An autosomal dominant form of non-cirrhotic portal hypertension
Authors: Avik Majumdar, Martin B. Delatycki, Peter Crowley, Julie Lokan, Benjamin Tharian, Peter W. Angus, Paul Gow
Journal: Journal of Hepatology (2015)

The familial aggregation idiopathic non-cirrhotic portal hypertension (INCPH) has been previously described, however, there have been no reports of Mendelian inheritance [1Khanna R. Sarin S.K. Non-cirrhotic portal hypertension – Diagnosis and management.J Hepatol. 2014; 60: 421-441Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 2Sarin S.K. Mehra N.K. Agarwal A. Malhotra V. Anand B.S. Taneja V. Familial aggregation in noncirrhotic portal fibrosis: a report of four families.Am J Gastroenterol. 1987; 82: 1130-1133PubMed Google Scholar, 3Barnett J.L. Moseley R.H. Appelman H.D. Familial septal cirrhosis.Gastroenterology. 1992; 102: 674-678Abstract Full Text PDF PubMed Google Scholar, 4Dumortier J. Boillot O. Chevalier M. Berger F. Potier P. Valette P.-J. et al.Familial occurrence of nodular regenerative hyperplasia of the liver: a report on three families.Gut. 1999; 45: 289-294Crossref PubMed Scopus (36) Google Scholar, 5Albuquerque A. Cardoso H. Lopes J. Cipriano A. Carneiro F. Macedo G. Familial occurrence of nodular regenerative hyperplasia of the liver.Am J Gastroenterol. 2013; 108: 150-151Crossref PubMed Scopus (7) Google Scholar]. We describe the first case of autosomal dominant inheritance of INCPH in a single family. Fig. 1 demonstrates the autosomal dominant inheritance pattern, including male-to-male transmission. I.6 suffered a fatal variceal haemorrhage and may have also been affected. In this patient however, secondary causes of portal hypertension could not be excluded given the lack of a comprehensive medical record. INCPH was diagnosed in all cases in accordance with criteria proposed by Schouten [[6]Schouten J.N.L. Garcia-Pagan J. Valla D.C. Janssen H.L.A. Idiopathic noncirrhotic portal hypertension.Hepatology. 2011; 54: 1071-1081Crossref PubMed Scopus (202) Google Scholar], excluding II.1 who died prior to liver biopsy being performed. The siblings and children of affected family members have been screened with upper gastrointestinal endoscopies, hepatosplenic ultrasound and full blood examination. II.3, a 67-year old male was referred to our centre in 1999, then aged 52, for liver transplantation assessment. He had been diagnosed with apparent cryptogenic cirrhosis at age 44, based on findings of portal hypertension on computed tomography scanning, in addition to splenomegaly, low-grade hepatic encephalopathy (HE) and thrombocytopaenia. He had required prophylactic endoscopic variceal band ligation for oesophageal varices. He had reported that his older sister (II.1) and paternal uncle (I.6) both had died of variceal haemorrhage. His father (I.2) had also died of portal hypertensive complications in his fifth decade, however he had a history of transfusion-related chronic hepatitis B infection. Over a period of 7 years follow-up the patient developed hepatopulmonary syndrome (HPS), ascites and worsening HE and subsequently underwent orthotopic liver transplantation aged 59. Portopulmonary hypertension was excluded on right-heart catheterisation. INCPH was diagnosed on the explant hepatectomy specimen. The patient remains well seven years post-transplantation, without clinical evidence of recurrent portal hypertension. II.4 was the younger sister of the proband and was referred for liver transplantation assessment at age 53 for progressive HE and HPS. She had been diagnosed with INCPH aged 29, after presenting with recurrent gastro-oesophageal variceal haemorrhage, which was managed with a lienorenal shunt. Intra-operative liver biopsy at the time of her surgical shunt demonstrated changes consistent with INCPH. A repeat liver biopsy at age 53 revealed identical findings. The patient died prior to being waitlisted for liver transplantation due to spontaneous intracranial haemorrhages aged 61. II.1 was the older sister of II.3 who suffered a fatal variceal haemorrhage aged 57. She did not undergo liver biopsy, however serological testing did not have evidence of secondary causes of INCPH. She did not have any risk factors for cirrhosis. III.1 is the nephew of II.3 and is a 54-year old male currently on the waiting list for liver transplantation for severe recurrent HE. He was first diagnosed with INCPH at age 27 following a variceal haemorrhage. He was managed initially with endoscopic sclerotherapy and subsequently variceal band ligation. Liver biopsy at the time excluded cirrhosis. He was stable for many years before developing HE. He has no evidence of HPS. IV.2 is a 29-year old male, who is the son of III.1. He was diagnosed with INCPH aged 22, after an oesophageal variceal haemorrhage. Liver biopsy demonstrated changes consistent with INCPH. He continues to undergo regular endoscopic variceal surveillance and is yet to develop other portal hypertensive complications. The explant hepatectomy from II.3 (Fig. 2A–F) showed nodules of regenerative hepatocytes surrounded by cords of atrophic hepatocytes (nodular regenerative hyperplasia), with congestion. The portal tracts were fibrotic with scarred, obliterated or arterialised portal veins, and slender portal-to-portal or incomplete peri-portal fibrous septa (incomplete septal cirrhosis). Inflammation was negligible. Biliary changes and cholate stasis were attributed to portal hypertensive biliopathy. Remote organised large portal vein thrombosis was favoured to be a secondary complication contributing to progressive liver disease and the need for transplantation. There were no other features to suggest an alternative cause (e.g. steatosis). Taken in the clinical context, these findings were consistent with a diagnosis of INCPH [[7]Hübscher S. Pathology of non-cirrhotic portal hypertension and incomplete septal cirrhosis. Mini-symposium: Liver pathology.Diagn Histopathol (Oxf). 2011; 17: 530-538Abstract Full Text Full Text PDF Scopus (15) Google Scholar]. Review of extant core biopsy material from IV.2 and II.4 suggested a similar pattern of changes (Fig. 2G and H). Reports of core biopsies from III.1 and II.4 describe findings in keeping with same process. To our knowledge, this is the first report of autosomal dominant INCPH. The phenotype of autosomal dominant INCPH appears to have more severe portal hypertensive complications, which are characterised by variceal haemorrhage, HE and HPS, compared to previous series of INCPH [1Khanna R. Sarin S.K. Non-cirrhotic portal hypertension – Diagnosis and management.J Hepatol. 2014; 60: 421-441Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 5Albuquerque A. Cardoso H. Lopes J. Cipriano A. Carneiro F. Macedo G. Familial occurrence of nodular regenerative hyperplasia of the liver.Am J Gastroenterol. 2013; 108: 150-151Crossref PubMed Scopus (7) Google Scholar, 8Hillaire S. Bonte E. Denninger M.-H. Casadevall N. Cadranel J.-F. Lebrec D. et al.Idiopathic non-cirrhotic portal hypertension in the West: a re-evaluation in 28 patients.Gut. 2002; 51: 275-280Crossref PubMed Scopus (228) Google Scholar, 9Krasinskas A.M. Eghtesad B. Kamath P.S. Demetris A.J. Abraham S.C. Liver transplantation for severe intrahepatic noncirrhotic portal hypertension.Liver Transpl. 2005; 11: 627-634Crossref PubMed Scopus (131) Google Scholar, 10Schouten J.N.L. Nevens F. Hansen B. Laleman W. van den Born M. Komuta M. Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.Aliment Pharmacol Ther. 2012; 35: 1424-1433Crossref PubMed Scopus (68) Google Scholar]. The implication of Mendelian inheritance of INCPH in this family is that there may potentially be a single gene or small group of genes responsible for the development of the disorder. Further studies are necessary to investigate the genetic origins of this condition, which may eventually lead to the identification of therapeutic targets for INCPH. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Avik Majumdar – acquisition of data, review and drafting of manuscriptMartin Delatycki – acquisition of data, review and drafting of manuscriptPeter Crowley – acquisition of data, review and drafting of manuscriptJulie Lokan – acquisition of data, review and drafting of manuscriptBenjamin Tharian – acquisition of data, review and drafting of manuscriptPeter Angus – acquisition of data, review and drafting of manuscriptPaul Gow – study concept, review of manuscript, study supervision