Altered carnitine-acylcarnitine profiles in levothyroxine-treated congenital hypothyroid patients with fatigue: An...

Congenital hypothyroidism (CH), characterized by insufficient thyroid hormone production at birth, is frequently associated with fatigue, particularly in cases with delayed diagnosis. This study employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to profile carnitine and acylcarnitines in late-diagnosed congenital hypothyroid patients receiving levothyroxine (LT4) therapy, with the aim of identifying metabolic alterations that may be associated with fatigue symptoms. A total of 56 late-diagnosed congenital hypothyroid patients and 107 age-, sex-, and BMI-matched healthy controls were enrolled. Blood samples were collected in EDTA tubes and as dried blood spots (DBS) on Whatman® 903 filter paper. LC-MS/MS was used to quantify free carnitine and 28 acylcarnitines, and plasma triglyceride (TG) levels were measured using a biochemical analyzer. Compared to healthy controls, congenital hypothyroid patients showed higher mean (±SD) concentrations of free carnitine (45.38 ± 12.61 vs. 41.54 ± 9.85 µmol/L; P = 0.049), total carnitines (67.33 ± 18.27 vs. 62.51 ± 14.13 µmol/L), and total acylcarnitines (21.95 ± 7.66 vs. 20.96 ± 5.61 µmol/L), although only free carnitine levels were statistically significant. Long-chain acylcarnitines were significantly lower in congenital hypothyroid patients (2.67 ± 0.87 µmol/L) compared to controls (3.15 ± 0.93 µmol/L; P = 0.0014). The β-oxidation ratio C0/(C16 + C18), a proxy for Carnitine Palmitoyltransferase I (CPT-I) activity, was significantly elevated in patients compared to healthy controls (34.55 ± 14.88 vs. 25.73 ± 6.87; P < 0.0001). Plasma TG levels were also significantly higher in patients (88.92 ± 59.54 mg/dL) than in controls (58.33 ± 15.79 mg/dL; P = 0.02). Metabolic profiling in congenital hypothyroid patients revealed impaired long-chain fatty acid oxidation and elevated triglyceride levels. These metabolic changes may contribute to fatigue symptoms and are potentially associated with reduced CPT-I activity, which is essential for mitochondrial β-oxidation. Additionally, mutations in the TPO and TSHR genes identified within this cohort may be linked to the observed metabolic alterations. Collectively, these findings suggest a possible interplay between genetic variants, disrupted lipid metabolism, and clinical features of congenital hypothyroidism.