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Abstract Details
Clinical course of non-alcoholic fatty liver disease and the implications for clinical trial design
J Hepatol. 2022 Jul 14;S0168-8278(22)02936-1. doi: 10.1016/j.jhep.2022.07.004.Online ahead of print.
1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. Electronic address: Allen.Alina@mayo.edu.
2Division of Quantitative Health Sciences, Mayo Clinic, Rochester, MN. Electronic address: Therneau@mayo.edu.
3Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. Electronic address: Dr.OmarTahmed@gmail.com.
4Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. Electronic address: TolgaGidener@gmail.com.
5Division of Quantitative Health Sciences, Mayo Clinic, Rochester, MN. Electronic address: Mara.Kristin@mayo.edu.
6Division of Quantitative Health Sciences, Mayo Clinic, Rochester, MN. Electronic address: Larson.Joseph@mayo.edu.
7Division of Quantitative Health Sciences, Mayo Clinic, Rochester, MN. Electronic address: canning.rachel@mayo.edu.
8Division of Quantitative Health Sciences, Mayo Clinic, Rochester, MN. Electronic address: benson.joanne@mayo.edu.
9Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. Electronic address: kamath.patrick@mayo.edu.
Abstract
Background and aims: The predicted risk and timeline to progression to liver outcomes in NAFLD are not well-characterized in the population. We aimed to examine the risk and time to progression to cirrhosis, hepatic decompensation and death in a contemporary population with long follow-up, in order to inform effectiveness endpoints and sample calculations in clinical trials of 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 5123 NAFLD individuals (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 two or more: 47% 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 minimum enrollment criteria of 2,886 subjects followed over 2 years to detect at least 15% relative decrease in liver 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. Reduction in liver related endpoints in clinical trials require large sample sizes and long follow-up.
Lay summary: For patients with compensated NASH 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 cirrhosis or death. The risk is three-fold higher in adults with cirrhosis and one decompensation. These results are reflective of placebo arm risks in drug clinical trials and are essential in the estimation of adequate sample sizes.