Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
Pathology. 2022 Oct;54(6):686-693. doi: 10.1016/j.pathol.2022.01.009. Epub 2022 May 5.
The significance of portal tract histological changes in non-alcoholic fatty liver disease (NAFLD) remains unclear. In 2019, CymaBay Therapeutics halted clinical trials of seladelpar (a PPARδ agonist) because initial end-of-treatment liver biopsies of patients with non-alcoholic steatohepatitis (NASH) showed concerning features of portal inflammation with plasma cells, interface hepatitis and focal bile duct abnormalities. Adjudication concluded that these findings were present in the initial, as well as the subsequent biopsies. Thus, this study's aim was to determine the prevalence and clinical significance of portal inflammation, portal plasma cells, interface hepatitis and features of bile duct damage in liver biopsies of adult patients with NAFLD. The pathology database was searched for cases of NAFLD, including steatosis alone and NASH, from January 2016 to October 2020. Liver biopsies were selected from age and sex matched adult patients with diagnoses of steatosis alone (n=10), NASH fibrosis stage 1 (n=10), stage 2 (n=10), stage 3 (n=10), and stage 4 (n=10). There were 24 males and 26 females with a mean age of 48 years (range 20-79). Exclusion criteria included age <18 years, daily alcohol intake >14 drinks per week, elevation of alkaline phosphatase level, comorbid chronic liver disease, or liver biopsy performed as part of a clinical trial for NASH. Control liver biopsies were selected from age and sex matched persons without significant steatosis and normal liver biochemical tests (n=10). Histological parameters were evaluated in 10 portal tracts or 10 septal areas in each liver biopsy. Portal inflammation and interface hepatitis were graded on a scale of 0-4. Portal plasma cells and bile duct damage were scored from 0-3. Ductular proliferation was assessed by CK7 immunostain and graded from 0-4. NASH biopsies with advanced fibrosis (stage 3 and 4) showed portal inflammatory infiltrates (score 2-3) with readily identifiable plasma cells (score 2), and mild to moderate interface hepatitis (score 2-3). All cases and controls showed focal, mild cholangiocyte changes, characterised by cytoplasmic vacuolation, segmental loss of nuclei, nuclear disarray and apoptosis. NASH patients with advanced fibrosis had frequent and diffuse cholangiocyte changes, along with focal lymphocytic cholangitis and moderate to marked ductular reaction (score 3-4). Histopathological features of advanced NASH frequently include increased portal inflammation with plasma cells, interface hepatitis, cholangiocyte injury and prominent ductular reaction.
非酒精性脂肪性肝病 (NAFLD) 中门管区组织学变化的意义尚不清楚。2019 年，CymaBay Therapeutics 停止了 seladelpar（PPARδ 激动剂）的临床试验，因为最初接受非酒精性脂肪性肝炎 (NASH) 治疗的患者的肝活检显示出具有浆细胞、界面肝炎和局灶性胆管异常的门管区炎症的令人担忧的特征。裁决结论认为，这些发现存在于最初的活检以及随后的活检中。因此，本研究旨在确定成人 NAFLD 患者肝活检中门管区炎症、门管区浆细胞、界面肝炎和胆管损伤特征的患病率和临床意义。从 2016 年 1 月至 2020 年 10 月，在病理数据库中搜索了包括单纯性脂肪变性和 NASH 在内的 NAFLD 病例。从年龄和性别匹配的单纯性脂肪变性患者（n=10）、NASH 纤维化 1 期（n=10）、2 期（n=10）、3 期（n=10）和 4 期（n=10）中选择肝活检。共有 24 名男性和 26 名女性，平均年龄为 48 岁（范围 20-79 岁）。排除标准包括年龄<18 岁、每周饮酒>14 杯、碱性磷酸酶水平升高、合并慢性肝病或作为 NASH 临床试验一部分进行的肝活检。选择年龄和性别匹配的无明显脂肪变性和正常肝功能试验的人员的对照肝活检（n=10）。在每个肝活检中评估 10 个门管区或 10 个间隔区的组织学参数。门管区炎症和界面肝炎按 0-4 级评分。门管区浆细胞和胆管损伤评分 0-3。通过 CK7 免疫染色评估小管增生，并按 0-4 级评分。伴有晚期纤维化（3 期和 4 期）的 NASH 活检显示门管区炎症浸润（评分 2-3），伴有易于识别的浆细胞（评分 2）和轻度至中度界面肝炎（评分 2-3）。所有病例和对照组均显示局灶性、轻度胆管细胞变化，特征为细胞质空泡化、核片段缺失、核排列紊乱和细胞凋亡。伴有晚期纤维化的 NASH 患者常伴有弥漫性胆管细胞变化、局灶性淋巴细胞性胆管炎和中度至显著的小管反应（评分 3-4）。晚期 NASH 的组织病理学特征常包括门管区炎症伴浆细胞增多、界面肝炎、胆管细胞损伤和明显的小管反应。
