Journal of Shanghai Jiao Tong University (Medical Science) >
Research progress in pathophysiological and molecular mechanism changes during decompensated phase of portal hypertension in liver cirrhosis
Received date: 2023-10-23
Accepted date: 2023-12-08
Online published: 2024-03-28
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)
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.
Qiang FAN , Guangbo WU , Jinbo ZHAO , Lei ZHENG , Meng LUO . 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 . DOI: 10.3969/j.issn.1674-8115.2024.03.011
| 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 | H?USSINGER 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. |
/
| 〈 |
|
〉 |