Untargeted Metabolomics Reveals Metabolic Reprogramming Linked to HCC Risk in Late Diagnosed Tyrosinemia Type 1.

Area of Science:

• Biochemistry
• Metabolomics
• Genetics

Background:

• Hereditary tyrosinemia type 1 (HT-1) is an inherited disorder affecting tyrosine metabolism, leading to severe organ dysfunction.
• Early diagnosis via newborn screening is crucial to prevent hepatocellular carcinoma (HCC), the most severe complication of HT-1.
• Understanding HT-1 pathophysiology is vital for improving diagnostic and therapeutic strategies.

Purpose of the Study:

• To explore the untargeted serum metabolomic profiles of HT-1 patients.
• To identify novel biomarkers and metabolic pathways associated with HT-1.
• To investigate metabolic alterations in patients treated with nitisinone (NTBC) after delayed diagnosis.

Main Methods:

• High-resolution untargeted metabolomics and liquid chromatography were used for serum analysis.
• 16 late-diagnosed Chilean HT-1 patients on NTBC therapy and 16 matched controls were analyzed.
• Statistically significant metabolite features were annotated and associated with metabolic pathways.

Main Results:

• 1066 significantly altered metabolite features were identified in HT-1 patients.
• Increased metabolites included aromatic compounds, acyl-carnitines, taurine-conjugated bile acids, and modified nucleobases.
• Decreased metabolites were primarily lipids, such as lysophosphatidylcholines and fatty acids.

Conclusions:

• Untargeted metabolomics revealed perturbed tyrosine and tryptophan pathways in HT-1 patients.
• A novel HT-1 metabolomic pattern showed dysregulated lipid and bile acid metabolism in NTBC-treated patients with delayed diagnosis.
• Observed metabolic alterations may reflect persistent disease adaptations and warrant further investigation for long-term complications, including HCC.