Angulo Paul, Kleiner David E, Dam-Larsen Sanne, Adams Leon A, Bjornsson Einar S, Charatcharoenwitthaya Phunchai, Mills Peter R, Keach Jill C, Lafferty Heather D, Stahler Alisha, Haflidadottir Svanhildur, Bendtsen Flemming
Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, Kentucky.
Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland.
Gastroenterology. 2015 Aug;149(2):389-97.e10. doi: 10.1053/j.gastro.2015.04.043. Epub 2015 Apr 29.
BACKGROUND & AIMS: Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD.
We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3-12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination.
Over a median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05-1.08), diabetes (HR, 1.61; 95% CI, 1.13-2.30), current smoking (HR, 2.62; 95% CI, 1.67-4.10), and statin use (HR, 0.32; 95% CI, 0.14-0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis.
In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.
肝活检标本的组织学分析可用于非酒精性脂肪性肝病（NAFLD）的分级和分期。我们进行了一项纵向研究，以探讨组织学特征对NAFLD患者的长期预后相关性。
我们对1975年至2005年期间在美国、欧洲和泰国医疗中心诊断为NAFLD的619例患者进行了回顾性分析。患者接受了实验室和活检分析，并在诊断后每3 - 12个月接受检查。分析的结局包括全因死亡率、肝移植和肝脏相关事件。通过对数秩分析比较累积结局。采用Cox比例风险回归来估计调整后的风险比（HRs）。风险时间从肝活检日期确定至结局日期或最后一次随访检查日期。
在中位随访期12.6年（范围0.3 - 35.1年）内，193例患者（33.2%）死亡或接受了肝移植。与死亡或肝移植显著相关的肝活检特征包括与0期相比的纤维化1期（HR，1.88；95%置信区间[CI]，1.28 - 2.77）、2期（HR，2.89；95% CI，1.93 - 4.33）、3期（HR，3.76；95% CI，2.40 - 5.89）和4期（HR，10.9；95% CI，6.06 - 19.62），以及年龄（HR，1.07；95% CI，1.05 - 1.08）、糖尿病（HR，1.61；95% CI，1.13 - 2.30）、当前吸烟（HR，2.62；95% CI，1.67 - 4.10）和使用他汀类药物（HR，0.32；95% CI，0.14 - 0.70）。26例患者（4.2%）发生了肝脏相关事件；与0期相比，纤维化3期（HR，14.2；95% CI，3.38 - 59.68）和4期（HR，51.5；95% CI，9.87 - 269.2）与这些事件显著相关。无论是否有脂肪性肝炎或NAFLD活动评分，有纤维化的患者的生存时间均短于无纤维化的患者。
在一项对NAFLD患者的纵向研究中，纤维化分期而非脂肪性肝炎的其他组织学特征与长期全因死亡率、肝移植和肝脏相关事件独立相关。
