Background: AHDS is a devastating disease caused by defects in the thyroid hormone (TH) transporter MCT8. Endocrine expression is heralded by systemic hyperthyroidism with elevated serum T3, mildly increased TSH and decreased T4. However, the brain is hypothyroid, causing severe psychomotor retardation. Therapeutic attempts with PTU+levothyroxine or the T3-analogue DITPA could normalize TH derangements but without any neurological improvement. Recently, in vitro and mouse studies support the therapeutic utility of triiodothyroacetic acid (TRIAC) in MCT8 deficiency.
Objective: To investigate the hormonal effects of TRIAC in AHDS.
Patients and methods: Five children diagnosed with AHDS between 8 months and −6 years of age, harbouring various defects in MCT8 (p.P215L, p.delF230, p.V254DfsX24, p.L304_I539del, p.G401R). TRIAC compassive treatment started with 10 μg/kg per day, doubling the dose every 2 weeks until normalization of TH parameters. Determination of serum TSH, FT3, FT4 by immunoassay, TRIAC and rT3 by RIA and SHBG by ELISA.
Results: At baseline, patients (9 mo8 years old) showed high FT3 (7.3±2.4 ng/dl; n<4) or T3: (4.2±0.2 nmol/l; n<3.8), low FT4 (0.6±0.08 ng/dl; n>0.8), borderline-high TSH (4.4±2.6 mU/l; n<4.5), low rT3 (3/5) (8.6±2.8 ng/dl; n>15) and high SHBG (207.6±55.8 nmol/l; n< 100). After mean 11.4 weeks and mean TRIAC dose of 33.3 μg/kg per day (2040), FT3 and T3 normalised (3.8±0.6 ng/dl -3/5-; T3 3.14 nmol/l -1/5-) and TSH decreased (1.99±1 μU/ml), but FT4 and rT3 remained low (7.8±4.9 ng/dl, 0.39±0.05 ng/dl) and SHBG elevated (221±59 nmol/l). Serum TRIAC increased ten-fold from baseline to final dose (12.8163.5 ng/dl).
Conclusions: TRIAC normalises hyperthyroidism and hyperthyrotropinmia in AHDS, but not FT4, rT3 or SHBG. The required dose is inversely related to age, possibly due to larger distribution volume of drugs in early childhood. Effects of TRIAC on child neurodevelopment and brain myelination are being prospectively evaluated by psychometric tests and MRI in periodic follow-up investigation.
Funding: This work was supported in part by the Paediatric Endocrinology Spanish Society, with the grant for Basic Research in 2014.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology