Role of thyrotropin-releasing hormone test in re-evaluation of congenital hypothyroidism

Abstract

The thyrotropin-releasing hormone (TRH) test is useful for differentiating central and primary hypothyroidism, and is also valuable for diagnosing hypothyroidism. The threshold of the TRH test is usually set at 10-40 mIU/L. However, some experts are of the opinion that the TRH test has a limited role in evaluating hypothyroidism because of the clinical application of the new-generation thyroid-stimulating hormone (TSH) assay. We reviewed a case series to analyze the clinical use of the TRH test in the re-evaluation of congenital hypothyroidism. In total, data on 228 children with eutopic thyroid glands and neonatal hyperthyrotropinemia under levothyroxine replacement were collected. Basal TSH levels were measured and the TRH test was performed at the age of 3 years for re-evaluation of congenital hypothyroidism, and statistical analysis was performed. All of the patients were followed up to avoid over- or under-treatment. At the age of 3 years, 31.6% of the patients still had hypothyroidism. There was no significant difference between basal TSH level and TRH test in the diagnosis of hypothyroidism (p = 0.23). The negative predictive value of the basal TSH level was 100%, however, the positive predictive value was only 43.6%. When the TSH level was near the upper limit of the normal range (4.5-8.5 mIU/L), the TRH test result had a better correlation with hypothyroidism than the basal TSH level (p = 0.03). The threshold of the TRH test set at 60 mIU/L had the greatest area under the curve, with a negative predictive value of 95.2% and a positive predictive value of 80.2%. Neonatal hyperthyrotropinemia was a risk factor for hypothyroidism. We suggest that the TRH test should be administered in children with a basal TSH value near the upper limit of the normal range, and the threshold of the TRH test should be set at 60 mIU/L.

Keywords: Congenital hypothyroidism; Neonatal hyperthyrotropinemia; Thyrotropin-releasing hormone test.

Figure 1

Receiver operating characteristic curve: initial confirmatory test versus permanent hypothyroidism (n = 280). The area‐under‐the‐curve (AUC) of thyroid‐stimulating hormone (TSH): 0.60 (95% CI, 0.51 to 0.69, p = 0.024). AUC of triiodothyronine (T3): 0.32 (95% CI, 0.24 to 0.41, p < 0.001). AUC of thyroxine (T4): 0.43 (95% CI, 0.34 to 0.52, p = 0.120). AUC of free‐T4 (fT4): 0.43 (95% CI, 0.34 to 0.52, p = 0.122).

Figure 2

Distribution of transient hyperthyrotropinemia (HT) and permanent congenital hypothyroidism (CH) according to basal thyroid‐stimulating hormone (TSH) and peak TSH of thyrotropin‐releasing hormone (TRH) test in patients with thyroid eutopia (n = 228).

Figure 3

(A) Receiver operating characteristic (ROC) curve: basal thyroid‐stimulating hormone (TSH) and peak TSH versus permanent hypothyroidism for patients with thyroid eutopia (n = 228). The area‐under‐the‐curve (AUC) of basal TSH: 0.950 (95% CI: 0.925 to 0.976, p < 0.001). AUC of peak TSH: 0.969 (95% CI: 0.951 to 0.987, p < 0.001). AUC of basal TSH & peak TSH: t = 1.44, p = 0.23. (B) ROC curve: basal TSH and peak TSH versus permanent hypothyroidism for patients with thyroid eutopia and basal TSH level >4.5 mIU/L(n = 165). The AUC of basal TSH: 0.917 (95% CI: 0.875 to 0.959, p < 0.001). AUC of peak TSH: 0.948 (95% CI: 0.918 to 0.978, p < 0.001). AUC of basal TSH & peak TSH: t = 1.44, p = 0.23. (C) ROC curve: basal TSH and peak TSH versus permanent hypothyroidism for patients with thyroid eutopia and basal TSH level 4.5∼8.5 mIU/L (n = 51). The AUC of basal TSH: 0.570 (95% CI: 0.28 to 0.86, p = 0.590). AUC of peak TSH: 0.909 (95% CI: 0.80 to 1.000, p = 0.003). AUC of basal & peak TSH: t = 4.522, p = 0.033.

Figure 4

Distribution of transient hyperthyrotropinemia (HT) and permanent congenital hypothyroidism (CH) according to basal thyroid‐stimulating hormone (TSH) and peak TSH in patients with thyroid eutopia with basal TSH < 20 mIU/L and peak TSH < 100mIU/L (n = 183). The higher and lower transverse dashed lines mean peak TSH 60 and 40 mIU/L, respectively; the left and right longitudinal dashed lines mean basal TSH 4.5 and 8.5 mIU/L, respectively.