Idiopathic non-cirrhotic portal hypertension

Idiopathic non-cirrhotic portal hypertension Sith Siramolpiwat1,2, Susana Seijo3* 1Chulabhorn International College of Medicine, Thammasat University, Pathumthani, 12120, Thailand 2Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand 3CTO, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA


Introduction
Idiopathic non-cirrhotic portal hypertension (INCPH) is characterized by intrahepatic portal hypertension in the absence of cirrhosis or other causes of liver disease and splanchnic venous thrombosis [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] .INCPH is considered a formal rare disease, as endorsed by many rare diseases networks and consortiums (Orpha number: ORPHA64743).INCPH has also been referred as non-cirrhotic portal fibrosis, hepatoportal sclerosis, incomplete septal cirrhosis, obliterative portal venopathy and partial nodular transformation.Histological findings are non-specific and comprise a wide range of features, from minor changes to sinusoidal dilatation, phlebosclerosis and portal fibrosis and nodular regenerative hyperplasia.It is still unclear whether this wide variety of histological changes reflects different stages of the disease, or a wider array of nosologic entities under the term "INCPH" that share the same clinical presentation.A recent retrospective study has shown how patients with obliterative portal venopathy (OPV) and absence of portal hypertension share some clinico-pathological features with INCPH patients and clear portal hypertension manifestations 1,4,5,7,12 .Authors proposed that OPV might represent a pre-symptomatic phase of INCPH.However, this association needs further validation with prospective studies.

Epidemiology
INCPH has a worldwide distribution but it seems to be especially prevalent in Asia (India, Nepal, and Japan) 3,6,10,14,21,22 .In Western series median age at diagnosis is 30-50 years, with a predominance of male gender 6,12,17 .In India the disease has also a male predominance but tend to debut at a younger age 1,15 .Conversely, in Japan there seems to be a female predominance with an onset on the fifth decade 1,3,5,7,8 .Differences in socioeconomic status, living conditions, and ethnicity may also play a role in the different prevalence across series and countries 3,6,8,13,18,23,24 .

Etiology and pathogenesis
The exact pathogenic mechanisms of INCPH remain unclear 1,[5][6][7]18,24 . To dae, five disease categories have been proposed to participate in the pathogenesis of the disease: immunological disorders, prothrombotic conditions, genetic factors, infection agents, and medications/toxins (figure 1 & table 1).Actually, a combination of more than one of these factors is frequently found in these patients.
The unifying hypothesis proposes that repeating microthrombotic events in small or medium branches of portal veins lead to INCPH 1,6,11,12,15 .However, the dual theory suggests that intrahepatic obstruction from obliterative portal venopathy, and an increased splenic blood flow jointly contribute to INCPH 1,5,6,12 .Proposed mechanisms for portal venules obliteration are aberrant coagulation activation or thrombosis, acquired or inherited disorders of vascular remodeling, and endothelial injury from immune cells 1,5,7,34 .Serum connective tissue growth factor, a modulator of potent fibrogenic cytokines, is significantly higher in INCPH patients than in HCV-infected patients or healthy controls 35 .Moreover, an imbalance between intrahepatic vasodilators and vasoconstrictors, a common feature in cirrhosis, has also been reported in hepatic tissue of INCPH patients 36 .A more recent pathogenic theory implicates myfibroblastic changes of portal venule endothelial cells (i.e., endothelial-mesenchymal theory) 37 .

Clinical manifestations
Patients with INCPH usually present with unequivocal signs of portal hypertension (table 1) 4,6,9,11,12,17,21,38 .In a recent series, 60% of patients were asymptomatic at diagnosis; INCPH was diagnosed during the investigation of thrombocytopenia and splenomegaly 6 .In symptomatic cases, variceal hemorrhage was the most frequent initial clinical manifestation.Notably, liver function tests are generally preserved in INCPH patients.This makes variceal bleeding usually well tolerated; with a 6-week mortality rate less than 4% 6,12 .In those patients without variceal bleeding at diagnosis, varices are found in almost 75% at initial endoscopy, mostly of them large, requiring primary prophylaxis 6 .In those without varices or with small varices at diagnosis, the annual incidence of developing varices or varices growth is similar to that reported in compensated cirrhotic patients.In this study, the 1-year probability of developing variceal bleeding despite primary prophylaxis was 9%, and variceal re-bleeding despite secondary prophylaxis was 22% 6 .
Ascites is present in around 30-50% of patients 6,12 .It usually develops in association with other concurrent events (e.g., infection, variceal bleeding).It is mainly transient and easily-controlled by correcting the trigger, and low-dose of diuretics 6,12 .Hepatic encephalopathy is rare.Most reported cases were as a results of trans-jugular intrahepatic portosystemic shunting (TIPSS) placement or triggered by infection 6,12 .Hepatopulmonary syndrome, portopulmonary hypertension and hepatocellular carcinoma have been sporadically reported in INCPH 1,5,7 .
Portal vein thrombosis was reported in up to 40% of cases 6,12,17,19 .HIV patients seem to have a higher risk of developing PVT than those without HIV 6 .Ultrasonographic surveillance for PVT in INCPH, particularly in highrisk patients, is recommended.Whether development of PVT affects the prognosis of INCPH requires further investigation, but it may preclude TIPSS implantation or liver transplantation 5,6,19 .

Diagnosis
The diagnosis requires the exclusion of other causes of liver diseases and/or portal hypertension.The absence of a specific positive diagnostic test probably favors INCPH underdiagnosis since a significant proportion of patients are erroneously diagnosed as cirrhotics 6,27,39 .The diagnosis criteria are 5 : 1) presence of unequivocal signs of portal hypertension (e.g., gastroesophageal varices, ascites, and/ or splenomegaly); 2) absence of cirrhosis, advanced fibrosis or other causes of chronic liver diseases that can cause portal hypertension and; 3) absence of thrombosis of the hepatic veins or of the portal vein.The current diagnostic tests for INCPH are detailed in table 2.
Histology findings in the liver biopsy are non-specific and very heterogeneous, ranging from minor changes to sinusoidal dilatation, phlebosclerosis, portal fibrosis and nodular regenerative hyperplasia.An adequate histological evaluation by an expert liver pathologist is crucial.Table 3 summarizes the morphological findings in the liver biopsy of patients with INCPH.

Treatment
There is no specific therapy for patients with INCPH; treatment is based on managing its complications, mainly portal hypertension and PVT.Data on specific management and prophylaxis of variceal bleeding in INCPH patients are scarce.Expert's opinion recommends following the guidelines of prophylaxis and management of portal hypertension in cirrhotic patients 5,25,26 .A recent cohort study reported good long-term outcome of INCPH by applying a management strategy based on current guidelines for cirrhotic variceal bleeding 6 .TIPSS is an effective alternative in patients who fail to respond to medical and endoscopic therapy.Although portal hypertension related complications are successfully controlled and liver function is usually well preserved, some patients may require a liver transplant (LT).The indications for LT include unmanageable portal hypertension complications, progressive liver failure, chronic hepatic encephalopathy, hepatopulmonary syndrome and hepatocellular carcinoma (table 1).Post-LT outcomes of INCPH patients are good and the disease tends not to recur 27 .However, data on this issue are still limited and mostly based on small cohorts.
Anticoagulation has been proposed to prevent disease progression regardless of PVT.However, there is not enough evidence to recommend this treatment.The potentially added risk of anticoagulation over the portal hypertension bleeding risk needs to be factored in the decision to initiate anticoagulation.It may, however, have a role in patients with underlying prothrombotic diseases or to treat PVT 6,25 .
Many questions remain open such as which patients may benefit from anticoagulation, which is the best drug or what is the optimal duration for anticoagulation.

Prognosis
INCPH patients have a benign long-term outcome, with a 5-year survival of nearly 100% 3,7,12 , which is probably by virtue of preserved liver synthetic function.However,  [43][44][45] Mandatory diagnostic tests 5,7,25 Medical history  over the past few years, studies have shown that some INCPH patients (3-15%) may develop severe liver-related complications that lead to death or liver transplantation 6,11,12 .The 10-year mortality rate of INCPH is between 18 and 44% (table 1).Two recent studies have shown that ascites is a poor predictor of survival 6,12 34 .
Two studies have concordantly shown that immunologic disorders or malignancy have a deleterious impact on INCPH long-term prognosis 6,11 .The study 12 that reported a mortality rate of 37% in INCPH included a significantly higher number of patients with immunologic disorder or malignancy compared to the other studies 6,11 .Whether INCPH patients with these associated disorders should be managed differently, other than correcting complications related to portal hypertension, merits further investigation.

Table 1 :
Clinical characteristics and outcomes of INCPH patients from 8 studiesGuido et al study included also n=94 patients with OPV without any clinical sign of portal hypertension.It should be noted that this study lacks of follow up so it is unknown whether portal hypertension may develop in some of the OPV patients as previously described by Cazals-Hatem et al.

Table 3 :
Histological features associated with INCPH References:

•
42vestigate presence of concomitant diseases • Investigate exposure to drugs, toxins • Investigate familial association Blood test • Rule out other causes of liver diseases (i.e.autoimmune hepatitis, cholestatic diseases, viral hepatitis)• Assess the presence of hypersplenism (i.e.thrombocytopenia, leukopenia, anemia) Determine the presence of radiological signs of portal hypertension such as splenomegaly, collaterals or ascites • Asses the patency of splanchnic venous axis • Assess liver morphology, parenchyma, and biliary tree.Most patients present radiological signs of chronic liver disease (i.e.liver surface nodularity) despite the lack of histologic cirrhosis27.Liver stiffness value is lower than the described cut-off values for diagnosis cirrhosis, varices and CSPH in cirrhosis The spleen/liver stiffness ratio is higher in INCPH compared to cirrhosis and chronic hepatitis42 a•

Table 2 :
Diagnostic tests for INCPHDoppler ultrasound in addition to CT angiography or MRI angiography is recommended b Values for HVPG and liver stiffness than those described for cirrhosis and CSPH can be helpful by ruling out cirrhosis in a patient with signs of PH.Abbreviations: ARFI: Acoustic radiation force impulse; CSPH: clinically significant portal hypertension; HVPG: hepatic venous pressure gradient; NALFD: non-alcoholic fatty liver disease. a . Development of ascites may indicate advance hepatic sinusoidal injury, what suggests severe liver-related complications.A study from Japan that compared the prognosis of patients with ascites in INCPH and cirrhosis and showed how patients with INCPH have a higher rate of variceal bleeding and PVT 34 .Conversely, ascites did not have any impact on INCPH survival as compared with cirrhosis (1-and 5-year survival was 100% in INCPH vs. 69.1% and 34.4% in cirrhosis)