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 [5]. Prior experience in our centre (unpublished) with SCH suggest that a higher cut-off of TSH up to 15 mIU/L was well tolerated by children without clinical deterioration.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.

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) 

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 state.

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 [6].

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 [4]. 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 [5].

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 [12]. Studies with thyroxine replacement for marginal elevations of TSH in obesity had questionable benefits [13].

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 benefits [13-15].

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 SCH.

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 manuscript preparation.

Funding: None; Competing interest: None stated.

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