Non-cirrhotic Intrahepatic Portal Hypertension Research Articles

Noncirrhotic portal fibrosis: a rare cause of end-stage liver disease requiring liver transplantation

Non-cirrhotic portal fibrosis (NCPF) is a disease of uncertain etiology characterized by periportal fibrosis and involvement of small and medium branches of the portal vein, resulting in the development of portal hypertension [1]. This has been reported from different parts of the world under a variety of names, such as idiopathic portal hypertension, hepatoportal sclerosis, and noncirrhotic intrahepatic portal hypertension, etc. In India, NCPF formed an important group of patients with portal hypertension, and accounted for 15–30% of all such patients in early nineties [2]. However, its incidence has considerably decreased over time and it is now believed to be a vanishing disease in the subcontinent [1]. Improvement in sanitary conditions and decrease in bacterial infections has lead to a decline in the incidence of the disease. Similar drop in the incidence of new cases has been reported from Japan and other countries [1, 3]. How NCPF differs from cirrhosis of liver has generated immense interest over the years, although at times it may not be possible to differentiate NCPF from Child A cirrhosis of liver. Majority of these patients present with features of portal hypertension and well-tolerated variceal bleeding and have good long-term prognosis [1, 4]. A long-term followup study of 59 patients with noncirrhotic intrahepatic portal hypertension in one hospital over 30-year period showed a 5-year survival of 90% and a 30-year survival of 55% [5]. However, a small proportion of patients do behave like endstage liver disease and develop features of decompensation in the form of ascites, jaundice and hepatic encephalopathy. This subgroup of NCPF with bad liver functions has been recognized and constitutes\10% of the patients, who have mild jaundice, mild ascites and low serum albumin [4, 6]. Nodular transformation of the liver with extensive subhepatic and portal fibrosis has been reported in these patients and the condition constitutes a late manifestation of NCPF. Incomplete septal cirrhosis and nodular regenerative hyperplasia may also be associated with NCPF or idiopathic portal hypertension and may be the late manifestation of this disorder [7–10]. These severe histological changes and abnormal liver function have been infrequently reported and require longer follow-up studies to look into this aspect. There are no large studies that have looked at the subgroup of patients who undergo decompensation; however, in some patients with NCPH, the complications of portal hypertension are sufficiently severe to warrant liver transplantation [7, 11–16]. The study in this issue of Hepatology International shows that small fraction of patients (*5%) do develop ascites, jaundice, and hepatic encephalopathy making it difficult to differentiate it from cirrhosis of liver [17]. Another interesting observation of this study is the overlap NCPF group which has features of both NCPF and cirrhosis and was not reported earlier. This was seen in ten patients in which cause of chronic liver disease was hepatitis C in five, hepatitis B in one and nonalcoholic fatty liver disease (NAFLD) in four patients. All ten patients in this group had characteristic portal vein changes. This may be in continuum with the spectrum of NCPF not defined earlier due to absence of serological markers of hepatitis B and C and recent identification of NAFLD as a cause of significant liver disease; although nodular regenerative hyperplasia and incomplete septal cirrhosis have been reported earlier. The existence of two diseases in a single S. Taneja Y. Chawla R. K. Dhiman (&) Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India e-mail: rkpsdhiman@hotmail.com

Idiopathic Noncirrhotic Intrahepatic Portal Hypertension is Associated with Sustained ADAMTS13 Deficiency

ADAMTS13 deficiency leading to excess ultralarge von Willebrand factor (VWF) multimers and platelet clumping is typically found in thrombotic thrombocytopenic purpura (a type of thrombotic microangiopathy). Idiopathic noncirrhotic intrahepatic portal hypertension (NCIPH) is a microangiopathy of portal venules associated with significant thrombocytopenia and predisposing gut disorders. To determine whether the portal microangiopathy in NCIPH is associated with ADAMTS13 deficiency. Plasma levels of ADAMTS13, anti-ADAMTS13 antibodies, and VWF were compared between cases (NCIPH patients) and controls (with chronic liver diseases of other etiology) matched for severity of liver dysfunction. Eighteen NCIPH patients [median (range) MELD score 12 (7-25)] and 25 controls [MELD score 11 (4-26)] were studied. ADAMTS13 activity was reduced in all 18 NCIPH patients and significantly lower than controls (median, IQR: 12.5%, 5-25% and 59.0%, 44-84%, respectively, P<0.0001) [normal range for plasma ADAMTS13 activity (55-160%)]. ADAMTS13 activity was <5% in 5/18 NCIPH patients (28%) and 0/25 controls (P=0.009). ADAMTS13 antigen levels were also decreased. Sustained low ADAMTS13 levels were seen in four NCIPH patients over 6 weeks to 11 months (highest ADAMTS13 level in each patient: <5%, 6%, 6%, and 25%), despite two patients having MELD score 12. Although nine cases had low titer anti-ADAMTS13 antibodies, there was no significant difference between cases and controls. Abnormally large VWF multimers were observed in 4/11 NCIPH patients (36%) and in 0/22 controls (P=0.008). Sustained deficiency of ADAMTS13 appears characteristic of NCIPH, irrespective of severity of liver disease.

Idiopathic noncirrhotic intrahepatic portal hypertension is an ongoing problem in India

We would like to thank Goel et al. for their reply to our review of idiopathic noncirrhotic portal hypertension (INCPH).1, 2 The authors studied the prevalence of INCPH among all new portal hypertension patients from July 2009 until July 2010. Eventually, 17 (39%) patients were diagnosed with INCPH. The authors described the morphological features observed in liver specimens from these 17 INCPH patients. Interestingly, neither the presence of nodular regenerative hyperplasia nor obliteration of portal venules (phlebosclerosis)—both the most frequently observed morphological features in liver specimens of Western INCPH patients—were found.3, 4 The apparent absence of these features in Indian INCPH patients could imply differences in pathophysiological mechanisms between patients from different continents. As reported by Goel et al., liver biopsy is mandatory in the diagnosis of INCPH. Its main role is the exclusion of liver cirrhosis, which may be very difficult to discern by radiological examinations only. In addition, the diagnosis of INCPH can be suggested or supported by the presence of morphological features such as nodular regenerative hyperplasia, phlebosclerosis, increased number of portal vascular channels, paraportal shunt vessels, and sinusoidal dilatation. However, one must take into account that these features can also be observed in patients without clinical signs of portal hypertension. J.N.L. Schouten M.D.*, H.L.A. Janssen Ph.D.*, * Department of Gastroenterology Hepatology, University Hospital Rotterdam, Rotterdam, The Netherlands.

Idiopathic noncirrhotic intrahepatic portal hypertension is an ongoing problem in India

Idiopathic noncirrhotic intrahepatic portal hypertension is an ongoing problem in India

Non-cirrhotic Intrahepatic Portal Hypertension: Associated Gut Diseases and Prognostic Factors

Non-cirrhotic intrahepatic portal hypertension (NCIPH) is generally regarded to have a benign prognosis. We have studied a cohort followed-up at a tertiary referral center and postulate that gut-derived prothrombotic factors may contribute to the pathogenesis and prognosis of NCIPH. We retrospectively analyzed prognostic indicators in 34 NCIPH patients. We also searched for associated gut diseases. Transplant-free survival in NCIPH patients from first presentation with NCIPH at 1, 5, and 10 years was 94% (SE: 4.2%), 84% (6.6%), and 69% (9.8%), respectively. Decompensated liver disease occurred in 53% of patients. Three (9%) patients had ulcerative colitis while five of 31 (16%) tested had celiac disease and on Kaplan-Meier analysis, celiac disease predicted reduced transplant-free survival (p=0.018). On multivariable Cox regression analysis, independent predictors of reduced transplant-free survival were older age at first presentation with NCIPH, hepatic encephalopathy, and portal vein thrombosis. Prevalence of elevated initial serum IgA anticardiolipin antibody (CLPA) was significantly higher in NCIPH (36% of patients tested), compared to Budd-Chiari syndrome (6%) (p=0.032, Fisher's exact test) and celiac disease without concomitant liver disease (0%) (p=0.007). We have identified prognostic factors and report progression to liver failure in 53% of NCIPH patients followed-up at our center. Our data supports a role for intestinal disease in the pathogenesis of intrahepatic portal vein occlusion leading to NCIPH.

Idiopathic non-cirrhotic intrahepatic portal hypertension: common cause of cryptogenic intrahepatic portal hypertension in a Southern Indian tertiary hospital

Patients with intrahepatic portal hypertension and negative etiological work-up for liver disease are often labeled as having cryptogenic cirrhosis. The aim of this study was to evaluate causes of liver disease in patients with unexplained intrahepatic portal hypertension. We retrospectively analyzed cause of liver disease in all patients with cryptogenic intrahepatic portal hypertension who underwent liver biopsies between June 2005 to June 2007 in our center. Five hundred and seventeen patients underwent liver biopsies of whom 227 had portal hypertension. Of these, the cause of liver disease could not be detected prior to liver biopsy in 62 patients. Causes of liver disease identified after liver biopsy in these 62 patients were: idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) (30 patients, 48%), cirrhosis (14), fatty liver disease (7) and other causes (11). Initial presentations in idiopathic NCIPH patients were splenomegaly and anemia (18 patients), variceal bleed (9) and ascites (3). Median age (range) of patients at first presentation was 32 (15-57) years, and 19 were male. Majority (90%) were in Child's class A. Hepatic vein pressure gradient was <5 mmHg in 2 of 7 NCIPH patients tested. We identified 30 patients with idiopathic NCIPH at our center over the 2 year study period. The clinical presentation and investigations of NCIPH closely mimic cryptogenic cirrhosis. Idiopathic NCIPH should be considered as a differential diagnosis of cryptogenic cirrhosis in India.

Idiopathic Non-Cirrhotic Intrahepatic Portal Hypertension Is Associated with Sustained ADAMTS13 Deficiency.

Idiopathic non-cirrhotic portal hypertension (NCPH) is caused by obliterative venopathy affecting the terminal radicals of the hepatic portal vein. It has been associated with areas of low socio-economic development. We observed a long history of thrombocytopenia and association with enteric disorders in a Caucasian population presenting with NCPH and postulated that the underlying mechanism could be deficiency of ADAMTS13, leading to the circulation of ultra large molecular weight von Willebrand factor (VWF) multimers and consequent platelet aggregate formation, causing occlusion of hepatic portal venules. ADAMTS13 activity was measured in all patients by a collagen binding assay, while antigen and IgG antibody were measured using ELISA kits (American Diagnostica Inc), normal ranges: 66–126%, 485–1242ng/ml and <11AU/ml, respectively. Plasma ADAMTS13 activity and antigen levels were measured in 14 patients with NCPH and 25 control patients with miscellaneous liver diseases associated with portal hypertension and Model for End Stage Liver Disease (MELD) scores indicating similar disease severity, median 12 (IQR 10–14) and 11 (8–16), for NCPH cases and controls. The platelet count was reduced in 13/14 NCPH cases median 69 x109/L (IQR 40–97) and 123 (85–193) in cases and controls, but did not correlate with MELD score or ADAMTS13 activity. ADAMTS13 activity was very low in 13/14 NCPH cases (median 12% (IQR <5–20)) and significantly lower than controls (59% (4–84), p<0.0001). In 4 cases, serial samples over several months revealed consistently low ADAMTS13 levels. There was a corresponding reduction in ADAMTS13 antigen, median 238ng/ml (IQR 186–361) and 584 (442–831), although NCPH cases showed a small excess of antigen over activity (antigen:activity ratio: median 25.7 (IQR 11.3–32.6) and 9.4 (8.1–13.8), in cases and controls, p<0.001), suggesting that an abnormal molecular species could be present. An inhibitor was not detected, although 10 cases and 15 controls had IgG anti-ADAMTS13: median levels 14.8AU/ml (8.8–20.0) and 13.4 (9.0–22.6), but these IgG levels did not correlate with activity. Non-inhibitory IgG antibodies to ADAMTS13 have been previously observed in certain other clinical groups (eg. coronary syndromes, sepsis, etc.). In NCPH, there was no correlation between ADAMTS13 level and either VWF antigen or VWF collagen binding activity. Increased very high molecular weight VWF multimers were observed in 4/11 NCPH cases and 0/22 controls. CD31 positive platelet aggregates were observed in the hepatic vessels of 7/20 (35%) NCPH cases and 1/15 (7%) controls. Our results suggest that sustained deficiency of ADAMTS13 associated with thrombocytopenia is characteristic of NCPH. It differs from other hepatic pathologies, where the decrease in ADAMTS13 has been reported to correlate with the severity of liver disease. NCPH also differs from thrombotic thrombocytopenic purpura because there is a chronic disease process, there is an absence of obvious red cell fragments and the primary organ affected is the liver. Since the predominant plasma source of ADAMTS13 appears to be hepatic stellate cells, the portal microcirculation is most at risk from pathological interactions of VWF and platelets if enteric factors further deplete circulating levels of ADAMTS13. The cause of the decreased ADAMTS13 remains to be elucidated, but could be due to decreased expression and synthesis, immune depletion (IgM and IgA anti-ADAMTS13 have not been investigated), or consumption in the circulation.

Non-cirrhotic intrahepatic portal hypertension

This is an introduction to the Gut tutorial “Non-cirrhotic intrahepatic portal hypertension” hosted on BMJ Learning—the best available learning website for medical professionals from the BMJ Group. The diagnosis of...

A CASE OF NON-CIRRHOTIC PORTAL-SYSTEMIC ENCEPHALOPATHY TREATED BY COIL EMBOLIZATION OF THE PORTASYSTEMIC SHUNT

Introduction: Intrahepatic portal-systemic venous shunts are defined as communication between the portal and the systemic venous circulation, measuring more than 1mm in diameter, and at least partially located inside the liver. The cause of this condition is disputed in many cases. It may be congenital or acquired secondary to portal hypertension. Here we describe a case of portal-systemic encephalopathy due to a spontaneous large-caliber portal-hepatic venous shunt. The encephalopathy was corrected with the treatment of the shunt. Case presentation: A 72-year-old man presented with recurrent episodes of change in mental status. His past medical history was unremarkable without history of hepatitis or cirrhosis. No history of trauma. Liver function was normal except for an elevated ammonia level. Hepatitis panel was negative. AMA, ANA and ASMA were all within normal limits. Abdominal ultra-sonography showed a large caliber portal-hepatic venous shunt in the posterior right lobe. Percutaneous transhepatic portography and hepatic venous angiogram were confirmatory. The treatment with coil embolization was successful, and his encephalopathy resolved postoperatively. Patient has been doing fine on one year follow up without recurrence of his encephalopathy. Discussion: A large intrahepatic portal-hepatic venous shunt is a rare condition. Most of the cases are primary as a congenital fistula or secondary to blunt trauma, hepatic tumor or liver biopsy. Spontaneous portal-hepatic shunt is very rare especially in non-cirrhotic patients. Most of these are asymptomatic discovered incidentally during imaging study done for not related causes. Few cases of portal hypertension had been reported secondary to intrahepatic portal shunt. Non-cirrhotic intrahepatic portal hypertension is difficult to evaluate. Encephalopathy secondary to porto-systemic shunt is seen mostly in patients with concomitant cirrhosis. The dramatic improvement of this patient's encephalopathy after the embolization of the shunt indicate that his encephalopathy was related at least in part to the shunt. Possibilities for treatment of such condition include embolization by interventional radiologist or surgery. The etiology of the shunt in this patient is unclear. Given the age of the patients and the absence of history of cirrhosis ortrauma, the shunt is thought to be spontaneous.

NONCIRRHOTIC PORTAL HYPERTENSION

This article reviews the different conditions leading to noncirrhotic intrahepatic portal hypertension, describes the related vascular lesions, and provides a review of the clinical characteristics, diagnosis, and treatment options available. Diseases associated with noncirrhotic portal hypertension are also specifically discussed.

Noncirrhotic intrahepatic portal hypertension.

Portal hypertension, widely recognized as a complication of cirrhosis, may also develop as an intrahepatic consequence of numerous hepatic disorders in the absence of cirrhosis. When gastrointestinal bleeding occurs in such cases, ruptured esophageal varices must be considered. Among chronic liver diseases, some, such as schistosomiasis, are commonly associated with portal hypertension and its complications. In others, including tuberculosis, amyloidosis, and polycystic disease, well-documented portal hypertension has been reported in only a small minority of cases. Nevertheless, because of the ever-present possibility of variceal hemorrhage whenever portal hypertension occurs, clinicians should be aware of these disorders. Acute conditions associated with noncirrhotic intrahepatic portal hypertension include acute (and particularly fulminant) viral or drug-induced hepatitis, acute alcoholic hepatitis, acute veno-occlusive disease, and acute fatty liver of pregnancy. Portal hypertension may be reversible following recovery in these settings. Particular attention is called to the increasing frequency of acute veno-occlusive disease on bone marrow transplant units, presumably as a complication of high-dose chemo- and radiotherapy.

Pregnancy following the surgical treatment of portal hypertension

The course and results of 10 pregnancies in 7 patients who had undergone surgical treatment up to 9 years previously for portal hypertension are described. Four patients had extrahepatic portal hypertension, two had noncirrhotic intrahepatic portal hypertension, and one had frank biliary cirrhosis. Eight live babies were produced with no maternal deaths; the commonest complication was anemia during pregnancy, but only one patient bled from esophageal varices after shunting. Pregnancy after decompression operations and in extrahepatic obstruction is reviewed, and the particular hazards associated with pregnancy are discussed.

Prolonged survival after portal decompression of patients with non-cirrhotic intrahepatic portal hypertension.

In a series of 251 good-risk patients undergoing portal decompression for intrahepatic portal hypertension, one fifth have been found not to have hepatic cirrhosis. Of these, 44 had only minor changes in hepatic architecture, and the clinical features and subsequent course have been compared and contrasted with a group of 201 cirrhotic patients who underwent portal decompression for similar indications. The degree of portal hypertension was comparable in both groups and it was not possible confidently to differentiate the condition from hepatic cirrhosis on either clinical or biochemical grounds in the individual case. The histological lesion was not progressive in the non-cirrhotic group and this was reflected in the far better survival of these patients. After five years 83% (30 of 36) of this group were alive compared with 43% (65 of 152) of the cirrhotic patients. After 10 years the cumulative survival was 77% (20 of 26) for those without cirrhosis, contrasted with 22% (19 of 87) for the cirrhotic patients.