EASL Clinical Practice Guidelines

Idiopathic non-cirrhotic portal hypertension

Introduction

Many disorders are associated with non-cirrhotic intrahepatic PH such as infiltrative diseases, vascular malignancies, schistosomiasis, congenital hepatic fibrosis and sarcoidosis [118]. The diagnosis of idiopathic non-cirrhotic portal hypertension (INCPH) can be made if all these disorders have been excluded and consequently no clear liver disease has been identified (Table 3). The nomenclature of this condition is ambiguous and it has been referred to as hepatoportal sclerosis, non-cirrhotic portal fibrosis, idiopathic PH, incomplete septal cirrhosis and nodular regenerative hyperplasia [119]. Agreement on a uniform nomenclature is an essential requirement. Since the focus of the current guideline is on vascular liver disease, we restrict our recommendations for INCPH which is thought to be caused largely by parenchymal vascular obstruction, while other forms of non-cirrhotic intrahepatic portal hypertension are associated with a large group of distinct liver diseases and presumably have less of a vascular etiology [118]. Thrombophilia, immunological disorders, specific medication (e.g. azathioprine and didanosine) and infections (e.g. HIV infection) have been identified as the major potential causes for portal venous obliteration [[120], [121]]. In Western INCPH patients, a 40% prevalence of thrombophilic disorders has been reported [120].

Table 3
Diagnostic criteria of idiopathic non-cirrhotic portal hypertension.∗


*All criteria must be fulfilled in order to diagnose INCPH. **Splenomegaly must be accompanied by additional signs of portal hypertension in order to fulfil this criterion. †Chronic liver disease must be excluded since severe fibrosis might be understaged on liver biopsy.

Clinical presentation

Clinical presentation is dependent on referral patterns and on the medical specialist who makes the diagnosis (e.g. hepatologist vs. haematologist). In large studies from India the majority of patients present with gastrointestinal haemorrhage related to PH. This is most commonly due to esophageal varices, although gastric varices and portal hypertensive gastropathy can occur in a minority. Commonly, and more often than in other causes of PH (e.g. liver cirrhosis and PVT), a large spleen is observed in patients with INCPH [[120], [122]]. At initial diagnosis, patients present mainly with normal liver function [[120], [121], [122]]. Only a minority demonstrate impaired liver function, mainly in the context of intercurrent conditions. The presence of ascites may be associated with poor survival [121]. Hepatic encephalopathy has been rarely reported but can be found due to massive portosystemic shunting [123].

Diagnosis

Diagnosis of INCPH remains a challenge because there is no single test that can be regarded as a gold standard. Patients with INCPH are often radiologically misclassified as cirrhotic since abdominal ultrasonography in these patients demonstrates liver surface nodularity and thickening of portal vein walls in combination with signs of PH [[120], [121]]. A clue for the correct non-invasive diagnosis of INCPH might be low liver stiffness measurement by transient elastography (<12 kPa) [[108], [124]]. A recent study demonstrated metabolomic analysis as a potential tool for the diagnosis of INCPH [125].

In order to exclude severe fibrosis or cirrhosis, liver histology remains essential in the diagnosis of INCPH. Macroscopical examination often reveals organised thrombi in the large portal vein branches, liver surface nodularity, and liver dysmorphism [126]. In the past, INCPH has been classified morphologically into four different categories: idiopathic PH (equivalent to hepatoportal sclerosis or non-cirrhotic portal fibrosis), nodular regenerative hyperplasia, partial nodular transformation and incomplete septal cirrhosis [119]. However, since all these entities share histopathological characteristics (obliterative vascular lesions), it has been suggested that INCPH can be viewed as a distinct single entity with various pathological aspects, rather than different clinicopathological entities [118]. The most prevalent histological features observed in INCPH patients are phlebosclerosis, nodular regeneration, sinusoidal dilatation, paraportal shunt vessels and perisinusoidal fibrosis [[120], [121], [127]]. Phlebosclerosis is generally regarded as the primary lesion in the development of the intrahepatic haemodynamic changes [128]. Potentially this obliteration of portal venules results in disturbed intrahepatic circulation and subsequently parenchymal remodeling (nodular regeneration). In order to demonstrate the presence of these lesions, large liver specimens containing a sufficient amount of portal tracts are needed (transjugular specimens often are too small). Nevertheless, a sufficient specimen size can show normal liver histology in liver biopsies from INCPH patients.

Natural history

Mortality by variceal haemorrhage in INCPH is significantly lower than that observed in cirrhotic patients, likely because of a preserved liver function [118]. In comparison to patients with cirrhosis a higher incidence of PVT has been reported in patients with INCPH [[120], [121], [129]]. Starting early anticoagulation therapy leads to recanalisation in 54% of patients [129]. A minority of patients develop liver failure over time, which might even necessitate a liver transplantation [[121], [123]]. A poor outcome can be implicated by a precipitating factor or an additional cause for liver damage [120]. Liver function impairment and ascites in these patients can possibly be explained by a reduction in portal flow and subsequently atrophy of the peripheral hepatic parenchyma. Despite low liver-related mortality, overall survival in INCPH patients is lower than generally considered as a result of high mortality related to INCPH associated disorders [121].

Treatment

Treatment and prophylaxis of variceal gastrointestinal bleeding

Data on the management or prophylaxis of variceal bleeding and INCPH are lacking [118]. Endoscopic therapy has been found to be effective in controlling acute variceal bleeding in 95% of the INCPH patients [130]. No data has yet been published regarding endoscopic band ligation in these patients. However, considering the superiority of ligation in patients with cirrhosis or EHPVO, applying this treatment in INCPH patients with varices is preferable. With uncontrolled bleeding, portal systemic shunting by insertion of TIPS should be considered. Although there is literature from India on emergency surgical shunting, this is currently not regarded to be superior to TIPS insertion, which is less invasive. Complications of portosystemic shunting such as hepatic encephalopathy are rare due to the preserved liver function in most of the patients [121]. Endoscopic therapy has been shown to reduce the risk of variceal rebleeding in patients with INCPH [131]. Data are lacking regarding the efficacy of non-selective beta blockers in the setting of INCPH, however in keeping with the good results of bleeding prophylaxis in the setting of cirrhosis we recommend to use the same approach in INCPH patients.

Anticoagulation

Anticoagulation therapy has been proposed by several investigators to prevent disease progression and to maintain portal vein patency [[120], [132]]. However, considering the fact that gastrointestinal bleeding is the main complication and the role of thrombophilia in the pathogenesis is uncertain, this treatment is still debated and cannot be generally recommended. Anticoagulation can only be considered in patients with INCPH with clear underlying prothrombotic conditions or in patients who develop PVT.

Liver transplantation

Several reports describe liver transplantation in the setting of INCPH [[120], [121], [123]]. The indications for liver transplantation are unmanageable PH-related complications and progressive liver failure.