If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Clinical Genetics, Austin Hospital, Melbourne, Victoria, AustraliaBruce Lefroy Centre, Murdoch Childrens Research Institute, Victoria, Australia
The familial aggregation idiopathic non-cirrhotic portal hypertension (INCPH) has been previously described, however, there have been no reports of Mendelian inheritance [
]. 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 [
], 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.
Fig. 1Autosomal dominant inheritance pattern of affected family members with non-cirrhotic portal hypertension. “Possibly affected” denotes family member with fatal variceal haemorrhage of unclear aetiology due to incomplete medical record.
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.
Case 2
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.
Case 3
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.
Case 4
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.
Case 5
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 [
]. 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.
Fig. 2Liver explant histopathology from II.3 (A–F), core biopsy from II.4 (G) and core biopsy from IV.2 (H). (A) Features of incomplete septal cirrhosis are seen with portal fibrous expansion and occasional delicate septa, but no well-developed nodularity or advanced fibrosis (trichrome stain, 40×). (B) Small portal tract with absent portal vein (trichrome, 200×). (C) Portal tract containing nodular fibrous scar at the site of portal vein branch (H&E, 200×). (D) Periportal hyperplasia and zone 3 atrophy with congestion (H&E, 100×). (E) Arterialised and narrowed portal vein branch (H&E, 200×). (F) Portal tract showing portal vein ectasia / “shunt vessels” (H&E, 100×). (G) Core biopsy from II.4 (aged 51) showing zonal congestion and atrophy with periportal hyperplasia, features suggesting nodular regenerative hyperplasia. There was also subtle architectural distortion, but no fibrosis (H&E, 200×). (H) Core biopsy from IV.2 (aged 22) showing subtle zones of atrophy and compression, with areas of regenerative hyperplasia, and delicate portal/periportal septa (reticulin stain, 100×). There were mildly prominent portal vein branches at the periphery of some portal tracts, and one large tract lacked an appropriately sized portal vein. There was no evidence of established cirrhosis. (This figure appears in colour on the web.)
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 [
]. 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.
Conflict of interest
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.
Author contributions
Avik Majumdar – acquisition of data, review and drafting of manuscript
Martin Delatycki – acquisition of data, review and drafting of manuscript
Peter Crowley – acquisition of data, review and drafting of manuscript
Julie Lokan – acquisition of data, review and drafting of manuscript
Benjamin Tharian – acquisition of data, review and drafting of manuscript
Peter Angus – acquisition of data, review and drafting of manuscript
Paul Gow – study concept, review of manuscript, study supervision
References
Khanna R.
Sarin S.K.
Non-cirrhotic portal hypertension – Diagnosis and management.
00194-4&id=gr1.jpg){kind=link}
00194-4&id=gr2.jpg){kind=link}