A Dynamic Aspartate-to-Alanine Aminotransferase Ratio Provides Valid Predictions of Incident Severe Liver Disease

Abstract

The aspartate-to-alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver-related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population-based health-examination surveys (FINRISK, 2002-2012; n = 18,067) with linked registry data for incident liver-related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver-related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol-related liver disease (ALD). The dynamic AAR model predicted liver-related outcomes both overall (optimism-corrected C-statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver-related outcomes within 10 years. In independent cohorts, the C-statistic for predicting liver-related outcomes up to a 10-year follow-up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area-under-the-curve (AUC) for detecting prevalent cirrhosis was 0.80-0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C-statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations.

FIG. 1

Association between transaminases and incident liver disease. (A) ALT and incident liver disease and (B) AST/ALT ratio and incident liver disease in the final prediction model in the FINRISK cohort.

FIG. 2

Box plots showing the distribution of the dAAR score by liver fibrosis stage in the different cohorts. (A) Swedish NAFLD, (B) Boston NAFLD, (C) hepatitis C, and (D) ALD cohorts. Graphs show interquartile range (box), median (horizontal line), and outliers (whiskers).

FIG. 3

Receiver operating characteristic plots for cirrhosis (fibrosis stage 4) and advanced fibrosis (stages 3‐4) in the different cohorts. (A) Swedish NAFLD, (B) Boston NAFLD, (C) hepatitis C, and (D) ALD cohorts.

FIG. 4

Cumulative incidence of severe liver disease by risk group. (A) AMORIS cohort and (B) FINRISK cohort. Analysis was performed using the Aalen‐Johansen method considering death without liver disease as a competing risk event. Follow‐up was 20 years for the AMORIS cohort and 10 years for the FINRISK cohort.

FIG. 5

Use of the dAAR score for prediction of liver outcomes and advanced fibrosis. (A) Interaction between AST/ALT ratio and ALT levels by age in the dAAR score. Risk is depicted by different colors, with green representing the lowest risk and red the highest risk. (B) The 10‐year cumulative incidence estimates from the FINRISK and AMORIS cohorts and likelihood of advanced liver fibrosis (%F3‐F4) or cirrhosis (%F4) in biopsied patient cohorts of NAFLD (Swedish and Boston cohorts combined), HCV, and ALD. The percentages for %F3‐F4 and %F4 depict the number of individuals with F3‐F4 or F4 on liver histology divided by the number of individuals in that specific risk category. For ALD, results are given both for the dAAR score with absolute ALT level and for the dAAR score with absolute AST level because performance of the AST model was substantially better in this cohort.