Decoding liver injury in cystic fibrosis: How to tell drug-induced liver injury from cystic fibrosis liver disease

BACKGROUND: Cystic fibrosis liver disease (CFLD) is a significant comorbidity in individuals with cystic fibrosis (CF), marked by biliary fibrosis and progressive cholestasis. The advent of CF transmembrane conductance regulator (CFTR) modulators has revolutionized care for lung disease, but their impact on liver-specific disease and outcomes remain unclear. Additionally, the risk of comorbid cholestatic liver injury from medications and progression of CFLD complicates the diagnostic landscape. AIM: To provide a clinical framework for differentiating CFLD and drug induced liver injury (DILI), including from CFTR modulators. METHODS: A comprehensive literature review was conducted using PubMed, EMBASE, and Cochrane Library databases through March 2025. Studies evaluating pathogenesis, clinical features, diagnostic strategies, and management of CFLD and CFTR modulator-related DILI were included. Data were synthesized to highlight distinguishing clinical and histopathologic features and to guide evidence-based management. RESULTS: CFLD typically presents with insidious progression, portal hypertension, and biliary cirrhosis, whereas CFTR modulator-induced DILI often manifests acutely with jaundice, elevated liver enzymes, and a temporal association with therapy initiation. Key differentiators include biochemical patterns, imaging findings, response to drug withdrawal, and, when necessary, liver histology. Management strategies range from dose modification and supportive care in DILI to ursodeoxycholic acid, nutritional optimization, and portal hypertension management in CFLD. CONCLUSION: Early recognition and differentiation between DILI and underlying CFLD are essential for optimizing therapy, preserving liver function, and guiding long-term management in patients with CF. As CFTR modulators become the cornerstone of CF management, vigilance for hepatotoxicity is critical. A multidisciplinary approach involving hepatology and CF care teams is recommended.