Objective: To explore and analyze the possible mechanism of liver injury in patients with coronavirus disease 2019 (novel coronavirus pneumonia, NCP). Methods: The correlation between ALT, AST and other liver enzyme changes condition and NCP patients' disease status reported in the literature was comprehensively analyzed. ACE2 expression in liver tissue for novel coronavirus was analyzed based on single cell sequencing (GSE115469) data. RNA-Seq method was used to analyze Ace2 expression and transcription factors related to its expression in liver tissues at various time-points after hepatectomy in mouse model of acute liver injury with partial hepatectomy. t-test or Spearman rank correlation analysis was used for statistical analysis. Results: ALT and AST were abnormally elevated in some patients with novel coronavirus infection, and the rate and extent of ALT and AST elevation in severe NCP patients were higher than those in non-severe patients. Liver tissue results of single cell sequencing and immunohistochemistry showed that ACE2 was only expressed in bile duct epithelial cells of normal liver tissues, and very low in hepatocytes. In a mouse model of acute liver injury with partial hepatectomy, Ace2 expression was down-regulated on the first day, but it was elevated up to twice of the normal level on the third day, and returned to normal level on seventh day when the liver recovered and hepatocyte proliferation stopped. Whether this phenomenon suggests that the bile duct epithelial cells with positive expression of Ace2 participate in the process of liver regeneration after partial hepatectomy deserves further study. In RNA-Seq data, 77 transcription factors were positively correlated with the expression of Ace2 (r > 0.2, FDR < 0.05), which were mainly enriched in the development, differentiation, morphogenesis and cell proliferation of glandular epithelial cells. Conclusion: We assumed that in addition to the over activated inflammatory response in patients with NCP, the up-regulation of ACE2 expression in liver tissue caused by compensatory proliferation of hepatocytes derived from bile duct epithelial cells may also be the possible mechanism of liver tissue injury caused by 2019 novel coronavirus infection.
目的： 探索和分析新型冠状病毒感染肺炎（NCP）患者发生肝损伤的可能机制。 方法： 综合分析已报道文献中NCP患者的丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）等肝酶变化情况与疾病状态的相关性；基于肝组织单细胞测序数据（GSE115469）分析新冠病毒受体血管紧张素转换酶2（ACE2）在肝组织中的表达；采用RNA-seq方法分析半肝切除急性肝损伤小鼠模型肝切除后不同时间点残肝组织中Ace2的表达及与其表达相关的转录因子。统计学方法采用t检验和Spearman秩相关分析。 结果： 部分新冠病毒感染者发生了ALT、AST异常升高，且NCP重症患者ALT、AST升高的比率及程度均高于非重症患者。肝组织单细胞测序和免疫组织化学检测结果显示，ACE2在正常肝组织中只在胆管上皮细胞表达，而在肝细胞中表达极低。在小鼠半肝切除急性肝损伤模型中，Ace2在术后第1天的急性损伤期表达下调，但在术后第3天的肝细胞增殖高峰期表达升高至正常水平的2倍以上，并在肝脏恢复、肝细胞增殖停止的第7天恢复到正常水平。这一现象是否提示ACE2表达阳性的胆管上皮细胞参与了部分肝切除后的肝再生过程，值得进一步的研究。RNA-seq数据中有77个转录因子与Ace2表达呈正相关（r > 0.2，FDR < 0.05），主要富集在腺体腔管表皮细胞的发育、分化、形态生成以及细胞增殖等功能。 结论： 除了NCP患者过度激活的炎症反应可导致肝损伤外，胆管上皮细胞来源肝实质细胞的代偿性增生所致病毒受体ACE2在肝组织中的表达上调，可能是新型冠状病毒感染肝细胞造成肝组织损伤的可能机制。.
Keywords: 2019 novel coronavirus (2019-nCoV); ALT; AST; Angiotensin converting enzyme 2 (ACE2); Hepatic regeneration; Liver function; Novel coronavirus pneumonia (NCP); Transcription factor.