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

Table 1 Comparing and contrasting characteristics of liver injury from cystic fibrosis liver disease vs cystic fibrosis transmembrane conductance regulator modulators

	CFLD	DILI
Clinical features	Spectrum from mild biochemical changes to hepatosplenomegaly, cirrhosis, and portal hypertension (ascites, variceal bleeding). Hepatomegaly is most common; splenomegaly also observed. Often asymptomatic until advanced stages (jaundice, pruritus, ascites)	Typically presents acutely after starting CFTR modulators. Jaundice and pruritus are common, especially in cholestatic or mixed injury patterns
Biochemical patterns	Elevated AST/ALT in 53%-93% of patients; GGT elevated in approximately 1/3. Cholestatic or mixed pattern with elevated ALP and GGT. LFTs may be intermittently normal	Hepatocellular or mixed injury more common. ALT/AST elevations > 3 times ULN in 5%-11%, > 5 times ULN in a subset. Often within weeks to months of drug initiation
Imaging findings	Ultrasound: Heterogeneous echogenicity, nodular contour, splenomegaly. Elastography: Elevated liver stiffness (> 5.9-9 kPa). MRI: Patchy focal fibrosis, high diagnostic accuracy, signs of portal hypertension	Imaging findings are nonspecific: Hepatomegaly, steatosis, biliary dilation. Elastography: Stiffness usually reflects inflammation/edema, not fibrosis
Histopathology	Focal biliary fibrosis, bile duct proliferation, bridging fibrosis, and multi-lobular cirrhosis. Nodular regenerative hyperplasia with portal hypertension	Acute injury with lobular disarray, hepatocellular necrosis, cholestasis, eosinophilic infiltrates. Severe: Extensive necrosis, ductular reactions, fibrosis
Diagnostic criteria	RUCAM used to assess causality. Biochemistry and imaging support diagnosis; biopsy helpful in uncertain cases. LFTs alone are not sufficient	RUCAM scores help determine likelihood of DILI. Useful in avoiding unnecessary CFTR therapy discontinuation
Response to CFTR modulators	ALP may decline, GGT stable, bilirubin may modestly increase (adults). AST may decrease in children; GGT may slightly rise but remains normal. Underlying CFLD does not increase DILI risk	Liver enzyme changes often reflect transporter inhibition (OATP1B1/1B3), not intrinsic toxicity. Most elevations are mild or transient

CFLD: Cystic fibrosis liver disease; DILI: Drug-induced liver injury; CFTR: Cystic fibrosis transmembrane conductance regulator; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; ALP: Alkaline phosphatase; LFT: Liver function test; MRI: Magnetic resonance imaging; RUCAM: Roussel Uclaf Causality Assessment Method; ULN: Upper limit of normal.