Endocrine Abstracts

Objectives: MCT8 deficiency results from a rare X-linked genetic defect in the thyroid hormone monocarboxylate transporter (MCT) 8. MCT8 deficiency is characterized by severe neurocognitive disabilities and peripheral thyrotoxicosis. Mortality rates in MCT8 deficiency are high with 30% dying during childhood. The T3 analogue triiodothyroacetic acid (Triac) has been proven to safely alleviate peripheral thyrotoxicosis in patients with MCT8 deficiency. As thyrotoxicosis is linked to increased mortality, we investigated whether Triac treatment could improve survival in paediatric and adult male patients with MCT8 deficiency.

Methods: We investigated the effects of Triac on all-cause mortality in patients with MCT8 deficiency. Genetic, clinical, biochemical and treatment data were collected from 173 sites in 48 countries through an international consortium on MCT8 deficiency, including Triac Trial, a Triac off-label cohort, and published cases in literature. The impact of mutations on MCT8 transporter function was assessed in transfected cells and classified as mild, moderate or severe loss-of-function (LoF). Baseline characteristics, including age at symptom onset, age at diagnosis, country of residency, LoF, disease features, presence of a feeding tube, and prior treatment aiming to alleviate thyrotoxicosis were compared using Mann-Whitney U and Chi-Square test (5% level of significance). Missing data were imputed with multiple imputation prior to Kaplan-Meier, Log-rank, and Cox proportional-hazards models carried out to estimate the effect of Triac on survival.

Results: We screened 484 males with MCT8 deficiency of whom 228 were included. Patients were excluded because (i) they were born before the disease’s discovery in 2004 (n = 152), (ii) limited data (n = 68) or (iii) unknown LoF (n = 36). Baseline characteristics between Triac-treated (n = 111) and untreated patients (n = 117) were similar, except for untreated patients residing less often in Western countries (57 vs 78%). Median follow-up after diagnosis was 4.8 years [IQR = 2.7–8.4] and we observed 32 deaths (5 treated vs 27 untreated). Triac-treated patients had a 3-times lower risk of all-cause mortality (HR = 0.28, 95%CI=0.09–0.91, P-value <0.05). No other baseline characteristics did significantly affect survival or the effect of Triac treatment.

Conclusions: In this international real-world cohort study, we showed that Triac treatment in paediatric and adult patients with MCT8 deficiency was associated with a 3-times lower risk on mortality. This corroborates previous findings indicating that Triac sustainably alleviated key clinical features resulting from peripheral thyrotoxicosis. To verify the robustness of our results, ongoing analyses aim to minimize confounding and immortal time bias, which pose potential threats to validity in cohort studies.