Aspartate aminotransferase to platelet ratio and fibrosis‐4 as biomarkers in biopsy‐validated pediatric cystic fibrosis liver disease

Abstract

Up to 10% of cystic fibrosis (CF) children develop cirrhosis by the first decade. We evaluated the utility of two simple biomarkers, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4, in predicting degree of fibrosis in pediatric CF liver disease (CFLD) validated by liver biopsy. In this retrospective, cross-sectional study, 67 children with CFLD had dual-pass liver biopsies and 104 age-and sex-matched CF children without liver disease (CFnoLD) had serum to calculate APRI and FIB-4 collected at enrollment. CFLD was defined as having two of the following: (1) hepatomegaly 6 splenomegaly; (2) >6 months elevation of ALT (>1.53 upper limit of normal ULN); or (3) abnormal liver ultrasound findings. Biopsies were staged according to Metavir classification by two blinded pathologists. Receiver operating characteristic (ROC) analysis and continuation ratio logistic regression were performed to assess the predictability of these biomarkers to distinguish CFLD from CFnoLD and determine fibrosis stage-specific cutoff values. The AUC for APRI was better than FIB-4 (0.75 vs. 0.60; P 5 0.005) for predicting CFLD and severe CFLD (F3-F4) (0.81). An APRI score >0.264 demonstrated a sensitivity (95% confidence interval [CI]) of 73.1% (60.9, 83.2) and specificity of 70.2% (60.4, 78.8) in predicting CFLD. A 50% increase in APRI was associated with a 2.4-fold (95% CI: 1.7, 3.3) increased odds of having CFLD. APRI demonstrated full agreement with histology staging 37% of the time, but was within one stage 73% of the time. Only FIB-4 predicted portal hypertension at diagnosis (area under the receiver operator characteristic curve [AUC] 5 0.91; P < 0.001). Conclusion: This is the first liver biopsyvalidated study of APRI and FIB-4 in pediatric CFLD. APRI appears superior to FIB-4 in differentiating CFLD versus CFnoLD. APRI also exhibited a high AUC in predicting severe liver fibrosis with specific cutoffs for lower stages. (HEPATOLOGY 2015;62:1576-1583

Features of Severe Liver Disease With Portal Hypertension in Patients With Cystic Fibrosis

“…APRi and FIB-4 scores exceeded the diagnostic thresholds reported by Leung et al (APRi >0.264 and FIB-4 >0.358) 10 in 96% and 90% of our patients, respectively. Additionally, these biomarkers were significantly different in CFLD patients with and without known varices as well as those who have and have not undergone liver transplantation (Table 4).…”

“…Key observations in this study include that severe CFLD: (a) arises early in life (median 10y) and new cases rarely appear in adulthood; (b) occurs in pancreatic insufficient patients (99%) or in patients who had two severe, loss-of function CFTR mutations (92%), which is considerably higher than the prevalence of pancreatic insufficient mutations in the general CF population (85%) 11 ; (c) occurs in males more frequently than females (63% vs 37%); (d) is associated with normal or mildly elevated liver enzymes and liver function tests, and having an APRi >0.264 10 and FIB-4 >0.358 10 in the majority of patients, and (e) causes more severe abnormality in bloodwork markers of disease severity in those patients with varices and in those requiring liver transplantation (i.e. platelets, albumin, INR, and total bilirubin).…”

“…These initial studies demonstrate that differences between established CF liver disease and CF patients with absence of liver disease can be shown. Based on a different definition of CFLD, APRi and FIB-4 were recently shown to predict CFLD with moderate sensitivity and specificity 10 . In nine of their CF patients with portal hypertension (which is the most comparable population to our 497 CF patients), they reported APRi and FIB-4 values of 0.96 and 0.76, respectively, compared to our median values of 1.15 and 1.16.…”

“…ULN for gamma-glutamyl transferase (GGT) was ≤ 30 IU/L 5-7 . The aspartate aminotransferase (AST) to platelet ratio index (APRi) and fibrosis index based on four factors (FIB-4) were also calculated 8-10 .…”

Prognostic significance of pretreatment albumin/globulin ratio in patients with hepatocellular carcinoma

“…The inflammation-based prognostic score such as Glasgow prognostic score,19 neutrophil-to-lymphocyte ratio,20 aspartate aminotransferase-to-platelet ratio,21 and platelet-to-lymphocyte ratio22 was proven to be independent prognostic parameters by previous studies. However, there are still some limitations for the use of these prognostic scores in patients with HCC.…”