ORIGINAL ARTICLE

E n d o c r i n e C a r e

Cardiovascular Risk Factors in Children With Long-

Standing Untreated Idiopathic Subclinical
Hypothyroidism

Manuela Cerbone, Donatella Capalbo, Malgorzata Wasniewska,

Giuseppina Mattace Raso, Sara Alfano, Rosaria Meli, Filippo De Luca, and
Mariacarolina Salerno
Pediatric Endocrinology Unit (C.M., D.C., S.A., M.S.), Department of Translational Medical Sciences, and
Department of Experimental Pharmacology (G.M.R., R.M.), University Federico II of Naples, 80131
Naples, Italy; Department of Pediatrics (M.W., F.D.L.), University of Messina, 98121 Messina, Italy

Context: Subclinical hypothyroidism (SH), defined as increased TSH serum levels and normal serum
free T4 concentrations, has been associated with an increased risk of coronary heart disease in
adults. Data in children and adolescents are scanty.

Objective: The objective of the study was to investigate the clinical and biochemical cardiovascular
risk factors in children with mild SH (serum TSH concentrations 4.510 mU/L).

Design and Setting: This is a cross-sectional and controlled study conducted at a tertiary referral
center on patients with persistent idiopathic long-standing (3.2 0.4 y) mild SH. At study entry
patients and controls underwent a clinical and biochemical assessment for cardiovascular risk.

Participants: Forty-nine children aged 8.5 0.5 years with SH and 49 controls were enrolled in the
study.

Main Outcome Measure: Systolic and diastolic blood pressure, body mass index (BMI), waist to
height ratio, lipid profile, homocysteine, high-sensitivity serum C-reactive protein, fibrinogen,
adiponectin, insulin, and homeostasis model assessment index were measured.

Results: Waist to height ratio (P .0001), atherogenic index (P .001), triglycerides to high-density
lipoprotein-cholesterol ratio (P .01), and homocysteine levels (P .002) were significantly higher
and high-density lipoprotein-cholesterol significantly lower (P .003) in SH subjects compared
with controls. No significant differences were found in the other clinical and biochemical cardio-
vascular risk factors analyzed. Multivariate regression model revealed that BMI and thyroid status
were the main independent factors affecting dependent variables. Even after an adjustment for
BMI, most of the variables still remained significantly associated with mean TSH levels or SH
duration.

Conclusions: Mild long-lasting untreated idiopathic SH may be associated with subtle proathero-
genic abnormalities. Although it is difficult to establish whether these mild abnormalities repre-
sent the early steps in the initiation of atherogenesis, these children need to be carefully monitored
for metabolic complications. (J Clin Endocrinol Metab 99: 26972703, 2014)

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: BMI, body mass index; BP, blood pressure; CV, cardiovascular; DBP, diastolic
Printed in U.S.A. BP; FT3, free T3; FT4, free T4; Hcy, homocysteine; HDL-C, high-density lipoprotein choles-
Copyright 2014 by the Endocrine Society terol; HOMA, homeostasis model assessment; hs-CRP, high-sensitivity serum C-reactive
Received March 17, 2014. Accepted May 9, 2014. protein; LDL-C, low-density lipoprotein-cholesterol; L-T4, levothyroxine; SBP, systolic BP;
First Published Online May 19, 2014 SDS, SD score; SH, subclinical hypothyroidism; Tg-Ab, thyroglobulin antibody; Total-C,
total cholesterol; TPO-Ab, thyroperoxidase antibody; WHtR, waist to height ratio.

doi: 10.1210/jc.2014-1761 J Clin Endocrinol Metab, August 2014, 99(8):26972703 jcem.endojournals.org 2697

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:49 For personal use only. No other uses without permission. . All rights reserved.
2698 Cerbone et al Cardiovascular Risk in Children With SH J Clin Endocrinol Metab, August 2014, 99(8):26972703

ubclinical hypothyroidism (SH) is a biochemical con- Patients and Methods

S dition characterized by increased TSH serum levels
above the upper limit of reference range, with normal se- Subjects and controls
Of a total of approximately 4300 children yearly seen in the
rum free T4 (FT4) concentrations. Depending on the de-
two pediatric endocrine units participating to the study, exclud-
gree of TSH elevation, SH can be defined as mild (TSH ing children with diabetes, 430 (10%) were affected by SH.
serum concentrations between 4.5 and 10 mU/L) or severe Among the SH subjects, 280 (6.5% of total cohort) had evidence
(TSH 10 mU/L) (1). of autoimmune disease, whereas the remaining 150 children
In adults, SH represents a common condition with a (3.5% of total cohort) had no signs of thyroid autoimmunity.
prevalence ranging from 4% to 20% and a tendency to Among the latter group, only children with persistent and
idiopathic SH confirmed after at least 2 years of follow-up were
progress to overt hypothyroidism (1). enrolled in the study on the basis of the following inclusion cri-
Data in children and adolescents are scanty, with a teria: 1) TSH values greater than 4.5 mU/L and less than 10 mU/L
prevalence lower than 2% (2). Differently from adults, SH with FT4 values within the reference range at the time of SH
in children seems to be a benign and remitting condition identification and confirmed for at least 2 years during the period
with a low risk of progression toward overt hypothyroid- preceding the study; 2) the absence of antithyroglobulin (Tg-Ab)
and antithyroperoxidase (TPO-Ab) antibodies and normal thy-
ism (35). Whether this condition in children results in
roid echogenicity on ultrasound; 3) the absence of palpable goi-
adverse health outcome is still unclear. Therefore, al- ter or symptoms related to hypothyroidism from the time of SH
though there is a general agreement in recommending identification to the beginning of the study; 4) adequate iodine
treatment in children who have serum TSH above 10 urinary excretion.
mU/L, the management of mild disease with TSH levels Previous treatment with L-T4 replacement therapy, chronic
between 4.5 and 10 mU/L is still a matter of debate (4, diseases, chromosomal and genetic syndromes, previous or cur-
rent thyroid diseases, use of drugs that may interfere with thyroid
6 8). function, previous irradiation in the neck region, detection of SH
American Thyroid Association guidelines suggest levo- at neonatal screening, premature or small-for-gestational-age
thyroxine (L-T4) treatment for adults with TSH levels be- children and familial hypercholesterolemia or familial CV dis-
tween 4.5 and 10 mU/L in the presence of symptoms of ease were considered exclusion criteria.
hypothyroidism, positive thyroid antibodies, or evidence Forty-nine children (27 males) aged 8.5 0.5 years with
long-standing (3.2 0.4 y) untreated and idiopathic SH fulfilling
of atherosclerotic cardiovascular (CV) disease (9).
the inclusion criteria were enrolled in the study on a first-come,
Thyroid hormones play a key role in the modulation of first -served basis.
several atherosclerotic factors. Indeed, the relationship be- In all patients included in the study, the absence of thyroid
tween overt hypothyroidism and atherosclerosis is well antibodies, goiter, symptoms related to hypothyroidism, and ad-
known (10). Whether SH is associated with an increased equate iodine urinary excretion as well as normal thyroid echo-
genicity were confirmed at least twice, at the diagnosis of SH and
risk of atherosclerotic disease is still controversial (1).
at study entry.
However, recent data suggest a clear link between SH and Forty-nine healthy euthyroid children, comparable for age,
an increased risk of coronary heart disease and heart fail- sex, height, and pubertal status were enrolled in the study as
ure (1114). This increased risk seems to be mediated by controls. They were selected from a group of healthy subjects
adverse CV changes such as dyslipidemia (15, 16), insulin recruited according to a cooperative study program between our
resistance (17), and diastolic dysfunction (11), which also centers and the family pediatricians.
SH children and controls were originating from the same geo-
may occur in subjects with mild SH. Most these abnor-
graphic region.
malities improve after L-T4 replacement therapy in sev- Informed consent was obtained by all parents and the study
eral, but not all, studies (1, 11, 18). was approved by the Ethics Committee of the institution.
It is well known that risk factors accelerating the de-
velopment of atherosclerotic CV disease begins in child- Study protocol
hood and may be predictive of CV risk in adulthood. The At study entry all SH subjects and controls underwent a clin-
Bogalusa Heart Study has shown that early atherosclerotic ical evaluation through the measurements of height, weight,
waist circumference, systolic (SBP) and diastolic BP (DBP).
lesions in children correlate with risk factors such as body
The degree of overall adiposity was expressed as BMI and
mass index (BMI), systolic and diastolic blood pressure calculated as weight (kilograms)/height (meters)2. Height and
(BP), triglycerides, total cholesterol (Total-C), low-density BMI were normalized by age and sex in accordance with Italian
lipoprotein-cholesterol (LDL-C) and high-density lipo- standards and expressed as SD score (SDS) (20).
protein cholesterol (HDL-C) (19). Waist circumference was measured, by the same operator, for
each center using a flexible steel tape while the subjects were
Therefore, we designed this open, cross-sectional and
standing, after gently exhaling, as the minimal circumference
controlled study to investigate the clinical and biochemical measurable on the horizontal plane between the lowest portion
CV risk factors in a population of children with long-term of rib cage and the iliac crest. Waist to height ratio (WHtR) was
untreated idiopathic mild SH. calculated and used as indicator of abdominal adiposity (21).

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:49 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-1761 jcem.endojournals.org 2699

SBP and DBP were measured at the right arm by a cuff ma-
nometer after 5 minutes of supine rest according to the fourth
report of the National High Blood Pressure Education Program
Working Group on High Blood Pressure in Children and Ado-
lescents. Two BP measurements were obtained 5 minutes apart,
and the means of the two SBP and DBP measurements were used
in the analysis.
A biochemical evaluation was performed at 8 AM after an
overnight fast by measurement of TSH, FT4, free T3 (FT3),
Tg-Ab and TPO-Ab, triglycerides, Total-C, HDL-C, homocys-
teine (Hcy), vitamin B12, folate, creatinine, glucose, insulin,
high-sensitivity serum C-reactive protein (hs-CRP), fibrinogen,
adiponectin, and urinary iodine excretion.
LDL-C was calculated using the Friedewald equation.
Atherogenic index, an index of severe cardiovascular risk, was
calculated by the ratio Total-C to HDL-C (22). Non-HDL-C,
calculated as the difference between Total-C and HDL-C, is a
measure of cholesterol associated with all apolipoprotein B-con-
taining particles and has been documented to be equivalent to
LDL-C in predicting CV disease (23). Moreover, the triglycerides
to HDL-C ratio (triglycerides to HDL-C), a predictor of small,
dense low-density lipoprotein particles, was also calculated as an
additional predictor of CV disease (24). The degree of insulin
resistance was evaluated using the homeostasis model assess-
ment (HOMA) by applying the following formula: fasting serum
insulin (milliunits per liter) fasting plasma glucose (millimoles
per liter)/22.5 (25).
hs-CRP levels were analyzed using a chemiluminescent tech-
nique on an IMMULITE 2000 (Diagnostic Products Corp). This
assay had an interassay coefficient of variation of 2.2% and a
detection threshold of 0.20 mg/L.
Fibrinogen was measured by Multifibren U Reagent, a bovine
thrombin reagent (Siemens Healthcare Diagnostics Products
GmbH).
Urine iodine levels were analyzed with an automated system
(Autoanalyzer 3 system; BranLuebbe GmbH).
Statistical analysis
Statistical analysis was performed using SPSS. Data are pre-
sented as mean SEM. Variables were analyzed by the Kolm-
ogorov-Smirnov test, and positively skewed variables (waist cir-
cumference, triglycerides, atherogenic index, triglycerides
/HDL-C) were log transformed for analysis.
Differences between groups were evaluated by linear regres-
sion after adjustment for BMI, age, and gender. Those factors
that were significantly different between the two groups were
then analyzed by a stepwise multiple regression analysis to study
the association of thyroid status with metabolic risk factors. In
this model the effects of several independent factors (age, gender,
BMI, mean TSH level, duration of SH, FT4) on waist circum-
ference, WHtR, HDL-C, atherogenic index, triglycerides to
HDL-C ratio, and Hcy in SH children were evaluated. Signifi-
cance was set at 5%.

Biochemical assays
TSH and FT4 dosages were measured by an electrochemilu- Results
minescence immunoassay using a commercial kit (Roche Diag-
nostics) (normal values: TSH, 0.3 4.2 mU/L; FT4, 0.8 1.7 ng/ Clinical and hormonal details of SH subjects and controls
dL; FT3, 2.0 4.4 pg/mL; Tg-Ab, 0 115 mIU/L; TPO-Ab, 0 34
at study entry are reported in Table 1. As expected, TSH
mUI/L).
Serum triglycerides, Total-C, and HDL-C were determined levels were significantly higher in the SH subjects than in
by an enzymatic in vitro test using Roche automated clinical the controls (6.28 0.2 vs 2.75 0.1 mU/L; P .0001),
chemistry analyzers (Roche Diagnostics). whereas FT4, FT3, urinary iodine excretion, and height
Serum insulin concentrations were measured by using a solid- were similar.
phase, enzyme-labeled chemiluminescent immunometric assay
Clinical and biochemical CV risk factors of the SH sub-
(IMMULITE 2000 Insulin; Diagnostic Products Corp).
Hcy levels were determined by a fluorescence polarization jects compared with the control group are shown in Table
immunoassay (Abbott); the inter- and intraassay coefficients of 2. At study entry, SBP and DBP were normal and similar
variance were 2% and 1%, respectively, and sensitivity was 0.8 in the two groups. In SH children, BMI was similar to
mol/L. controls, whereas waist circumference and WHtR were
Total adiponectin levels were measured by the Quantikine
human adiponectin/Acrp30 immunoassay (R&D Systems), with
significantly higher (P .0001).
inter- and intraassay coefficients of variation of 6.8% and 2.5%, Triglycerides, Total-C, and non-HDL-C serum levels
respectively, and a sensitivity of 0.246 ng/mL. were comparable between the two groups. However,

Table 1. Clinical and Hormonal Details of Children With SH Compared With Healthy Controls at Study Entry
SH Children Controls
(n 49) (n 49) P Value
Sex (male/female) 27/22 27/22 ns
Chronological age, y 8.5 0.5 8.6 0.4 ns
Height (SDS) 1.1 0.1 1.3 0.1 ns
TSH, mU/L 6.28 0.2 2.75 0.1 .0001
FT4, ng/dL 1.32 0.03 1.27 0.02 ns
FT3, pg/mL 4.5 0.1 4.2 0.1 ns
Iodine urinary excretion, g/L 164.0 17.6 192.2 37.4 ns
Abbreviation: ns, not significant. Data are expressed as mean SEM.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:49 For personal use only. No other uses without permission. . All rights reserved.
2700 Cerbone et al Cardiovascular Risk in Children With SH J Clin Endocrinol Metab, August 2014, 99(8):26972703

Table 2. Traditional and Nontraditional Risk Factors for CV Disease in Children With SH Compared With Healthy
Controls
SH Children Controls P
(n 49) (n 49) Valuea
SBP, mm Hg 100.8 1.5 102.7 1.3 ns
DBP, mm Hg 64.9 1.2 63.9 1.3 ns
BMI (SDS) 1.2 0.1 1.0 0.08 ns
Waist circumference, cm 69.3 2.6 61.2 1.4 .0001
WHtR 0.55 0.01 0.49 0.007 .0001
Triglycerides, mg/dL 67.7 4.0 60.3 3.6 ns
Total-C, mg/dL 161.0 3.9 160.9 3.2 ns
HDL-C, mg/dL 52.6 1.8 62.2 1.8 .003
LDL-C, mg/dL 95.0 3.7 85.9 3.0 ns
Non-HDL-C, mg/dL 108.6 4.1 98.8 3.2 ns
Triglycerides/HDL-C 1.45 0.13 1.04 0.08 .01
Atherogenic index 3.2 0.1 2.6 0.08 .001
Hcy, mol/L 9.0 0.3 7.7 0.2 .002
Glucose, mg/dL 78.6 1.3 75.0 1.3 ns
Insulin, mU/L 5.7 0.6 4.7 0.5 ns
HOMA index 1.1 0.1 0.9 0.1 ns
Fibrinogen, mg/dL 278.7 9.5 293.8 8.5 ns
hs-CRP, mg/L 0.20 0.02 0.24 0.02 ns
Adiponectin, g/mL 12.5 0.9 13.3 1.0 ns
Abbreviation: ns, not significant. Data are expressed as mean SEM.
a
P value adjusted for BMI.

mean HDL-C serum levels were significantly lower (P thyroid status were the main independent factors affecting
.003), whereas the atherogenic index (P .001) and the dependent variables. Indeed, even after adjustment for
triglycerides to HDL-C ratio (P .01) were significantly BMI, most of the variables remained still significantly as-
higher in the SH subjects compared with the controls, even sociated with mean TSH levels or SH duration, thus sug-
after adjustment for waist circumference and WHtR. gesting that the effects of thyroid status on CV risk factors
Moreover, a trend toward higher LDL-C levels (95.0 were not mediated or confounded by adiposity (Table 3).
3.7 vs 85.9 3.0 mg/dL) was observed in the SH subjects No significant associations were found between FT4 levels
compared with the controls, although this difference did and risk factors.
not reach statistical significance (Table 2). Serum Hcy lev-
els were significantly higher in the SH subjects than in the
Discussion
healthy children (P .002). However, these parameters
were all still within the normal range for age (26, 27). No To our knowledge, this is the first study investigating early
significant differences were found in vitamin B12, folate, CV risk factors in a cohort of children and adolescents
and creatinine. Glucose, insulin, HOMA index, fibrino- with mild, long-term, idiopathic SH.
gen, hs-CRP, and adiponectin concentrations were similar Results of this controlled study suggest that untreated
in the SH subjects and the controls. children with long-standing SH may develop a cluster of
The multivariate regression model performed to eval- subtle metabolic abnormalities as increased abdominal
uate the effects of age, gender, BMI, and thyroid status on adiposity and slight alterations in lipid profile and Hcy
the CV risk factors in the SH group revealed that BMI and levels.

Table 3. Association Between CV Risk Factors, Thyroid Function, and BMI

Mean TSH SH Duration BMI

P Value P Value P Value

Waist circumference 0.117 ns 0.15 ns 0.70 .0001
WHtR 0.24 .05 0.19 ns 0.71 .0001
HDL-C 0.22 ns 0.3 .03 0.33 .01
Atherogenic index 0.15 ns 0.35 .007 0.43 .001
Triglycerides/HDL-C 0.08 ns 0.3 .05 0.2 ns
Hcy 0.009 ns 0.43 .004 0.03 ns
Abbreviation: ns, not significant.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:49 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-1761 jcem.endojournals.org 2701

Thyroid hormone plays an essential role in the modu- by the different design of the studies. Indeed, the study
lation of several atherosclerotic factors (10). In particular, from Nader et al was retrospective and cross-sectional
thyroid hormone has a direct effect on the synthesis, me- with a wide range in subjects age (from 2 to 19 y) and TSH
tabolism, and mobilization of lipids by decreasing intes- levels that ranged from below to above the normal values,
tinal cholesterol absorption and increasing hepatic cho- whereas we enrolled only prepubertal children with mild
lesterol synthesis (28). TSH alterations. Our results are in agreement with those
The role of TSH on atherosclerotic disease is still de- reported by Paoli-Valeri et al (32), who investigated 17
bated. However, clinical studies documented that adults children with well-defined idiopathic SH and documented
with SH develop alterations of cardiac performance, en- normal levels of triglycerides, Total-C, and LDL-C and
dothelial function, BP, lipid profile, and homocysteine lev- decreased HDL-C, even though children were followed up
els (11). Moreover, a linear relationship between TSH, only for a 4-month period. In addition, in our study the
lipids, and BP has been suggested, even for TSH concen- atherogenic risk profile was also suggested by an increased
trations within the reference range (29). These evidences atherogenic index and plasma triglyceride to HDL-C ra-
suggest that TSH might be implicated in the regulation of tio, which are both useful indexes to identify subjects at
the lipid profile and BP to some extent, irrespectively of higher risk for CV disease (22, 24). Moreover, the triglyc-
FT4 and FT3 action. eride to HDL-C ratio has been recently proposed in ado-
Furthermore, a recent experimental study documented lescents as a helpful index in predicting increased arterial
a role of TSH in lipid biosynthesis; indeed, TSH, is able to stiffness and therefore in identifying subjects requiring in-
promote the expression of 3-hydroxy-3-methyl-glutaryl tervention to prevent atherosclerotic CV disease (35).
coenzyme A reductase, a rate-limiting enzyme in choles- Although a recent population-based study conducted
terol synthesis, through its action on the TSH receptor in children and adolescents (aged 317 years) suggests a
expressed on liver cells. Therefore, increased TSH levels linear relationship between TSH levels and BP (33), we did
might result in an up-regulation of hepatic 3-hydroxy-3- not confirm this correlation; moreover, we did not find
methyl-glutaryl coenzyme A reductase expression and in- significant differences in SBP and DBP between SH chil-
creased cholesterol biosynthesis (30). dren and controls. It is noteworthy that studies on the
So far, only a few studies have investigated the rela- relationship between TSH levels and BP yielded contrast-
tionship between SH and CV risk factors in children and ing results also in adults (29, 36), leading to the conclusion
adolescents, leading to contrasting results (3134). that this is still an open issue that remains to be further
Overall, most of the studies are limited by several crit- investigated.
icisms: first of all, populations included are often widely According with our previous studies (3, 4, 6) we did not
heterogeneous in terms of etiology, severity, and duration observe any significant effect of SH on BMI, even after
of the SH, which is often too short; furthermore, the pres- several years of follow-up without any therapeutic inter-
ence of several confounding factors, such as obesity and vention. However, in the present study, an increased
autoimmunity, frequently make evaluating the direct im- WHtR was observed in the SH children with respect to the
pact of SH on cardiovascular risk difficult. controls. WHtR has been identified as a useful parameter
Therefore, to minimize the effects of additional con- in detecting abdominal adiposity and related cardiometa-
founders, we designed our study including a selected and bolic risk also among normal-weight children (21, 37, 38).
homogeneous population of prepubertal children with Several studies in adults have shown that WHtR is a good
mild, idiopathic, long-lasting SH compared with a control predictor of hypertension, diabetes, and dyslipidemia
group matched for gender, age, and height. (39). Values of WHtR in our cohort of SH children were
In addition, nonconventional CV risk factors were also significantly higher than healthy controls and were above
evaluated to extensively assess the early risk profile in the limit of 0.5, which is considered the boundary value
these children. indicating an increased metabolic risk (37, 39).
In our cohort of SH children, triglycerides, Total-C, Recently a great number of studies has focused on hy-
and LDL-C were comparable with controls, whereas perinsulinemia and insulin resistance as independent risk
HDL-C was decreased, although still within normal val- factors for atherosclerosis. To date there are no consistent
ues. In a recent retrospective study on a large cohort of data about insulin sensitivity in patients with SH, with
healthy children, Nader et al (31) found that triglyceride only a few studies reporting increased insulin levels or
concentrations were positively correlated with TSH and HOMA index in SH subjects compared with controls (17).
negatively correlated with FT4 levels. In contrast, we did Nader et al (31) investigated children and adolescents with
not observe a relationship between triglycerides and TSH SH and documented an impaired insulin sensitivity in
or FT4 levels. This discrepancy probably may be explained these subjects. We did not find any significant difference

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:49 For personal use only. No other uses without permission. . All rights reserved.
2702 Cerbone et al Cardiovascular Risk in Children With SH J Clin Endocrinol Metab, August 2014, 99(8):26972703

between SH children and controls in glucose, insulin lev- proatherogenic abnormalities as documented by slight al-
els, and HOMA index or significant correlations between terations in visceral adiposity, lipid profile, and Hcy levels.
TSH levels and these parameters. Because insulin resis- In view of the cross-sectional design of the study, it is
tance physiologically increases during adolescence, we difficult to establish the clinical significance of these subtle
cannot exclude that our results reflect the prepubertal age abnormalities or whether they might represent the early
of children enrolled in the study. steps in the initiation of atherogenesis. However, our pre-
In addition to traditional CV risk factors, we also pro- liminary data suggest that SH children need to be carefully
vided data on emerging nontraditional CV markers, such monitored to verify whether these metabolic abnormali-
as hs-CRP, fibrinogen, adiponectin, and Hcy. ties may place them at a higher risk of future cardiovas-
Even though there is compelling evidence suggesting a cular disease.
crucial role for inflammation in the initiation and pro-
gression of atherosclerosis, our results do not suggest an
association between mild SH and inflammation, hs-CRP Acknowledgments
and fibrinogen being similar in the SH subjects and in the
controls. Moreover, no significant differences were noted Address all correspondence and requests for reprints to: Mari-
acarolina Salerno, MD, PhD, Pediatric Endocrinology Unit, De-
in adiponectin, a protein secreted by adipose tissue, with
partment of Translational Medical Sciences, University Fed-
antiinflammatory and antiatherogenic properties. erico II of Naples, Via South Pansini, 5, 80131 Naples, Italy.
In keeping with our data, most studies evaluating non- E-mail: salerno@unina.it.
traditional CV risk factors in adults with SH did not find Disclosure Summary: The authors have nothing to disclose.
consistent abnormalities, thus suggesting that these in-
dexes do not significantly contribute to an increased CV
risk in mild SH (11, 40, 41). References
Conversely, in the current study, we found Hcy levels
1. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012;
significantly higher in SH children compared with con- 379:11421154.
trols, although still within the normal range for age and 2. Wu T, Flowers JW, Tudiver F, Wilson JM, Punyasavatsut N. Sub-
sex (27). Elevated plasma Hcy levels are considered to be clinical thyroid disorders and cognitive performance among adoles-
cents in the United States. BMC Pediatr. 2006;6:12.
an independent risk factor for CV disease (42). The mech- 3. Wasniewska M, Salerno M, Cassio A, et al. Prospective evaluation
anism of Hcy action on the CV system has not been still of the natural course of idiopathic subclinical hypothyroidism in
completely understood; however, elevated Hcy levels have childhood and adolescence. Eur J Endocrinol. 2009;160:417 421.
4. Cerbone M, Bravaccio C, Capalbo D, et al. Linear growth and in-
a direct endothelial cytotoxicity, enhance oxidation of
tellectual outcome in children with long-term idiopathic subclinical
low-density lipoprotein, and increase platelet adhesive- hypothyroidism. Eur J Endocrinol. 2011;164:591597.
ness and proliferation of smooth muscle cells (42). High 5. Radetti G, Maselli M, Buzi F, et al. The natural history of the normal/
Hcy levels have been documented in hypothyroid subjects, mild elevated TSH serum levels in children and adolescents with
Hashimotos thyroiditis and isolated hyperthyrotropinaemia: a
probably due to the effect of thyroid hormone on renal 3-year follow-up. Clin Endocrinol (Oxf). 2012;76:394 398.
Hcy clearance as well as on enzymes involved in folate 6. Wasniewska M, Corrias A, Aversa T, et al. Comparative evaluation
metabolism (43). To date, the role of Hcy as a CV risk of therapy with L-thyroxine versus no treatment in children with
idiopathic and mild subclinical hypothyroidism. Horm Res Paedi-
factor in adults and adolescents with mild SH has been atr. 2012;77:376 381.
investigated in only a few studies, yielding conflicting re- 7. Cerbone M, Agretti P, De Marco G, et al. Non-autoimmune sub-
sults (11, 16). clinical hypothyroidism due to a mutation in TSH receptor: report
on two brothers. Ital J Pediatr. 2013;39:5.
A multivariate analysis performed to identify the major
8. Di Mase R, Cerbone M, et al. Bone health in children with long-term
determinants of the metabolic abnormalities detected in idiopathic subclinical hypothyroidism. Ital J Pediatr. 2012;38:56.
our SH children revealed that the most independent factor 9. Garber JR, Cobin RH, Gharib H, Hennessey JV, et al. American
associated with CV risk was the duration of SH. The de- Association of Clinical Endocrinologists and American Thyroid As-
sociation Taskforce on Hypothyroidism in Adults. Clinical practice
gree of SH, as indicated by the mean TSH concentration in guidelines for hypothyroidism in adults: cosponsored by the Amer-
the years preceding the study, played a minor role being ican Association of Clinical Endocrinologists and the American Thy-
correlated only with the increased visceral adiposity. roid Association. Thyroid. 2012;22:1200 1235.
10. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis.
Therefore, long-lasting untreated subclinical hypothy- J Clin Endocrinol Metab. 2003;88:2438 2444.
roidism seems to play a direct role on early atherosclerotic 11. Biondi B, Cooper DS. The clinical significance of subclinical thyroid
changes not mediated by visceral adiposity or other con- dysfunction. Endocr Rev. 2008;29:76 131.
12. Rodondi N, den Elzen WP, Bauer DC, et al. Thyroid Studies Col-
founding factors.
laboration. Subclinical hypothyroidism and the risk of coronary
In summary, our study suggests that mild, long-stand- heart disease and mortality. JAMA. 2010;304:13651374.
ing untreated idiopathic SH may be associated with subtle 13. Gencer B, Collet TH, Virgini V, et al. Thyroid Studies Collabora-

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:49 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-1761
tion. Subclinical thyroid dysfunction and the risk of heart failure
events: an individual participant data analysis from 6 prospective
cohorts. Circulation. 2012;126:1040 1049.
14. Razvi S, Weaver JU, Vanderpump MP, Pearce SH. The incidence of
ischemic heart disease and mortality in people with subclinical hy-
pothyroidism: reanalysis of the Whickham Survey cohort. J Clin
Endocrinol Metab. 2010;95:1734 1740.
15. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado
thyroid disease prevalence study. Arch Intern Med. 2000;160:526
534.
16. Duntas LH, Wartofsky L. Cardiovascular risk and subclinical hy-
pothyroidism: focus on lipids and new emerging risk factors. What
is the evidence? Thyroid. 2007;17:10751084.
17. Maratou E, Hadjidakis DJ, Kollias A, et al. Studies of insulin resis-
tance in patients with clinical and subclinical hypothyroidism. Eur
J Endocrinol. 2009;160:785790.
18. Villar HCCE, Saconato H, Valente O, Atallah N. Thyroid hor-
mone replacement for subclinical hypothyroidism. Cochrane Data-
base Syst Rev. 2007:CD003419.
19. Berenson GS, Srinivasan SR, Nicklas TA. Atherosclerosis: a nutri-
tional disease of childhood. Am J Cardiol. 1998;82:22T29T.
20. Cacciari E, Milani S, Balsamo A, et al. Italian cross-sectional growth
charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest.
2006;29:581593.
21. Maffeis C, Banzato C, Talamini G. Obesity Study Group of the
Italian Society of Pediatric Endocrinology and Diabetology. Waist-
to-height ratio, a useful index to identify high metabolic risk in
overweight children. J Pediatr. 2008;152:207213.
22. Castelli WP. Lipid, risk factors and ischaemic heart disease. Ath-
erosclerosis. 1996;124:S1S9.
23. van Deventer HE, Miller WG, Sakurabayashi I, et al. Non-HDL
cholesterol shows improved accuracy for cardiovascular risk score
classification compared to direct or calculated LDL cholesterol in a
dyslipidemic population. Clin Chem. 2011;57:490 501.
24. Salazar MR, Carbajal HA, Espeche WG, et al. Identifying cardio-
vascular disease risk and outcome: use of the plasma triglyceride/
high-density lipoprotein cholesterol concentration ratio versus met-
abolic syndrome criteria. J Intern Med. 2013;273:595 601.
25. Matthews DR, Hosker JP, Rudensky AS, Naylor BA, Treacher DF,
Turner RC. Homeostasis model assessment: insulin resistance and
-cell function from fasting plasma glucose and insulin concentra-
tions in man. Diabetologia. 1985;28:412 419.
26. National Cholesterol Education Program. Report of the Expert
Panel on Blood Cholesterol Levels in Children and Adolescents.
Pediatrics. 1992;89(suppl):525584.
27. Vilaseca MA, Moyano D, Ferrer I, Arthuc R. Total homocysteine in
pediatric patients. Clin Chem. 1997;43:690 692.
28. Pearce EN. Update in lipid alterations in subclinical hypothyroid-
ism. J Clin Endocrinol Metab. 2012;97:326 333.
29. Asvold BO, Bjro T, Vatten LJ. Associations of TSH levels within
the reference range with future blood pressure and lipid concentra-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:49 For personal use only. No other uses without permission. . All rights reserved.
jcem.endojournals.org 2703
tions: 11-year follow-up of the HUNT study. Eur J Endocrinol.
2013;169:73 82.
30. Tian L, Song Y, Xing M, et al. A novel role for thyroid-stimulating
hormone: up-regulation of hepatic 3-hydroxy-3-methyl-glutaryl-
coenzyme A reductase expression through the cyclic adenosine
monophosphate/protein kinase A/cyclic adenosine monophos-
phate-responsive element binding protein pathway. Hepatology.
2010;52:14011409.
31. Nader NS, Bahn RS, Johnson MD, Weaver AL, Singh R, Kumar S.
Relationships between thyroid function and lipid status or insulin
resistance in a pediatric population. Thyroid. 2010;20:13331339.
32. Paolo-Valeri M, Guzman M, Jimenez-Lopez V, Arias-Ferreira A,
Briceno-Fernandez M, Arata-Bellabarba G. Atherogenic lipid pro-
file in children with subclinical hypothyroidism. An Pediatr. 2005;
62:128 134.
33. Ittermann T, Thamm M, Wallaschofski H, Rettig R, Vlzke H.
Serum thyroid-stimulating hormone levels are associated with blood
pressure in children and adolescents. J Clin Endocrinol Metab.
2012;97:828 834.
34. Atabek ME, Pirgon O, Erkul I. Plasma homocysteine concentrations
in adolescents with subclinical hypothyroidism. J Pediatr Endocri-
nol Metab. 2003;16:12451248.
35. Urbina EM, Khoury PR, McCoy CE, Dolan LM, Daniels SR, Kim-
ball TR. Triglyceride to HDL-C ratio and increased arterial stiffness
in children, adolescents, and young adults. Pediatrics. 2013;131:
e1082 e1090.
36. Liu D, Jiang F, Shan Z, et al. A cross-sectional survey of relationship
between serum TSH level and blood pressure. J Hum Hypertens.
2010;24:134 138.
37. Mokha JS, Srinivasan SR, Dasmahapatra P, et al. Utility of waist-
to-height ratio in assessing the status of central obesity and related
cardiometabolic risk profile among normal weight and overweight/
obese children: the Bogalusa Heart Study. BMC Pediatr. 2010:11;
10:73.
38. Capalbo D, Mattace Raso G, et al. Cluster of cardiometabolic risk
factors in children with GH deficiency: a prospective, case-control
study. Clin Endocrinol (Oxf). 2014;80(6):856 862.
39. Schneider HJ, Klotsche J, Stalla GK, Wittchen HU. Obesity and risk
of myocardial infarction: the INTERHEART study. Lancet. 2006;
367:1052.
40. Hueston WJ, King DE, Geesey ME. Serum biomarkers for cardio-
vascular inflammation in subclinical hypothyroidism. Clin Endo-
crinol (Oxf). 2005;63:582587.
41. Altinova AE, Toruner FB, Aturk M, et al. Adiponectin levels and
cardiovascular risk factors in hypothyroidism and hyperthyroidism.
Clin Endcorinol (Oxf). 2006;65:530 535.
42. Fonseca V, Guba S, Fink L. Hyperhomocysteinemia and the endo-
crine system: implications for atherosclerosis and thrombosis. En-
docr Rev. 1999;20:738 759.
43. Barbe F, Klein M, Chango A, et al. Homocysteine, folate, vitamin
B12, and transcobalamins in patients undergoing successive hypo-
and hyperthyroid states. J Clin Endocrinol Metab. 2001;86:1845
1846.