Pathophysiology of cystic fibrosis-related liver disease

Cystic fibrosis liver disease (CFLD) is a significant nonpulmonary complication of cystic fibrosis, affecting approximately 5-10% of patients. It encompasses a spectrum of hepatic abnormalities ranging from mild, transient elevations in liver enzymes to advanced CFLD (aCFLD), which is marked by clinically relevant portal hypertension due to cirrhotic or noncirrhotic liver pathology. This review focuses on aCFLD as the clinically meaningful form of the disease and summarizes recent mechanistic insights into its pathogenesis that may inform the development of targeted therapeutic strategies.

CFLD pathogenesis has been traditionally linked to defective bile secretion. Emerging evidence, however, highlights additional contributors, including cholangiocyte immune dysregulation, gut dysbiosis, and intestinal barrier dysfunction, which together promote hepatic inflammation. Furthermore, recent studies underscore the role of vascular alterations independent of cirrhosis, specifically noncirrhotic portal hypertension, as the main clinical feature in aCFLD. These findings support a multifactorial, multihit model of disease in the pathogenesis of CFLD.

The complex interplay of these factors suggests that effective treatment for aCFLD may require a multifaceted approach. Advances in understanding the gut-liver axis and vascular contributions provide new therapeutic targets. Future research should focus on validating these findings and evaluating the efficacy of cystic fibrosis transmembrane conductance regulator modulators and microbiome-targeted treatments in altering the course of CFLD.