Anticoagulating Budd-Chiari syndrome patients presenting with variceal bleed: A retrospective study.

BACKGROUND AND AIM: This aims to study incidence of re-bleeding on anticoagulation and survival of Budd-Chiari syndrome (BCS) patients presenting with variceal bleeding. METHODS: Budd-Chiari syndrome patients presenting with variceal bleed between 01/01/2007 and 01/05/2019 were retrospectively studied. Patients underwent endoscopic treatment ± endovascular therapy, followed by anticoagulation. Variceal re-bleed (on anticoagulation) and survival were studied. RESULTS: Of 376 BCS patients diagnosed during the study period, 40 (10.7%) patients, presenting with variceal bleed (age 33 [25-40] years; male patients 70%; Rotterdam score 1.13 [0.63-1.22]), Group 1 were compared with 40 randomly selected age-matched BCS patients presenting with ascites, no bleeds (40 [23-42] years; male patients 42.5%; Rotterdam score 1.11 [1.09-1.16]), Group 2. The commonest site of obstruction was hepatic vein (65%) in Group 1 and combined hepatic veins and inferior vena cava (57.5%) in Group 2 (P < 0.01). Thirty-six Group 1 patients underwent endoscopic intervention (variceal ligation, 33; sclerotherapy, 2; glue injection, 1). Endovascular intervention was performed in 30 Group 1 patients (angioplasty ± stent, 22; endovascular shunt, 8) and in 34 Group 2 patients (angioplasty ± stent, 26; endovascular shunt, 8). All 80 patients were started on anticoagulation. Variceal bleed on anticoagulation occurred in five patients in Group 1 and three patients in Group 2. One-year and 5-year survival were 94.2% and 87.5%, respectively, in Group 1 and 100% and 80%, respectively, in Group 2. CONCLUSIONS: About one-tenth of BCS patients present with variceal bleed. On management with endoscopic ± endovascular therapy, followed by anticoagulation, variceal re-bleed in these patients were comparable with those in BCS patients presenting with ascites and survival was excellent at 1 and 5 years.

What makes non-cirrhotic portal hypertension a common disease in India? Analysis for environmental factors.

In India, an unexplained enteropathy is present in a majority of non-cirrhotic intrahepatic portal hypertension (NCIPH) patients. Small intestinal bacterial contamination and tropical enteropathy could trigger inflammatory stimuli and activate the endothelium in the portal venous system. Groundwater contaminated with arsenic is an environmental factor of epidemic proportions in large areas of India which has similar consequences. Von Willebrand factor (a sticky protein) expressed by activated endothelium may promote formation of platelet microthrombi and occlusion of intrahepatic portal vein branches leading to NCIPH. Environmental factors linked to suboptimal hygiene and sanitation, which enter through the gastrointestinal (GI) tract, predispose to platelet plugging onto activated endothelium in portal microcirculation. Thus, NCIPH, an example of poverty linked thrombophilia, is a disease mainly affecting the lower socio-economic strata of Indian population. Public health measures to improve sanitation, provide clean drinking water and eliminate arsenic contamination of drinking water are urgently needed. Till such time as these environmental factors are addressed, NCIPH is likely to remain 'an Indian disease'.

Long-term outcomes following percutaneous hepatic vein recanalization for Budd-Chiari syndrome.

BACKGROUND & AIMS: A proportion of patients with Budd-Chiari Syndrome (BCS) associated with stenosis or short occlusion of the hepatic vein (HV) or upper inferior vena cava (IVC) can be treated with recanalization by percutaneous venoplasty ± HV stent insertion. We studied the long-term outcomes of this approach. METHODS: Single-centre retrospective analysis of patients referred for radiological assessment ± intervention over a 27-year period. Of 155 BCS patients, 63 patients who underwent venoplasty were studied and compared to a previously reported series treated by TIPSS (n = 59). RESULTS: Patients treated with HV interventions (32 venoplasty alone, 31 endovascular stents): mean age, 34.9 ± 10.9; M:F ratio 27:36; median follow-up, 113.0 months; 62% of patients had ≥1 haematological risk factor. Technical success was 100%, with symptom resolution in 73%. Cumulative secondary patency at 1, 5, 10 years was 92%, 79%, 79% and 69%, 69%, 64% in the stenting and venoplasty groups respectively. Where long-term patency was not achieved, 10 patients required TIPSS, and 8 underwent surgery. Actuarial survival at 1, 5, 10 years was 97%, 89% and 85%. When compared to TIPSS, HV interventions resulted in similar patency and survival rates but significantly lower procedural complications (9.5% vs 27.1%) and hepatic encephalopathy (0% vs 18%). Patient age predicted survival following multivariate analysis. CONCLUSIONS: Our data support the stepwise approach to management of BCS, with very good outcomes from venoplasty combined with stenting when required. TIPSS should only be offered where HV interventions are not feasible or unsuccessful.

Good long-term outcome of Budd-Chiari syndrome with a step-wise management.

UNLABELLED: Budd-Chiari syndrome (BCS) is a rare, life-threatening disease caused by obstruction of hepatic venous outflow. The aim of the study was to assess long-term outcome and identify prognostic factors in BCS patients managed by a step-wise approach using anticoagulation, angioplasty/thrombolysis, transjugular intrahepatic portosystemic shunting (TIPS), and orthotopic liver transplantation (OLT). We reviewed long-term data on 157 patients previously included by the European Network for Vascular Disorders of the Liver, a multicenter prospective study of newly diagnosed BCS patients in nine European countries. Patients were followed for a median of 50 months (range, 0.1-74.0). During the study, 88 patients (56%) received at least one invasive intervention (22 patients angioplasty/thrombolysis, 62 TIPS, and 20 OLT) and 36 (22.9%) died. Most interventions and/or deaths occurred in the first 2 years after diagnosis. The Rotterdam score was excellent in predicting intervention-free survival, and no other variable could significantly improve its prognostic ability. Moreover, BCS-TIPS prognostic index (PI) score (based on international normalized ratio, bilirubin, and age) was strongly associated with survival and had a discriminative capacity, which was superior to the Rotterdam score. CONCLUSIONS: The current study confirms, in a large cohort of patients with BCS recruited over a short period, that a step-wise treatment approach provides good long-term survival. In addition, the study validates the Rotterdam score for predicting intervention-free survival and the BCS-TIPS PI score for predicting survival.

Centrifugal technique of plasma exchange and low-dose steroid to treat very severe alcoholic hepatitis patients: A retrospective analysis.

BACKGROUND: Low-volume plasma exchange (PLEX) and low-dose steroid improve survival in severe alcoholic hepatitis. We aimed to compare one-year survival of very severe alcoholic hepatitis (VSAH) patients treated with centrifugal PLEX (cPLEX), membrane PLEX (mPLEX) or standard medical treatment (SMT). METHODS: We retrospectively analyzed survival in consecutive VSAH patients treated at our department from November 2017 to September 2021. PLEX patients received low-volume PLEX along with low-dose steroid (tab. prednisolone 10 mg or 20 mg daily). To adjust for baseline differences between the three treatment (cPLEX, mPLEX or SMT) groups, propensity score (PS) matching was done. Acute-on-chronic liver failure (ACLF) was defined as per European Association for the Study of the Liver (EASL). The primary study outcome was one-year transplant-free survival of PS-matched VSAH patients treated with cPLEX compared to SMT. RESULTS: Of 101 PLEX-eligible VSAH patients, 30 patients were treated with cPLEX, 21 with mPLEX and 50 with SMT. On comparing 30 PS-matched patients each in the cPLEX group vs. the SMT group, transplant-free survival in the cPLEX group was 86.7% at one month, 70% at three months and 52.4% at one year and in the SMT group was 33.3% at one month, 23.3% at three months and 16.7% at one year with hazard ratio (HR [95% CI]) in favor of the cPLEX group (0.29 [0.15-0.56], p < 0.001). Total 21 patients each (PS-matched) in cPLEX and mPLEX groups were compared and one-year survival was better with cPLEX (0.33 [0.16-0.69], p = 0.001). The sub-group analysis of VSAH (PS-matched cohort) patients with ACLF also showed better survival with cPLEX compared to SMT (0.38 [0.17-0.83], p = 0.003) and compared to mPLEX (0.43 [0.17-0.95], p = 0.03). CONCLUSION: Better one-year transplant-free survival was noted among PS-matched VSAH patients treated with cPLEX (and low-dose steroid) compared to SMT (without steroid).

Porto-pulmonary hypertension exacerbated by platelet transfusion in a patient with ADAMTS13 deficiency.

We propose that porto-pulmonary hypertension (PPH) may arise as a consequence of deficiency of ADAMTS13 (a plasma metalloprotease that regulates von Willebrand factor size and reduces its platelet adhesive activity) and provide a clinical case history to support our hypothesis. A patient with non-cirrhotic intrahepatic portal hypertension (NCIPH), ulcerative colitis and celiac disease developed symptoms of PPH, which had advanced beyond levels which would have made her an eligible candidate for liver transplantation (mean pulmonary artery pressure (PAP) 49 mm Hg). She was known to have severe ADAMTS13 deficiency, which we considered to be causative of, or contributory to her NCIPH. We postulated that increasing porto-systemic shunting associated with advancing portal hypertension would make the next encountered vascular bed, the lung, susceptible to the pathogenic process that was previously confined to the portal system, with pulmonary hypertension as its consequence. Her pulmonary artery pressures fell significantly during the next year on weekly replacement of plasma ADAMTS13 by infusions of fresh frozen plasma and conventional drug treatment of her pulmonary hypertension. Her pulmonary artery pressures had fallen to acceptable levels when, in response to platelet infusion, it rose precipitously and dangerously. The sequence strongly supports our hypothesis that PPH is a consequence of ADAMTS13 deficiency and is caused by platelet deposition in afferent pulmonary vessels.

Activation of FoxO3a/Bim axis in patients with Primary Biliary Cirrhosis.

BACKGROUND/AIMS: Impaired regulation of apoptosis has been suggested to play a role in the pathogenesis of Primary Biliary Cirrhosis (PBC). In this study, we analysed a signalling pathway that comprises the transcription factor FoxO3a and its downstream target Bim, a Bcl-2 interacting mediator of apoptosis. MATERIALS & METHODS: The tissues examined included livers explanted from patients with cirrhotic PBC, primary sclerosing cholangitis (PSC), alcoholic liver disease (ALD) and liver biopsies from patients with non-cirrhotic PBC. Large margin resections of hepatocellular carcinoma were used as controls. RESULTS: Expression of FoxO3a and Bim mRNA was significantly enhanced in both non-cirrhotic and end-stage PBC (2.2-fold and 4.3-fold increases, respectively), but not in the other disorders. Similarly, FOXO3a protein level was increased in end-stage PBC (P < 0.05 vs. control). A significant increase in Bim mRNA in non-cirrhotic and cirrhotic PBC was observed (2.2-fold and 8.2-fold respectively). In addition, the most pro-apoptotic isoform of Bim dominated in livers of PBC patients (2.5- fold increase vs. control; P < 0.05). Enhanced FoxO3a and Bim expression was associated with a substantial activation of caspase-3 in PBC (2-fold increase vs. controls; P < 0.0001), whereas it was decreased in both ALD and PSC (46% and 67% reductions respectively). The relationship between FoxO3a and Bim was further investigated in the livers of FoxO-deficient mice. The somatic deletion of FoxO3a caused a significant decrease in Bim, but not caspase-3 protein expression confirming the crucial role of FoxO3a in induction of Bim gene transcription. CONCLUSIONS: Our results imply that the FoxO3/Bim signalling pathway can be of importance in the livers of patients with PBC.

Use of serum vitamin B12 level as a marker to differentiate idiopathic noncirrhotic intrahepatic portal hypertension from cryptogenic cirrhosis.

BACKGROUND AND AIMS: Idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) is often mis-diagnosed as cryptogenic cirrhosis. Serum vitamin B12 levels can be raised in cirrhosis, probably because of excess release or reduced clearance. Because NCIPH is characterised by long periods of preserved liver function, we examined whether serum B12 level could be used as a marker to differentiate NCIPH from cryptogenic cirrhosis. METHODS: We analysed serum B12 levels in 45 NCIPH and 43 cryptogenic cirrhosis patients from January 2009 to September 2011. RESULTS: Serum B12 levels were significantly lower in NCIPH patients than in cryptogenic cirrhosis patients (p < 0.001) and were useful in differentiating the two disorders (area under ROC: 0.84; 95% C.I: 0.76-0.93). Low serum B12 level (≤250 pg/ml) was noted in 25/72 (35%) healthy controls, 14/42 (33%) NCIPH patients, and 1/38 (3 %) cryptogenic cirrhosis patients. In patients with intrahepatic portal hypertension of unknown cause, serum B12 level ≤ 250 pg/ml was useful for diagnosing NCIPH (positive predictive value: 93 %, positive likelihood ratio 12.7), and serum B12 level >1,000 pg/ml was useful in ruling out NCIPH (negative predictive value: 86 %, negative likelihood ratio: 6.67). Low serum B12 levels (≤250 pg/ml) correlated with diagnosis of NCIPH after adjusting for possible confounders (O.R: 13.6; 95% C.I:1.5-126.2). Among patients in Child's class A, serum B12 level was ≤250 pg/ml in 14/35 NCIPH patients compared with 1/21 cryptogenic cirrhosis patients (O.R: 13.3; 95% C.I: 1.6-111). CONCLUSION: Serum vitamin B12 level seems to be a useful non-invasive marker for differentiation of NCIPH from cryptogenic cirrhosis.

A study of aetiology of portal hypertension in adults (including the elderly) at a tertiary centre in southern India.

BACKGROUND & OBJECTIVES: There are only a few studies on aetiology of portal hypertension among adults presenting to tertiary care centres in India; hence we conducted this study to assess the aetiological reasons for portal hypertension in adult patients attending a tertiary care centre in southern India. METHODS: Causes of portal hypertension were studied in consecutive new adult patients with portal hypertension attending department of Hepatatology at a tertiary care centre in south India during July 2009 to July 2010. RESULTS: A total of 583 adult patients (>18 yr old) were enrolled in the study. After non-invasive testing, commonest causes of portal hypertension were cryptogenic chronic liver disease (35%), chronic liver disease due to alcohol (29%), hepatitis B (17%) or hepatitis C (9%). Of the 203 patients with cryptogenic chronic liver disease, 39 had liver biopsy - amongst the latter, idiopathic non cirrhotic intrahepatic portal hypertension (NCIPH) was seen in 16 patients (41%), while five patients had cirrhosis due to non alcoholic fatty liver disease. Fifty six (10%) adult patients with portal hypertension had vascular liver disorders. Predominant causes of portal hypertension in elderly (>60 yrs; n=83) were cryptogenic chronic liver disease (54%) and alcohol related chronic liver disease (16%). INTERPRETATION & CONCLUSIONS: Cryptogenic chronic liver disease was the commonest cause of portal hypertension in adults, followed by alcohol or hepatitis B related chronic liver disease. Of patients with cryptogenic chronic liver disease who had liver biopsy, NCIPH was the commonest cause identified. Vascular liver disorders caused portal hypertension in 10 per cent of adult patients. Cryptogenic chronic liver disease was also the commonest cause in elderly patients.

Focused panel sequencing points to genetic predisposition in non-cirrhotic intrahepatic portal hypertension patients in India.

OBJECTIVE: Non-cirrhotic intrahepatic portal hypertension (NCIPH), a portal microangiopathy affecting small portal vein radicles, is a disease of Indian sub-continent. NCIPH appears to be a complex disease with interactions between inherited and acquired factors, though the exact pathophysiological mechanism is unknown. We aimed at investigating the genetic variants that might contribute to susceptibility to NCIPH. METHODS: In this case-control study, we analyzed genes associated with microangiopathy-VWF-ADAMTS13 (von Willebrand factor and its cleavase enzyme - a disintegrin and matrix metalloprotease with thrombospondin type-1 motifs member 13) and alternative complement system vitamin B12 metabolism and with familial NCIPH. RESULT: Eighty-four Indian patients with liver biopsy-proven NCIPH (cases) and 103 healthy controls (matched for residential region of India) were included in the study. Targeted next-generation sequencing (NGS) panel, comprising 11 genes of interest, was done on 54 cases. Genotyping of selected variants was performed in 84 cases and 103 healthy controls. We identified variants in MBL2, CD46 and VWF genes either associated or predisposing to NCIPH. We also identified a single case with a novel compound heterozygous mutation in MBL2 gene, possibly contributing to development of NCIPH. CONCLUSION: In this first of a kind comprehensive gene panel study, multiple variants of significance have been noted, especially in ADAMTS13-VWF and complement pathways in NCIPH patients in India. Functional significance of these variants needs to be further studied.

Improving Transplant-free Survival With Low-volume Plasma Exchange to Treat Children With Rodenticide Induced Hepatotoxicity.

Background: In a prior report, no patient with rodenticidal hepatotoxicity who met Kochi criteria (MELD score ≥36 or baseline INR ≥6 with hepatic encephalopathy) (PMID: 26310868) for urgent liver transplantation survived with medical management alone. Plasma exchange (PLEX) may improve survival in these patients. Objectives: We describe our experience with low-volume PLEX (PLEX-LV) in treating rodenticide ingestion induced hepatotoxicity in children. Methods: From prospectively collected database of rodenticidal hepatotoxicity patients managed as in-patient with department of Hepatology from December 2017 to August 2021, we retrospectively studied outcomes in children (≤18 years). Hepatotoxicity was categorized as acute liver injury (ALI, coagulopathy alone) or acute liver failure (ALF, coagulopathy and encephalopathy). Kochi criteria was used to assess need for urgent liver transplantation. The primary study outcome was one-month survival. Results: Of the 110 rodenticidal hepatotoxicity patients, 32 children (females: 56%; age: 16 [4.7-18] years; median, range) constituted the study patients. The study patients presented 4 (1-8) days after poison consumption (impulsive suicidal intent:31, accidental:1). Twenty children (62%) had ALI [MELD: 18 (8-36)] and 12 (38%) had ALF [MELD: 37 (24-45)].All children received standard medical care, including N-acetyl cysteine; ALF patients also received anti-cerebral edema measures. None of the patient families opted for liver transplantation. Seventeen children (ALI: 6, ALF: 11) were treated with PLEX-LV (3 [1-5] sessions, volume of plasma exchanged per session: 26 [13-38] ml/kg body weight) and peri-procedure low dose prednisolone.At 1 month, 28 of the 32 children (87.5%) were alive (4 ALF patients died). Of 10 children who met Kochi listing criteria for urgent liver transplantation, two children were ineligible for PLEX-LV (due to hemodynamic instability) and of the remaining 8 children treated by PLEX-LV, 6 (75%) survived. Conclusions: PLEX-LV shows promise as an effective non-liver transplant treatment in children with rodenticidal hepatotoxicity.

Impaired fibrinolysis as a risk factor for Budd-Chiari syndrome.

In Budd-Chiari syndrome (BCS), thrombosis develops in the hepatic veins or inferior vena cava. To study the relationship between hypofibrinolysis and BCS, we measured plasma levels of fibrinolysis proteins in 101 BCS patients and 101 healthy controls and performed a plasma-based clot lysis assay. In BCS patients, plasminogen activator inhibitor 1 (PAI-1) levels were significantly higher than in controls (median, 6.3 vs 1.4 IU/mL, P < .001). Thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor levels were lower than in controls (13.8 vs 16.9 microg/mL and 0.91 vs 1.02 U/L, both P < .001). Median plasma clot lysis time (CLT) was 73.9 minutes in cases and 73.0 minutes in controls (P = .329). A subgroup of cases displayed clearly elevated CLTs. A CLT above the 90th or 95th percentile of controls was associated with an increased risk of BCS, with odds ratios of 2.4 (95% confidence interval, 1.1-5.5) and 3.4 (95% confidence interval, 1.2-9.7), respectively. In controls, only PAI-1 activity was significantly associated with CLT. Analysis of single nucleotide polymorphisms of fibrinolysis proteins revealed no significant differences between cases and controls. This case-control study provides the first evidence that an impaired fibrinolytic potential, at least partially caused by elevated PAI-1 levels, is related to the presence of BCS.

Low Volume Plasma Exchange and Low Dose Steroid Improve Survival in Patients With Alcohol-Related Acute on Chronic Liver Failure and Severe Alcoholic Hepatitis - Preliminary Experience.

Background: Alcohol-related acute on chronic liver failure (A-ACLF) patients have high short-term mortality and are poor candidates for steroid therapy. Plasma exchange (PLEX) improves survival in ACLF patients. We analyzed our experience with low volume PLEX (50% of plasma volume exchanged per session) and low dose steroids to treat A-ACLF patients. Methods: We retrospectively compared the efficacy of low volume PLEX and low-dose steroids with standard medical treatment (SMT) in A-ACLF patients treated at our center between November 2017 to June 2019. The primary study outcome was one-year survival. Results: Twenty-one A-ACLF patients in PLEX group [age 40 (29-56) years, median (range); MELD score 31 (29-46)] and 29 A-ACLF patients in SMT group [age 41.5 (28-63) years, MELD score 37 (21-48)] were studied. All 50 study patients had severe alcoholic hepatitis [mDF 84.7 (50-389)]. PLEX group patients had 3 (1-7) PLEX sessions with 1.5 (1.4-1.6) liters of plasma exchanged per session and oral Prednisolone 20 mg daily, tapered over 1 month. Kaplan Meier analysis showed better survival over 1 year in the PLEX group compared to the SMT group (P = 0.03). There was renal dysfunction in 10 patients in the PLEX group, which normalized in six patients after PLEX. Conclusion: In this preliminary report, compared to SMT, low volume PLEX and low dose steroid improved survival over one year in A-ACLF patients with severe alcoholic hepatitis. In patients with renal dysfunction, 60% showed improvement in renal function with PLEX. Studies with a larger number of patients are needed to validate these results.

Proteomic analysis reveals that apolipoprotein A1 levels are decreased in patients with Budd-Chiari syndrome.

BACKGROUND & AIMS: Budd-Chiari syndrome (BCS) is a rare vascular liver disorder caused by thrombosis of the hepatic veins. In some patients, no known thrombophilic factor can be identified. This study aimed to identify novel factors that might play a role in thrombosis in BCS-patients by using a proteomic approach. METHODS: The abundance of plasma clot-bound proteins was compared between nine BCS-patients and nine controls by using two-dimensional difference gel electrophoresis. The protein with the most significant decrease in patients was identified by mass spectrometry. Plasma levels of this protein were measured and the results were validated in a large cohort of BCS-patients. RESULTS: A total of 26 protein spots significantly differed (p<0.001). The spot that decreased with the highest statistical significance in patients was identified by mass spectrometry as apolipoprotein A1 (apo A1). The mean level of apo A1 in the plasma of these BCS-patients (0.74 g/L) was also significantly lower than in controls (1.45 g/L, p=0.002). This finding was validated in a large cohort of 101 BCS-patients and 101 controls (0.97 g/L vs. 1.32 g/L, p<0.0001). There was no major correlation between plasma levels of apo A1 and various liver function tests. CONCLUSIONS: BCS-patients show decreased clot-bound protein abundance and plasma levels of apo A1. Decreased levels of apo A1 may play a role in the etiology of thrombosis in BCS-patients and possibly in other patients with venous thrombosis.

Idiopathic noncirrhotic intrahepatic portal hypertension is associated with sustained ADAMTS13 Deficiency.

BACKGROUND: 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. AIM: To determine whether the portal microangiopathy in NCIPH is associated with ADAMTS13 deficiency. METHODS: 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. RESULTS: 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). CONCLUSIONS: Sustained deficiency of ADAMTS13 appears characteristic of NCIPH, irrespective of severity of liver disease.

Non-cirrhotic intrahepatic portal hypertension: associated gut diseases and prognostic factors.

BACKGROUND/AIMS: 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. METHODS: We retrospectively analyzed prognostic indicators in 34 NCIPH patients. We also searched for associated gut diseases. RESULTS: 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). CONCLUSIONS: 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.

Reticuloendothelial activation correlates with disease severity and predicts mortality in severe alcoholic hepatitis.

BACKGROUND: Overactivation of reticuloendothelial cells lining liver sinusoids - Kupffer cells (macrophages) and sinusoidal endothelial cells - may narrow the sinusoidal lumen, impair perfusion in liver microcirculation and contribute to disease severity in alcoholic hepatitis. AIM: The aim of the article was to assess reticuloendothelial activation in patients with severe alcoholic hepatitis (SAH). METHODS: In SAH patients, we prospectively studied baseline reticuloendothelial activation markers [serum ferritin, sCD163 and plasma von Willebrand factor (VWF) antigen] and Macrophage Activation Syndrome (MAS) criteria, correlated them with disease severity scores [model for end-stage liver disease (MELD) and Sequential Organ Failure Assessment (SOFA) scores] and analyzed their ability to predict survival over a 90-day follow-up period. RESULTS: A total of 50 SAH patients [45 (37-49) years, median (interquartile range), 49 males, discriminant function, 76.2 (54.5-106.6); MELD score, 30 (26.2-36)] were studied. 41 SAH patients (82%) had ferritin >500 ng/mL, and all (100%) had markedly raised sCD163 and VWF levels. The median sCD163 level was 10-fold higher than healthy controls and the median VWF level was 5-fold above the upper limit of normal. In total, 37 SAH patients (74%) met MAS criteria. Reticuloendothelial activation markers correlated with MELD and SOFA scores (P < 0.05). VWF was an independent marker to predict mortality in SAH [adjusted hazard ratio, 1.002 (1.000-1.004)]. CONCLUSIONS: The reticuloendothelial system was markedly activated and correlated with disease severity scores in SAH patients.VWF predicted short-term mortality independent of MELD and sCD163. Further larger multicentric studies are needed to validate these findings.

Etiology, management, and outcome of the Budd-Chiari syndrome.

BACKGROUND: The Budd-Chiari syndrome (BCS) is hepatic venous outflow obstruction. What is known about the syndrome is based on small studies of prevalent cases. OBJECTIVE: To characterize the causes and treatment of incident BCS. DESIGN: Consecutive case series of patients with incident BCS, enrolled from October 2003 to October 2005 and followed until May 2006. SETTING: Academic and nonacademic hospitals in France, Spain, Italy, Great Britain, Germany, Belgium, the Netherlands, Portugal, and Switzerland. PATIENTS: Persons older than 16 years with definite hepatic outflow obstruction diagnosed by imaging. Persons with hepatic outflow obstruction due to heart failure, sinusoidal obstruction syndrome, cancer, or liver transplantation were excluded. MEASUREMENTS: Signs and symptoms; laboratory and imaging findings; diagnosis; treatment; and overall, transplantation-free, and intervention-free survival. RESULTS: 163 incident cases of BCS were identified. Median follow-up was 17 months (range, 0.1 to 31 months). Most patients (84%) had at least 1 thrombotic risk factor, and many (46%) had more than 1; the most common was myeloproliferative disorders (49% of 103 tested patients). Patients were mainly treated with anticoagulation (140 patients [86%]), transjugular intrahepatic portosystemic shunting (56 patients [34%]), or liver transplantation (20 patients [12%]), and 80 patients (49%) were managed noninvasively. Only 3 patients underwent surgical shunting. The survival rate was 87% (95% CI, 82% to 93%) at 1 year and 82% (CI, 75% to 88%) at 2 years. LIMITATION: Treatment was not standardized across all centers, and data on important clinical variables were missing for some patients. CONCLUSION: Most patients with BCS have at least 1 thrombotic risk factor, and many have more than 1; myeloproliferative disorders are most common. One- and 2-year survival rates are good with contemporary management, which includes noninvasive therapies (anticoagulation and diuretics) and invasive techniques. Transjugular intrahepatic portosystemic shunting seems to have replaced surgical shunting as the most common invasive therapeutic procedure. PRIMARY FUNDING SOURCE: Fifth Framework Programme of the European Commission.

Paroxysmal nocturnal hemoglobinuria in Budd-Chiari syndrome: findings from a cohort study.

BACKGROUND/AIMS: A well recognized cause of Budd-Chiari syndrome (BCS) is paroxysmal nocturnal hemoglobinuria (PNH). PNH is an acquired disorder of hematopoietic stem cells, characterized by intravascular hemolysis and venous thrombosis. Testing for this hematological disorder should be considered in all BCS patients. METHODS: Using data from the EN-Vie study, a multi-center study of 163 patients with BCS, we investigated the relationship between BCS and PNH in 15 patients with combined disease and compared the results to 62 BCS patients in whom PNH was excluded. RESULTS: Median follow-up for the study group (n=77) was 20 months (range 0-44 months). BCS patients with PNH presented with a significantly higher percentage of additional splanchnic vein thrombosis (SVT) as compared to BCS patients without PNH (47% vs. 10%, p=0.002). During follow-up, type and frequency of interventions for BCS was similar between both groups. Six patients with BCS and PNH were successfully treated with a transjugular intrahepatic portosystemic shunt (TIPS). Of 15 patients with PNH, six underwent allogenic stem cell transplantation after diagnosis of BCS. PNH was successfully cured in five cases. There was no significant difference in survival between BCS patients with and without PNH. CONCLUSIONS: This study shows that despite a higher frequency of additional SVT, short-term prognosis of BCS patients with PNH does not differ from BCS patients without PNH. Treatment with TIPS can be safely performed in patients with PNH. Stem cell transplantation appears to be a feasible treatment option for PNH in BCS patients.

TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.

BACKGROUND & AIMS: Budd-Chiari syndrome (BCS) is a rare and life-threatening disorder secondary to hepatic venous outflow obstruction. Small series of BCS patients indicate that transjugular intrahepatic portosystemic shunt (TIPS) may be useful. However, the influence of TIPS on patient survival and factors that predict the outcome of TIPS in BCS patients remain unknown. METHODS: One hundred twenty-four consecutive BCS patients treated with TIPS in 6 European centers between July 1993 and March 2006 were followed until death, orthotopic liver transplantation (OLT), or last clinical evaluation. RESULTS: Prior to treatment with TIPS, BCS patients had a high Model of End Stage Liver Disease and high Rotterdam BCS prognostic index (98% of patients at intermediate or high risk) indicating severity of liver dysfunction. However, 1- and 5-year OLT-free survival were 88% and 78%, respectively. In the high-risk patients, 5-year OLT-free survival was much better than that estimated by the Rotterdam BCS index (71% vs 42%, respectively). In the whole population, bilirubin, age, and international normalized ratio for prothrombin time independently predicted 1-year OLT-free survival. A prognostic score with a good discriminative capacity (area under the curve, 0.86) was developed from these variables. Seven out of 8 patients with a score >7 died or underwent transplantation vs 5 out of 114 patients with a score <7. CONCLUSIONS: Long-term outcome for patients with severe BCS treated with TIPS is excellent even in high-risk patients, suggesting that TIPS may improve survival. Furthermore, we identified a small subgroup of BCS patients with poor prognosis despite TIPS who might benefit from early OLT.