**7. Cystic fibrosis-related liver disease and prognosis**

As the life expectancy of patients with CF continues to improve, cystic fibrosis-related liver disease (CFLD) is becoming increasingly more prevalent with an incidence estimated of up to 30%, according to multiple studies. Liver disease firstly manifests in its most simple form as biochemical derangements in liver enzymes. Structural disease develops next and manifests as fatty infiltration on ultrasound scan or increased bile content in liver parenchyma. Decom‐ pensated liver disease occurs last, which can involve portal hypertension, ascites, variceal disease, and impaired coagulation. These disease processes occur as a consequence of altered viscous bile due to abnormal CFTR-regulated ion transport across cholangiocytes. Conse‐ quently, biliary flow is reduced and there is obstruction of intrahepatic bile ducts. This causes damage to hepatocytes and cholangiocytes through inflammatory processes, bile duct proliferation, and portal tract fibrosis. The pathogenesis of fatty liver disease in CF is less well understood and has been loosely attributed to fatty acid deficiency, malnutrition, and insulin resistance [40].

Attempts have been made to link the development of CFLD with the presence of certain underlying CFTR mutations, the assumption being that CFLD would be seen with increasing frequency in patients with the classically severe or high-risk phenotypes as described above. However, this relationship has not been demonstrated to date. Non-CFTR modifier genes have been proposed to increase susceptibility to development of CFLD and it is thought that identifying these genetic modifiers may allow early identification of patients at risk. To date only polymorphisms in the SERPINA1 allele, which codes for an alpha-1 antitrypsin, has been demonstrated to be significantly related to CFLD and portal hypertension [41].

Liver disease is widely cited as the third most common cause of death in CF patients after respiratory failure and transplant complications, with a mortality rate estimated at 2.5% [30] and a higher mortality risk is observed in those with liver disease than in those without [40]. However, there continues to be massive variability in the severity of CFLD without adequate explanation as to why it affects only certain patients, thus it is a complex prognostic index.
