肝硬化失代偿期门静脉高压症病理生理及分子机制改变的研究进展

doi:10.3969/j.issn.1674-8115.2024.03.011

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (3): 379-384.doi: 10.3969/j.issn.1674-8115.2024.03.011

• 综述 • 上一篇

肝硬化失代偿期门静脉高压症病理生理及分子机制改变的研究进展

樊强(), 吴广博, 赵劲博, 郑磊, 罗蒙()

上海交通大学医学院附属第九人民医院普外科，上海 201999

收稿日期:2023-10-23 接受日期:2023-12-08 出版日期:2024-03-28 发布日期:2024-04-29
通讯作者: 罗蒙 E-mail:13472665251@163.com;luosh9hospital@sina.com
作者简介:樊强（1984—），男，博士生；电子信箱：13472665251@163.com。
基金资助:
国家自然科学基金青年项目(82100639);国家自然科学基金面上项目(81970526);上海交通大学医学院附属第九人民医院基础研究助推计划种子基金(JYZZ162)

Research progress in pathophysiological and molecular mechanism changes during decompensated phase of portal hypertension in liver cirrhosis

FAN Qiang(), WU Guangbo, ZHAO Jinbo, ZHENG Lei, LUO Meng()

Department of General Surgery, Shanghai Ninth People's hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China

Received:2023-10-23 Accepted:2023-12-08 Online:2024-03-28 Published:2024-04-29
Contact: LUO Meng E-mail:13472665251@163.com;luosh9hospital@sina.com
Supported by:
Youth Project of the National Natural Science Foundation of China(82100639);General Project of the National Natural Science Foundation of China(81970526);Fundamental Research Program Funding of Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine(JYZZ162)

摘要/Abstract

摘要：

多种病因引起的肝硬化可导致门静脉高压症。处于肝硬化失代偿期的门静脉高压症患者预后显著不佳。由多种并发症引起的患者内环境紊乱通常会演变为肝内外器官功能衰竭。对于由不同病因引起的肝硬化，在早期尚可应用一些缓解药物，但目前关于肝硬化失代偿期门静脉高压症患者疾病进展的机制尚不明确，也缺乏针对疾病进展的有效治疗方案。因此，揭示肝硬化失代偿期门静脉高压症的病理生理机制，以及寻找治疗疾病的有效药物靶点，成为当前研究的重点。该文总结了在肝硬化失代偿期肝内外器官衰竭的病理生理改变，简述了肝内血管阻力、门静脉系统、心血管系统及炎症介质等相关细胞分子调节机制。通过全面分析肝硬化失代偿期门静脉高压症的病理生理发展进程，能够更好地理解引起病情恶化或缓解的潜在细胞分子机制，有助于提高疾病的诊断准确性和对疾病分期的正确把握。此外，发现阻断疾病恶化的药物治疗靶点将指导临床工作者更好地应对难治性门静脉高压症，改善患者预后。

关键词: 肝硬化, 门静脉高压症, 病理生理机制, 治疗靶点

Abstract:

Cirrhosis caused by multiple etiologies can lead to portal hypertension. The prognosis of patients with portal hypertension in decompensated cirrhosis is significantly poor. Disorders in the patient′s internal environment caused by various complications often evolve into organ failure both inside and outside the liver. For cirrhosis caused by different etiologies, there are still some relief drugs used in the early stages, but the mechanism of disease progression in patients with decompensated cirrhosis and portal hypertension is currently unclear, and there is a lack of effective treatment plans for disease progression. Therefore, revealing the pathophysiological mechanisms of decompensated cirrhosis with portal hypertension and seeking effective drug targets for treating this disease have become the focus of current research. This article summarizes the pathological and physiological changes of intrahepatic and extrahepatic organ failure during the decompensated phase of liver cirrhosis, and briefly describes the cellular and molecular regulatory mechanisms related to intrahepatic vascular resistance, portal system, cardiovascular system, and inflammatory mediators. By comprehensively analyzing the pathological and physiological development process of decompensated cirrhosis with portal hypertension, the potential cellular and molecular mechanisms that cause disease deterioration or remission can be better understood, which can help improve the accuracy of disease diagnosis and the correct grasp of disease staging. In addition, identifying drug treatment targets to block the progression of the disease will guide clinical staff to better cope with refractory portal hypertension, and even improve the prognosis of patients.

Key words: liver cirrhosis, portal hypertension, pathophysiological mechanism, therapeutic target

中图分类号:

R657.3⁺4

樊强, 吴广博, 赵劲博, 郑磊, 罗蒙. 肝硬化失代偿期门静脉高压症病理生理及分子机制改变的研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(3): 379-384.

FAN Qiang, WU Guangbo, ZHAO Jinbo, ZHENG Lei, LUO Meng. Research progress in pathophysiological and molecular mechanism changes during decompensated phase of portal hypertension in liver cirrhosis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(3): 379-384.

参考文献 50

1	MOREAU R, JALAN R, GINES P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis[J]. Gastroenterology, 2013, 144(7): 1426-1437, 1437.e1-1437.e9.
2	BAJAJ J S, O'LEARY J G, LAI J C, et al. Acute-on-chronic liver failure clinical guidelines[J]. Am J Gastroenterol, 2022, 117(2): 225-252.
3	TREBICKA J, FERNANDEZ J, PAPP M, et al. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology[J]. J Hepatol, 2020, 73(4): 842-854.
4	GUSTOT T, FERNANDEZ J, GARCIA E, et al. Clinical course of acute-on-chronic liver failure syndrome and effects on prognosis[J]. Hepatology, 2015, 62(1): 243-252.
5	BERZIGOTTI A. Advances and challenges in cirrhosis and portal hypertension[J]. BMC Med, 2017, 15(1): 200.
6	BERNARDI M, CARACENI P. Novel perspectives in the management of decompensated cirrhosis[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(12): 753-764.
7	BOSCH J, GROSZMANN R J, SHAH V H. Evolution in the understanding of the pathophysiological basis of portal hypertension: how changes in paradigm are leading to successful new treatments[J]. J Hepatol, 2015, 62(1 Suppl): S121-S130.
8	AMIN A A, ALABSAWY E I, JALAN R, et al. Epidemiology, pathophysiology, and management of hepatorenal syndrome[J]. Semin Nephrol, 2019, 39(1): 17-30.
9	BOSCH J, BERZIGOTTI A, GARCIA-PAGAN J C, et al. The management of portal hypertension: rational basis, available treatments and future options[J]. J Hepatol, 2008, 48(Suppl 1): S68-S92.
10	BOSCH J, IWAKIRI Y. The portal hypertension syndrome: etiology, classification, relevance, and animal models[J]. Hepatol Int, 2018, 12(Suppl 1): 1-10.
11	CERINI F, VILASECA M, LAFOZ E, et al. Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats[J]. J Hepatol, 2016, 64(4): 834-842.
12	GRACIA-SANCHO J, MARRONE G, FERNÁNDEZ-IGLESIAS A. Hepatic microcirculation and mechanisms of portal hypertension[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(4): 221-234.
13	GRACIA-SANCHO J, RUSSO L, GARCÍA-CALDERÓ H, et al. Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver[J]. Gut, 2011, 60(4): 517-524.
14	ALBILLOS A, LLEDÓ J L, ROSSI I, et al. Continuous prazosin administration in cirrhotic patients: effects on portal hemodynamics and on liver and renal function[J]. Gastroenterology, 1995, 109(4): 1257-1265.
15	NAVASA M, CHESTA J, BOSCH J, et al. Reduction of portal pressure by isosorbide-5-mononitrate in patients with cirrhosis. Effects on splanchnic and systemic hemodynamics and liver function[J]. Gastroenterology, 1989, 96(4): 1110-1118.
16	BELLIS L, BERZIGOTTI A, ABRALDES J G, et al. Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis[J]. Hepatology, 2003, 37(2): 378-384.
17	SCHWABL P, BRUSILOVSKAYA K, SUPPER P, et al. The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats[J]. Sci Rep, 2018, 8(1): 9372.
18	BOSCH J, GRACIA-SANCHO J, ABRALDES J G. Cirrhosis as new indication for statins[J]. Gut, 2020, 69(5): 953-962.
19	POSE E, SOLÀ E, LOZANO J J, et al. Treatment with simvastatin and rifaximin restores the plasma metabolomic profile in patients with decompensated cirrhosis[J]. Hepatol Commun, 2022, 6(5): 1100-1112.
20	BOIKE J R, THORNBURG B G, ASRANI S K, et al. North American practice-based recommendations for transjugular intrahepatic portosystemic shunts in portal hypertension[J]. Clin Gastroenterol Hepatol, 2022, 20(8): 1636-1662.e36.
21	SHARPTON S R, LOOMBA R. Emerging role of statin therapy in the prevention and management of cirrhosis, portal hypertension, and HCC[J]. Hepatology, 2023, 78(6): 1896-1906.
22	WIEST R, GROSZMANN R J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough[J]. Hepatology, 2002, 35(2): 478-491.
23	PIZCUETA P, PIQUÉ J M, FERNÁNDEZ M, et al. Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition[J]. Gastroenterology, 1992, 103(6): 1909-1915.
24	TURCO L, REIBERGER T, VITALE G, et al. Carvedilol as the new non-selective beta-blocker of choice in patients with cirrhosis and portal hypertension[J]. Liver Int, 2023, 43(6): 1183-1194.
25	RADWAN H, IBRAHIM O, BADRA G, et al. Effects of adding hypertonic saline solutions and/or etilefrine to standard diuretics therapy in cirrhotic patients with ascites[J]. Eur Rev Med Pharmacol Sci, 2022, 26(18): 6608-6619.
26	ALUKAL J J, JOHN S, THULUVATH P J. Hyponatremia in cirrhosis: an update[J]. Am J Gastroenterol, 2020, 115(11): 1775-1785.
27	ANGELI P, GARCIA-TSAO G, NADIM M K, et al. News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond the International Club of Ascites (ICA) consensus document[J]. J Hepatol, 2019, 71(4): 811-822.
28	POZZI M, CARUGO S, BOARI G, et al. Evidence of functional and structural cardiac abnormalities in cirrhotic patients with and without ascites[J]. Hepatology, 1997, 26(5): 1131-1137.
29	ENGELMANN C, CLÀRIA J, SZABO G, et al. Pathophysiology of decompensated cirrhosis: portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction[J]. J Hepatol, 2021, 75(Suppl 1): S49-S66.
30	HÄUSSINGER D, SCHLIESS F. Pathogenetic mechanisms of hepatic encephalopathy[J]. Gut, 2008, 57(8): 1156-1165.
31	JIMÉNEZ W, RODÉS J. Impaired responsiveness to endogenous vasoconstrictors and endothelium-derived vasoactive factors in cirrhosis[J]. Gastroenterology, 1994, 107(4): 1201-1203.
32	GANDHI K D, TAWEESEDT P T, SHARMA M, et al. Hepatopulmonary syndrome: an update[J]. World J Hepatol, 2021, 13(11): 1699-1706.
33	ARROYO V, ANGELI P, MOREAU R, et al. The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis[J]. J Hepatol, 2021, 74(3): 670-685.
34	CLÀRIA J, STAUBER R E, COENRAAD M J, et al. Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure[J]. Hepatology, 2016, 64(4): 1249-1264.
35	WANG R, TANG R Q, LI B, et al. Gut microbiome, liver immunology, and liver diseases[J]. Cell Mol Immunol, 2021, 18(1): 4-17.
36	BETRAPALLY N S, GILLEVET P M, BAJAJ J S. Gut microbiome and liver disease[J]. Transl Res, 2017, 179: 49-59.
37	WIEST R, CADELINA G, MILSTIEN S, et al. Bacterial translocation up-regulates GTP-cyclohydrolase I in mesenteric vasculature of cirrhotic rats[J]. Hepatology, 2003, 38(6): 1508-1515.
38	TAZI K A, MOREAU R, HERVÉ P, et al. Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up-regulation in cirrhotic rats: role of Akt signaling[J]. Gastroenterology, 2005, 129(1): 303-314.
39	WREE A, MCGEOUGH M D, INZAUGARAT M E, et al. NLRP3 inflammasome driven liver injury and fibrosis: roles of IL-17 and TNF in mice[J]. Hepatology, 2018, 67(2): 736-749.
40	SZABO G, PETRASEK J. Inflammasome activation and function in liver disease[J]. Nat Rev Gastroenterol Hepatol, 2015, 12(7): 387-400.
41	ADEBAYO D, MORABITO V, ANDREOLA F, et al. Mechanism of cell death in acute-on-chronic liver failure: a clinico-pathologic-biomarker study[J]. Liver Int, 2015, 35(12): 2564-2574.
42	LI W B, DENG M H, LOUGHRAN P A, et al. LPS induces active HMGB1 release from hepatocytes into exosomes through the coordinated activities of TLR4 and caspase-11/GSDMD signaling[J]. Front Immunol, 2020, 11: 229.
43	ENGELMANN C, SHEIKH M, SHARMA S, et al. Toll-like receptor 4 is a therapeutic target for prevention and treatment of liver failure[J]. J Hepatol, 2020, 73(1): 102-112.
44	ENGELMANN C, ADEBAYO D, ORIA M, et al. Recombinant alkaline phosphatase prevents acute on chronic liver failure[J]. Sci Rep, 2020, 10(1): 389.
45	BROZ P, DIXIT V M. Inflammasomes: mechanism of assembly, regulation and signalling[J]. Nat Rev Immunol, 2016, 16(7): 407-420.
46	PRAKTIKNJO M, SCHIERWAGEN R, MONTEIRO S, et al. Hepatic inflammasome activation as origin of Interleukin-1α and Interleukin-1β in liver cirrhosis[J]. Gut, 2021, 70(9): 1799-1800.
47	GARCIA-MARTINEZ R, CARACENI P, BERNARDI M, et al. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications[J]. Hepatology, 2013, 58(5): 1836-1846.
48	DOMENICALI M, BALDASSARRE M, GIANNONE F A, et al. Posttranscriptional changes of serum albumin: clinical and prognostic significance in hospitalized patients with cirrhosis[J]. Hepatology, 2014, 60(6): 1851-1860.
49	ALCARAZ-QUILES J, CASULLERAS M, OETTL K, et al. Oxidized albumin triggers a cytokine storm in leukocytes through P38 mitogen-activated protein kinase: role in systemic inflammation in decompensated cirrhosis[J]. Hepatology, 2018, 68(5): 1937-1952.
50	BERNARDI M, ANGELI P, CLARIA J, et al. Albumin in decompensated cirrhosis: new concepts and perspectives[J]. Gut, 2020, 69(6): 1127-1138.

[1]	李倩玉, 郭文韵, 钱逸斐, 李松玲, 朱子俊, 刘艳丰. ASGR1在肝细胞癌中的意义及机制研究[J]. 上海交通大学学报（医学版）, 2023, 43(9): 1107-1114.
[2]	王青, 韩晓, 张晓波. 表观遗传修饰调控肺炎免疫应答的研究进展[J]. 上海交通大学学报（医学版）, 2023, 43(7): 931-938.
[3]	石翠翠, 张洁, 黄鹤鸣, 桑玉尔, 李光明. 肝硬化患者胰岛素抵抗的临床分析[J]. 上海交通大学学报（医学版）, 2023, 43(2): 188-193.
[4]	薛淋淋, 李秉翰, 常丽仙, 李卫昆, 刘春云, 刘立. 丙型病毒性肝炎肝硬化失代偿期患者发生细菌感染的列线图预测模型构建及评价[J]. 上海交通大学学报（医学版）, 2023, 43(1): 52-60.
[5]	张宸溪, 曹竹君, 项晓刚, 谢青, 耿嘉蔚. 人血清白蛋白治疗失代偿期肝硬化的研究进展[J]. 上海交通大学学报（医学版）, 2023, 43(1): 95-100.
[6]	胡婵婵, 范毅, 徐源, 胡志坚, 曾奕明. 脂质代谢在肺癌发生发展及诊疗领域中的研究进展[J]. 上海交通大学学报（医学版）, 2022, 42(12): 1766-1771.
[7]	熊雷, 易茜, 许明芳, 陈健. MRPL12在肺腺癌中的表达和预后分析[J]. 上海交通大学学报(医学版), 2021, 41(8): 1033-1040.
[8]	郑磊，林佳昀，张驰豪，赵治锋，李泓杰，戚晓亮，火海钟#，罗蒙#. 肝硬化门静脉高压症大鼠肠系膜上动脉重构的实验研究[J]. 上海交通大学学报(医学版), 2020, 40(10): 1340-1346.
[9]	宋亚兰，罗玲，张运芝. 肝硬化失代偿期患者并发肠梗阻的临床特点及相关危险因素分析[J]. 上海交通大学学报（医学版）, 2017, 37(7): 993-.
[10]	黄小平，王艳，孙蔚，黄燕，陈丽，甘建和. 失代偿期肝硬化患者血清中前列腺素E2水平对感染的预测价值研究[J]. 上海交通大学学报（医学版）, 2016, 36(7): 992-.
[11]	赵丹，毛华，黄纯炽，等. 乙型肝炎后肝硬化患者食管静脉曲张发生的无创性预测指标研究[J]. 上海交通大学学报（医学版）, 2015, 35(3): 386-.
[12]	谷雷雷，张欣欣. 乙型肝炎肝硬化患者的抗病毒治疗[J]. 上海交通大学学报（医学版）, 2015, 35(11): 1717-.

肝硬化失代偿期门静脉高压症病理生理及分子机制改变的研究进展

Research progress in pathophysiological and molecular mechanism changes during decompensated phase of portal hypertension in liver cirrhosis

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献 50

相关文章 12

编辑推荐

Metrics