Highlights
- •Population-derived estimates of progression risk are essential in estimating the sample size for interventional trials in NAFLD.
- •Among adults with compensated NASH cirrhosis, the risk of progression to decompensation or death is 10% per year.
- •Among adults with first decompensation, the risk of progression to subsequent liver events of death is 32% per year.
- •Trials in compensated cirrhosis would require at least 2,886 participants followed for ≥2 years to detect a ≥15% relative decrease in liver-related endpoints.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: July 14, 2022
Accepted:
July 4,
2022
Received in revised form:
June 26,
2022
Received:
November 23,
2021
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
