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