Prolonged Hepatic Biomarker, Fibrosis Score Elevation Linked to Poor PBC Prognosis

Prolonged elevation of multiple hepatic biomarkers and fibrosis scores is associated with a greater risk of negative clinical outcomes in patients with primary biliary cholangitis (PBC), irrespective of alkaline phosphatase (ALP) strata, according to findings from a recent study.1

Leveraging patient data from Komodo's Healthcare Map, the study found increasing magnitude and duration beyond established thresholds of ALP, alanine aminotransferase (ALT); aspartate aminotransferase (AST); total bilirubin (TB); AST/platelet ratio index (APRI); and fibrosis-4 (FIB-4) were associated with an increased risk of hospitalization for hepatic decompensation, liver transplantation, or death.1

“While ALP is a valuable and informative indicator of treatment response, it alone may not fully capture the risk for negative clinical outcomes,” Kris Kowdley, MD, director at Liver Institute Northwest and senior scientific advisor and medical director at Velocity Clinical Research, and colleagues wrote.1 “Emerging evidence suggests that other biochemical parameters in addition to ALP and TB may be associated with the risk for liver transplantation or death in patients with PBC.”

Ursodeoxycholic acid (UDCA) is the first-line pharmacotherapy for PBC. Current guidelines recommend evaluating biochemical response, including changes in serum ALP, AST, ALT, TB, after 1 year of treatment using established criteria and risk scores, most of which use a reduction of ALP levels to 1.4 to 3 × upper limit of normal (ULN) as the primary marker of response. However, other hepatic biomarkers are also associated with the risk of hepatic decompensation, liver transplantation, and/or death and have been hypothesized to be viable prognostic tools in PBC.2

To evaluate whether longitudinal monitoring of liver biochemistries and fibrosis scores provides additional prognostic value in PBC, investigators conducted a retrospective cohort study using data from Komodo's Healthcare Map for adult patients diagnosed with PBC between July 2014 and February 2022.1

Investigators examined the proportion of time that biomarkers and fibrosis scores exceeded normal limits or specific thresholds as a time-dependent covariate using fixed thresholds for hepatic biomarkers. The composite endpoint was the first occurrence of hospitalization for a decompensation event, liver transplantation, or death. Patients were censored at the initiation of second-line treatment, end of enrollment, or end of follow-up, whichever occurred first.1

Of the 113,446 adult patients with PBC in the Komodo Health Database, 3974 met all eligibility criteria and were included in subsequent analyses. Among the cohort, patients were predominantly female (88.2%) and White (49.4%) with a mean age of 59.4 years.1

Investigators stratified patients into 3 ALP strata:

• ALP ≤ ULN (n = 1443)
• ALP>ULN to ≤ 1.67 × ULN (n = 1279)
• ALP > 1.67 × ULN (n = 1252)

During a median follow-up time of 2.5 (interquartile range, 1.3–4.2) years, hepatic decompensation occurred in 3.4% of patients, affecting a greater proportion of patients with ALP > 1.67 × ULN than those with ALP ≤ 1.67 × ULN (4.9% vs 2.7%).1

Upon analysis, increasing magnitude and duration beyond established thresholds of PBC disease progression biomarkers, including ALP, ALT, AST and TB, and fibrosis scores, including APRI and FIB-4, were associated with an increased risk of negative outcomes.1

Investigators noted patients with FIB-4 ≥ 3.25 and/or APRI > 0.5 had a consistently increased risk for negative outcomes compared to those with FIB-4 < 1.3 and/or APRI ≤ 0.5. Despite low ALP levels ≤ 1.67 × ULN, patients with ALT ≥ 2 × ULN or AST ≥ 1.5 × ULN had a greater risk for negative outcomes than patients with ALT or AST<ULN.1

Further analysis revealed TB levels > 1.0 × ULN were also associated with an increased risk of negative outcomes, regardless of ALP levels. Specifically, investigators called attention to a nearly 6-fold increase in the risk of a negative outcome in patients with elevations of TB ≥ 0.6 × ULN and ALP ≥ ULN for 100% of follow-up time relative to patients who never exceeded these thresholds during follow-up.1

“Our data suggest an increased risk of negative outcomes across multiple hepatic biomarkers and composite fibrosis scores, with a greater risk for patients whose biomarkers and fibrosis scores remain above thresholds for longer periods of time,” investigators concluded.1 “These findings support the importance of continued monitoring of ALT, AST, FIB-4 and APRI, along with ALP and TB, when assessing the need to initiate first- and second-line therapies.”

References

1. Kowdley KV, Victor DW, MacEwan JP, et al. Longitudinal Relationship Between Elevated Liver Biochemical Tests and Negative Clinical Outcomes in Primary Biliary Cholangitis: A Population-Based Study. Alimentary Pharmacology and Therapeutics. https://doi.org/10.1111/apt.70120

2. Cortez-Pinto H, Liberal R, Lopes S, et al. Predictors for incomplete response to ursodeoxycholic acid in primary biliary cholangitis. Data from a national registry of liver disease. United European Gastroenterol J. doi:10.1002/ueg2.12095.