BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but identifying patients with increased risk of mortality and liver-specific morbidity remains a challenge. Non-alcoholic steatohepatitis (NASH) is thought to enhance this risk; therefore, resolution of NASH is a major endpoint in current pharmacologic studies. Herein, we aim to investigate the long-term prognosis of a large cohort of NAFLD patients, and to study the specific effect of NASH and fibrosis stage on prognosis. METHODS We conducted a retrospective cohort study of 646 biopsy-proven NAFLD patients. Each case was matched for age, sex and municipality to ten controls. Outcomes on mortality and severe liver disease, defined as cirrhosis, liver decompensation/failure or hepatocellular carcinoma, were evaluated using population-based registers. Cox regression models adjusted for age, sex and type 2 diabetes were used to examine the long-term risk according to fibrosis stage. Likelihood ratio tests were used to assess whether adding NASH to these models increased the predictive capacity. Laplace regression was used to estimate the time to severe liver disease according to stage of fibrosis. RESULTS During a follow-up of mean 20years (range 0-40) equivalent to 139,163 person-years, 12% of NAFLD patients and 2.2% of controls developed severe liver disease (p<0.001). Compared to controls, the risk of severe liver disease increased per stage of fibrosis (hazard ratio ranging from 1.9 in F0 to 104.9 in F4). Accounting for the presence of NASH did not change these estimates significantly (likelihood ratio test >0.05 for all stages of fibrosis). Similar results were seen for overall mortality. The lower end of the 95% confidence interval for the 10th percentile of time to development of severe liver disease was 22-26years in F0-1, 9.3years in F2, 2.3years in F3, and 0.9years to liver decompensation in F4. CONCLUSIONS In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. LAY SUMMARY Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but reaching an accurate prognosis remains challenging. We investigate the long-term prognosis of a large cohort of NAFLD patients. In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions.

中文翻译：

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在活检证实的 NAFLD 中，纤维化阶段而不是 NASH 可预测死亡率和严重肝病发展的时间

背景和目的 非酒精性脂肪性肝病 (NAFLD) 在一般人群中非常常见，但识别死亡率和肝脏特异性发病率风险增加的患者仍然是一个挑战。非酒精性脂肪性肝炎 (NASH) 被认为会增加这种风险；因此，NASH 的消退是当前药理学研究的主要终点。在此，我们旨在调查大量 NAFLD 患者的长期预后，并研究 NASH 和纤维化分期对预后的具体影响。方法 我们对 646 名经活检证实的 NAFLD 患者进行了回顾性队列研究。每个病例在年龄、性别和城市方面与 10 个对照相匹配。死亡率和严重肝病的结果，定义为肝硬化、肝功能失代偿/衰竭或肝细胞癌，使用基于人口的登记册进行评估。针对年龄、性别和 2 型糖尿病进行调整的 Cox 回归模型用于根据纤维化阶段检查长期风险。似然比测试用于评估将 NASH 添加到这些模型中是否会增加预测能力。拉普拉斯回归用于根据纤维化阶段估计严重肝病的时间。结果 在平均 20 年（0-40 年）相当于 139,163 人年的随访期间，12% 的 NAFLD 患者和 2.2% 的对照组发生了严重的肝病（p<0.001）。与对照组相比，每个纤维化阶段发生严重肝病的风险都会增加（风险比从 F0 的 1.9 到 F4 的 104.9）。考虑到 NASH 的存在并没有显着改变这些估计值（似然比检验 > 0。05 适用于纤维化的所有阶段）。总体死亡率也有类似的结果。发生严重肝病的时间的第 10 个百分位数的 95% 置信区间的下限在 F0-1 中为 22-26 年，在 F2 中为 9.3 年，在 F3 中为 2.3 年，在 F4 中为 0.9 年至肝功能失代偿。结论 在这项有史以来最大规模的活检证实 NAFLD 研究中，NASH 的存在并未增加肝脏特异性发病率或总体死亡率的风险。根据纤维化阶段对严重肝病发展时间的了解可用于个体患者咨询和公共卫生决策。概述 非酒精性脂肪性肝病 (NAFLD) 在一般人群中非常常见，但要达到准确的预后仍然具有挑战性。我们调查了大量 NAFLD 患者的长期预后。在这项有史以来最大规模的活检证实 NAFLD 研究中，NASH 的存在并未增加肝脏特异性发病率或总体死亡率的风险。根据纤维化阶段对严重肝病发展时间的了解可用于个体患者咨询和公共卫生决策。