The main purpose of our retrospective study was to evaluate the medical care of the patients with subclinical hypothyroidism (sHT) and to investigate the rationale for administering L-thyroxine (LT-4) to young sHT patients.
The term subclinical hypothyroidism (sHT) indicates the presence of thyroid dysfunction without obvious symptoms of thyroid deficiency [
In the clinical practice, sHT is diagnosed in the presence of mildly elevated serum concentrations of TSH with normal concentrations of serum-free and total triiodothyronine (T3) and thyroxine (T4) [
The 2001 review of studies in adult and elderly patients showed that although subclinical hypothyroidism is mild thyroid gland failure, it is clinically important, with adverse clinical consequences, and should be treated with L-thyroxine in most, if not all, cases [
The aim of our retrospective observational study was to evaluate the course of subclinical hyperthyrotropinemia in children and adolescents and estimate the medical care of the patients with sHT: the rationale for administering L-thyroxine to young patients with sHT was investigated.
The study methodology was based on a retrospective review of the charts of 261 patients. The patients were referred to the Endocrinology Outpatient Clinic of the Medical University with suspicion of subclinical hypothyroidism and were examined between 2009 and 2014. The study was performed in a non-iodine-deficient area. Children and adolescents diagnosed with subclinical thyroid disease who were under concomitant therapy with lithium salts, antiepileptic agents, glucocorticoids, or iodinated drugs, as well as children with positive screening for congenital hypothyroidism, were not enrolled into the study. Other exclusion criteria were (1) serum concentration of thyroid-stimulating hormone (TSH) below <4 mIU/mL or above >10 mIU/mL, (2) Hashimoto’s thyroiditis, (3) trisomy 21 and/or diabetes mellitus, (4) earlier treatment of previously diagnosed SH, (5) one/incidental finding of elevated TSH level between 4.0 and 10.0 mIU/mL, (6) palpable goiter, (7) age under 2 years, and (8) lack of anthropometric data.
We collected the following data: gender, age at presentation of subclinical hypothyroidism (sHT), auxological data: height and weight, serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3), titer of anti-thyroid autoantibodies: antiperoxidase (anti-TPO) and antithyroglobulin (anti-TG), positive family history, absence or presence of clinical symptoms suggesting thyroid disease, and length of follow-up at the Outpatient Clinic. Serum concentrations of TSH and fT4 were measured with a chemiluminescent immunometric assay (Siemens, Immulite 2000 Free T4, Immulite 2000 Third-Generation TSH, USA). The concentrations of anti-thyroid peroxidase antibody (anti-TPO Abs) and autoantibodies to thyroglobulin (anti-TG Ab) were determined with enzyme-labeled, chemiluminescent sequential immunometric assay (Siemens, Immulite 2000 anti-TPO Ab, Immulite 2000 Anti-TG Ab, USA). The reference levels for fT4 were 11.5–22.7 pmol/L (0.8–1.9 ng/dL). Anti-TG Abs and anti-TPO Abs were considered undetectable below 40 and 35 IU/mL, respectively. Thyroid ultrasound examination was performed at least once during the follow-up period, using Acuson Antares (Siemens Medical Solution USA, Inc.) with a VFX 13-5 linear transducer. Diffuse low echogenicity was considered an indicator of a thyroid autoimmune disorder. Subclinical hypothyroidism was diagnosed in patients with no evident clinical manifestation of hypothyroidism, regardless of their age, if TSH was between 4.0 and 10.0 mIU/mL in at least two consecutive assays and fT4 remained within the normal range. Overt hypothyroidism was diagnosed if TSH was higher than 10.0 mIU/mL and fT4 was below the lower limit of the reference range. Thyroid autoimmunity was documented by the presence of thyroid autoantibodies (anti-TPO Abs and/or anti-TG Abs). Hashimoto’s thyroiditis (autoimmune thyroid disease) was diagnosed in the presence of anti-TPO Abs and/or anti-TG Abs, with concomitant subclinical or overt hypothyroidism.
A standard stadiometer was used to measure the patients’ height. hSDS (height standard deviation scores) were calculated from population standards for healthy children using the following formula: hSDS = child’s height − height for 50 pc/0.5
Body mass index (BMI) was expressed as kg/m2, whilst BMI
Clinical presentations suggesting subclinical hypothyroidism, such as constipation, impaired concentration, cold intolerance, chronic fatigue, menstrual disorder, dry skin, and hair loss, were detected at physical examination or during anamnesis.
A cumulative dose of L-thyroxine was expressed as a mean dosage, using the recommended amount of LT-4 on the first and last available visit in relation to body weight and was presented as
Statistical analysis was performed using PQ Stat software. Categorical variables were presented as percentages (%); continuous variables were ordered as means ± standard deviations (SD) and medians. The distribution plot was verified using Lilliefors test. The comparison between two groups of categorical variables was examined with Fisher’s test. The comparison between continuous variables was examined with Student’s
The process of patients’ selection is presented in Figure
Characteristics of the study group by gender (baseline data).
Girls ( |
Boys ( |
|
|
---|---|---|---|
Age, mean | 10.02 ± 4.32 | 8.72 ± 4.15 |
|
BMI |
0.36 ± 1.76 | 0.23 ± 1.51 |
|
hSDS, mean | −0.29 ± 1.84 | −0.43 ± 1.75 |
|
TSH, mean | 5.79 ± 1.34 | 5.51 ± 1.0 |
|
FU, mean (months) | 15.78 ± 14.58 | 13.38 ± 12.30 |
|
Positive family history (%) | 2 (6.25) | 2 (8.0) |
|
Presence of symptoms (%) | 27 (84.4) | 17 (68.0) |
|
BMI
Exclusion criteria: patients referred to the Outpatient Clinic with diagnosis of sHT.
Out of 55 sHT patients, 33 (60.0%) started L-thyroxine therapy. Table
Baseline comparison of patients treated with LT-4 (group T1) and patients without treatment (group T0).
Group T1 ( |
Group T0 |
|
|
---|---|---|---|
Age, mean | 9.75 ± 4.0 | 9.0 ± 4.67 |
|
BMI |
0.12 ± 1.57 | 0.58 ± 1.75 |
|
hSDS, mean | −0.32 ± 1.89 | −0.38 ± 1.66 |
|
TSH, mean | 5.9 ± 1.36 | 5.33 ± 0.85 |
|
FU, mean (months) | 20.66 ± 13.08 | 5.85 ± 8.63 |
|
Positive family history (%) | 4 (11.8) | 0 (0) |
|
Presence of symptoms (%) | 25 (73.5) | 19 (86.4) |
|
BMI
Patients’ complaints/features at first examination.
Group T0 ( |
Group T1 ( |
|
|
---|---|---|---|
Obesity (%) | 6 (27.3) | 2 (6.1) |
|
Overweight (%) | 6 (27.3) | 10 (30.3) |
|
Weight deficiency (%) | 3 (13.6) | 4 (12.1) |
|
Significant weight deficiency (%) | 3 (13.6) | 3 (9.1) |
|
Short stature (%) | 4 (18.2) | 6 (18.2) |
|
Hair loss (%) | 1 (4.5) | 0 (0.0) |
|
Constipation (%) | 1 (4.5) | 0 (0.0) |
|
Impaired concentration (%) | 0 (0.0) | 2 (6.1) |
|
Cold intolerance (%) | 0 (0.0) | 3 (9.1) |
|
Menstrual disorder (%) | 1 (4.5) | 1 (3.0) |
|
Chronic fatigue (%) | 0 (0.0) | 1 (3.0) |
|
Dry skin (%) | 1 (4.5) | 5 (15.2) |
|
The mean cumulative dose of L-thyroxine used in 33 patients was
During the observation period 15 (68.2%) children and adolescents without treatment became euthyroid (TSH < 4.0 mIU/mL): 11 within three months from the last determination of TSH level, 1 at 3–6 months, and 3 at 6–12 months. In 7 (31.8%) patients, the TSH concentration remained above the reference range but under <10.0 mIU/mL at the end of follow-up.
In our study, 4 (7.3%) patients (3 girls and 1 boy) had baseline TSH levels over 7.5 mIU/mL, of whom only 1 showed progression to overt hypothyroidism. The patient, a 5.5-year-old girl, had baseline TSH of 8.14 mIU/mL, positive family history towards thyroid gland disease, and a BMI
We identified a group of 31 children and adolescents, with a mean age of
Comparison of patients with elevated TSH detected only once (group non-sHT) and patients followed up for a long time (group-sHT)—baseline data.
Group-sHT ( |
Group non-sHT ( |
|
|
---|---|---|---|
Age, mean | 9.45 ± 4.25 | 8.7 ± 4.24 |
|
BMI |
0.30 ± 1.64 | 0.84 ± 1.48 |
|
hSDS, mean | −0.35 ± 1.79 | 0.15 ± 1.37 |
|
TSH, mean | 5.67 ± 1.2 | 5.1 ± 1.16 |
|
Positive family history (%) | 4 (7.3) | 5 (16.1) |
|
Presence of symptoms (%) | 44 (80.0) | 12 (38.7) |
|
BMI
Our retrospective study aimed to evaluate the course of sHT in children and adolescents and to establish the rationale for substitutional therapy induction in this group of patients. The results of our analysis showed that there was no clear clinical or laboratory explanation as to why treatment was initiated in young patients with subclinical hypothyroidism. Positive family history seemed to be the only discriminant; sHT patients with L-thyroxine therapy more frequently had family members with diagnosed thyroid disorders. Despite the small size of the study group, we confirmed a low incidence of conversion of sHT to overt hypothyroidism.
According to the literature, the prevalence of subclinical hypothyroidism in the young population is estimated to be less than 2% [
The cut-off point of TSH concentration at which pediatricians should diagnose their patients with subclinical hypothyroidism has not as yet been determined. In our center, the diagnosis is made when the TSH level is at least 4.0 mIU/mL (reference limit), regardless of age. The cut-off point in the study by Lazar et al. [
The symptoms of hypothyroidism are neither sensitive nor specific. Indeed, patients in a euthyroid state are difficult to distinguish from patients with thyroid hormone deficiency because the clinical manifestation is affected by disease duration, its severity, and individual sensitivity to thyroid hormone deficiency. Patients who report many or newly developed symptoms are most likely to have subclinical or overt hypothyroidism. In their review, Gawlik et al. [
The data available in the literature are still controversial regarding the indications and effects of substitution therapy on improving the growth status of children with short stature and subclinical hypothyroidism. In their prospective study of 39 patients with short stature and sHT, Cetinkaya et al. [
Cerbone et al. [
The recommendations concerning overweight young patients with sHT are more precise: pharmacological treatment should be avoided, since moderately elevated levels of TSH are a consequence rather than a cause of overweight. In obese children with sHT, first, a dietary-behavioral management intervention should be recommended in order to reduce weight, irrespective of the use of levothyroxine [
In our study, the vast majority of patients 44/55 (80.0%) showed at least one nonpathognomonic symptom, some of them suggesting hypothyroidism. Analyzing overweight, obesity, and short stature, we noticed a similar incidence between patients who were referred for LT-4 therapy and those who were not. The type of symptoms did not affect the decision whether to initiate treatment.
There are no clear guidelines on the management of subclinical hypothyroidism in young patients, the frequency of TSH measurements, and the length of follow-up in patients without therapy. According to the European Thyroid Association Guidelines for the Management of Subclinical Hypothyroidism in Pregnancy and in Children for 2014, the decision whether or not to treat should be made after discussing with the parents the side effects and risks as well as the potential benefits of therapy with L-thyroxine. The 2014 cross-sectional, controlled study by Cerbone et al. [
Bona et al. [
Our study aimed to analyze the management of patients diagnosed with sHT and to establish the factors that encouraged physicians to prescribe thyroid hormones. There were no differences with regard to age at baseline, TSH level, BMI
The mean dosage of L-thyroxine applied in our patients, sufficient to maintain TSH within its normal ranges, was
In our study, a vast majority (68.2%) of patients without therapy with L-thyroxine normalized their TSH concentration and became euthyroid during their follow-up period. At the end of follow-up, none of the patients showed a highly elevated TSH serum level above 10 mIU/mL, though 31.8% still had TSH above the upper limit of the reference range. Similar results were presented by Wasniewska et al. [
In another recently published longitudinal study, Wasniewska et al. [
Our study raises the following questions: how often should TSH concentrations be determined in order to accurately and reliably evaluate the course of sHT? How long should the follow-up of patients after normalization of TSH last? Does it depend on family history? The child’s wellbeing must always be considered. Multiple TSH determinations are associated with stress and discomfort connected with blood collection and medical visits. Thus, establishing the exact frequency of determining thyroid gland parameters seems paramount. The economic aspect should not be disregarded either: too frequent and unnecessary visits generate costs, which is a serious limiting factor in health care. Moreover, TSH assessment must be performed in appropriate measurement conditions (without infection symptoms, etc.) and cannot be used as a routine laboratory test.
In our study, out of the 55 patients who met the criteria for sHT, only 1 (1.8%) girl proceeded to overt hypothyroidism. According to the longitudinal study conducted by Lazar et al. [
The main limitation of our study was its retrospective character and the small number of patients; however our center is the largest one in the southern Poland. Only one patient during the follow-up developed an overt thyroid dysfunction; therefore the survival analysis was not performed in this study. The study with its limitations was aimed at being another contribution to the debate on the desirability of creation the algorithms for appropriate care of patients with SH.
Further prospective, longitudinal, and case-controlled studies are warranted in order to establish final treatment indications, if any, and the recommended mean dosage of LT-4. The optimal dose should on the one hand prevent children and adolescents with sHT from proceeding to overt thyroid disease and on the other hand not cause an excess of thyroid hormones, which may affect the body’s metabolic processes. To this end, our center has just begun a 2-year prospective controlled study approved by the Ethics Committee.
The study was approved by the Ethics Committee of the Medical University of Silesia. The patients’ rights were also approved according to the Declaration of Helsinki.
The authors declare that there are no competing interests regarding the publishing of this paper.
The authors wish to thank Sandra K. Lindon for proofreading the paper.