{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T12:43:38Z","timestamp":1763037818605,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T00:00:00Z","timestamp":1673308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Portopulmonary hypertension (PoPH) and hepatopulmonary syndrome are severe pulmonary complications associated with liver cirrhosis (LC) and portal hypertension. Three key pathways, involving endothelin, nitric oxide, and prostacyclin, have been identified in the development and progression of pulmonary arterial hypertension (PAH). To obtain a good effect with PAH-specific drugs in PoPH patients, it is important to diagnose PoPH at an early stage and promptly initiate therapy. The majority of therapeutic drugs are contraindicated for Child-Pugh grade C LC, and their effects decrease in the severe PAH stage. Among many LC patients, the measurement of serum brain natriuretic peptide levels might be useful for detecting PoPH. Previously, liver transplantation (LT) for PoPH was contraindicated; however, the indications for LT are changing and now take into account how well the PoPH is controlled by therapeutic drugs. In Japan, new registration criteria for deceased-donor LT have been established for PoPH patients. PoPH patients with a mean pulmonary arterial pressure &lt;35 mmHg and pulmonary vascular resistance &lt;400 dyn\/s\/cm\u22125 are indicated for LT, regardless of whether they are using therapeutic drugs. Combined with PAH-specific drugs, LT may lead to excellent long-term outcomes in PoPH patients. We aimed to review current therapies for PoPH, including LT.<\/jats:p>","DOI":"10.3390\/jcm12020562","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T03:40:35Z","timestamp":1673408435000},"page":"562","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Current Therapy and Liver Transplantation for Portopulmonary Hypertension in Japan"],"prefix":"10.3390","volume":"12","author":[{"given":"Katsutoshi","family":"Tokushige","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Tokyo Women\u2019s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomomi","family":"Kogiso","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Gastroenterology, Tokyo Women\u2019s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroto","family":"Egawa","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatic Surgery, Tokyo Women\u2019s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1111\/j.1872-034X.2009.00552.x","article-title":"Hepatopulmonary syndrome and portopulmonary hypertension","volume":"39","author":"Umeda","year":"2009","journal-title":"Hepatol. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1164\/rccm.200510-1668OC","article-title":"Pulmonary arterial hypertension in France: Results from a national registry","volume":"173","author":"Humbert","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1164\/arrd.1983.127.4.437","article-title":"Primary pulmonary hypertension and cirrhosis: Are they related?","volume":"127","author":"McDonnell","year":"1983","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1053\/jhep.2003.50060","article-title":"Diagnosis of portopulmonary hypertension in candidates for liver transplantation: A prospective study","volume":"37","author":"Colle","year":"2003","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1002\/hep.21431","article-title":"Portopulmonary hypertension: Results from a 10-year screening algorithm","volume":"44","author":"Krowka","year":"2006","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hayashi, R., Kogiso, T., Kikuchi, N., Yamamoto, K., Nakamura, S., Egawa, H., Hagiwara, N., and Tokushige, K. (2022). Portopulmonary hypertension and the risk of high right ventricular systolic pressure in liver transplant candidates. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0267125"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1002\/lt.23485","article-title":"Portopulmonary hypertension: An update","volume":"18","author":"Safdar","year":"2012","journal-title":"Liver Transpl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1111\/j.1600-6143.2006.01432.x","article-title":"Successful liver transplantation following medical management of portopulmonary hypertension: A single-center series","volume":"6","author":"Sussman","year":"2006","journal-title":"Am. J. Transplant."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/lt.20016","article-title":"Hepatopulmonary syndrome and portopulmonary hypertension: A report of the multicenter liver transplant database","volume":"10","author":"Krowka","year":"2004","journal-title":"Liver Transpl."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1111\/crj.12774","article-title":"Bosentan therapy for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: A systemic review and meta-analysis","volume":"12","author":"Chen","year":"2018","journal-title":"Clin. Respir. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1080\/14656566.2017.1378347","article-title":"Oral treprostinil in the treatment of pulmonary arterial hypertension","volume":"18","author":"Feldman","year":"2017","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00535-019-01645-y","article-title":"Transition in the etiology of liver cirrhosis in Japan: A nationwide survey","volume":"55","author":"Enomoto","year":"2020","journal-title":"J. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1111\/hepr.13560","article-title":"Prevalence and characteristics of portopulmonary hypertension in cirrhotic patients who underwent both hepatic vein and pulmonary artery catheterization","volume":"50","author":"Atsukawa","year":"2020","journal-title":"Hepatol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1801913","DOI":"10.1183\/13993003.01913-2018","article-title":"Haemodynamic definitions and updated clinical classification of pulmonary hypertension","volume":"53","author":"Simonneau","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/hep.22275","article-title":"Clinical risk factors for portopulmonary hypertension","volume":"48","author":"Kawut","year":"2008","journal-title":"Hepatology"},{"key":"ref_16","first-page":"63","article-title":"Current status of portopulmonary hypertension and hepatopulmonary syndrome","volume":"7","author":"Kodama","year":"2020","journal-title":"EC Gastroenterol. Dig. Syst."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e928004","DOI":"10.12659\/AJCR.928004","article-title":"A case of hypopituitarism complicated by non-alcoholic steatohepatitis and severe pulmonary hypertension","volume":"22","author":"Suzuki","year":"2021","journal-title":"Am. J. Case Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1097\/MPG.0b013e3181a1c496","article-title":"Rapid progression from hepatopulmonary syndrome to portopulmonary hypertension in an adolescent female with hypopituitarism","volume":"50","author":"Justino","year":"2010","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.2169\/internalmedicine.0027-17","article-title":"Hormone-replacement therapy for hepatopulmonary syndrome and NASH associated with hypopituitarism","volume":"57","author":"Torii","year":"2018","journal-title":"Intern. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.vph.2015.04.005","article-title":"IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: Role of epigenetic regulation","volume":"73","author":"Yang","year":"2015","journal-title":"Vasc. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1002\/2211-5463.12369","article-title":"MiR-322-5p targets IGF-1 and is suppressed in the heart of rats with pulmonary hypertension","volume":"8","author":"Connolly","year":"2018","journal-title":"FEBS Open Bio."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1159\/000511001","article-title":"Recent advances in systemic therapy for hepatocellular carcinoma in an aging society: 2020 update","volume":"9","author":"Kudo","year":"2020","journal-title":"Liver Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1007\/s10147-010-0089-y","article-title":"Current status of molecularly targeted therapy for hepatocellular carcinoma: Clinical practice","volume":"15","author":"Kudo","year":"2010","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1002\/hep.31865","article-title":"Successful management with dual therapy of lenvatinib and macitentan for HCC With portopulmonary hypertension","volume":"74","author":"Ishikawa","year":"2021","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e13203","DOI":"10.1111\/petr.13203","article-title":"The efficacy of serum brain natriuretic peptide for the early detection of portopulmonary hypertension in biliary atresia patients before liver transplantation","volume":"22","author":"Yoshimaru","year":"2018","journal-title":"Pediatr. Transplant."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.chest.2018.11.030","article-title":"Therapy for pulmonary arterial hypertension in adults: Update of the CHEST guideline and expert panel report","volume":"155","author":"Klinger","year":"2019","journal-title":"Chest"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1183\/09031936.00032407","article-title":"Experience with inhaled iloprost and bosentan in portopulmonary hypertension","volume":"30","author":"Hoeper","year":"2007","journal-title":"Eur. Respir. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/S2213-2600(19)30091-8","article-title":"Macitentan for the treatment of portopulmonary hypertension (PORTICO): A multicentre, randomised, double-blind, placebo-controlled, phase 4 trial","volume":"7","author":"Sitbon","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.jhep.2020.02.021","article-title":"Portopulmonary hypertension in the current era of pulmonary hypertension management","volume":"73","author":"Savale","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Takahashi, Y., Yamamoto, K., Sakao, S., Takeuchi, T., Suda, R., Tanabe, N., and Tatsumi, K. (2021). The clinical characteristics, treatment, and survival of portopulmonary hypertension in Japan. BMC Pulm. Med., 21.","DOI":"10.1186\/s12890-021-01452-3"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/S0168-8278(96)80241-8","article-title":"Changes in plasma endothelin-1 and big endothelin-1 induced by transjugular intrahepatic portosystemic shunts in patients with cirrhosis and refractory ascites","volume":"25","author":"Martinet","year":"1996","journal-title":"J. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"G27","DOI":"10.1152\/ajpgi.90405.2008","article-title":"Endothelin antagonism in portal hypertensive mice: Implications for endothelin receptor-specific signaling in liver disease","volume":"297","author":"Feng","year":"2009","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1002\/hep.510280308","article-title":"Beneficial hemodynamic effects of bosentan, a mixed ET(A) and ET(B) receptor antagonist, in portal hypertensive rats","volume":"28","author":"Sogni","year":"1998","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1053\/jlts.2000.6356","article-title":"Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation","volume":"6","author":"Krowka","year":"2000","journal-title":"Liver Transpl."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1002\/lt.500030503","article-title":"Severe pulmonary hypertension in liver transplant candidates","volume":"3","author":"Ramsay","year":"1997","journal-title":"Liver Transpl. Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1002\/hep.26745","article-title":"Pulmonary complications in chronic liver disease","volume":"59","author":"Machicao","year":"2014","journal-title":"Hepatology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1053\/jlts.2002.31343","article-title":"Outcome of liver transplantation for patients with pulmonary hypertension","volume":"8","author":"Starkel","year":"2002","journal-title":"Liver Transpl."},{"key":"ref_38","unstructured":"(2020, September 09). Selection Criteria of Recipients Who Expect Deceased-Donor Liver Ransplantation in Japan. Available online: https:\/\/www.mhlw.go.jp\/content\/10900000\/000696415.p."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/2\/562\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:05:46Z","timestamp":1760119546000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/2\/562"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,10]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["jcm12020562"],"URL":"https:\/\/doi.org\/10.3390\/jcm12020562","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2023,1,10]]}}}