Successful treatment of noncirrhotic portal hypertension with eculizumab in paroxysmal nocturnal hemoglobinuria: A case report
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摘要
BACKGROUND Idiopathic non-cirrhotic portal hypertension(INCPH) is mainly associated with thrombophilia in Western countries. Paroxysmal nocturnal hemoglobinuria(PNH) is a rare hematologic disease that manifests with hemolytic anemia,thrombosis, and peripheral blood cytopenias. Portal and hepatic venous thrombosis were reported in PNH. A rare case of INCPH complicating PNH is described.CASE SUMMARY A 63-year old woman with a 2-year past medical history of PNH without treatment was admitted because of jaundice and refractory ascites requiring large volume paracentesis. Liver histology revealed portal venopathy with portal fibrosis and sclerosis, nodular regenerative hyperplasia, parenchymal ischemic changes, and focal sinusoidal and perivenular fibrosis without bridging fibrosis or cirrhosis, all indicative of INCPH. The flow cytometry confirmed PNH diagnosis and eculizumab treatment was initiated. Her condition was improved gradually, bilirubin was normalized 6 months following initiation of eculizumab,and 1 year later diuretics were stopped.CONCLUSION Eculizumab improved intravascular hemolysis and reversed clinical manifestations of INCPH in a patient with paroxysmal nocturnal hemoglobinuria.
BACKGROUND Idiopathic non-cirrhotic portal hypertension(INCPH) is mainly associated with thrombophilia in Western countries. Paroxysmal nocturnal hemoglobinuria(PNH) is a rare hematologic disease that manifests with hemolytic anemia,thrombosis, and peripheral blood cytopenias. Portal and hepatic venous thrombosis were reported in PNH. A rare case of INCPH complicating PNH is described.CASE SUMMARY A 63-year old woman with a 2-year past medical history of PNH without treatment was admitted because of jaundice and refractory ascites requiring large volume paracentesis. Liver histology revealed portal venopathy with portal fibrosis and sclerosis, nodular regenerative hyperplasia, parenchymal ischemic changes, and focal sinusoidal and perivenular fibrosis without bridging fibrosis or cirrhosis, all indicative of INCPH. The flow cytometry confirmed PNH diagnosis and eculizumab treatment was initiated. Her condition was improved gradually, bilirubin was normalized 6 months following initiation of eculizumab,and 1 year later diuretics were stopped.CONCLUSION Eculizumab improved intravascular hemolysis and reversed clinical manifestations of INCPH in a patient with paroxysmal nocturnal hemoglobinuria.
BACKGROUND Idiopathic non-cirrhotic portal hypertension(INCPH) is mainly associated with thrombophilia in Western countries. Paroxysmal nocturnal hemoglobinuria(PNH) is a rare hematologic disease that manifests with hemolytic anemia,thrombosis, and peripheral blood cytopenias. Portal and hepatic venous thrombosis were reported in PNH. A rare case of INCPH complicating PNH is described.CASE SUMMARY A 63-year old woman with a 2-year past medical history of PNH without treatment was admitted because of jaundice and refractory ascites requiring large volume paracentesis. Liver histology revealed portal venopathy with portal fibrosis and sclerosis, nodular regenerative hyperplasia, parenchymal ischemic changes, and focal sinusoidal and perivenular fibrosis without bridging fibrosis or cirrhosis, all indicative of INCPH. The flow cytometry confirmed PNH diagnosis and eculizumab treatment was initiated. Her condition was improved gradually, bilirubin was normalized 6 months following initiation of eculizumab,and 1 year later diuretics were stopped.CONCLUSION Eculizumab improved intravascular hemolysis and reversed clinical manifestations of INCPH in a patient with paroxysmal nocturnal hemoglobinuria.
引文
1 Schouten JN,Garcia-Pagan JC,Valla DC,Janssen HL.Idiopathic noncirrhotic portal hypertension.Hepatology 2011;54:1071-1081[PMID:21574171 DOI:10.1002/hep.24422]
2 Sarin SK,Kumar A,Chawla YK,Baijal SS,Dhiman RK,Jafri W,Lesmana LA,Guha Mazumder D,Omata M,Qureshi H,Raza RM,Sahni P,Sakhuja P,Salih M,Santra A,Sharma BC,Sharma P,Shiha G,Sollano J;Members of the APASL Working Party on Portal Hypertension.Noncirrhotic portal fibrosis/idiopathic portal hypertension:APASL recommendations for diagnosis and treatment.Hepatol Int2007;1:398-413[PMID:19669336 DOI:10.1007/s12072-007-9010-9]
3 Wanless IR.Micronodular transformation(nodular regenerative hyperplasia)of the liver:a report of 64cases among 2,500 autopsies and a new classification of benign hepatocellular nodules.Hepatology 1990;11:787-797[PMID:2189821 DOI:10.1002/hep.1840110512]
4 Mazumder DN,Das Gupta J,Santra A,Pal A,Ghose A,Sarkar S.Chronic arsenic toxicity in west Bengal--the worst calamity in the world.J Indian Med Assoc 1998;96:4-7,18[PMID:9601181]
5 Vispo E,Moreno A,Maida I,Barreiro P,Cuevas A,Albertos S,Soriano V.Noncirrhotic portal hypertension in HIV-infected patients:unique clinical and pathological findings.AIDS 2010;24:1171-1176[PMID:20299955 DOI:10.1097/QAD.0b013e3283389e26]
6 De Gottardi A,Rautou PE,Schouten J,Rubbia-Brandt L,Leebeek F,Trebicka J,Murad SD,Vilgrain V,Hernandez-Gea V,Nery F,Plessier A,Berzigotti A,Bioulac-Sage P,Primignani M,Semela D,Elkrief L,Bedossa P,Valla D,Garcia-Pagan JC;VALDIG group.Porto-sinusoidal vascular disease:proposal and description of a novel entity.Lancet Gastroenterol Hepatol 2019;4:399-411[PMID:30957754 DOI:10.1016/S2468-1253(19)30047-0]
7 Elkrief L,Rautou PE.Idiopathic non-cirrhotic portal hypertension:the tip of the obliterative portal venopathies iceberg?Liver Int 2016;36:325-327[PMID:26872111 DOI:10.1111/liv.13048]
8 Brodsky RA.Paroxysmal nocturnal hemoglobinuria.Blood 2014;124:2804-2811[PMID:25237200DOI:10.1182/blood-2014-02-522128]
9 Khanna R,Sarin SK.Idiopathic portal hypertension and extrahepatic portal venous obstruction.Hepatol Int 2018;12:148-167[PMID:29464506 DOI:10.1007/s12072-018-9844-3]
10 Schouten JN,Verheij J,Seijo S.Idiopathic non-cirrhotic portal hypertension:a review.Orphanet J Rare Dis 2015;10:67[PMID:26025214 DOI:10.1186/s13023-015-0288-8]
11 Saifee S,Joelson D,Braude J,Shrestha R,Johnson M,Sellers M,Galambos MR,Rubin RA.Noncirrhotic portal hypertension in patients with human immunodeficiency virus-1 infection.Clin Gastroenterol Hepatol 2008;6:1167-1169[PMID:18639498 DOI:10.1016/j.cgh.2008.04.023]
12 Maida I,Garcia-Gasco P,Sotgiu G,Rios MJ,Vispo ME,Martin-Carbonero L,Barreiro P,Mura MS,Babudieri S,Albertos S,Garcia-Samaniego J,Soriano V.Antiretroviral-associated portal hypertension:a new clinical condition?Prevalence,predictors and outcome.Antivir Ther 2008;13:103-107[PMID:18389904]
13 Roulot D,Degott C,Chazouillères O,Oberti F,Calès P,Carbonell N,Benferhat S,Bresson-Hadni S,Valla D.Vascular involvement of the liver in Turner's syndrome.Hepatology 2004;39:239-247[PMID:14752843 DOI:10.1002/hep.20026]
14 Austin A,Campbell E,Lane P,Elias E.Nodular regenerative hyperplasia of the liver and coeliac disease:potential role of IgA anticardiolipin antibody.Gut 2004;53:1032-1034[PMID:15194657 DOI:10.1136/gut.2003.036806]
15 Okuda K,Kono K,Ohnishi K,Kimura K,Omata M,Koen H,Nakajima Y,Musha H,Hirashima T,Takashi M.Clinical study of eighty-six cases of idiopathic portal hypertension and comparison with cirrhosis with splenomegaly.Gastroenterology 1984;86:600-610[PMID:6698361]
16 Hillaire S,Bonte E,Denninger MH,Casadevall N,Cadranel JF,Lebrec D,Valla D,Degott C.Idiopathic non-cirrhotic intrahepatic portal hypertension in the West:a re-evaluation in 28 patients.Gut 2002;51:275-280[PMID:12117894 DOI:10.1136/gut.51.2.275]
17 Siramolpiwat S,Seijo S,Miquel R,Berzigotti A,Garcia-Criado A,Darnell A,Turon F,Hernandez-Gea V,Bosch J,Garcia-Pagán JC.Idiopathic portal hypertension:natural history and long-term outcome.Hepatology 2014;59:2276-2285[PMID:24155091 DOI:10.1002/hep.26904]
18 Cazals-Hatem D,Hillaire S,Rudler M,Plessier A,Paradis V,Condat B,Francoz C,Denninger MH,Durand F,Bedossa P,Valla DC.Obliterative portal venopathy:portal hypertension is not always present at diagnosis.J Hepatol 2011;54:455-461[PMID:21087805 DOI:10.1016/j.jhep.2010.07.038]
19 Kamath PS,Carpenter HA,Lloyd RV,McKusick MA,Steers JL,Nagorney DM,Miller VM.Hepatic localization of endothelin-1 in patients with idiopathic portal hypertension and cirrhosis of the liver.Liver Transpl 2000;6:596-602[PMID:10980059 DOI:10.1053/jlts.2000.9735]
20 Rother RP,Bell L,Hillmen P,Gladwin MT.The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin:a novel mechanism of human disease.JAMA 2005;293:1653-1662[PMID:15811985 DOI:10.1001/jama.293.13.1653]
21 Ignarro LJ.Endothelium-derived nitric oxide:actions and properties.FASEB J 1989;3:31-36[PMID:2642868 DOI:10.1096/fasebj.3.1.2642868]
22 Miyata T,Yamada N,Iida Y,Nishimura J,Takeda J,Kitani T,Kinoshita T.Abnormalities of PIG-Atranscripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria.N Engl J Med 1994;330:249-255[PMID:8272086 DOI:10.1056/nejm199401273300404]
23 Bessler M,Mason PJ,Hillmen P,Miyata T,Yamada N,Takeda J,Luzzatto L,Kinoshita T.Paroxysmal nocturnal haemoglobinuria(PNH)is caused by somatic mutations in the PIG-A gene.EMBO J 1994;13:110-117[PMID:8306954 DOI:10.1002/j.1460-2075.1994.tb06240.x]
24 Devalet B,Mullier F,Chatelain B,DognéJM,Chatelain C.Pathophysiology,diagnosis,and treatment of paroxysmal nocturnal hemoglobinuria:a review.Eur J Haematol 2015;95:190-198[PMID:25753400DOI:10.1111/ejh.12543]
25 Ziakas PD,Poulou LS,Rokas GI,Bartzoudis D,Voulgarelis M.Thrombosis in paroxysmal nocturnal hemoglobinuria:sites,risks,outcome.An overview.J Thromb Haemost 2007;5:642-645[PMID:17319910 DOI:10.1111/j.1538-7836.2007.02379.x]
26 Hillmen P,Young NS,Schubert J,Brodsky RA,SociéG,Muus P,R?th A,Szer J,Elebute MO,Nakamura R,Browne P,Risitano AM,Hill A,Schrezenmeier H,Fu CL,Maciejewski J,Rollins SA,Mojcik CF,Rother RP,Luzzatto L.The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.N Engl J Med 2006;355:1233-1243[PMID:16990386 DOI:10.1056/NEJMoa061648]
27 Brodsky RA,Young NS,Antonioli E,Risitano AM,Schrezenmeier H,Schubert J,Gaya A,Coyle L,de Castro C,Fu CL,Maciejewski JP,Bessler M,Kroon HA,Rother RP,Hillmen P.Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria.Blood 2008;111:1840-1847[PMID:18055865 DOI:10.1182/blood-2007-06-094136]
28 Kelly RJ,Hill A,Arnold LM,Brooksbank GL,Richards SJ,Cullen M,Mitchell LD,Cohen DR,Gregory WM,Hillmen P.Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria:sustained efficacy and improved survival.Blood 2011;117:6786-6792[PMID:21460245 DOI:10.1182/blood-2011-02-333997]
29 Hillmen P,Muus P,R?th A,Elebute MO,Risitano AM,Schrezenmeier H,Szer J,Browne P,Maciejewski JP,Schubert J,Urbano-Ispizua A,de Castro C,SociéG,Brodsky RA.Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria.Br J Haematol2013;162:62-73[PMID:23617322 DOI:10.1111/bjh.12347]
2 Sarin SK,Kumar A,Chawla YK,Baijal SS,Dhiman RK,Jafri W,Lesmana LA,Guha Mazumder D,Omata M,Qureshi H,Raza RM,Sahni P,Sakhuja P,Salih M,Santra A,Sharma BC,Sharma P,Shiha G,Sollano J;Members of the APASL Working Party on Portal Hypertension.Noncirrhotic portal fibrosis/idiopathic portal hypertension:APASL recommendations for diagnosis and treatment.Hepatol Int2007;1:398-413[PMID:19669336 DOI:10.1007/s12072-007-9010-9]
3 Wanless IR.Micronodular transformation(nodular regenerative hyperplasia)of the liver:a report of 64cases among 2,500 autopsies and a new classification of benign hepatocellular nodules.Hepatology 1990;11:787-797[PMID:2189821 DOI:10.1002/hep.1840110512]
4 Mazumder DN,Das Gupta J,Santra A,Pal A,Ghose A,Sarkar S.Chronic arsenic toxicity in west Bengal--the worst calamity in the world.J Indian Med Assoc 1998;96:4-7,18[PMID:9601181]
5 Vispo E,Moreno A,Maida I,Barreiro P,Cuevas A,Albertos S,Soriano V.Noncirrhotic portal hypertension in HIV-infected patients:unique clinical and pathological findings.AIDS 2010;24:1171-1176[PMID:20299955 DOI:10.1097/QAD.0b013e3283389e26]
6 De Gottardi A,Rautou PE,Schouten J,Rubbia-Brandt L,Leebeek F,Trebicka J,Murad SD,Vilgrain V,Hernandez-Gea V,Nery F,Plessier A,Berzigotti A,Bioulac-Sage P,Primignani M,Semela D,Elkrief L,Bedossa P,Valla D,Garcia-Pagan JC;VALDIG group.Porto-sinusoidal vascular disease:proposal and description of a novel entity.Lancet Gastroenterol Hepatol 2019;4:399-411[PMID:30957754 DOI:10.1016/S2468-1253(19)30047-0]
7 Elkrief L,Rautou PE.Idiopathic non-cirrhotic portal hypertension:the tip of the obliterative portal venopathies iceberg?Liver Int 2016;36:325-327[PMID:26872111 DOI:10.1111/liv.13048]
8 Brodsky RA.Paroxysmal nocturnal hemoglobinuria.Blood 2014;124:2804-2811[PMID:25237200DOI:10.1182/blood-2014-02-522128]
9 Khanna R,Sarin SK.Idiopathic portal hypertension and extrahepatic portal venous obstruction.Hepatol Int 2018;12:148-167[PMID:29464506 DOI:10.1007/s12072-018-9844-3]
10 Schouten JN,Verheij J,Seijo S.Idiopathic non-cirrhotic portal hypertension:a review.Orphanet J Rare Dis 2015;10:67[PMID:26025214 DOI:10.1186/s13023-015-0288-8]
11 Saifee S,Joelson D,Braude J,Shrestha R,Johnson M,Sellers M,Galambos MR,Rubin RA.Noncirrhotic portal hypertension in patients with human immunodeficiency virus-1 infection.Clin Gastroenterol Hepatol 2008;6:1167-1169[PMID:18639498 DOI:10.1016/j.cgh.2008.04.023]
12 Maida I,Garcia-Gasco P,Sotgiu G,Rios MJ,Vispo ME,Martin-Carbonero L,Barreiro P,Mura MS,Babudieri S,Albertos S,Garcia-Samaniego J,Soriano V.Antiretroviral-associated portal hypertension:a new clinical condition?Prevalence,predictors and outcome.Antivir Ther 2008;13:103-107[PMID:18389904]
13 Roulot D,Degott C,Chazouillères O,Oberti F,Calès P,Carbonell N,Benferhat S,Bresson-Hadni S,Valla D.Vascular involvement of the liver in Turner's syndrome.Hepatology 2004;39:239-247[PMID:14752843 DOI:10.1002/hep.20026]
14 Austin A,Campbell E,Lane P,Elias E.Nodular regenerative hyperplasia of the liver and coeliac disease:potential role of IgA anticardiolipin antibody.Gut 2004;53:1032-1034[PMID:15194657 DOI:10.1136/gut.2003.036806]
15 Okuda K,Kono K,Ohnishi K,Kimura K,Omata M,Koen H,Nakajima Y,Musha H,Hirashima T,Takashi M.Clinical study of eighty-six cases of idiopathic portal hypertension and comparison with cirrhosis with splenomegaly.Gastroenterology 1984;86:600-610[PMID:6698361]
16 Hillaire S,Bonte E,Denninger MH,Casadevall N,Cadranel JF,Lebrec D,Valla D,Degott C.Idiopathic non-cirrhotic intrahepatic portal hypertension in the West:a re-evaluation in 28 patients.Gut 2002;51:275-280[PMID:12117894 DOI:10.1136/gut.51.2.275]
17 Siramolpiwat S,Seijo S,Miquel R,Berzigotti A,Garcia-Criado A,Darnell A,Turon F,Hernandez-Gea V,Bosch J,Garcia-Pagán JC.Idiopathic portal hypertension:natural history and long-term outcome.Hepatology 2014;59:2276-2285[PMID:24155091 DOI:10.1002/hep.26904]
18 Cazals-Hatem D,Hillaire S,Rudler M,Plessier A,Paradis V,Condat B,Francoz C,Denninger MH,Durand F,Bedossa P,Valla DC.Obliterative portal venopathy:portal hypertension is not always present at diagnosis.J Hepatol 2011;54:455-461[PMID:21087805 DOI:10.1016/j.jhep.2010.07.038]
19 Kamath PS,Carpenter HA,Lloyd RV,McKusick MA,Steers JL,Nagorney DM,Miller VM.Hepatic localization of endothelin-1 in patients with idiopathic portal hypertension and cirrhosis of the liver.Liver Transpl 2000;6:596-602[PMID:10980059 DOI:10.1053/jlts.2000.9735]
20 Rother RP,Bell L,Hillmen P,Gladwin MT.The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin:a novel mechanism of human disease.JAMA 2005;293:1653-1662[PMID:15811985 DOI:10.1001/jama.293.13.1653]
21 Ignarro LJ.Endothelium-derived nitric oxide:actions and properties.FASEB J 1989;3:31-36[PMID:2642868 DOI:10.1096/fasebj.3.1.2642868]
22 Miyata T,Yamada N,Iida Y,Nishimura J,Takeda J,Kitani T,Kinoshita T.Abnormalities of PIG-Atranscripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria.N Engl J Med 1994;330:249-255[PMID:8272086 DOI:10.1056/nejm199401273300404]
23 Bessler M,Mason PJ,Hillmen P,Miyata T,Yamada N,Takeda J,Luzzatto L,Kinoshita T.Paroxysmal nocturnal haemoglobinuria(PNH)is caused by somatic mutations in the PIG-A gene.EMBO J 1994;13:110-117[PMID:8306954 DOI:10.1002/j.1460-2075.1994.tb06240.x]
24 Devalet B,Mullier F,Chatelain B,DognéJM,Chatelain C.Pathophysiology,diagnosis,and treatment of paroxysmal nocturnal hemoglobinuria:a review.Eur J Haematol 2015;95:190-198[PMID:25753400DOI:10.1111/ejh.12543]
25 Ziakas PD,Poulou LS,Rokas GI,Bartzoudis D,Voulgarelis M.Thrombosis in paroxysmal nocturnal hemoglobinuria:sites,risks,outcome.An overview.J Thromb Haemost 2007;5:642-645[PMID:17319910 DOI:10.1111/j.1538-7836.2007.02379.x]
26 Hillmen P,Young NS,Schubert J,Brodsky RA,SociéG,Muus P,R?th A,Szer J,Elebute MO,Nakamura R,Browne P,Risitano AM,Hill A,Schrezenmeier H,Fu CL,Maciejewski J,Rollins SA,Mojcik CF,Rother RP,Luzzatto L.The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.N Engl J Med 2006;355:1233-1243[PMID:16990386 DOI:10.1056/NEJMoa061648]
27 Brodsky RA,Young NS,Antonioli E,Risitano AM,Schrezenmeier H,Schubert J,Gaya A,Coyle L,de Castro C,Fu CL,Maciejewski JP,Bessler M,Kroon HA,Rother RP,Hillmen P.Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria.Blood 2008;111:1840-1847[PMID:18055865 DOI:10.1182/blood-2007-06-094136]
28 Kelly RJ,Hill A,Arnold LM,Brooksbank GL,Richards SJ,Cullen M,Mitchell LD,Cohen DR,Gregory WM,Hillmen P.Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria:sustained efficacy and improved survival.Blood 2011;117:6786-6792[PMID:21460245 DOI:10.1182/blood-2011-02-333997]
29 Hillmen P,Muus P,R?th A,Elebute MO,Risitano AM,Schrezenmeier H,Szer J,Browne P,Maciejewski JP,Schubert J,Urbano-Ispizua A,de Castro C,SociéG,Brodsky RA.Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria.Br J Haematol2013;162:62-73[PMID:23617322 DOI:10.1111/bjh.12347]