Biopsy Validated Study of Biomarkers for Liver Fibrosis and Transplant Prediction in Inherited Cholestasis

Abstract

Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are inherited cholestatic disorders with risk of developing end-stage liver disease requiring liver transplantation (LT). We investigated aspartate aminotransferase-to-platelet ratio index (APRI), Fibrosis-4 score (FIB-4), and conjugated bilirubin as biomarkers to assess fibrosis severity and risk for LT among children with ALGS and PFIC. This multicenter, cross-sectional study included 64 children with ALGS or PFIC (per genetics or strict clinical criteria) with APRI, FIB-4, and conjugated bilirubin levels collected within ±90 days of their most recent liver biopsy. A single, blinded pathologist staged all biopsies (metavir; F0-F2: nonsevere, F3-F4: severe). Logistic regression and area under the receiver operating characteristic curve analysis (AUC) were used to assess biomarker associations with fibrosis severity and risk for LT. In ALGS, only APRI distinguished F3-F4 (AUC 0.72, P = 0.012), with a cutoff greater than 2.97 demonstrating a sensitivity of 61.5% (95% confidence interval 0.32, 0.86) and specificity of 81.5% (0.62, 0.94). In ALGS, a 50% increase of APRI increased the odds of F3-F4 by 1.31-fold (1.04, 1.65; P = 0.023). In ALGS, APRI (AUC 0.87; P < 0.001) and FIB-4 (AUC 0.84; P < 0.001) were able to predict risk for LT. In PFIC, only APRI distinguished F3-4 (AUC 0.74, P = 0.039), with a cutoff greater than 0.99 demonstrating a sensitivity of 80% (0.44, 0.98) and specificity of 64.3% (0.35, 0.87). In PFIC, only FIB-4 was able predict risk for LT (AUC 0.80; P = 0.002). In ALGS or PFIC, conjugated bilirubin could not distinguish F3-F4 or predict risk for LT. Conclusion: This liver biopsy-validated study suggests that APRI is able to distinguish F3-F4 from F0-F2 in ALGS and PFIC. APRI and FIB-4 may also serve as predictors of risk for LT in ALGS (APRI and FIB-4) and PFIC (FIB-4). (Hepatology Communications 2020;4:1516-1526). A lagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) represent distinct but rare inherited cholestatic disorders that display wide variability in degrees of liver fibrosis, progression of disease, and time to transplant. (1-8) Although genetic analysis is emphasized for either diagnosis, percutaneous liver biopsy has historically been an essential tool for histologic staging and monitoring progression of disease. (9,10) Risks of liver biopsies are relatively low; however, there is still potential for bleeding, patient discomfort, infection, and side effects of anesthesia. (10,11) An autosomal dominant disorder, ALGS is characterized by bile duct paucity and often presents with extrahepatic clinical features such as vertebral abnormalities, renal or cardiac disease, posterior embryotoxon,

Native liver survival in bile salt export pump deficiency: results of a retrospective cohort study

“…Another important novel finding of our analysis is the missing impact of liver fibrosis on the outcome of partial biliary diversion and long-term SNL. In contrast to our expectations and previous reports 25 we could not demonstrate a worse outcome in patients with advanced fibrosis as compared with patients with lower-grade fibrosis. The risk of surgery and postoperative complications must be compared with the chance of avoiding transplantation with its lifelong consequences and/or the benefit of transplant-free years.…”

Long-Term Outcome after Liver Transplantation for Progressive Familial Intrahepatic Cholestasis

“…Shiau et al showed recently (Hepatology Communications) that an increase in Fibrosis-4 score was associated with 1.36-fold higher odds for LT in PFIC patients. In addition, the aminotransferase-to-platelet ratio index or Fibrosis-4 score appear to associate with risk for future LT in children with PFIC [ 43 ].…”

“…In view of the often postpartum onset of the disease or early manifestation of symptoms, suspected HCC should be taken into account regardless of its size and extent, but after exclusion of distant metastases. As these patients are often infants, histological confirmation should not be mandatory, but should be supplemented by elevated AFP values, high-grade suspected imaging and the determination of biomarkers [ 43 ].…”

Opinion paper on the diagnosis and treatment of progressive familial intrahepatic cholestasis

“…Progression of PFIC can vary widely between individuals, 2 and several biomarkers have been reported as surrogate indicators of disease progression. 28 , 30 , 31 , 32 , 36 , 37 , 38 , 53 , 54 Notably, a decrease in SBA levels has been shown to correlate with reduction in pruritus severity. 55 In addition, elevated circulating values have also been linked with poor native liver survival in children.…”