Combined Levothyroxine and Propylthiouracil Treatment in Children with Monocarboxylate Transporter 8 Deficiency: A Multicenter Case Series of 12 Patients

Abstract

Objective: To evaluate the combined administration of propylthiouracil (PTU) and levothyroxine (LT4) in managing monocarboxylate transporter 8 (MCT8) deficiency and identify optimal therapeutic dosages. Methods: This multicenter case series involved 12 male patients with MCT8 deficiency whose parents/guardians consented to PTU and LT4 treatment. Data were collected from January 2008 to June 24, 2024. The study focused on treatment safety and outcomes, analyzing baseline and last encounter biochemical, metabolic, and anthropometric parameters. Statistical analyses included Wilcoxon signed ranks tests and generalized estimated equations to assess effects on thyroid and metabolic markers, and receiver operating characteristics curves to predict optimal dose. Results: Patients showed a significant reduction in serum total triiodothyronine (TT3) concentration and TT3/TT4 ratio, with increased serum TT4 and free T4 (fT4) concentrations. The use of PTU effectively reduced TT3 concentration by 25% at an average dose of 6.8 mg/kg/day, while LT4 increased fT4 concentration by 40% from baseline at an average dose of 4.3 µg/kg/day. Thyrotropin concentration was undetectable on treatment. No statistical differences were observed in metabolic and physical parameters between baseline and last encounter overall for the group, but six of eight patients for whom these data were available had an increase in weight (z-score). There were no adverse effects on liver function or granulocyte numbers noted throughout the period of observation. Conclusion: Combined treatment with PTU and LT4 normalized serum T3, fT4, and TT4 in patients with MCT8 deficiency. Individualized dose adjustments were crucial for achieving therapeutic goals, indicating the need for personalized treatment plans.

Keywords: Allan–Herndon–Dudley syndrome; congenital hypothyroidism; hyperthyroidism; thyroid hormone transport.

FIG. 1.

Boxplot showing the comparison between baseline and last encounter after treatment. (a) Total T3 concentrations, ***p < 0.001. (b) TT3/TT4 ratio, **p < 0.001. (c) TSH concentration, ***p = 0.001. (d) fT4 concentration, ***p = 0.003. (e) Total T4 concentrations, **p = 0.005. (f) AST concentrations, *p = 0.013. (g) ALT concentrations, p = 0.110. ALT, alanine aminotransferase; AST, aspartate aminotransferase; fT4, free thyroxine; TSH, thyrotropin; TT3, total triiodothyronine.

FIG. 2.

Representation of the progression of clinical and biochemical parameters in patients over the course of treatment. Of note, these parameters were not available in all 12 patients in this study. Each patient’s baseline measurements are depicted by the open symbol, while the change up to the last encounter is represented in the solid symbol. Arrows indicate the direction of change from baseline to the last encounter, with upward arrows signifying an increase and downward arrows a decrease. (A) Ferritin levels, (B) sex hormone binding globulin (SHBG), (C) creatinine kinase, (D) total cholesterol, (E) heart rate, and (F) body weight (z-score) of patients with (square) and without (circle) feeding tubes.

FIG. 3.

Levothyroxine (LT4) dosing for targeted TSH suppression. The dose–response relationship of LT4 and undetectable TSH levels. Receiver operating characteristic (ROC) curve that determines the optimal total daily dose per kg of LT4 that correlates with achieving undetectable TSH levels.