnosis

Table III. Preliminary evidence for reversible morbidity markers in iron-deficiency anemia and CKD.


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Summary

References

SCH is a relatively common clinical entity that presents a challenge to researchers and clinicians alike. Thyroid dysfunction affects multiple systems, and, although unambiguous data regarding the short- and long-term effects of SCH on the conditions reviewed here are not yet available, the sum of the evidence suggests that SCH may negatively affect cardiovascular health, cognition, pregnancy outcomes, iron-deficiency anemia, and renal disease to varying degrees. The conflicting results of studies in the current literature that have attempted to define the relationship of SCH with clinical outcomes may be due to imprecise and unconfirmed laboratory assessments of thyroid function, resulting in the inclusion of patients without persistent TSH elevations; misdiagnosis of SCH, particularly in the elderly, may also be an issue. Future studies which employ multiple and more rigorous assays of thyroid function may provide for a better understanding of the at-risk patient population. Future findings will not only clarify the role of SCH but will also identify patients for whom levothyroxine therapy will provide the most benefit. At present, although evidence is not definitive in every disease state, guidelines suggest that levothyroxine treatment is warranted when TSH levels exceed 10 mIU/l in patients who are also at risk of conditions including HF and cardiovascular mortality [1].

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Acknowledgments Mariana Ovnic, PhD, of Complete Publication Solutions, Horsham, PA, USA, provided medical writing and editorial support to the authors in the development of this manuscript. Financial support to Complete Publication Solutions for medical writing and editorial assistance was provided by AbbVie. AbbVie provided suggestions for topic ideas and authors for this manuscript. AbbVie had the opportunity to review and comment on the manuscript. This manuscript reflects the opinions of the authors as to the scope of the endeavor, the focus of review, the methods for identifying the most recent literature, and the addition of relevant citations of great clinical importance. Each author reviewed the manuscript, providing extensive comment on the main clinical points to be emphasized, limitations of the literature cited, and relevance of these limitations to apply the information to clinical care, at all stages of development. Ramon Espaillat, an employee of AbbVie, is one of the authors of this manuscript and was involved in the development and review of the manuscript with the other author and the medical writer. The authors determined final content, and both authors read and approved the manuscript. The authors maintained complete control over the content of the manuscript. No payment was made to the authors for the writing of the manuscript. Declaration of interest: The authors have received no financial support in conceiving of, planning, researching, editing, and directing the completion of this manuscript. J. V. Hennessey has received consulting fees from AbbVie for the education of personnel in bioequivalence issues and FDA labeling of levothyroxine in 2013. R. Espaillat is an AbbVie employee and may hold AbbVie stock or stock options.


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