Levothyroxine therapy in pediatric CH patients remodels sphingolipid metabolism, reducing ceramides and increasing sphingomyelins.

Early levothyroxine (LT4) replacement is crucial for preventing neurodevelopmental impairment in congenital hypothyroidism (CH). Current treatment monitoring primarily relies on thyroid-stimulating hormone (TSH) and thyroxine (T4) levels, which may not fully capture the systemic metabolic adaptations occurring during therapy. Hypothyroidism is known to be associated with dyslipidemia and increased cardiovascular risk, often not fully corrected by standard hormone replacement. This study aimed to explore the broader metabolomic and inflammatory changes associated with LT4 response, particularly focusing on sphingolipid metabolism, to provide complementary insights beyond traditional thyroid markers.

This prospective longitudinal study enrolled 11 pediatric CH patients to investigate metabolic and inflammatory responses to levothyroxine (LT4) therapy. Plasma samples were collected at two key time points: at diagnosis (Pre Tx) and after biochemical euthyroidism was achieved following LT4 treatment (Post Tx), with a mean follow-up period of 2.7 months. Metabolomic profiling was performed using tandem mass spectrometry to identify changes in circulating metabolites. Inflammatory status was assessed by measuring plasma levels of tumor necrosis factor-alpha (TNF-α) and interleukin 10 (IL-10). Nutritional status, specifically length-for-age Z-score, was also evaluated to monitor growth parameters.

LT4 therapy in pediatric CH patients was associated with significant changes in circulating sphingolipids. A group of nine metabolites effectively discriminated between Pre Tx and Post Tx samples. The most prominent metabolic shifts involved sphingolipid metabolism, characterized by a notable reduction in ceramides (Cer) and hexosylceramides (HexCer), alongside increased levels of specific sphingomyelins (SM). These changes suggest a remodeling of lipid pathways. Circulating TNF-α and IL-10 concentrations were markedly elevated at diagnosis. Although both cytokines showed a decreasing trend following LT4 therapy, no statistically significant differences were observed between the Pre Tx and Post Tx time points. Nutritional assessment revealed a modest increase in length-for-age Z-score in the Post Tx group, indicating some improvement in growth.

The main metabolic changes involved sphingolipid metabolism, characterized by reduced ceramides (Cer) and hexosylceramides (HexCer), together with increased levels of specific sphingomyelins (SM).