Murillo-Vallés et al. BMC Pediatrics (2020) 20:282 https://doi.org/10.1186/s12887-020-02177-8 RESEARCH ARTICLE Open Access Subclinical hypothyroidism in childhood, treatment or only follow-up? Marta Murillo-Vallés1, Santiago Martinez1, Cristina Aguilar-Riera2* , Miguel Angel Garcia-Martin3, Joan Bel-Comós1 and Maria Luisa Granada Ybern3 Abstract Background: Subclinical hypothyroidism (SH) is defined as serum levels of thyroid-stimulating hormone (TSH) above the upper limit with normal concentrations of free T4 (fT4). Its management remains challenging. The aim of the study was to evaluate clinical and laboratory findings as well as the clinical course of children with SH followed in a third level hospital. Sixty-five patients aged between 2 and 18 years old were retrospectively studied. Methods: The patients were followed for a median period of 9 months (range 6 months to 24 months). Those who normalized TSH levels were discharged (Group 1). If TSH persisted mildly elevated (5-10μUI/mL) with normal fT4 and negative TPOAb/TgAb, they were classified as Group 2 and followed semi-annually without treatment. Those patients whose TSH raised ≥10μUI/mL or who maintained TSH 5-10μUI/mL and positive TPOAb/TgAb were considered suitable for thyroxin therapy (Group 3, G3). Results: In 89% of our patients, TSH concentrations spontaneously reverted to normality or remained stable without treatment (Groups 1 and 2), whereas less than 11% progressed to clinical hypothyroidism (Group 3). Baseline TSH was significantly lower in group 1 than in group 3. In group 3 the prevalence of female sex (71%) was higher and TPO antibodies were present in 85% of patients. The risk of developing overt hypothyroidism in patients with positive anti-thyroid antibodies respect to those who normalized TSH was 45 (95%CI 6.5–312.5). Conclusion: Baseline TSH, female sex and the presence of thyroid autoimmunity were the best predictors of the evolution to SH over time. Keywords: Subclinical hypothyroidism, Cut-off, Child, Screening Background and represents a frequent cause of referral to a pediatric Subclinical hypothyroidism (SH), also known as isolated endocrinologist. hyperthyrotropinemia, is defined as serum thyroid- TSH normal range (0.4–0.5μUI/mL to 4.0–5.0μUI/ stimulating hormone (TSH) concentrations above the mL) depends on the method used, with large variations upper limit of the reference range and normal concen- found between different TSH assays. Idiopathic SH is trations of free T4 (fT4). This situation occurs in less characterized by mild elevations of TSH concentrations than 3% of children and adolescents [1, 2], but it is a levels (5-10μUI/mL) with peripheral hormones fT4 and cause of concern for parents and primary care physicians triiodothyronine within normal ranges, absence of thyroid autoimmunity or other conditions that may account for the increase in TSH, such as certain medica- tions or genetic disorders (Down syndrome, Pseudohy- * Correspondence: c_aguilarriera@hotmail.com 2 Pediatrics Section, Germans Trias i Pujol University Hospital, Autonomous poparathyroidism and others), and without clinical signs University of Barcelona, Badalona, Spain or symptoms of thyroid failure. 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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Murillo-Vallés et al. BMC Pediatrics (2020) 20:282 Page 2 of 6 The natural course of idiopathic SH is unclear. Most All patients had an initial TSH concentration mildly ele- patients normalize TSH values and a small percentage vated (5-10μUI/mL) with fT4 within the normal reference progresses to overt hypothyroidism [3–7]. The risk of range. The patients were followed for a median period of progression to overt hypothyroidism depends on the 9 months (range 6–24 months). Those patients who nor- cause of SH with high risk in autoimmune forms. There malized TSH levels at the follow-up were discharged is a lack of conclusive studies that determine whether (Group 1, G1); follow-up median period 6 months (range these children with SH might benefit from levothyroxine 3–9 months) whereas those who persisted with elevated treatment [7–9]. TSH were followed. If TSH persisted mildly elevated (5- On the other hand, adverse health outcomes of SH in 10μUI/mL) with normal fT4 and negative TPOAb/TgAb, childhood remain controversial. Although it might not they were classified as Group 2 (G2) and followed semi- produce adverse effects on growing and development annually without treatment, follow-up median period 12 processes [5, 8, 10], it has been recently associated with months (range 9–24 months). Those patients whose TSH overweight/obesity and metabolic abnormalities [11, 12]. raised ≥10μUI/mL or who maintained TSH 5-10μUI/mL Nevertheless, prospective studies that determine those and positive TPOAb/TgAb (regardless fT4 levels) were deleterious effects are lacking. considered overt hypothyroidism and suitable for thyroxin This study aimed to analyze the characteristics and replacement therapy due to hypothyroidism/thyroiditis natural evolution of a cohort of children with SH (Group 3, G3), follow-up median period 12 months (range referred to a third level hospital. 9–24 months). Methods Biochemical and hormonal determinations We analyzed retrospectively patients who were diagnosed Blood samples were drawn at 8 a.m. after an overnight with SH and referred to the Endocrinology Unit of our fast. Samples were centrifuged and sera kept frozen at − hospital between 2014 and 2018. SH was defined as TSH 20 °C until analysis. Analysis of serum TSH was concentration mildly elevated (5-10μUI/mL) with fT4 performed with CLIA with the aid of an Abbott ARCHI- within the normal reference range (0.7–1.48 ng/dL). Pa- TECT instrument (Abbott Diagnostics Division). Total tients were assessed at the time of diagnosis, at month 3 coefficient of variation (CV) was < 3.3%, functional sensi- and every 6 months during follow-up if necessary. tivity was 0.0038μUI/mL; reference range [99% confidence interval (CI)]: 0.35–4.94μUI/mL; fT4 was measured by Patients Abbott ARCHITECT instrument (Abbott Diagnostics Inclusion criteria were as follows: patients referred for SH Division; total CV was < 7%, sensitivity of the assay was < aged 2 to 18 years old with at least two analytical records: 0.4 ng/dL; reference range (99% CI): 0.70–1.48 ng/dL one at the time of diagnosis and another one during the (conversion factor ng/dL *12.87 = pmol/L). TPOAb were follow-up. Patients under 2-years-old and who received measured by an Abbott ARCHITECT instrument (Abbott pharmacological treatment that could alter the TSH con- Diagnostics Division). Total CV was < 7.6%, sensitivity of centrations (anticonvulsants, antipsychotics, glucocorti- the assay was 0.16 IU/mL; reference range: < 5.61 IU/mL. coids, iodine or iodine-rich diet) were excluded. We also excluded patients with genetic syndromes or under an acute disease. All patients resided in an area by the Medi- Statistical analyses terranean Sea in an iodine-sufficient population. The normality of the evaluated variables was established All patients had a complete clinical record, physical using the Kolmogorov-Smirnov test. Quantitative examination including anthropometric characteristics variables are presented as mean ± SD or as median (height, weight), and thyroid exploration at the time of (interquartile range: 25th–75th percentile) whereas diagnosis and during follow-up visits. We calculated qualitative variables are expressed as percentages. Differ- body mass index (BMI) and represented the results as ences among groups were assessed by the ANOVA or standard deviation (SD) according to age and sex. Obes- the non-parametric Kruskal Wallis test. To determine ity was considered if the BMI-SD was above 2 for the differences between groups, the Student’s T test or non- reference population. Short stature was considered if the parametric Mann-Whitney U test was used, and to height-SD was below 2 for the reference population. compare variables at baseline and at follow-up, we used Thyroid function test consisted of TSH, fT4 and the Wilcoxon test. Differences in proportions were thyroid autoantibodies (anti-peroxidase (TPOAb) and analyzed by the χ2 test or Ficher’s exact test. All tests antithyroglobulin (TgAb)). If necessary –p.e. with were two-tailed and a p value < 0.05 was considered sta- palpable goiter, persisted elevated TSH or positive auto- tistically significant. Statistical analyses were performed immunity–, a thyroid ultrasound was made to assess using the SPSS package 12.0 and MedCalc Software thyroid size and echogenicity. 12.7.0 (Acacialaan 22, B-8400 Ostend, Belgium). Murillo-Vallés et al. BMC Pediatrics (2020) 20:282 Page 3 of 6 The relative risk was calculated as the ratio of the pro- Regarding clinical characteristics, the medians of weight, portions of cases having a positive antibodies in the G3 height and BMI were within the normal ranges (− 0.39SD, group (6 out of 7), respect to group G1 (0 out of 44). This − 0.47SD and − 0.5SD respectively) with 13.8% of obesity test was performed with the aid of MedCalc Statistical and 12,3% of patients with short stature. No patient had Software version 19.1.7 (MedCalc Software Ltd., Ostend, goiter on physical examination. Belgium; https://www.medcalc.org; 2020) The program There was a family history of thyroid disease in 8 cases calculates the relative risk with 95% confidence interval, (12.3%). the z-statistic and associated P-value. If P is less than 0.05, At the time of diagnosis, all patients were asymptom- it can be concluded that the proportions are significantly atic of thyroid dysfunction, and these patients were different in the two groups, and there is an increased risk observed without treatment. in one group compared to the other. Table 2 shows the clinical and laboratory characteris- The study was approved by the Ethics Committee. All tics of patients classified into 3 different groups accord- patients or legal surrogates gave informed consent prior ing to evolution. TSH concentrations returned to to participation. normal ranges in 44 patients (67.6%) (G1), 14 patients (21.5%) maintained slightly elevated TSH concentrations with negative thyroid antibodies (G2) and 7 patients Results (10.7%) had TSH ≥10μUI/mL or TSH 5-10μUI/mL and The study included 65 patients diagnosed with SH (51% positive TPOAb/TgAb (6 patients) (G3). female). The median age at diagnosis was 7.75 (4.4–9.17) The prevalence of females was higher in the G3 (71%), years old. Clinical and laboratory findings at the time of but in the other two groups, the distribution was similar diagnosis are shown in Table 1. The main reason for the (50% in G1 and 57% G2). Regarding the age as well as a study of thyroid function was routine analytical (41,5%, family history of autoimmune diseases, no differences n: 27), obesity (13,8%, n: 9), short stature (12.3%, n: 8), were found among the 3 groups. asthenia (10.7%, n: 7) or others (18.4%, n: 14). Mean baseline TSH concentrations differed among the 3 groups (p = 0.012), significant differences were found in TSH values between G1 and G3 (F = 4.768; p = 0.016) Table 1 Anthropometrical, clinical and laboratory characteristics at baseline whereas no differences were found between G1 and G2 or between G2 and G3. No differences were found in n: 65 fT4 concentrations at baseline among the 3 groups (F = Female (%) 33 (51%) 3.083; p = 0.053) (Fig. 1). The percentage change of TSH Age (years) 7.75 (4.4–9.17) at follow-up with respect to baseline was 47.8% decrease Referral for analytic study: in group 1, a 6.9% decrease in group 2 and a 24.7% in- Routine 27 (41.5%) crease in group 3 (Table 2). Obesity 9 (13.8%) BMI evolution was evaluated during the study and no Short stature 8 (12.3%) significant difference was found in obesity (BMI-SD > 2) prevalence during follow-up in all patients (13,8 to Asthenia 7 (10.7%) 10.7%). In terms of height there were no differences. Others 14 (21,5%) Thyroid autoimmunity was observed in 85% of pa- Clinical features: tients of G3 and none of G1 and G2 (p > 0.001). The risk BMI-SD −0.5 [(−1.09)-(+ 0.86)] of developing overt hypothyroidism in patients with Weight-SD −0.39 [− 0.99)-(+ 1.2)] positive anti-thyroid antibodies with respect to those Height-SD − 0.47 [(− 1.38)-(+ 0.75)] who normalized TSH was 45 (95%CI 6.5–312.5). Of all the patients, 35,3% underwent a thyroid ultra- Obesity (BMI-SD ≥2) 9 (13.8%) sound and a structure suggestive of thyroiditis (heteroge- Short stature (<2SD) 8 (12.3%) neous, hypoechoic and in some cases enlarged Goiter 0 ultrasound pattern) was found in 6 patients, all in the Familiar history (Autoimmune disease) 8 (12.3%) G3. There was 1 patient with nodules on ultrasound Laboratory results: without other significant findings; the rest of the patients TSH (μUI/mL) 6.7 (6.1–7.8) presented a normal ultrasound. Free thyroxin (ng/dL) 1.1 (1.0–1.3) Discussion TPO positivity 6 (9.2%) In general terms, SH seems to affect less than 3% of the US performed (%) 23 (35,3%) child population and usually displays a natural course Data are expressed as median (IQR) or percentage (%) towards the maintenance or spontaneous resolution in Murillo-Vallés et al. BMC Pediatrics (2020) 20:282 Page 4 of 6 Table 2 Clinical and laboratory characteristics among groups Group 1 Group 2 Group 3 Significance N 44 (67,6%) 14 (21,5%) 7 (10,7%) Female 51.2% 42.9% 71.4% N.S. Age at baseline (years) 6.7 (4.0–9.2) 8.17 (6.48–9.48) 8.17 (7.4–9.17) N.S. Familiar History (Autoimmune disease) 11.4% 7.1% 14.3% N.S. a TSH (μUI/mL) at baseline 6.6 (6.02–7.35) 7.05 (6.07–8.12) 8.2 (6.7–9.4) 0.012 Free thyroxin (ng/dL) at baseline 1.15(1.02–1.3) 1.0(0.95–1.3) 1.0(0.88–1.1) 0.03 )b, c d TSH (μUI/mL) at follow-up 3.7(2.94–4.27 6.1(5.17–8.0) 1.0(088–1.1) < 0.001 Free thyroxin (ng/dL) at follow-up 1.07 (0.98–1.2) 1.04(0.9–1.19) 0.88 (0.83–1.1) N.S. Percentage change in TSH (baseline vs follow up) −47.8 −6.9 ((−17.3)-1.9) d 24.7 (14.6–95.5) < 0.001 ((−35.3)-(− 56.7))b,c BMI-SD −0.61 [(−1.1)-0.83] 0.21 [(− 0.62)-1.18] 0.43[(− 0.68) − 0.85] NS Obesity (BMI ≥2 SD) 6 (13,6%) 3 (21,4%) 0 (0%) N.S. Height-SD -0.85 [(− 0.98)-0.67] −0.45 [(2.27)-0.82] 0.35 [(−2.2)-1.4] N.S. Height-SD <2SD 1 (2,2%) 5 (35,7%) 2 (28,5%) N.S. TPOAb/TgAb positivity 0 (0%) 0 (0%) 6 (85%) 0.001 Performed US 10 (22%) 6 (42%) 7 (100%) Tiroiditis by US 0 (0%) 1 (16%) 6 (83%) 0.04 N.S.: non significant a : p < 0.016group 1 vs group 3 b : p < 0.001 group 1 vs group 2 c p < 0.001 group 1 vs group 3 d : p < 0.001 group 2 vs group 3 Quantitative variables are expressed as median (IQ range p25-p75) Qualitative variables are expressed as N (%) Fig. 1 TSH values at baseline and follow-up. Patients were classified into three groups according TSH levels at the end of the follow up. Group 1 (G1): TSH ≤5μUI/mL (n: 44); Group 2 (G2): TSH 5-10μUI/mL, normal fT4 and negative TPOAb/TgAb (n: 14); Group 3 (G3): suitable for thyroxin therapy due to TSH ≥10μUI/mL or TSH 5-10μUI/mL and positive TPOAb/TgAb (n: 7) Murillo-Vallés et al. BMC Pediatrics (2020) 20:282 Page 5 of 6 variable time in most cases (68–88%) and only a few TPOAb at diagnosis were associated with an increased cases progress to overt hypothyroidism or autoimmune risk of progression in some but not all studies [7]. thyroiditis. There are few studies to date that evaluate Treatment with levothyroxine was initiated in all pa- SH and its evolution in childhood [5, 10, 13, 14]. In our tients who presented TSH ≥10μUI/mL or TSH 5-10μUI/ study, most of the patients either normalized their TSH mL and positive TPOAb/TgAb (G3). The dilemma arises levels or maintained their TSH levels under subclinical in deciding whether patients with maintained mildly range values (89%). Only a small percentage presented elevated TSH (G2) should be treated or not with overt hypothyroidism or autoimmune thyroiditis and levothyroxine and what benefits it can bring against pos- needed treatment (11%). These data are similar to those sible consequences of SH, since good-quality studies of a 2-year prospective study presented by Wasniewska examining the effect of treatment of SH in children are et al., in which 88% of patients normalized o preserved lacking [9, 24–26]. In our case, no patients were treated their TSH levels and 12% developed hypothyroidism [5]. since none presented associated symptoms or alterations In an attempt to anticipate events, Lazar et al. found that could be related to it. that predictive factors for sustained abnormal TSH levels The current study has its limitations. For instance, it is were initial TSH > 7.5μUI/mL and female gender [1]. Re- a retrospective study with a small number of patients, cently, Gammons et al. concluded that a TSH >8μUI/ and genetic causes such as alterations in the TSH recep- mL would be the cut-off point to refer to a pediatric tor that could explain mildly elevated TSH have not endocrinologist for evaluation and management [15]. Al- been investigated. On the other hand, the possible im- though, because of the small number of patients, an pact on growth and intellectual development has not AUC could not be assessed to determine the cutoff level been assessed in this study. of TSH that predicts evolution towards hypothyroidism, in our cohort baseline TSH levels of G3 were signifi- Conclusion cantly higher. Although SH in childhood is a frequent issue and a mat- Regarding the weight, in our study, no significant ter of concern between primary care pediatrics, it seems changes were detected between obesity prevalence at to be a benign and remitting condition; based on our re- baseline and during follow-up in all the patients, and the sults and in comparison, with the literature, expectant BMI-SD did not worsen during follow-up in any patient. behavior is the best option, always individualizing each However, in the G2 group, those who persisted with a patient. Perhaps repeating a second determination by TSH 5-10μUI/mL had a higher prevalence of obesity, the primary care pediatrician of TSH and fT4 in 1–3 which would suggest that it may have a role in increas- months and if alteration persists refer to specialist many ing TSH levels. It is thought that the mildly elevated cases could be resolved and, therefore, save time and TSH is the consequence of obesity rather than the cause, resources. as an attempt to increase energy expenditure, with an However, in the case of pediatric SH, prospective stud- improvement of the thyroid function parameters when ies are lacking to determine a sensitive and specific level lowering the BMI, as has been mentioned on multiples of TSH to predict the progression to hypothyroidism. It studies [16–21]. Contrary to what one would expect, is important to determine if it is a process with negative none of the patients with obesity belonged to the G3 or positive autoimmunity, since on this latter case, the with overt hypothyroidism. probability of progression to hypothyroidism is greater. It is known that autoimmunity is a key factor that de- As seen in the current study, baseline TSH, female sex termines the major progression to hypothyroidism. In and the presence of thyroid autoimmunity were the best our study, almost all patients in G3 met this condition predictors of the evolution to SH over time. and 71.4% were women, which is a distribution that Abbreviations already occurs in most autoimmune diseases. Our results TPOAb: Anti-peroxidase thyroid autoantibody; TgAb: Antithyroglobulin are in agreement with Wasnieska et al. [22] who studied thyroid autoantibody; AUC: Area Under Curve; BMI: Body mass index; the long term evolution of a large cohort of girls with CI: Confidence interval; fT4: Free T4; G1: Group 1; G2: Group 2; G3: Group 3; ROC: Receiver Operating Characteristic; SD: Standard deviation; subclinical hypothyroidism and found that underlying SH: Subclinical hypothyroidism; TSH: Thyroid-stimulating hormone; CV: Total Hashimoto thyroiditis was the main factor to become coefficient of variation overtly hypothyroid or require L-T4 treatment. In fact, it has been reported that in children with Hashimoto thy- Acknowledgments We thank Dr. Silvia Rodriguez-Fernandez (Immunology Section, Germans roiditis the evolution of thyroid status is frequently char- Trias i Pujol Research Institute, Badalona, Spain) for her help proofreading this acterized by a spontaneous worsening over time, even in work. the cases who initially present with a mild biochemical Authors’ contributions picture [23]. Lazarus et al. analyzed the results of 7 ob- MM conceptualized and designed the study, proposed the new terminology, servational studies and showed that elevated TgAb and controlled the analyses, drafted the first and final manuscript. SM organized Murillo-Vallés et al. BMC Pediatrics (2020) 20:282 Page 6 of 6 the data collection, carried out the initial analyses, and drafted the initial treatment in children with idiopathic and mild subclinical hypothyroidism. manuscript. CA organized the data collection, carried out the initial analyses Horm Res Paediatr. 2012;77(6):376–81. and submitted the manuscript. MG performed the statistical analysis. JB 10. Radetti G, Maselli M, Buzi F, Corrias A, Mussa A, Cambiaso P, et al. The reviewed the manuscript and approved the final manuscript. MG reviewed natural history of the normal/mild elevated TSH serum levels in children the statistical analysis and reviewed the final manuscript. All authors were and adolescents with Hashimoto’s thyroiditis and isolated involved in writing the manuscript and approved the final version. hyperthyrotropinaemia: a 3-year follow-up. Clin Endocrinol. 2012 Mar;76(3): 394–8. Funding 11. Reinehr T. Thyroid function in the nutritionally obese child and adolescent. There is no funding source. Curr Opin Pediatr. 2011 Aug;23(4):415–20. 12. Cerbone M, Capalbo D, Wasniewska M, Mattace Raso G, Alfano S, Meli R, et al. Cardiovascular risk factors in children with long-standing untreated Availability of data and materials idiopathic subclinical hypothyroidism. J Clin Endocrinol Metab. 2014 Aug; The datasets during and/or analyzed during the current study are available 99(8):2697–703. from the corresponding author on reasonable request. 13. Such K, Gawlik A, Dejner A, Wasniewska M, Zachurzok A, Antosz A, et al. Evaluation of subclinical hypothyroidism in children and adolescents: a Ethics approval and consent to participate single-center study. Int J Endocrinol. 2016;2016:1–7. This article was approved by the ethics committee Centre de comitè d’ètica 14. Ergin Z, Savaş-Erdeve Ş, Kurnaz E, Çetinkaya S, Aycan Z. Follow-up in de la Investigació Clínica Hospital Universitari Germans Tries i Pujol (CEI- children with non-obese and non-autoimmune subclinical hypothyroidism. HUGTiP) as it contains human data. Informed verbal consent was obtained J Pediatr Endocrinol Metab. 2018 Oct 25;31(10):1133–8. from all individual participants or legal surrogates included in the study to 15. Gammons S, Presley BK, White PC. Referrals for elevated thyroid stimulating use their data. The ethics committee agreed as it is a prospective study hormone to pediatric endocrinologists. J Endocr Soc. 2019 Nov 1;3(11): without intervention and with anonymous data. 2032–40. 16. Radetti G, Kleon W, Buzi F, Crivellaro C, Pappalardo L, di Iorgi N, et al. Consent for publication Thyroid function and structure are affected in childhood obesity. 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