Introduction:
Cystic fibrosis-related hepatobiliary involvement (CFHBI) is common in people with cystic fibrosis (PwCF) with a varying severity. A wide spectrum of hepatic manifestations are noted in CF including but not limited to steatosis, intermittent or persistent elevated liver enzymes, abnormalities noted on radiological imaging and end-stage liver disease. The pathophysiology of CFHBI is poorly understood but likely multifactorial including non-specific and related extrahepatic causes such as malnutrition, drug-related toxicities, viral/bacterial infections, and hepatic congestion, but also could be due to the effects of CFTR dysfunction in the biliary epithelia 1 or vascular abnormalities including obliterative portal venopathy or non-cirrhotic portal hypertension 2,3. The clinically significant pathognomonic finding of focal biliary fibrosis is noted in approximately 30% of PwCF with a varying degree of severity4-9. In autopsy studies, focal biliary fibrosis has been documented up to 70% of PwCF 10. However, only about 5-10% of PwCF progress to the severe form of fibrosis namely the multilobular cirrhosis usually by the end of the first decade of life4-9. Along with multilobular cirrhosis (with or without portal hypertension), the other phenotypes of advanced CF-related liver disease (aCFLD) include one (or more) of the following: nodular liver, advanced hepatic fibrosis (F4 of the METAVIR staging) and non-cirrhotic portal hypertension (obliterative portal venopathy).
The prevalence of clinically defined CFHBI varies but is generally felt to occur in 30-40% of PwCF in most studies depending on the definition utilized 7,11,12. To minimize confusion, experts proposed an unified approach for the classification of CFHBI11,13. According to the Cystic Fibrosis Foundation 2021 Annual Registry, aCFLD accounts for the third leading cause of mortality in PwCF accounting for 2.6% of the deaths after respiratory and transplant-related complications 14. Even though this is relatively small portion of the population, aCFLD may adversely impact lung function and nutritional status 7,15, and is strongly associated with CF related diabetes (CFRD)16, all of which may further impact morbidity and mortality. This is supported by a review of the French CF Registry finding that liver involvement at baseline was an independent risk factor for lung transplant or death 17 and a review of the United Kingdom CF registry concluding that aCFLD also has significantly increased all-cause mortality with a hazard ratio (HR) of 1.54 18.
Historically, CFHBI was viewed as a complication impacting PwCF almost exclusively prior to 20 years of age 5. However, as survival for PwCF improves, liver involvement among adults with CF is increasingly recognized. A report by the National Institutes of Health (NIH) proposed a modified criteria to evaluate CFHBI among adults that revealed 47% of their population had some degree of hepatic involvement and that CHHBI was more common among adults than previously reported19. Importantly though, aCFLD remains a rare finding among adults with single-center studies concluding that adult CFHBI is a largely a benign condition 20-23 and well-illustrated by the French CF Modifier Gene Study 7 (seeFigure 1 )