Normal Values for the fT3/fT4 Ratio: Centile Charts (0-29 Years) and Their Application for the Differential Diagnosis of Children with Developmental Delay

Abstract

Primary congenital hypothyroidism is easily diagnosed on the basis of elevated plasma levels of thyroid-stimulating hormone (TSH). In contrast, in the rare disorders of thyroid hormone resistance, TSH and, in mild cases, also thyroid hormone levels are within the normal range. Thyroid hormone resistance is caused by defects in hormone metabolism, transport, or receptor activation and can have the same serious consequences for child development as congenital hypothyroidism. A total of n = 23,522 data points from a large cohort of children and young adults were used to generate normal values and sex-specific percentiles for the ratio of free triiodothyronine (T3) to free thyroxine (T4), the fT3/fT4 ratio. The aim was to determine whether individuals with developmental delay and genetically confirmed thyroid hormone resistance, carrying defects in Monocarboxylate Transporter 8 (MCT8), Thyroid Hormone Receptor alpha (THRα), and Selenocysteine Insertion Sequence-Binding Protein 2 (SECISBP2), had abnormal fT3/fT4 ratios. Indeed, we were able to demonstrate a clear separation of patient values for the fT3/fT4 ratio from normal and pathological controls (e.g., children with severe cerebral palsy). We therefore recommend using the fT3/fT4 ratio as a readily available screening parameter in children with developmental delay for the identification of thyroid hormone resistance syndromes. The fT3/fT4 ratio can be easily plotted on centile charts using our free online tool, which accepts various SI and non-SI units for fT3, fT4, and TSH.

Keywords: MCT8 deficiency; SECISBP2 mutations; SLC16A2 mutations; THRA mutations; TSH; fT3/fT4 ratio; peripheral thyroid hormone resistance; reference values; thyroid hormone.

Figure 1

Thyroid hormone production, metabolism, and action on target cells. T4 is produced exclusively in the thyroid gland by iodination of thyroglobulin (Tg) by thyroid peroxidase (TPO), which is the sole source of plasma T4. Plasma T4 can be further deiodinated in peripheral tissues by deiodinases 1 and 2 (DIO 1 + 2) to T3, which is then red-secreted into the circulation and accounts for 80% of plasma T3, while 20% of plasma T3 is produced primarily in the thyroid gland. The actual ratio of plasma T3 to T4 is, therefore, the result of variable primary production in the thyroid, tightly regulated peripheral metabolism of T4 to T3, and its re-secretion. In the target cells, only the active hormone T3 binds the thyroid hormone receptors alpha and beta. To exert this final T3 effect, T3 can be transported directly from the plasma to the target cell, or it can be produced locally in the target cell from T4 by deiodinase 2. In the pituitary, the T3 effect leads to downregulation of TSH production, which is the key step in the negative thyroid–pituitary feedback loop that keeps thyroid hormone levels stable in the plasma [5,18].

Figure 2

Normal percentiles of TSH, fT3, fT4, and the fT3/fT4 ratio derived from n = 23,522 data points of individuals (n = 11,325 females; n = 12,197 males) aged 0–29 years from the joint KiGGS baseline, KiGGS Wave 2, and LIFE studies based on the general pediatric and young adult population of Germany. The colored lines represent the 97th, 90th, 75th, 50th, 25th, 10th, and 3rd percentiles; pink represents female patients and blue represents male patients. NB: Point clouds for the fT3/fT4 centile charts are shown on Figure S1.

Figure 3

Individual fT3/fT4 ratio data points plotted against the percentiles for male and female patients with THRA mutations. Information on the individual patients can be found in Table S1. The colored lines represent the 97th, 90th, 75th, 50th, 25th, 10th, and 3rd percentiles. The two female patients with the lowest fT3/fT4 ratio carried mutations in the C-terminal part of the THRα protein.

Figure 4

Individual fT3/fT4 ratio data points plotted against the percentiles for male and female patients with SLC16A2 mutations. Information on individual patients can be found in Table S1. (a) We present repeated measurements for two mildly affected male patients (diamonds, patient 2; triangle, patient 3) and one severely affected male patient (squares, patient 1). (b) Triangles represent a female patient treated with levothyroxine (LT4) and later by addition of 6-n-propyl-2 thiouracil (PTU), which normalized the fT3/fT4 ratio. The colored lines represent the 97th, 90th, 75th, 50th, 25th, 10th, and 3rd percentiles.

Figure 5

Individual fT3/fT4 ratio data points plotted against the percentiles for male and female patients with SECISBP2 mutations. Information on individual patients can be found in Table S1. The colored lines represent the 97th, 90th, 75th, 50th, 25th, 10th, and 3rd percentiles.

Figure 6

Individual fT3/fT4 ratio data points plotted against the percentiles for male and female patients with severe cerebral palsy, who served as pathological controls with global developmental delay and without any problems in their thyroid hormone system. Information on the patients can be found in Table S1. The colored lines represent the 97th, 90th, 75th, 50th, 25th, 10th, and 3rd percentiles.