Association Between Noninvasive Fibrosis Markers and Postoperative Mortality After Hepatectomy for Hepatocellular Carcinoma
Authors: Felipe B. Maegawa, Lauren Shehorn, Hassan Aziz, John Kettelle, Tun Jie, Taylor S. Riall
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The selection criteria for hepatectomy for hepatocellular carcinoma (HCC) is not well established. The role of noninvasive fibrosis markers in this setting is unknown in the US population. <h3>Objective</h3> To evaluate whether aspartate aminotransferase–platelet ratio index (APRI) and fibrosis 4 (Fib4) values are associated with perioperative mortality and overall survival after hepatectomy for HCC. <h3>Design, Setting, and Participants</h3> In a multicenter cohort study, Veterans Administration Corporate Data Warehouse was used to evaluate a retrospective cohort of 475 veterans who underwent hepatectomy for HCC between January 1, 2000, and December 31, 2012, in Veterans Administration hospitals. Data analysis occurred between September 30, 2016, and December 30, 2017. Logistic regression, survival analysis, and change in concordance index analysis were performed to evaluate the association between APRI and Fib4 values and mortality. <h3>Exposures</h3> The cohort was stratified based on preoperative APRI and Fib4 values. Analysis was performed accounting for the validated and established predictors of outcome. <h3>Main Outcomes and Measures</h3> Thirty-day mortality, 90-day mortality, and overall survival were the primary outcomes. An APRI value greater than 1.5 was considered high risk (cirrhosis), and an Fib4 value greater than 4.0 was considered high risk (advanced fibrosis). Portal hypertension (diagnosis of ascites or encephalopathy indicates presence of portal hypertension) and Child-Turcotte-Pugh (CTP) class (A indicates preserved liver function; B, mild to moderate liver dysfunction) served as 2 other measures of liver function. <h3>Results</h3> A total of 475 patients with HCC underwent hepatectomy. The mean (SD) age was 65.6 (9.4) years; Model for End-Stage Liver Disease score, 8.9 (3.1); and body mass index, 28.1 (4.9) (calculated as weight in kilograms divided by height in meters squared). A total of 361 patients (76.0%) were men, 294 (61.9%) were white; 308 (64.8%) were hepatitis C positive, and 346 (72.8%) were categorized as CTP class A. The most common surgical procedure was partial lobectomy, with 321 (67.6%) procedures. The APRI value greater than 1.5 vs 1.5 or lower was associated with increased 30-day mortality (odds ratio [OR], 6.45; 95% CI, 2.80-14.80) and 90-day mortality (OR, 2.65; 95% CI, 1.35-5.22), as was Fib4 greater than 4.0 vs Fib4 4.0 or lower for 30-day mortality (OR, 5.41; 95% CI, 2.35-12.50) and 90-day mortality (OR, 2.74; 95% CI, 1.41-5.35). Survival analysis showed that overall survival was significantly different for APRI greater than 1.5 vs 1.5 or lower (mean survival time, 3.6 vs 5.4 years; log-rank<i>P</i> &lt; .001) and Fib4 greater than 4.0 vs 4.0 or lower (mean survival time, 4.1 vs 5.3 years; log rank<i>P</i> = .01). Adjusted Cox proportional hazards regression analysis revealed that elevated APRI was significantly associated with worse survival (hazard ratio [HR], 1.13; 95% CI, 1.03-1.23) but Fib4 values were not (HR, 1.04; 95% CI, 0.99-1.09). Change in concordance index showed that APRI and Fib4 improved the ability of CTP class and portal hypertension to predict postoperative mortality. <h3>Conclusions and Relevance</h3> Elevated APRI and Fib4 values, which are noninvasive markers of fibrosis, were associated with higher perioperative mortality. The APRI was also associated with worse overall survival. Use of APRI and Fib4 measures improved the ability of established markers to predict postoperative mortality. These findings suggest incorporating APRI and Fib4 to the selection process for hepatectomy for HCC as predictors associated with mortality may be warranted.