肝肺综合征研究进展
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摘要
肝肺综合征(hepato-pulmonary syndrome,HPS)是在慢性肝病和(或)门脉高压的基础上出现肺内血管异常扩张、气体交换障碍、动脉血氧合作用异常,导致低氧血症及一系列的病理生理变化和临床表现,是终末期肝脏病的严重肺部并发症。动物实验表明肺微血管扩张、血管新生和血管内单核巨噬细胞聚集是导致气体交换异常的主要原因,但具体机制仍不明确。目前HPS尚缺乏有效的治疗药物,肝移植仍是最有效的治疗方法。本研究将重点讨论HPS的发病机制和临床诊治相关的新进展。
Hepato-pulmonary syndrome(HPS)is a severe pulmonary complication of the end-stage liver disease,based on chronic liver disease and/or portal hypertension,pulmonary vascular dilatation,gas exchange disorder,and arterial oxygenation abnormality occur,resulting in hypoxemia and a series of pathophysiological changes and clinical manifestations.Animal experiments have revealed that pulmonary microvascular dilatation,angiogenesis,and accumulation of intravascular mononuclear macrophages were the main causes of gas exchange abnormality,but the specific mechanism is still unclear.HPS is lack of effective drug treatment,and liver transplantation is the only effective therapy.In this review,we focus on the recent advances in pathogenesis,clinical diagnosis and treatment of HPS.
Hepato-pulmonary syndrome(HPS)is a severe pulmonary complication of the end-stage liver disease,based on chronic liver disease and/or portal hypertension,pulmonary vascular dilatation,gas exchange disorder,and arterial oxygenation abnormality occur,resulting in hypoxemia and a series of pathophysiological changes and clinical manifestations.Animal experiments have revealed that pulmonary microvascular dilatation,angiogenesis,and accumulation of intravascular mononuclear macrophages were the main causes of gas exchange abnormality,but the specific mechanism is still unclear.HPS is lack of effective drug treatment,and liver transplantation is the only effective therapy.In this review,we focus on the recent advances in pathogenesis,clinical diagnosis and treatment of HPS.
引文
[1] RAEVENSS, GEETSA, VANSC, etal.Hepatopulmonarysyndromeandportopulmonary hypertension:recent knowledge in pathogenesis and overview of clinical assessment[J]. Liver Int,2015,35(6):1646-1660.
[2] KROWKA M J,FALLON M B,KAWUT S M,et al.International liver transplant society practice guidelines:diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension[J].Transplantation,2016,100(7):1440-1452.
[3] ZHANG J,FALLON M B.Hepatopulmonary syndrome:update on pathogenesis and clinical features[J].Nat Rev Gastroenterol Hepatol,2012,9(9):539-549.
[4] SOULAIDOPOULOSS, CHOLONGITASE,GIANNAKOULAS G,et al.Review article:update on current and emergent data on hepatopulmonary syndrome[J].World J Gastroenterol,2018,24(12):1285-1298.
[5] LI T H,LEE P C,LEE K C,et al.Down-regulation of common NFκB-iNOS pathway by chronic thalidomide treatment improves hepatopulmonary syndrome and muscle wasting in rats with biliary cirrhosis[J].Sci Rep,2016,6:39405.
[6] HE J, YI B, CHEN Y, et al. The ET-1-mediated carbonylationanddegradationofANXA1 induce inflammatory phenotype and proliferation of pulmonary artery smooth muscle cells in HPS[J].PloS one,2017,12(4):e0175443.
[7] YI B,ZENG J, WANG G,et al.Annexin A1 protein regulates the expression of PMVEC cytoskeletal proteins in CBDL rat serum-induced pulmonary microvascular remodeling[J].J Transl Med,2013,11:98.
[8] ROBERTS K E,KAWUT S M,KROWKA M J,et al.Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease[J].Gastroenterology,2010,139(1):130-139.
[9] FERNANDEZ M,MEJIAS M,GARCIA-PRAS E,et al.Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats[J].Hepatology,2007,46(4):1208-1217.
[10] LIU C,GAO J,CHEN B,et al.Cyclooxygenase-2promotes pulmonaryintravascularmacrophageaccumulationby exacerbatingBMPsignalinginratexperimental hepatopulmonary syndrome[J].Biochem Pharmacol,2017,138:205-215.
[11] WU W,ZHANG J,YANG W,et al.Role of splenic reservoir monocytes in pulmonary vascular monocyte accumulation in experimental hepatopulmonary syndrome[J].J Gastroenterol Hepatol,2016,31(11):1888-1894.
[12] LI X,CHEN Y,CHANG Y,et al.CXCR2is involved in pulmonary intravascular macrophage accumulation and angiogenesis in a rat model of hepatopulmonary syndrome[J].Clin Sci(Lond),2017,131(2):159-168.
[13] MACHICAO V I,BALAKRISHNAN M,FALLON M B.Pulmonary complications in chronic liver disease[J].Hepatology,2014,59(4):1627-1637.
[14] DUBROCK H M, KROWKA M J. Do late bubbles correspond to early hepatopulmonary syndrome[J].Ann Hepatol,2017,16(4):476-477.
[15] ALLER R,MOYA J L,MORRIRA V,et al.Diagnosis and grading of intrapulmonary vascular dilatation in cirrhotic patients with contrast transesophageal echocardiography[J].J Hepatol,1999,31(6):1044-1052.
[16] IYER V N,SWANSON K L,CARTIN-CEBA R,et al.Hepatopulmonary syndrome:favorable outcomes in the MELD exception era[J]. Hepatology,2013,57(6):2427-2435.
[17] DE QUEIROS A S,BRANDAOSC,MACEDO L G,et al.Evaluation of normality and reproducibility parameters of scintigraphy with(99m)Tc-MAA in the diagnosis of intrapulmonary vascular dilatations[J].Ann Nucl Med,2015,29(1):46-51.
[18] ARGUEDAS M R,ABRAMS G A,KROWKA M J,et al.Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation[J].Hepatology,2003,37(1):192-197.
[19] ZHAO H,TSAUO J, MA H Y,et al. The role of macroaggregatedalbuminlungperfusionscanin hepatopulmonary syndrome:arewereadytodraw conclusions[J].Liver Int,2015,35(7):1918-1919.
[20] GRILO I,PASCASIO J M,TIRADO J L,et al.The utility of the macro-aggregated albumin lung perfusion scan in the diagnosis and prognosis of hepatopulmonary syndrome in cirrhotic patients candidates for liver transplantation[J].Rev Esp Enferm Dig,2017,109(5):335-343.
[21] PORRES-AGUILAR M,ALTAMIRANO J T,TORREDELGADILLO A,et al.Portopulmonary hypertension and hepatopulmonary syndrome:a clinician-oriented overview[J].Eur Respir Rev,2012,21(125):223-233.
[22] SWANSON K L,WIESNER R H,KROWKA M J.Natural history of hepatopulmonary syndrome:Impact of liver transplantation[J].Hepatology,2005,41(5):1122-1129.
[23] AL-HARBI A,ABDULLAH K,AL-ABDULKAREEM A,et al. Prevalence, severity, and prognostic effect of hepatopulmonary syndrome in liver transplant candidates[J].Ann Transplant,2016,21:180-184.
[24] SAIGAL S,CHOUDHARY N,SARAF N,et al.Excellent outcome of living donor liver transplantation in patients with hepatopulmonary syndrome:a single centre experience[J].Clin Transplant,2013,27(4):530-534.
[25] WIKLUND L,HARALDSSON A,SELIMOVIC N,et al.Extracorporeal membrane oxygenation as a bridge to lung transplantation in a patient with persistent severe portopulmonaryarterialhypertensionfollowingliver transplantation[J].Eur J Cardiothorac Surg,2011,39(5):777-778.
[26] STRATTA C,LAVEZZO B,BALLARIS M A,et al.Extracorporeal membrane oxygenation rescue therapy in a caseofportopulmonaryhypertensionduringliver transplantation:a case report[J].Transplant Proc,2013,45(7):2774-2775.
[27] GRILO-BENSUSANI, PASCASIO-ACEVEDOJM.Hepatopulmonary syndrome:what we know and what we would like to know[J].World J Gastroenterol,2016,22(25):5728-5741.
[28] ROMA J,BALBI E,PACHECO-MOREIRA L,et al.Methylene blue used as a bridge to liver transplantation postoperative recovery:a case report[J].Transplant Proc,2010,42(2):601-604.
[29] NAYYAAR D,MAN H S,GRANTON J,et al.Proposed management algorithm for severe hypoxemia after liver transplantation in the hepatopulmonary syndrome[J].Am J Transplant,2015,15(4):903-913.
[30] RABILLER A,NUNES H,LEBREC D,et al.Prevention of gram-negativetranslocationreducestheseverityof hepatopulmonary syndrome[J].Am J Respir Crit Care Med,2002,166(4):514-517.
[31] GUPTA S, FAUGHNAN M E, LILLY L, et al.Norfloxacin therapy for hepatopulmonary syndrome:apilot randomized controlled trial[J].Clin Gastroenterol Hepatol,2010,8(12):1095-1098.
[32] KO M T,HUANG H C,LEE W S,et al.Metformin reduces intrahepatic fibrosis and intrapulmonary shunts in biliary cirrhotic rats[J].J Chin Med Assoc,2017,80(8):467-475.
[33] LIU C W,YANG Y Y.Dual organ beneficial effects of metformin in cirrhotic rats with hepatopulmonary syndrome[J].J Chin Med Assoc,2017,80(8):463-464.
[34] CHANG C C,LEE W S,HSIEH H G,et al.Selective cyclooxygenaseinhibitionbySC-560 improves hepatopulmonary syndrome in cirrhotic rats[J].PloS one,2017,12(6):e0179809.
[35] ZHAO X, LIU J, YANG S, et al. Diammonium glycyrrhizinate alleviates hepatopulmonary syndrome via restoring superoxide dismutase 3activity in rats[J].Eur J Pharmacol,2017,807:144-150.
[2] KROWKA M J,FALLON M B,KAWUT S M,et al.International liver transplant society practice guidelines:diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension[J].Transplantation,2016,100(7):1440-1452.
[3] ZHANG J,FALLON M B.Hepatopulmonary syndrome:update on pathogenesis and clinical features[J].Nat Rev Gastroenterol Hepatol,2012,9(9):539-549.
[4] SOULAIDOPOULOSS, CHOLONGITASE,GIANNAKOULAS G,et al.Review article:update on current and emergent data on hepatopulmonary syndrome[J].World J Gastroenterol,2018,24(12):1285-1298.
[5] LI T H,LEE P C,LEE K C,et al.Down-regulation of common NFκB-iNOS pathway by chronic thalidomide treatment improves hepatopulmonary syndrome and muscle wasting in rats with biliary cirrhosis[J].Sci Rep,2016,6:39405.
[6] HE J, YI B, CHEN Y, et al. The ET-1-mediated carbonylationanddegradationofANXA1 induce inflammatory phenotype and proliferation of pulmonary artery smooth muscle cells in HPS[J].PloS one,2017,12(4):e0175443.
[7] YI B,ZENG J, WANG G,et al.Annexin A1 protein regulates the expression of PMVEC cytoskeletal proteins in CBDL rat serum-induced pulmonary microvascular remodeling[J].J Transl Med,2013,11:98.
[8] ROBERTS K E,KAWUT S M,KROWKA M J,et al.Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease[J].Gastroenterology,2010,139(1):130-139.
[9] FERNANDEZ M,MEJIAS M,GARCIA-PRAS E,et al.Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats[J].Hepatology,2007,46(4):1208-1217.
[10] LIU C,GAO J,CHEN B,et al.Cyclooxygenase-2promotes pulmonaryintravascularmacrophageaccumulationby exacerbatingBMPsignalinginratexperimental hepatopulmonary syndrome[J].Biochem Pharmacol,2017,138:205-215.
[11] WU W,ZHANG J,YANG W,et al.Role of splenic reservoir monocytes in pulmonary vascular monocyte accumulation in experimental hepatopulmonary syndrome[J].J Gastroenterol Hepatol,2016,31(11):1888-1894.
[12] LI X,CHEN Y,CHANG Y,et al.CXCR2is involved in pulmonary intravascular macrophage accumulation and angiogenesis in a rat model of hepatopulmonary syndrome[J].Clin Sci(Lond),2017,131(2):159-168.
[13] MACHICAO V I,BALAKRISHNAN M,FALLON M B.Pulmonary complications in chronic liver disease[J].Hepatology,2014,59(4):1627-1637.
[14] DUBROCK H M, KROWKA M J. Do late bubbles correspond to early hepatopulmonary syndrome[J].Ann Hepatol,2017,16(4):476-477.
[15] ALLER R,MOYA J L,MORRIRA V,et al.Diagnosis and grading of intrapulmonary vascular dilatation in cirrhotic patients with contrast transesophageal echocardiography[J].J Hepatol,1999,31(6):1044-1052.
[16] IYER V N,SWANSON K L,CARTIN-CEBA R,et al.Hepatopulmonary syndrome:favorable outcomes in the MELD exception era[J]. Hepatology,2013,57(6):2427-2435.
[17] DE QUEIROS A S,BRANDAOSC,MACEDO L G,et al.Evaluation of normality and reproducibility parameters of scintigraphy with(99m)Tc-MAA in the diagnosis of intrapulmonary vascular dilatations[J].Ann Nucl Med,2015,29(1):46-51.
[18] ARGUEDAS M R,ABRAMS G A,KROWKA M J,et al.Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation[J].Hepatology,2003,37(1):192-197.
[19] ZHAO H,TSAUO J, MA H Y,et al. The role of macroaggregatedalbuminlungperfusionscanin hepatopulmonary syndrome:arewereadytodraw conclusions[J].Liver Int,2015,35(7):1918-1919.
[20] GRILO I,PASCASIO J M,TIRADO J L,et al.The utility of the macro-aggregated albumin lung perfusion scan in the diagnosis and prognosis of hepatopulmonary syndrome in cirrhotic patients candidates for liver transplantation[J].Rev Esp Enferm Dig,2017,109(5):335-343.
[21] PORRES-AGUILAR M,ALTAMIRANO J T,TORREDELGADILLO A,et al.Portopulmonary hypertension and hepatopulmonary syndrome:a clinician-oriented overview[J].Eur Respir Rev,2012,21(125):223-233.
[22] SWANSON K L,WIESNER R H,KROWKA M J.Natural history of hepatopulmonary syndrome:Impact of liver transplantation[J].Hepatology,2005,41(5):1122-1129.
[23] AL-HARBI A,ABDULLAH K,AL-ABDULKAREEM A,et al. Prevalence, severity, and prognostic effect of hepatopulmonary syndrome in liver transplant candidates[J].Ann Transplant,2016,21:180-184.
[24] SAIGAL S,CHOUDHARY N,SARAF N,et al.Excellent outcome of living donor liver transplantation in patients with hepatopulmonary syndrome:a single centre experience[J].Clin Transplant,2013,27(4):530-534.
[25] WIKLUND L,HARALDSSON A,SELIMOVIC N,et al.Extracorporeal membrane oxygenation as a bridge to lung transplantation in a patient with persistent severe portopulmonaryarterialhypertensionfollowingliver transplantation[J].Eur J Cardiothorac Surg,2011,39(5):777-778.
[26] STRATTA C,LAVEZZO B,BALLARIS M A,et al.Extracorporeal membrane oxygenation rescue therapy in a caseofportopulmonaryhypertensionduringliver transplantation:a case report[J].Transplant Proc,2013,45(7):2774-2775.
[27] GRILO-BENSUSANI, PASCASIO-ACEVEDOJM.Hepatopulmonary syndrome:what we know and what we would like to know[J].World J Gastroenterol,2016,22(25):5728-5741.
[28] ROMA J,BALBI E,PACHECO-MOREIRA L,et al.Methylene blue used as a bridge to liver transplantation postoperative recovery:a case report[J].Transplant Proc,2010,42(2):601-604.
[29] NAYYAAR D,MAN H S,GRANTON J,et al.Proposed management algorithm for severe hypoxemia after liver transplantation in the hepatopulmonary syndrome[J].Am J Transplant,2015,15(4):903-913.
[30] RABILLER A,NUNES H,LEBREC D,et al.Prevention of gram-negativetranslocationreducestheseverityof hepatopulmonary syndrome[J].Am J Respir Crit Care Med,2002,166(4):514-517.
[31] GUPTA S, FAUGHNAN M E, LILLY L, et al.Norfloxacin therapy for hepatopulmonary syndrome:apilot randomized controlled trial[J].Clin Gastroenterol Hepatol,2010,8(12):1095-1098.
[32] KO M T,HUANG H C,LEE W S,et al.Metformin reduces intrahepatic fibrosis and intrapulmonary shunts in biliary cirrhotic rats[J].J Chin Med Assoc,2017,80(8):467-475.
[33] LIU C W,YANG Y Y.Dual organ beneficial effects of metformin in cirrhotic rats with hepatopulmonary syndrome[J].J Chin Med Assoc,2017,80(8):463-464.
[34] CHANG C C,LEE W S,HSIEH H G,et al.Selective cyclooxygenaseinhibitionbySC-560 improves hepatopulmonary syndrome in cirrhotic rats[J].PloS one,2017,12(6):e0179809.
[35] ZHAO X, LIU J, YANG S, et al. Diammonium glycyrrhizinate alleviates hepatopulmonary syndrome via restoring superoxide dismutase 3activity in rats[J].Eur J Pharmacol,2017,807:144-150.