The incidence of congenital hypothyroidism (CH) has increased in several countries. Lower cut-off in screening programs have led to an increase in the proportion of transient hypothyroidism (TH) cases diagnosed, leading to debate on the associated clinical and economic impact. This study aimed to identify factors that would allow discrimination between TH and permanent CH (PH) in patients with a eutopic thyroid gland.
Sixty-six patients with CH from 3 different hospitals were studied: 26 cases of TH, and 40 cases of PH. Laboratory findings and clinical parameters were analysed in 56 patients with eutopic thyroid gland.
Initial serum thyroid stimulating hormone levels and L-thyroxine dose at 12 and 24 months of age were significantly higher in PH than TH patients with a eutopic thyroid gland. The area under the curve for the 12-month and 24-month dose for the prediction of TH in eutopic CH was 0.799 (95% confidence interval [CI], 0.678-0.919;
Infants with CH requiring lower L-thyroxine doses (<3.25 µg/kg) are likely to have TH, and thus might be re-evaluated at 12 months or 24 months rather than 3 years of age.
In developed countries, the introduction of screening programs for congenital hypothyroidism (CH) has enabled effective detection of this condition in neonates. In response to screening, the prevalence of CH has increased, particularly for patients with a eutopic (normally located) thyroid gland and a mild elevation in thyroid-stimulating hormone (TSH; hyperthyrotropinemia)
In this study, we investigate the differences between TH and PH in patients with a eutopic thyroid gland, and attempt to identify factors enabling their distinction.
Two hundred and sixty-eight children, who underwent a thyroid function test (TFT) owing to suspected CH (elevated TSH on neonatal screening test or prolonged jaundice) at St. Vincent's Hospital, Bucheon St. Mary's Hospital, and Yeouido St. Mary's Hospital of The Catholic University of Korea between January 2004 and April 2014 were enrolled in this study. Medical records were reviewed retrospectively, and patients were confirmed as having primary CH (TSH>10 mU/L and/or fT4 <0.7 ng/dL in venous blood). L-thyroxine treatment was started immediately in infants diagnosed with primary CH, at a dose of 10-15 µg/kg. One hundred and thirty-one patients were confirmed as having primary CH and treated with L-thyroxine. Of these, 29 patients were excluded owing to incomplete medical records, and a further 36 were excluded as the follow-up period was less than 3 years. Sixty-six patients with CH with follow-up at least 3 years after initial diagnosis were included in the final analysis (
Patients were treated with L-thyroxine until 3 years of age and re-evaluated after 4 weeks of discontinuing medication; followup was carried out at least 4 years from the initial diagnosis. Thyroid ultrasonography or a Technetium-99 (Tc-99m) thyroid scan was performed either at diagnosis or at the 3-year follow-up. Either thyroid ultrasonography and/or a thyroid scan were performed to identify patients with thyroid dysgenesis. Thyroid scans were conducted on 27 patients and ultrasonography on 65; however, one patient with TH underwent neither. Nine patients with PH had thyroid agenesis or dysplasia: 4 of these had thyroid agenesis, 2 had agenesis with an ectopic sublingual thyroid gland, and 3 had thyroid hypoplasia. Ultrasonography showed that 56 patients had a eutopic thyroid gland. These were subsequently divided into 2 groups, TH (transient eutopic hypothyroidism: TSH<5 mU/L) and PH (permanent eutopic hypothyroidism: TSH>10 mU/L). Follow-up was carried out every 1-3 months for patients with hyperthyrotropinemia (TSH, 5-10 mU/L). These patients were all defined as having either PH or TH after the follow-up period. The TH group contained patients for whom treatment could be discontinued at the 3-year follow-up, and the PH group contained patients for whom treatment continued (
All patients were monitored 1 month after L-thyroxine discontinuation, and every 6 months thereafter. Serum triiodothyronine (T3), fT4, and TSH levels were measured by chemiluminescent microparticle immunoassay with the Architect i2000 analyser (Abbott, Abbott Park, IL, USA). Reference values were as follows: T3. 0.58-1.9 ng/mL; fT4, 0.7-1.79 ng/dL; and TSH, 0.35-4.95 µIU/mL. L-thyroxine dose per kilogram body weight was calculated at the onset of treatment, at 12 months of age (12M dose), and at 24 months of age (24M dose).
This study complied with the recommendations of the Declaration of Helsinki and was approved by the Institutional Review Boards of St. Vincent's Hospital, Bucheon St. Mary's Hospital, and Yeouido St. Mary's Hospital of The Catholic University of Korea.
Statistical analyses were performed with PASW Statistics ver. 18.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as the mean±standard deviation. Continuous data were analysed using the Student
Of the 56 study patients, 25 patients were assigned to the TH group and 31 patients to the PH group. None of the patients had associated malformations. Baseline clinical and laboratory values for patients with eutopic thyroid gland are presented in
The ROC curves predicting TH using initial TSH level, 12M dose, and 24M dose are shown in
In the present study, the prevalence of TH was 39.4%, which is comparable with that in other recent studies which showed values of 38%-54.9%
In this retrospective review of pediatric patients with CH with a eutopic thyroid gland, initial venous TSH concentration, 12M dose, and 24M dose were significantly higher in PH than TH cases. Among these patients, a 12M and 24M dose >3.25 µg/kg indicated a higher chance of developing PH. Current guidelines recommend the administration of 10-15 µg/kg of L-thyroxine after the initial diagnosis of CH, followed by dose titration at 1- to 3-month intervals to maintain a venous TSH concentration within the average range
TSH concentrations in venous blood at initial diagnosis were higher for PH than TH in this study. This has also been shown in several other studies
Several reports have suggested that preterm and low birth weight infants have a higher tendency to have TH
Otherwise, the prevalence of thyroid dyshormonogenesis was 75% (31 from 40 patients with PH). It is various from 31.3% to 76.9% in several studies
In contrast to past standards, current guidelines recommend early treatment with L-thyroxine (where possible at less than 2 weeks of age) when the venous TSH concentration is >20 mU/L irrespective of fT4 concentration, and "playing safe" by treating with L-thyroxine during early childhood when TSH levels are low (6-20 mU/L) and fT4 levels are normal
The results of this study suggest that infants with CH who require lower L-thyroxine doses by 12 months and 24 months of age are likely to have TH. Therefore, infants with CH requiring lower L-thyroxine doses (3.25 µg/kg at 12 months and 24 months) may be re-evaluated at 12 months or 24 months rather than 3 years of age by decreasing the dose of L-thyroxine.
No potential conflict of interest relevant to this article was reported.
Flow diagram of the study population with congenital hypothyroidism. TBG, thyroxine binding globulin; TSH, thyroid-stimulating hormone.
Receiver operating characteristic (ROC) curve of initial serum TSH, L-thyroxine dose at 12 months of age (12M dose), and 24 months of age (24M dose) reflecting transient congenital hypothyroidism. The cutoff values of 12M dose and 24M dose were 3.25 µg/kg (area under the curve=0.799; 95% CI, 0.678-0.919;
Clinical characteristics of the two groups with eutopic thyroid gland in ultrasonography (n=56)
Characteristic | TH group | PH group | |
---|---|---|---|
No. of patients | 25 (39.4) | 31 (60.6) | |
Sex | 1.000 | ||
Female | 13 (52.0) | 16 (51.7) | |
Male | 12 (48.0) | 15 (48.3) | |
Birth weight (g) | 0.277 | ||
<2,500 | 2 (8.0) | 6 (19.4) | |
≥2,500 | 23 (92.0) | 25 (80.6) | |
Gestational age (wk) | 0.623 | ||
<37 | 3 (12.0) | 4 (12.9) | |
≥37 | 22 (88.0) | 27 (87.1) | |
Serum TSH (mU/L) | 60.5±78.3 | 89.4±67.1 | 0.038 |
Serum fT4 (pmol/L) | 0.98±0.48 | 1.00±0.48 | 0.707 |
Serum T3 (ng/mL) | 1.3±0.4 | 1.8±3.7 | 0.478 |
L-thyroxine dose (μg/kg) | |||
Initial | 10.2±1.8 | 11.3±5.5 | 0.323 |
12 Months | 3.1±1.1 | 4.5±1.5 | <0.001 |
24 Months | 2.5±1.0 | 4.2±0.8 | <0.001 |
Values are presented as number (%) or mean±standard deviation.
TH, transient hypothyroidism; PH, permanent hypothyroidism; TSH, thyroid stimulating hormone; fT4, free thyroxine; T3, triiodothyronine.