Correspondence to: Dr M Sridhar, Consultant Pediatrician, Apollo children’s Hospital, No. 15, Shafee Mohammed Road,
Thousand Lights, Chennai 600 006, India.
Email: [email protected]   

TSH is secreted in a pulsatile manner and shows diurnal variation. The levels may vary based on the time of sampling as well as its relation to food [6]. Most of the commercially available kits use third generation TSH assays like radioimmunoassay, chemiluminescence or electrochemiluminescence method. There is no biolo-gical reference range derived from these kits based on studies in pediatric population in India. The reference range given in the kit by the manufacturers of these assays vary. TSH above the laboratory reference ranges are considered abnormal by most pediatricians. These factors add to the difficulty in interpreting the TSH values and in decision-making for the clinician [7]. Two large population studies from India by Marwaha, et al. [8,9] reported normograms for TSH in Indian children. In study amongst children 5-16 yrs, the mean and 97th percentile for TSH (radioimmunoassay method) was, 3.17 and 7.5, respectively. This gives us a range of 1.33-5.01 mIU/L as normal values for our population. Almost 12% of the reference population had TSH values above the normal range provided by the test kit manufacturer. Such patients need long-term follow up for development of overt hypothyroidism.

SCH is most commonly (50-80% of cases) caused by chronic autoimmune thryoiditis, which is typically characterized by high titers of thyroid peroxidase antibodies, thyroglobulin antibodies and rarely TSH-receptor blocking antibodies [10]. There are many causes of potentially reversible/irreversible subclinical hypo-thyroidism [11] (Box I). Non-thyroidal causes include diabetes mellitus, cystic fibrosis, celiac disease, and chronic renal failure [12].

Mutations in several proteins involved in TSH action have been demonstrated. Loss of function mutations in the TSH receptor gene have been demonstrated [13,14]. Dual oxidase 2 (DUOX2), phosphodiesterase 8B and thyroidperoxidase mutations have also been reported as causes of mild elevations of TSH [15-17]. Congenital conditions are commonly associated with SCH. SCH is also associated with Down syndrome; present in up to 32% of these patients. Anti-thyroid antibodies were not more likely to be found in this group than in patients with a normal TSH [18]. Almost one-third patients with William syndrome also have SCH with negative anti-thyroid antibodies [19].

Abnormal sialylation of the carbohydrate moiety of TSH with resultant reduced metabolic clearance may also contribute to elevated TSH in occasional cases of hypothyroidism [20].

Large scale population studies focussing on the prevalence of SCH among children, especially from India are limited. With the difficulty in defining normal TSH, the prevalence reported in different studies may vary depending on the cut-off value. The sample selection in many of the studies is strictly not representative of the general pediatric population. In some follow-up studies, a mildly elevated TSH has been documented to normalize after few months [21]. Persistently elevated TSH over a period of time may be the best indicator to assess the true prevalence of SCH in the pediatric population.

Marwaha, et al. [22] conducted a large nationwide survey on the thyroid status after 2 decades of salt iodization in India. The prevalence of subclinical and overt hypothyroidism was 6.1% and 0.4%, respectively among the study population (total population of 38961 children). TSH elevation was found more common among children with goiter. The prevalence of goitre among the studied population was 15.5%, much above 5% prescribed by WHO. Further, thyroid autoimmunity, as defined by positive thyroperoxidase antibody titers, was observed in 3.6% of the study population and was more common among girls. In another study from Chandigarh, India, goiter prevalence was 15.1% and that of SCH was 2.6%. The population studied was iodine sufficient in that study with prevalence of autoimmunity not significantly different from the controls [23]. A study from USA, done primarily to assess cognitive parameters among adolescents with thyroid disorders, the prevalence of SCH was 1.7% [4]. Lazar, et al.[21], in a retrospective analysis from an insurance-based large database of children between 6 months to 16 years of age, reported a prevalence of elevated TSH (5.5-10.0 mIU/6) to be 2.9% [21]. Transiently elevated TSH may occasionally be diagnosed as part of newborn screening program. In a large series from China, the incidence was 1 in 8809 neonates [24]. The TSH elevation was treated with thyroxine replacement, considering its critical role in neurocognitive development, with a favourable outcome at 2-3 years follow up. Long term follow-up of these children was not available to know whether the TSH rise was transient or persisted beyond 3 years of age. SCH is observed more commonly in obese children when compared with normal weight controls; excess adipose tissue is hypothesized to signal elevation in TSH [25].

Children with Down syndrome are at increased risk – upto 28 times the normal population – for hypothyroidism. Autoimmune predisposition or dysgenesis may contribute to thyroid dysfunction among children with this chromosomal anomaly [26]. In this setting, SCH may warrant treatment as the progression to overt hypothyroidism is more likely.

Type 1 diabetes predisposes children to thyroid dysfunction. In a study by Soliman, et al. [27], the prevalence of SCH in children (mean age 10 yrs) with type I diabetes was 11.2%. Other conditions which may be associated with elevated risk for SCH include antiepileptic drug usage and celiac disease.

Most patients with SCH exhibit few or no signs or symptoms of hypothyroidism. It has been suggested that some patients have functional, clinical, or biochemical manifestations of hypothyroidism that are more common than age-matched controls [28]. Goiter is the most common manifestation [12]. The abnormalities found most commonly in the pediatric population include weight gain, increased cholesterol levels, impaired growth velocity, anemia, sleepiness, weakness, and impaired psychomotor and cognitive development [5].

There are very few prospective studies evaluating the natural progression of SCH in pediatric age group (Table I). In a study from India, a cohort of 32 children with SCH and autoimmune thyroiditis (AIT) and goiter were followed. Development of overt hypothyroidism (12.5% in this cohort) was insidious, and was not accompanied by symptoms and signs [29]. In a larger study on 323 children with either Hashimoto or idiopathic SCH followed up for 3 years, 13.5% of SCH developed overt hypothyroidism. The study could not detect predictive factors for progression of SCH to overt hypothyroidism in idiopathic SCH [30]. Wasniewska, et al. [31] followed up 92 patients with idiopathic SCH over 2 years, and none of them developed overt hypothyroidism. Lazar, et al. [21] studied 3510 patients with SCH over 5 years and showed that 73.6% of them normalized TSH. Elevated antibodies (thyroid peroxidise (TPOab) and thryoglobulin antibodies (TGab)) may predict future overt hypothyroidism and TPOab>TGab may predict impending thyroid failure in AIT [32,33]. Leonardi, et al. [35] studied 44 Italian children "false positive" to neonatal screening for congenital hypothyroidism; 28 of them had SCH on re-testing at 2-3 years of age. Twenty of these 28 children were treated with replacement therapy and then withdrawn from therapy 2-3 months prior to re-evaluation. Out of the 28 children with SCH, TSH was normal in 9 children (32%) and persistently elevated in the remaining 19 (62%) at 4.1-6.6 yrs of age. At 7.2-9.5 yrs of age, TSH remained normal in 9 children who previously normalized their thyroid function, returned to normal in 5 out of 19 of the children with previous elevated TSH and persisted above normal in remaining fourteen childrens.

TABLE I Natural History and Progression of SCH in Pediatric Case Series

This aspect has been even less investigated and a summary of the evidence is presented in Table II. Wasniewska, et al. [37] compared thyroxine treated and untreated SCH over 2 years and found no significant changes in TSH values in both groups. Cetinkaya, et al. [38] treated 39 children with short stature and SCH; improvement in height was significant in pre-pubertal as compared to pubertal age group, with no progression to overt hypothyroidism in any in the cohort. Chase, et al. [39] noted a similar significant height increase in the pre-pubertal age group as compared to the pubertal age group when children with SCH and type 1 diabetes were given thyroxine replacement therapy. Aijaz, et al. [5] studied short term thyroxine replacement therapy and its effects in neuropsychological outcome and concluded no significant change .

TABLE II Studies Reporting Effect of Replacement Therapy in Childhood SCH 

Based on available literature, SCH seems to be a benign condition which requires periodic follow-up and monitoring of thyroid function tests. Expectant management is the norm for this condition. Natural progression to OH does occur but lot less frequently than expected. There appeared to be no long-term effects of untreated SCH on growth, puberty or neuro-cognitive function; however, there is a lack of high-quality evidence.

We propose an algorithm (Fig. 1) for management of subclinical hypothyroidism in pediatric age group. The first step in our setting on patients with elevated TSH, especially below 10mIU/L, is to repeat the test on another day, preferably from another laboratory with a different kit. SCH in adults is associated with dyslipidemia and subtle cardiac dysfunction, with reasonable benefit of treatment of SCH on those parameters. However, pediatric studies focussing on the same are scarce and more research is needed on these issues in this age group.

Fig.1 Approach to subclinical hypothyroidism (SCH) in children.

Girls, goiter, family history of thyroid disorder, other autoimmune problems, markedly elevated TPO titers (at least 3 times the upper limit of normal and symptoms which may correlate with hypothyroidism are risk factors; a clinical decision to start on thyroxine may be taken if any or combination of above is present.

SCH is a biochemical entity commonly faced by practising pediatricians. Several factors including clinical condition of the child and laboratory factors influencing TSH levels should be considered while interpreting the results. Clinical decision to treat marginal elevation in TSH should be made keeping in mind that more often TSH normalizes without treatment if followed up over a period of time. Even if the decision to treat the slightly elevated TSH is made, a clear plan should be made to stop treatment and reassess after 1-2 years to see if the treatment is required lifelong.

Contributors: Both authors searched the literature, drafted the article and finalized the manuscript.

Funding: None; Competing interests: None stated

1. Surks MI, Ortiz GH, Sawin CT. Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management. JAMA. 2004;291:228-38.

2. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526-34.

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 Clin. 2003;44:209-18.

4. Wu T, Flowers JW, Tudiver F. Subclinical thyroid disorders and cognitive performance among adolescents in the United States. BMC Pediatr. 2006;6:12.

5. Aijaz NJ, Flaherty EM, Preston T. Neurocognitive function in children with compensated hypothyroidism: lack of short term effects on or off thyroxin. BMC Endocr Disord. 2006;6:2.

6. Scobbo RR, Vondohlen TW, Hassan M, Islam S. Serum TSH variability in normal individuals: the influence of time of sample collection. W V Med J. 2004;100: 138-42.

7. Sarkar R. TSH comparison between chemiluminescence (Architect) and electrochemiluminescence (Cobas) immunassays: An Indian population perspective. Indian J Clin Biochem. 2014;29:189-95.

8. Marwaha RK, Tandon N, Desai AK, Kanwar R, Aggarwal R, Sastry A, et al. Reference range of thyroid hormones in healthy school-age children: Country-wide data from India. Clin Biochem. 2010;43:51-6.

9. Marwaha RK, Tandon N, Desai A, Kanwar R, Grewal K, Aggarwal R, et al. Reference range of thyroid hormones in normal Indian school-age children. Clin Endocrinol(Oxf). 2008;68:369-74.

10. Palmieri EA, Fazio S, Lombardi G. Subclinical hypothyroidism and cardiovascular risk: A reason to treat? Treat Endocrinol. 2004;3:233-44.

11. Papi G, Uberti ED, Betterle C. Subclinical Hypothryoidism. Curr Opin Endocrinol Diabetes Obes. 2007;14:197-208.

12. Cooper DS. Clinical practice. Subclinical hypothyroidism. N Engl J Med. 2001; 345:260-5.

13. Narumi S, Muroya K, Abe Y, Yasui M, Asakura Y, Adachi M, et al. TSHR mutations as a cause of congenital hypothyroidism in Japan: A population-based genetic epidemiology study. J Clin Endocrinol Metab. 2009;94:1317-23.

14. Nicoletti A, Bal M, De Marco G, Baldazzi L, Agretti P, Menabo S, et al. Thyrotropin-stimulating hormone receptor gene analysis in pediatric patients with non-autoimmune subclinical hypothyroidism. J Clin Endocrinol Metab. 2009;94:4187-94.

15. De Marco G, Agretti P, Montanelli, Dicosmo C, Bagattini B, De Servi M, et al. Identification and functional analysis of novel dual oxidase 2 (DUOX2) mutations in children with congenital or subclinical hypothyroidism. J Clin Endocrinol Metab. 2011;96:E1335-9.

16. Grandone A, Perrone L, Cirillo G, Di Sessa A, Corona AM, Amato A, et al. Impact of phosphodiesterase 8B gene rs4704397 variation on thyroid homeostasis in childhood obesity. Eur J Endocrinol. 2012;166:255-60.

17. Turkkahraman D, Alper OM, Aydin F, Yildiz A, Pehlivanoglu S, Luleci G, et al. Final diagnosis in children with subclinical hypothyroidism and mutation analysis of the thyroid peroxidise gene (TPO). J Pediatr Endocrinol Metab. 2009;22:845-51.

18. Rubello D, Pozzan GB, Casara D, Girelli ME, Boccato S, Rigon F, et al. Natural course of subclinical hypothyroidism in Down’s syndrome: Prospective study results and therapeutic considerations. J Endocrinol Invest. 1995;18:35-40.

19. Schaub RL, Hale DE, Rose SR. The spectrum of thyroid abnormalities in individuals with 18q deletions. J Clin Endocrinol Metab. 2005;90:2259-63.

20. Persani L, Borgato S, Romoli R, Asteria C, Pizzocaro A, Beck-Peccoz P. Changes in the degree of sialylation of carbohydrate chains modify the biological properties of circulating thyrotropin isoforms in various physiological and pathological states. J Clin Endocrinol Metab. 1998;83:2486-92.

21. 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. 2009;94:1678-82.

22. Marwaha RK, Tandon N, Garg MK, Desai A, Kanwar R, Sastry A, et al. Thyroid status two decades after salt iodization: country-wide data in school children from India. Clin Endocrinol (Oxf). 2012;76:905-10.

23. Das S, Bhansali A, Dutta P, Aggarwal A, Bansal MP, Garg D, et al. Persistence of goitre in the post-iodization phase: micronutrient deficiency or thyroid autoimmunity? Indian J Med Res. 2011;133:103-9.

24. Xiao Chen X, Feng Qin Y , Lian Zhou X, Lai Yang R, Hua Shi Y, Qing Mao H, et al. Diagnosis and treatment of subclinical hypothyroidism detected by neonatal screening. World J Pediatr. 2011;7:350-4.

25. Torun E, Cindemir E, Özgen IT, Öktem F. Subclinical hypothyroidism in obese children. Dicle MedJ. 2013;40:5-8.

26. Cebeci AN, Güven A, Yýldýz M. Profile of hypothyroidism in Down’s syndrome. J Clin Res Pediatr Endocrinol. 2013;5:116-20.

27. Soliman GZA, Bahagt NM, EL-mofty Z. Prevalence of thyroid disorder in Egyptian children with type I diabetes mellitus and the prevalence of thyroid antibodies among them. Thyroid Disorders Ther. 2013;2:1.

28. Zulewski H, Müller B, Exer P, Miserez AR. Estimation of tissue hypothyroidism by a new clinical score: Evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab. 1997;82:771-6.

29. Gopalakrishnan S, Chugh PK, Chhillar M. Goitrous autoimmune thyroiditis in a pediatric population: A longitudinal study. Pediatrics. 2008;122:e670-4.

30. Radetti G, Gottardi E, Bona G, Corrias A, Salardi S, Loche S, et al. The natural history of euthyroid Hashimoto’s thyroiditis in children. J Pediatr. 2006;149:827-32.

31. Wasniewska M, Salerno M, Cassio A, Corrias A, Aversa T, Zirilli G, et al. Prospective evaluation of the natural course of idiopathic subclinical hypothyroidism in childhood and adolescence. Eur J Endocrinol. 2009;160:417-21.

32. Radetti G, Maselli M, Buzi F, Corrias A, Mussa A, Cambiaso P, et al. The natural history of the normal/mild elevated TSH serum levels in children and adolescents with Hashimoto’s thyroiditis and isolated hyperthyro-tropinaemia: A 3-year follow-up. Clin Endocrinol (Oxf). 2012;76:394-8.

33. Zois C, Stavrou I, Svarna E, Seferiadis K, Tsatsoulis A. Natural course of autoimmune thyroiditis after elimination of iodine deficiency in northwestern Greece. Thyroid. 2006;16:289-93.

34. Jaruratanasirikul S, Leethanaporn K, Khuntigij P, Sriplung H. The clinical course of Hashimoto’s thryoiditis in children and adolescents: 6 years longitudinal follow-up. J Pediatr Endocrinol Metab. 2001;14:177-84.

35. 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.

36. Moore DC. Natural course of subclinical hypothyroidism in childhood and adolescence. Arch Pediatr Adolesc Med. 1996;150:293-7.

37. 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.

38. Cetinkaya E, Aslan A, Vidinlisan S, Ocal G. Height improvement by L-thyroxine treatment in subclinical hypothyroidism. Pediatr Int. 2003;45:534-7.