Progress in Etiology and Pathogenesis of Liver Fibrosis
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摘要: 肝纤维化（hepatic fibrosis，HF）是由遗传相关疾病、慢性病毒性肝炎、酒精性肝炎、胆汁淤积和药物性肝损伤等多种慢性肝病引起的过度修复反应产生多种细胞外基质（extracellular matrix,ECM）的异常沉积的结果。肝纤维化的发生发展机制和肝星状细胞（hepatic stellate cells，HSC）、肝巨噬细胞、内质网应激（endoplasmic reticulum stress，ERs）和自噬等有关。肝脏的纤维化是一个动态发展过程，在没有干预的情况下会继续发展成为肝硬化，甚至发展为肝细胞癌。因此，延缓或者逆转肝纤维化的发生具有非常重要的临床意义。对肝纤维化病因和发生发展机制总结，为抗肝纤维化的药物研究提供参考。Abstract: Liver fibrosis （HF） is the result of abnormal deposition of various extracellular matrix （ECM） caused by the over-repair response of various chronic liver diseases, such as genetic-related diseases, chronic viral hepatitis, alcoholic hepatitis, cholestasis and drug-induced liver injury. The pathogenesis of hepatic fibrosis is related to hepatic stellate cell （HSC）, hepatic macrophage, endoplasmic reticulum stress （ERs） and autophagy. Liver fibrosis is a dynamic process that can progress to cirrhosis or even hepatocellular carcinoma without intervention. Therefore, delaying or reversing the occurrence of liver fibrosis has very important clinical significance. The purpose of this review is to summarize the etiology, occurrence and development mechanism of liver fibrosis and provide a reference for the research of anti-liver fibrosis drugs.
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Key words:
- Liver fibrosis /
- Etiology /
- Hepatic stellate cell /
- Endoplasmic reticulum stress
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表 1 遗传相关因素导致肝纤维化
Table 1. Liver fibrosis due to genetically related factors
疾病名称 基因 基因功能 组织损伤的原因 相关临床表现 进行性家族性肝内胆汁淤积症3型 ABCB4 胆汁磷脂分泌 磷脂和其他外来物质的堆积；胆汁淤积的损害 表现在儿童早期，黄疸，脾肿大，门静脉高压和身心发育迟缓 威尔逊病 ATP7B 铜离子运输 肝内Cu2+蓄积 可无症状或伴有纤维化、急性肝炎、终末期肝病 阿尔斯特伦综合征 ALMS1 中心体和基底相关
蛋白：微管组织发病机制不明：可能与细胞内钙信号有关 多器官功能障碍：肝脏受累可从脂肪性肝炎到门脉高压症和肝硬化，并可导致肝性脑病和危及生命的食管静脉曲张 遗传性果糖不耐受 ALDOB 将果糖转化为三糖，
进入糖酵解和糖异生1-磷酸果糖的积累和无机磷水平的耗尽，抑制糖原分解 遗传性果糖不耐受、肝毒性、肝功能障碍进展为肝硬化 糖原沉积病IV型 GBE1 糖原分支酶 积累无支链糖原引起肝毒性 典型的肝病表现包括肝功能不全、进展为肝硬化、5岁前不能正常生长。非进行性肝亚型表现为肝肿大、肝功能不全、肌病和低眼压；但可能存活，不会进一步发展为肝硬化。 酪氨酸血症I型 FAH 酪氨酸分解代谢的
最后一步富马酸乙酰乙酯和酪氨酸在肝细胞中的蓄积及其对细胞的氧化损伤 表现为肝或肾功能衰竭；在婴儿期早期；与肝脏相关的症状是低白蛋白血症，肝脏合成功能降低，导致脂肪变性、肝硬化和肝细胞癌 精氨酸琥珀酸裂解酶缺乏症 ASL 将精氨酸琥珀酸分解成
精氨酸和琥珀酸的
尿素循环酶尿素循环中间产物，特别是氨的积累 两种形式：婴儿期早发伴有高氨血症和呕吐，发育迟缓，或晚发性高氨血症发作，肝硬化和神经系统症状 柠檬酸缺乏症 SLC25A13 钙结合线粒体载体蛋白Aralar2（细胞质谷氨酸与线粒体天冬氨酸通过线粒体内膜交换） 瓜氨酸血症与氨蓄积 新生儿肝内胆汁淤积：胆汁淤积，纤维化，肝硬化；迟发性瓜氨酸血症2：神经精神症状 非酒精性脂肪性肝病（NAFLD） PNPLA3 甘油三酯脂肪酶和视黄酸酯酶活性的多效性作用 甘油三酯蓄积、维甲酸受体信号转导受损及HSC纤维化通路激活 肝脏脂肪变性、纤维化、肝硬化、肝细胞癌 
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