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

      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

      Keywords

      Linked Article

      • Portal hypertension is a key determinant of the risk for liver-related events in non-alcoholic fatty liver disease
        Journal of Hepatology
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          Studies on the natural history of non-alcoholic fatty liver disease (NAFLD) are crucial for the understanding of the specific risk of developing NAFLD-related complications. Hence, the study by Allen AM et al.1 describing the clinical course of 5,123 patients with NAFLD over a median follow-up time of 6.4 years is a valuable contribution to the field. When drawing conclusions, especially on the expected disease course, it is, however, important to reflect on the specific characteristics of the respective patient cohort from which results have been obtained.
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      • NASH cirrhosis trials and major adverse liver outcomes: Big data needed
        Journal of HepatologyVol. 78Issue 1
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          Although non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease and cirrhosis, approved therapies for NAFLD are not yet accessible.1,2 The NAFLD spectrum is distributed into 1) non-alcoholic fatty liver (NAFL or steatosis); 2) the progressive form, non-alcoholic steatohepatitis (NASH); and 3) NAFLD or NASH with various stages of fibrosis (F0–F4).3,4 Natural history studies have informed us about the histological progression and regression of this disease.
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