Liver biochemistry abnormalities are common and may reflect benign transient changes or underlying liver disease. An evidence-based, stepwise approach can optimize diagnostic efficiency while minimizing unnecessary testing in the pediatric population with cystic fibrosis (CF). This review presents a structured framework to differentiate transient (<6 months) from chronic (>6 months) liver biochemistry abnormalities, with a particular focus on drug-induced liver injury (DILI), including cystic fibrosis transmembrane conductance regulator (CFTR) modulators-associated hepatotoxicity and emerging fatty liver disease or metabolic dysfunction-associated steatotic liver disease (MASLD).

Risk stratification should guide decisions on monitoring versus escalation to imaging and invasive diagnostics. Special considerations for high-risk CF populations with portal hypertension or cirrhosis are discussed to inform effective clinical management.