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 )