Indian Pediatr 2018;55:219-221|
Subclinical Hypothyroidism: A Prospective Observational Study from Southern India
Shriraam Mahadevan2, Latha
Vishwanathan1 and Anbezhil
From Departments of 1Pediatrics and 2Pediatric
Endocrinology, Apollo Children’s Hospital, Chennai, Tamil Nadu, India.
Correspondence to: Dr Shriraam Mahadevan, Consultant
Apollo Children’s Hospital, No. 15, Shafee Mohammed Road, Thousand
Lights, Chennai 600 006, Tamil Nadu, India.
Received: May 17, 2017;
Initial review: June 21, 2017;
Accepted: December 01, 2017.
December 14, 2017.
mIU/mL during follow-up were started on thyroxine. Others were followed
up with 3-monthly thyroid function tests up to one year. Results:
At the end of our study period 3 (7.5%) were overtly hypothyroid, 16
(40%) remained as subclinical hypothyroid, and 21 (52.5%) became
euthyroid. Evidence of auto- immunity at baseline was a significant (P<0.05)
risk factor for progression to overt hypothyroidism. Conclusions:
Subclinical hypothyroidism in children, with thyroid stimulating hormone
upto 15 mIU/L and irrespective of thyroid autoimmunity, needs only
periodic clinical and biochemical follow up. Thyroid autoimmunity may
point to an increased probability of progression to overt
Objective: To assess the natural history and progression of
subclinical hypothyroidism and to study factors which help predict
evolution of subclinical hypothyroidism into overt hypothyroidism.
Methods: Longitudinal study in 40 children (2-16 yrs) presenting
with subclinical hypothyroidism in a tertiary care unit in Chennai,
India. Patients showing evidence of overt hypothyroidism or thyroid
Keywords: Autoimmunity, Euthyroid, Outcome, TPO antibody.
ubclinical hypothyroidism (SCH) is a biochemical
condition characterized by serum levels of thyroid stimulating hormone
(TSH) above the statistically defined upper limit of reference range,
with normal concentration of thyroid hormones and without clinical
features of hypothyroidism . SCH is a not an uncommon condition with
incidence of about 2% in pediatric age group, though large
epidemiological studies are scarce [2,3]. SCH is often detected
incidentally as patients exhibit few or no signs of thyroid dysfunction.
There is a paucity of studies evaluating the natural history of SCH from
Clinicians often consider TSH abnormal when its value
exceeds the upper reference range of the laboratory, which may result in
unnecessary long term thyroxine replacement. This prospective study was
done to assess the natural history of SCH and evaluate factors that may
help predict evolution to overt hypothyroidism.
This longitudinal study was done in a pediatric
tertiary care hospital between January 2015 and April 2017. The study
was approved by the Institutional Ethics Committee. Parents of children
(2-16 years) with SCH (TSH <15 mIU/L were approached for inclusion in
the study. After thorough history and clinical examination thyroid
function testing (free T4 and TSH) was done. If TSH was elevated it was
re-measured along with thyroid peroxidase (TPO) antibody titres on a
subsequent visit. Children recovering from recent acute illness, or
other comorbidities like seizure disorder, renal or hepatic dysfunction
were excluded. All children who presented to our services between
January 2015 to April 2016 and satisfied the above criteria were
included based on time sampling principle. Thyroid function tests were
repeated at 3, 6 and 12 months or earlier if worsening of symptoms
noted. Based on existing published literature, thyroxine replacement in
a SCH patient is usually considered when TSH is more than 10 mIU/L
irrespective of autoimmunity . Prior experience in our centre
(unpublished) with SCH suggest that a higher cut-off of TSH up to
15 mIU/L was well tolerated by children without clinical deterioration.
Hence a cut-off of 15 mIU/L was used to start treatment in this study.
All thyroid function tests were conducted by
chemiluminescence assay and the reference ranges used for inclusion in
our study according to age is as follows: TSH: 2-5 years: 0.4 - 6.0 mIU/L,
6- 14 years: 0.4-5 mIU/L, 15-16 years: 0.4-4.2 mIU/L, normal range of
free T4 for all the age groups was: 0.8-2 ng/dL. The thyroperoxidase
(TPO) antibody test was done using chemiluminescent microparticle immuno-assay
(CMIA) and normal titres were <5.6 IU/L.
In case a TSH value
³15 mIU/L was
detected anytime during the study or overt hypothyroidism diagnosed,
thyroxine replacement was started. After 1 year, euthyroid antibody
positive children were off the study but kept under follow-up, as were
the SCH children with or without antibody positivity.
All categorical variables were expressed as
percentages. Comparison of categorical variables was done by Chi-square
or Fisher’s exact test. Data analysis was done using SPSS version 16.0
and ‘P’ values <0.05 was considered statistically significant.
We enrolled 49 patients in this study. Nine patients
were excluded either due to initiation of thyroxine therapy elsewhere or
were lost to follow up. The complaints necessitating thyroid function
evaluation were obesity in 28 (70%), constipation in 5 (12.5%), poor
growth in 3 (7.5%), and menstrual issues, gynecomastia, dry skin and
goiter in one patient each.
At the end of the study period 3/40 (7.5%) became
overtly hypothyroid, 16/40 (40%) remained SCH and 21/40 (52.5%) became
euthyroid, respectively. Among 3 children with overt hypothyroidism (2
girls, 1 boy), two were obese and one had poor growth; all three had
autoimmunity and did not have goiter. Serum TSH was between 5-10 mIU/L
in one and between 10-15 mIU/L in other two. Goiter was seen in one
child who had raised TPO levels and become euthyroid on follow-up.
For patients with TSH between 10-15 mIU/L at
presentation, the positive predictive value (PPV) was 20%, and the
negative predictive value (NPV) was 96.7% for progression to overt
hypothyroidism. Three out of 8 patients with positive TPO antibody titre
became overtly hypothyroid. For patients with elevated TPO antibody
titre, PPV was 37.5% and NPV was 100% for progression to overt
hypothyroidism. Patient profile at presentation and outcome at one year
of follow up is shown in Table I.
TABLE I Profile of Patients with Subclinical Hypothyroidism at Presentation and at One-year Follow-up (N=40)
Parameters at enrolment
TSH at diagnosis between 5-10 mIU/L
TSH at diagnosis between >10 and <15 mIU/L
Elevated TPO antibody titre
Family history of thyroid disease
OH: Overt hypothyroidism, SCH: subclinical hypothyroidism,
TSH: thyroid stimulating hormone, TPO: thyroid peroxidase.
Presence of thyroid autoimmunity was the most
significant risk factor for progression to overt hypothyroidism (P<0.005).
There was no statistically significant difference when comparing
the sex distribution or family history of thyroid disease between those
who became hypothyroid and SCH/euthyroid.
We observed that, in the absence of positive thyroid
antibodies, subclinical hypothyroidism in a child often runs a benign
course as most of them either revert to euthyroid state or remain in SCH
One of the limitations of our study was the
relatively short duration of follow-up. Another limitation of our study
was lack of urinary iodine levels, due to financial and logistic
reasons, a factor that might influence autoimmunity .
The proportion of children with SCH in the present
study who progressed to overt hypothyroidism was similar to previous
studies [7-9]. In another Indian study, 12.5% children with SCH
and goiter had developed overt hypothyrodism . Children without
evidence of autoimmunity ran a benign course which was similar to
observations made in other studies or reviews [10,11]. Majority of our
children became euthyroid during the study. The reasons for reverting
back to euthyroid state may include simple obesity, recovering phase of
recent acute illness or subacute thyroiditis and relapsing and remitting
condition like autoimmunity .
Obesity was the overwhelming reason for checking
thyroid status in our cohort. It is increasingly recognized that TSH
elevation may occur due to obesity per se. Although the exact
mechanism of TSH elevation in obesity is unclear, the role of leptin has
been postulated . Studies with thyroxine replacement for marginal
elevations of TSH in obesity had questionable benefits .
The untreated children in our cohort did not have
worsening of their presenting symptoms clinically. This study set-up was
not ideal to see whether a therapeutic trial with thyroxine would
benefit improvement of symptoms. Previous studies on thyroxine
replacement therapy in SCH have not shown any appreciable clinical
Our experience from this study adds to the increasing
evidence for expectant management in SCH. Thyroid antibody positivity
may point to an increased probability of conversion to overt
hypothyroidism. However, even in the presence of autoimmunity, children
often revert to euthyroidism or remain as SCH. We conclude that
subclinical hypothyroidism in children, even up to a TSH of 15 mIU/L,
irrespective of autoimmunity may be periodically followed up clinically
and biochemically. Longitudinal studies with a larger cohort and longer
duration of follow-up are needed to further analyze the prognosis of
Acknowledgements: Dr Vanishree Shriraam,
Associate Professor, Department of Community Medicine, Sri Ramachandra
Medical College for help in statistical analysis. We also thank AHERF
(Apollo Hospital Education and Research Foundation) for their help in
completion of the study.
Contributors: All authors contributed for study
concept, case recruitment, data collection, outcome assessment, and
Funding: None; Competing interest: None
What This Study Adds?
• Subclinical hypothyroidism in children
with TSH up to 15 mIU/L may be observed without treatment,
especially in the absence of thyroid autoimmunity.
1. Surks MI, Ortiz GH, Sawin CT. Subclinical thyroid
disease: Scientific review and guidelines for diagnosis and management.
2. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The
Colorado thyroid disease prevalence study. Arch Intern Med.
3. Paoli-Valeri M, Maman-Alvardo D, Jiménez-Lopez V.
Frequency of subclinical hypothyroidism among healthy children and those
with neurological conditions in the state of Mérida, Venezuela. Invest
4. Gopalakrishnan S, Chugh PK, Chhillar M. Goitrous
autoimmune thyroiditis in a pediatric population: A longitudinal study.
5. Shriraam M, Sridhar M. Subclinical hypothyroidism
in children. Indian Pediatr. 2014;51:889-95.
6. Palaniappan S, Shanmughavelu L, Prasad HK,
Subramaniam S, Krishnamoorthy N, Lakkappa L. Improving iodine
nutritional status and increasing prevalence of autoimmune thyroiditis
in children. Indian J Endocrinol Metab. 2017;21:85-89.
7. Leonardi D, Polizzotti N, Carta A, Gelsomino R,
Sava L, Vigneri R, et al. Longitudinal study of thyroid function
in children with mild hyperthyrotropinemia at neonatal screening for
congenital hypothyroidism. J Clin Endocrinol Metab. 2008;93:2679-85.
8. Moore DC. Natural course of subclinical
hypothyroidism in childhood and adolescence. Arch PediatrAdolesc Med.
9. Lazar L, Frumkin RB, Battat E, Lebenthal Y,
Phillip M, Meyerovitch J. Natural history of thyroid function tests over
5 years in a large pediatric cohort. J Clin Endocrinol Metab.
10. Valenzise M, Aversa T, Zirilli G, Salzano G,
Corica D, Santucci S, et al. Analysis of the factors affecting
the evolution over time of subclinical hypothyroidism in children.
Italian J Pediatr. 2017;43:2.
11. Lee YJ, Jung SY, Jung HW, Kim SY, Lee YA, Lee SY,
et al. Unfavorable course of subclinical hypothyroiditis in
children with Hashimoto’s thyroiditis compare to those with isolated
non-autoimmune hyperthryoptropinemia. J Korean Med Sci. 2017;32:124-9.
12. Nannipieri M, Cecchetti F, Anselmino M, Camastra
S, Niccolini P, Lamacchia M, et al. Expression of thyrotropin and
thyroid hormone receptors in adipose tissue of patients with morbid
obesity and/or type 2 diabetes: Effects of weight loss. Int J Obes.
13. Sanyal D, Raychaudhuri M. Hypothyroidism and
obesity: An intriguing link. Indian J Endocrinol Metab. 2016;20:554-7.
14. Aijaz NJ, Flaherty EM, Preston T. Neurocognitive
function in children with compensated hypothyroidism: lack of short term
effects on or off thyroxine. BMC Endocr Disord. 2006;6:2.
15. Wasniewska M, Corrias A, Aversa T, Valenzise M,
Mussa A, De Martino L, et al. Comparative evaluation of therapy
with L-Thyroxine versus no treatment in children with idiopathic and
mild subclinical hypothyroidism. Horm Res Paediatr. 2012;77:376-81.