Breath-Based Diagnostics in Liver Diseases: Dynamic Assessment of Hepatic Metabolic Reserve and Liver Fibrosis

The global burden of chronic liver disease continues to rise, driven largely by metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease. Accurate assessment of hepatic fibrosis and metabolic reserve remains central to prognostication and clinical decision-making. While liver biopsy and conventional laboratory-based scoring systems remain standard tools, they provide static or indirect measures of liver function and have important limitations. Breath testing has emerged as a noninvasive, physiologically grounded approach to assess real-time hepatic metabolic capacity. Isotope-based breath tests utilize ¹³C-labeled substrates that undergo hepatic metabolism, generating measurable ¹³CO₂ in exhaled breath, thereby reflecting enzymatic activity, mitochondrial function, hepatic perfusion, and functional hepatocyte mass. Breath test kinetics also capture the functional consequences of hepatic fibrosis, offering a complementary perspective to structural assessment tools. In parallel, volatile organic compound analysis enables the detection of endogenous metabolic signatures associated with oxidative stress and fibrogenesis. Recent advances have led to the development of multisubstrate platforms such as the Liver Isoform Breath Assessment (LIBRA), which simultaneously interrogates multiple hepatic metabolic pathways to provide a composite measure of dynamic liver function. Preliminary data suggest that LIBRA may have clinical utility in fibrosis risk stratification, prediction of hepatic decompensation, and transplant evaluation. Breath testing represents a promising adjunct to existing diagnostic strategies by integrating structural and functional dimensions of liver disease. Further large-scale validation studies are needed to establish standardized thresholds and define the role of LIBRA in routine clinical practice.