Clinical course of non-alcoholic fatty liver disease and the implications for clinical trial design

Abstract

Background & aims: The predicted risk and timeline to progression to liver-related outcomes in the population with NAFLD are not well-characterized. We aimed to examine the risk and time to progression to cirrhosis, hepatic decompensation and death in a contemporary population over a long follow-up period, to obtain information to guide endpoint selection and sample size calculations for clinical trials on NAFLD-related cirrhosis.

Methods: This is a retrospective study of prospectively collected data in a medical record linkage system, including all adults diagnosed with NAFLD between 1996-2016 by clinical, biochemical and radiological criteria in Olmsted County, Minnesota and followed until 2019. Liver-related outcomes and death were ascertained and validated by individual medical record review. Time and risk of progression from NAFLD to cirrhosis to decompensation and death were assessed using multistate modeling.

Results: A total of 5,123 individuals with NAFLD (median age 52 years, 53% women) were followed for a median of 6.4 (range 1-23) years. The risk of progression was as follows: from NAFLD to cirrhosis: 3% in 15 years; compensated cirrhosis to first decompensation: 33% in 4 years (8%/year); first decompensation to ≥2 decompensations: 48% in 2 years. Albumin, bilirubin, non-bleeding esophageal varices and diabetes were independent predictors of decompensation. Among the 575 deaths, 6% were liver related. Therapeutic trials in compensated cirrhosis would require enrolment of a minimum of 2,886 individuals followed for >2 years to detect at least a 15% relative decrease in liver-related endpoints.

Conclusion: In this population-based cohort with 23 years of longitudinal follow-up, NAFLD was slowly progressive, with liver-related outcomes affecting only a small proportion of people. Large sample sizes and long follow-up are required to detect reductions in liver-related endpoints in clinical trials.

Lay summary: For patients with compensated non-alcoholic steatohepatitis-related cirrhosis, the time spent in this state and the risk of progression to decompensation are not well-known in the population. We examined the clinical course of a large population-based cohort over 23 years of follow-up. We identified that adults with compensated cirrhosis spend a mean time of 4 years in this state and have a 10% per year risk of progression to decompensation or death. The risk of further progression is 3-fold higher in adults with cirrhosis and one decompensating event. These results are reflective of placebo arm risks in drug clinical trials and are essential in the estimation of adequate sample sizes.

Keywords: MAFLD; cirrhosis; endpoints; outcomes; progression.

Figure 1.. Study flowchart and algorithm to validate NAFLD cases.

Figure 2.. Time-in-state and transition risk between the following disease states: NAFLD, compensated cirrhosis, first decompensation, two or more decompensating events/liver transplantation and death.

The number of years on the top bar represents the mean time spent in each state (15 years in pre cirrhotic NAFLD, 4 years in compensated cirrhosis, 2 years in cirrhosis with 1 decompensation, and 2 years in a state of 2 or more the compensating events. Individuals entered the pre cirrhotic NAFLD state at the time of diagnosis. Entry into the state of cirrhosis and decompensation occurred either as a transition from previous states or at the time of new diagnosis (top “New diagnosis” arrows) for those who were diagnosed in late stage NAFLD. The horizontal arrows represent cumulative risk of transition to any subsequent disease state after the mean time spent in that state (eg. 3% transitioned from NAFLD to a subsequent state of cirrhosis or decompensation/HCC/liver transplantation (either sequentially or by skipping an intermediate state) after 15 years. Lower vertical arrows illustrate cumulative risk of transition from each disease state directly to death. The results above results are from the multistate model.

Figure 3.. Distribution of outcomes up to 20 years after NAFLD diagnosis.

The colored areas represent the “fate” of participants at each two-year intervals after diagnosis: the proportion of individuals in each of the states of NAFLD alive (orange), alive with cirrhosis/liver transplant (purple), dead after cirrhosis (green), dead without cirrhosis (pink) and those who were diagnosed with other liver disease after NAFLD (including deaths in this state). The proportions of individuals in each state add to 100% at each time interval. At any time frame the proportion of those alive with cirrhosis in the population is 1%. Cumulatively, at 20 years, 50% were alive with NAFLD, 1.1% alive with NASH cirrhosis/LT, 26% were alive or dead after subsequent diagnosis with another liver disease in addition to NAFLD, 19.8% died without cirrhosis and 2.4% died after NASH cirrhosis/LT. The results above are from the multistate model.

Figure 4.. Survival probability in NAFLD (black) compared to expected survival for the Minnesota age-matched population (red).

A. Overall. In reference to the expected (E) Minnesota death rates for a population age 50, those with NAFLD had a higher observed (O) mortality: O/E (95% CI): 1.41 (1.31-1.52), p<0.001 (log-rank test) B. Men and women. In reference to the general population, the observed mortality was proportionally higher in women: O/E (95% CI): 1.52 (1.37-1.69) than men: O/E (95%CI): 1.30 (1.16-1.45), p-value women versus men=0.042 (log-rank test)

Figure 4.. Survival probability in NAFLD (black) compared to expected survival for the Minnesota age-matched population (red).

A. Overall. In reference to the expected (E) Minnesota death rates for a population age 50, those with NAFLD had a higher observed (O) mortality: O/E (95% CI): 1.41 (1.31-1.52), p<0.001 (log-rank test) B. Men and women. In reference to the general population, the observed mortality was proportionally higher in women: O/E (95% CI): 1.52 (1.37-1.69) than men: O/E (95%CI): 1.30 (1.16-1.45), p-value women versus men=0.042 (log-rank test)