BioMarkers:
Indirect laboratory biomarkers for screening hepatobiliary involvement in PwCF:
Conventional markers of liver disease, such as aspartate transferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) along with platelet levels are obtained annually for PwCF. These commonly employed indirect blood tests used independently or in combination (AST to platelet ratio index (APRI), fibrosis index (FIB-4) based on four factors (age, AST, ALT, and platelets), GGT to platelet ratio (GPR), and AST/ALT ratio) have been widely studied.29-34. These tests have been extensively utilized and validated in other chronic liver diseases such as viral hepatitis (hepatitis B and hepatitis C), and nonalcoholic fatty liver disease in both children and adults 28,35,36. The tests are based on the general principle that AST remains stable or increases, ALT typically increases with worsening fibrosis, and platelet levels decrease with the development of portal hypertension, with or without cirrhosis 37,38.
A number of studies have reported statistically different values among these conventional markers of liver disease among PwCF with aCFLD compared to those without liver disease 39-44. Among these, GPR (≥0.28), APRI (≥0.425) have the diagnostic precision with the highest AURUC’s, generally between 0.75 to 0.929,31,32. Importantly though, these tests have shown differences between disease classifications (e.g. normal and advanced liver disease) but their utility in detecting early disease, identifying small, incremental disease progression, or predicting the development of aCFLD are not clear.
Even though these tests are simple, noninvasive, and cost-effective, they have a number of major drawbacks. Non-specific elevation of liver enzymes in PwCF is not uncommon due to reasons such as intercurrent infections and medications (CFTR modulator therapies, and antibiotics)45,46. In a prospective CF study, by age 21 years, at least one increased liver enzyme (ALT, AST, and GGT) was noted in all participants, and most elevations were noted in the early years of life 4,45. Therefore, persistently elevated liver enzymes are generally more valuable in the predicting liver disease 4,45. Also, in people with aCFLD, liver enzymes can be near normal with advanced stages of fibrosis5. Standalone, they demonstrate poor sensitivity and specificity but can be effectively incorporated into the algorithmic approach of liver involvement evaluation 27. Another challenge in utilizing these tests is the wide range of values that extend between disease category and determining the definition of the upper limit of normal 32. Additionally, the lack of adjustment for confounding variables such as age, sex, and modulator status may further complicate the interpretation of these markers among PwCF. All non-invasive tests utilized in CFHBI are summarized in