Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
Division of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States.
J Hepatol. 2022 Nov;77(5):1237-1245. doi: 10.1016/j.jhep.2022.07.004. Epub 2022 Jul 16.
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.
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.
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.
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.
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.
非酒精性脂肪性肝病（NAFLD）人群中，与肝脏相关结局相关的预测风险和进展时间尚不清楚。我们旨在通过长期随访，检查当代人群中从非酒精性脂肪性肝病到肝硬化、肝失代偿和死亡的风险和进展时间，为非酒精性脂肪性肝病相关肝硬化的临床试验选择终点和样本量计算提供信息。
这是一项回顾性研究，对明尼苏达州奥姆斯特德县的医疗记录链接系统中前瞻性收集的数据进行了研究，该系统包括 1996 年至 2016 年间通过临床、生化和影像学标准诊断为非酒精性脂肪性肝病的所有成年人，并随访至 2019 年。通过单独的医疗记录审查确定和验证与肝脏相关的结局和死亡。使用多状态建模评估从非酒精性脂肪性肝病进展为肝硬化、肝失代偿和死亡的时间和风险。
共有 5123 名非酒精性脂肪性肝病患者（中位年龄 52 岁，53%为女性）接受了中位 6.4 年（范围 1-23 年）的随访。进展风险如下：从非酒精性脂肪性肝病到肝硬化：15 年内 3%；代偿性肝硬化至首次失代偿：4 年内 33%（8%/年）；首次失代偿至≥2 次失代偿：2 年内 48%。白蛋白、胆红素、无出血性食管静脉曲张和糖尿病是非失代偿的独立预测因素。在 575 例死亡中，6%与肝脏有关。在代偿性肝硬化的治疗性试验中，需要招募至少 2886 名随访>2 年的个体，以检测至少 15%的相对减少与肝脏相关的终点。
在这项具有 23 年纵向随访的基于人群的队列研究中，非酒精性脂肪性肝病进展缓慢，只有一小部分患者出现与肝脏相关的结局。为了在临床试验中检测与肝脏相关终点的减少，需要进行大样本量和长期随访。
非酒精性脂肪性肝病（NAFLD）患者的肝脏相关结局对人群的影响较小，而对于代偿性非酒精性脂肪性肝炎相关肝硬化患者，处于该状态的时间和进展为失代偿的风险在人群中尚不清楚。我们研究了一个大型基于人群的队列超过 23 年的临床病程。我们发现，代偿性肝硬化患者平均需要 4 年时间才能达到这种状态，每年有 10%的风险进展为失代偿或死亡。肝硬化和一次失代偿事件的进一步进展风险增加了 3 倍。这些结果反映了药物临床试验安慰剂组的风险，对估计适当的样本量至关重要。
