Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification

Abstract

Background & aims: Hepatocellular carcinoma (HCC) risk varies dramatically in patients with cirrhosis according to well-described, readily available predictors. We aimed to develop simple models estimating HCC risk in patients with alcohol-related liver disease (ALD)-cirrhosis or non-alcoholic fatty liver disease (NAFLD)-cirrhosis and calculate the net benefit that would be derived by implementing HCC surveillance strategies based on HCC risk as predicted by our models.

Methods: We identified 7,068 patients with NAFLD-cirrhosis and 16,175 with ALD-cirrhosis who received care in the Veterans Affairs (VA) healthcare system in 2012. We retrospectively followed them for the development of incident HCC until January 2018. We used Cox proportional hazards regression to develop and internally validate models predicting HCC risk using baseline characteristics at entry into the cohort in 2012. We plotted decision curves of net benefit against HCC screening thresholds.

Results: We identified 1,278 incident cases of HCC during a mean follow-up period of 3.7 years. Mean annualized HCC incidence was 1.56% in NAFLD-cirrhosis and 1.44% in ALD-cirrhosis. The final models estimating HCC were developed separately for NAFLD-cirrhosis and ALD-cirrhosis and included 7 predictors: age, gender, diabetes, body mass index, platelet count, serum albumin and aspartate aminotransferase to √alanine aminotransferase ratio. The models exhibited very good measures of discrimination and calibration and an area under the receiver operating characteristic curve of 0.75 for NAFLD-cirrhosis and 0.76 for ALD-cirrhosis. Decision curves showed higher standardized net benefit of risk-based screening using our prediction models compared to the screen-all approach.

Conclusions: We developed simple models estimating HCC risk in patients with NAFLD-cirrhosis or ALD-cirrhosis, which are available as web-based tools (www.hccrisk.com). Risk stratification can be used to inform risk-based HCC surveillance strategies in individual patients or healthcare systems or to identify high-risk patients for clinical trials.

Lay summary: Patients with cirrhosis of the liver are at risk of getting hepatocellular carcinoma (HCC or liver cancer) and therefore it is recommended that they undergo surveillance for HCC. However, the risk of HCC varies dramatically in patients with cirrhosis, which has implications on if and how patients get surveillance, how providers counsel patients about the need for surveillance, and how healthcare systems approach and prioritize surveillance. We used readily available predictors to develop models estimating HCC risk in patients with cirrhosis, which are available as web-based tools at www.hccrisk.com.

Keywords: Cirrhosis; HCC; Liver cancer; NAFLD; Non-alcoholic fatty liver disease; Risk model; Surveillance.

Conflict of interest statement

Declaration of Personal Conflicts of Interests

None

Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Figures

Figure 1.. Cumulative incidence curves showing the probability of developing HCC in a cohort of patients followed from 2012 to 2018, plotted by

a. Etiology of cirrhosis (ALD vs. NAFLD) and b. FIB-4 score >3.25 or ≤3.25. c. Table showing the incidence of HCC in this population by cirrhosis etiology and FIB-4 score

Figure 2.. Predicted vs observed cumulative incidence of HCC based on predictive models developed for a. ALDcirrhosis; b. NAFLD-cirrhosis and c. ALD or NAFLD-cirrhosis.

Patients in each subgroup are divided into thirds (low, medium and high) based on the predicted risk. The plots show excellent overlap between observed and predicted cumulative incidence.

Figure 3.. Decision curves comparing the standardized net benefit achieved by screening based on HCC risk predicted by the model (i.e. screening only patients who exceed a certain threshold probability – blue line) to the “screen-all” (green line) or “screen-none” (orange line) strategies.

The vertical axis shows standardized net benefit, which is the proportion of total possible net benefit and would be achieved by a risk model with 100% sensitivity and specificity. The horizontal axis shows different 5-year HCC risk thresholds that might be used to recommend screening. For example, the AASLD recommends screening when annual HCC risk exceeds 1.5% in patients with cirrhosis, or 5-year risk exceeds 7.5%, marked with a vertical dotted line. The Figures illustrate that the net benefit of screening based on our models (blue line) is greater than the net benefit of the “screen-all” strategy (green line), for both patient groups. The Figures also show that for a wide range of plausible screening thresholds the risk model-based screening has superior standardized net benefit than the screen-all strategy.

Figure 4.. HCC risk stratification using prediction models.

Risk estimation models can be used to stratify risk in patients. Outreach efforts to improve screening uptake, future screening strategies and clinical trials can utilize the categorization of patients into low, medium and high-risk categories.