Hepatology Laboratory, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
Scottish National Blood Transfusion Service, Jack Copland Centre, Edinburgh EH14 4BE, United Kingdom.
World J Gastroenterol. 2024 Aug 21;30(31):3705-3716. doi: 10.3748/wjg.v30.i31.3705.
Metabolic dysfunction-associated steatotic liver disease (MASLD), characterised by hepatic lipid accumulation, causes inflammation and oxidative stress accompanied by cell damage and fibrosis. Liver injury (LI) is also frequently reported in patients hospitalised with coronavirus disease 2019 (COVID-19), while pre-existing MASLD increases the risk of LI and the development of COVID-19-associated cholangiopathy. Mechanisms of injury at the cellular level remain unclear, but it may be significant that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19, uses angiotensin-converting expression enzyme 2 (ACE2), a key regulator of the 'anti-inflammatory' arm of the renin-angiotensin system, for viral attachment and host cell invasion.
To determine if hepatic ACE2 levels are altered during progression of MASLD and in patients who died with severe COVID-19.
ACE2 protein levels and localisation, and histological fibrosis and lipid droplet accumulation as markers of MASLD were determined in formalin-fixed liver tissue sections across the MASLD pathological spectrum (isolated hepatocellular steatosis, metabolic dysfunction-associated steatohepatitis (MASH) +/- fibrosis, end-stage cirrhosis) and in post-mortem tissues from patients who had died with severe COVID-19, using ACE2 immunohistochemistry and haematoxylin and eosin and picrosirius red staining of total collagen and lipid droplet areas, followed by quantification using machine learning-based image pixel classifiers.
ACE2 staining is primarily intracellular and concentrated in the cytoplasm of centrilobular hepatocytes and apical membranes of bile duct cholangiocytes. Strikingly, ACE2 protein levels are elevated in non-fibrotic MASH compared to healthy controls but not in the progression to MASH with fibrosis and in cirrhosis. ACE2 protein levels and histological fibrosis are not associated, but ACE2 and liver lipid droplet content are significantly correlated across the MASLD spectrum. Hepatic ACE2 levels are also increased in COVID-19 patients, especially those showing evidence of LI, but are not correlated with the presence of SARS-CoV-2 virus in the liver. However, there is a clear association between the hepatic lipid droplet content and the presence of the virus, suggesting a possible functional link.
Hepatic ACE2 levels were elevated in nonfibrotic MASH and COVID-19 patients with LI, while lipid accumulation may promote intra-hepatic SARS-CoV-2 replication, accelerating MASLD progression and COVID-19-mediated liver damage.
代谢相关脂肪性肝病（MASLD）的特征是肝内脂质蓄积，引起炎症和氧化应激，伴有细胞损伤和纤维化。在因 2019 年冠状病毒病（COVID-19）住院的患者中也经常报告肝损伤（LI），而预先存在的 MASLD 增加了 LI 和 COVID-19 相关胆管病的发展风险。细胞水平的损伤机制尚不清楚，但可能很重要的是，引起 COVID-19 的严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）使用血管紧张素转换酶 2（ACE2）作为肾素-血管紧张素系统“抗炎”分支的关键调节剂，用于病毒附着和宿主细胞入侵。
确定 MASLD 进展过程中肝 ACE2 水平是否发生改变，以及在因 COVID-19 而死亡的患者中是否发生改变。
使用 ACE2 免疫组织化学和苏木精和伊红以及总胶原和脂质滴面积的苦味酸红染色，以及使用基于机器学习的图像像素分类器进行定量，在 MASLD 病理谱（孤立性肝细胞脂肪变性、代谢相关脂肪性肝炎（MASH） +/-纤维化、终末期肝硬化）的福尔马林固定肝组织切片以及因 COVID-19 而死亡的患者的死后组织中，确定 ACE2 蛋白水平和定位以及组织学纤维化和脂质滴积聚作为 MASLD 的标志物。
ACE2 染色主要为细胞内，集中在中央小叶肝细胞的细胞质和胆管胆管细胞的顶膜中。引人注目的是，与健康对照组相比，非纤维化 MASH 中的 ACE2 蛋白水平升高，但在进展为纤维化的 MASH 中以及在肝硬化中则没有升高。ACE2 蛋白水平与组织学纤维化无关，但 ACE2 与肝内脂质滴含量在 MASLD 谱中呈显著相关。COVID-19 患者的肝 ACE2 水平也升高，尤其是那些有 LI 证据的患者，但与肝内 SARS-CoV-2 病毒的存在无关。然而，肝内脂质滴含量与病毒的存在之间存在明显关联，表明可能存在功能联系。
非纤维化 MASH 和 COVID-19 伴有 LI 的患者中肝 ACE2 水平升高，而脂质蓄积可能促进肝内 SARS-CoV-2 复制，加速 MASLD 进展和 COVID-19 介导的肝损伤。
