Understanding the Similarities and Differences between Hepatic and Pulmonary Veno-Occlusive Disease.

Hepatic veno-occlusive disease (HVOD), alias sinusoidal obstruction syndrome, may develop as a complication of chemotherapy in the setting of hematopoietic stem cell transplantation. HVOD is less frequently described after exposure to chemotherapy in the nontransplant setting and can also be a complication after ingestion of toxins, such as pyrrolizidine alkaloids. Veno-occlusive disease may also affect the lungs, and it is therefore termed pulmonary veno-occlusive disease (PVOD). Similarly, PVOD can develop after exposure to chemotherapeutic agents in the treatment of solid and hematological malignancies. In addition, PVOD has also been linked to autoimmune disorders and occupational solvent exposure. Finally, the heritable form of PVOD is due to biallelic mutations of the EIF2AK4 gene. Both HVOD and PVOD share common histopathological features and pathophysiologic mechanisms. Both clinical disorders are rare complications that can appear after exposure to the common inciting trigger of chemotherapeutic agents. The present review aims to summarize the current knowledge of HVOD and PVOD and to describe both similarities as well as differences regarding both conditions.

Recent developments in the field of vascular liver diseases.

Knowledge in the field of vascular liver disease is continuously expanding. The present update will discuss recent data on i) the Abernethy malformation in adults; ii) portal vein thrombosis in cirrhosis; iii) advancing expertise in recanalization of the portal vein and iv) experience in using direct oral anticoagulants in the field of vascular liver disease.

Safety of supramesocolic surgery in patients with portal cavernoma without portal vein decompression. Large single centre experience.

BACKGROUND: Supra-mesocolic surgery (SMS) is complicated in patients with portal vein cavernoma (PC) and portal decompression is recommended. The aim of this study was to report a large single centre of SMS in patients with PC without portal decompression. METHODS: Between 2006 and 2013, all patients who met inclusion criteria were analyzed retrospectively. The primary endpoint was the feasibility rate, surgical and postoperative outcome. The secondary endpoints were the long-term outcome of patients who underwent biliary bypass for cholangitis. Risk factors for complications were studied. RESULTS: Thirty patients underwent 51 procedures. Pancreatitis was the main etiology of PC (19/30) and biliary obstruction was mainly related to the underlying disease and not to portal cholangiopathy (12/14). All planned procedures were successfully completed. Fourteen patients underwent biliary bypass. Median blood loss (250 ml), transfusion (n = 7), mortality (n = 0), overall morbidity (n = 12) and the median hospital stay (10 days). Good long-term control of cholangitis was achieved in the 9 patients alive with available follow-up. Significant risk factors for complications were a previous abdominal wall scar, previous intra-abdominal surgical field and liver fibrosis. CONCLUSION: SMS can be safely performed in patients with PC. In patients with risk factors for complications, portal decompression should be discussed.

Interplay of Inflammation and Endothelial Dysfunction in Bone Marrow Transplantation: Focus on Hepatic Veno-Occlusive Disease.

Endothelial cells are unique multifunctional cells with basal and inducible metabolic and synthetic functions. Various stimuli can induce physiological or pathological changes in endothelial cell biology. Hematopoietic stem cell transplantation (HSCT) requires high-dose irradiation and/or chemotherapy and is associated with increased risk of bacterial infections and immune reactions. These factors can affect endothelial cells. This review provides an overview of the effects of HSCT on endothelial cells, based on findings observed in cultured cells as well as in patients. We first describe to what extent irradiation and chemotherapy constitute direct and indirect triggers for endothelial cell activation and injury. Then, we highlight the role of the endothelium in several complications of HSCT, including capillary leak syndrome, engraftment syndrome, transplant-associated microangiopathy, graft-versus-host disease, and diffuse alveolar hemorrhages. We also analyze in detail available data on sinusoidal obstruction syndrome, previously known as veno-occlusive disease of the liver, where liver sinusoidal endothelial cells are first injured and eventually lead to sinusoid occlusion and liver cell damage. Finally, we open the question of the possible contribution of endothelial damage to cardiovascular events occurring long after HSCT.

The coagulation system in patients with end-stage liver disease.

In patients with cirrhosis, routine laboratory tests for primary hemostasis and coagulation usually show anomalies that are associated with excess bleeding in other settings, in particular low platelet counts and prolonged prothrombin time. However, under conditions similar to those in vivo, primary hemostasis and thrombin production do not appear to be decreased in patients with cirrhosis, particularly when the platelet count is above 75,000/µl. Furthermore, there is laboratory and epidemiological evidence of a mild procoagulant and prothrombotic state in patients with cirrhosis. Bleeding is mainly because of portal hypertension rather than defective hemostasis. There is some evidence that anticoagulation therapy is not associated with an excess of severe bleeding and that it could improve the outcome in patients without portal vein thrombosis. At present, there is no clear evidence that portal vein thrombosis is responsible for the progression of liver disease and that anticoagulation therapy would improve the outcome of patients with portal vein thrombosis.

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.

Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis.

Myeloproliferative neoplasms (MPNs) are the most common cause of Budd-Chiari syndrome (BCS) and nonmalignant, noncirrhotic portal vein thrombosis (PVT). In this meta-analysis, we determined the prevalence of MPNs and their subtypes as well as JAK2V617F and its diagnostic role in these uncommon disorders. MEDLINE and EMBASE databases were searched. Prevalence of MPNs, JAK2V617F, and MPN subtypes were calculated using a random-effects model. A total of 1062 BCS and 855 PVT patients were included. In BCS, mean prevalence of MPNs and JAK2V617F was 40.9% (95% CI, 32.9%-49.5%) and 41.1% (95% CI, 32.3%-50.6%), respectively. In PVT, mean prevalence of MPNs and JAK2V617F was 31.5% (95% CI, 25.1%-38.8%) and 27.7% (95% CI, 20.8%-35.8%), respectively. JAK2V617F and MPNs were more frequent in BCS compared with PVT (P = .03 and P = .09, respectively). Polycythemia vera was more prevalent in BCS than in PVT (P = .001). JAK2V617F screening in splanchnic vein thrombosis (SVT) patients without typical hematologic MPN features identified MPN in 17.1% and 15.4% of screened BCS and PVT patients, respectively. These results demonstrate a high prevalence of MPNs and JAK2V617F in SVT patients and show differences in underlying etiology between these disorders. Furthermore, these results validate routine inclusion of JAK2V617F in the diagnostic workup of SVT patients.

The JAK2 46/1 haplotype in Budd-Chiari syndrome and portal vein thrombosis.

The germline JAK2 46/1 haplotype has been associated with the development of JAK2(V617F)-positive as well as JAK2(V617F)-negative myeloproliferative neoplasms (MPNs). In this study we examined the role of the 46/1 haplotype in the etiology and clinical presentation of patients with splanchnic vein thrombosis (SVT), in which MPNs are the most prominent underlying etiological factor. The single-nucleotide polymorphism rs12343867, which tags 46/1, was genotyped in 199 SVT patients. The 46/1 haplotype was overrepresented in JAK2(V617F)-positive SVT patients compared with controls (P < .01). Prevalence of the 46/1 haplotype in JAK2(V617F)-negative SVT patients did not differ from prevalence in the controls. However, JAK2(V617F)-negative SVT patients with a proven MPN also exhibited an increased frequency of the 46/1 haplotype (P = .06). Interestingly, 46/1 was associated with increased erythropoiesis in JAK2(V617F)-negative SVT patients. We conclude that the 46/1 haplotype is associated with the development of JAK2(V617F)-positive SVT. In addition, our findings in JAK2(V617F)-negative SVT patients indicate an important role for the 46/1 haplotype in the etiology and diagnosis of SVT-related MPNs, independent of JAK2(V617F), that requires further exploration.

High-b-value diffusion-weighted MR imaging of benign hepatocellular lesions: quantitative and qualitative analysis.

PURPOSE: To analyze the signal intensity (SI) of benign hepatocellular lesions in high-b-value diffusion-weighted (DW) magnetic resonance (MR) images and to compare the apparent diffusion coefficient (ADC) values of focal nodular hyperplasias (FNHs) with those of hepatocellular adenomas (HCAs). MATERIALS AND METHODS: This retrospective study was approved by institutional review board, with waiver of informed consent. Inclusion criteria were consecutive patients with diagnosed FNH or HCA who underwent MR imaging with a DW sequence of the liver at three b values, 0, 150, and 600 sec/mm2. The final study population included 67 patients (seven men, 60 women) with 90 hepatocellular lesions (54 FNHs, 36 HCAs). The mean ADC was compared between the lesions and the liver. Receiver operating characteristic analysis was performed to evaluate the diagnostic value of ADC for differentiating HCAs and FNHs. RESULTS: The mean ADC value of all FNHs and HCAs was significantly lower than that of the liver (P=.004). An ADC ratio below 15% was observed in 50 of 54 (93%) FNHs and in 29 of 36 (81%) HCAs. The mean ADC value of FNHs was significantly higher than that of HCAs (P<.001). The area under the receiver operating characteristic curve was 0.760. With a cutoff value of 1.37×10(-3) mm2/sec, the sensitivity and specificity for differentiating HCA from FNH were 70% and 76%, respectively. There was no significant difference in ADC values between HCA subtypes. The SI of most FNHs and HCAs (78 of 90, 87%) increased with increasing b values, whereas none showed a decrease in SI with increasing b values. When the DW MR criteria for benign and malignant liver tumors were applied, 44 of 90 (49%) lesions would have been considered malignant lesions, whereas the other lesions (46 of 90, 51%) would have been considered indeterminate. CONCLUSION: On DW MR images, benign hepatocellular lesions often show findings that suggest restricted diffusion.

Obliterative portal venopathy: findings at CT imaging.

PURPOSE: To retrospectively analyze the computed tomographic (CT) findings in a single-center series of adult patients with biopsy-proved obliterative portal venopathy (OPV) and to compare them with those observed in patients with cirrhosis. MATERIALS AND METHODS: The requirement for informed consent was waived. This institutional review board-approved study included 42 consecutive patients with a histologically proved diagnosis of OPV who underwent CT at diagnosis. The clinical characteristics at diagnosis were recorded, and CT examination results were reviewed. Two radiologists evaluated portal vein patency and intrahepatic portal branches, the morphologic changes in the liver, the presence of hepatic nodules, and signs of portal hypertension in consensus. The control group consisted of 42 patients who had histologically proved cirrhosis. CT findings were compared between the OPV patient group and the cirrhotic group and also among the conditions associated with patients with OPV. The Fisher exact test was used. P values of .05 or less were considered to indicate significant differences. RESULTS: The following CT findings were observed significantly more frequently in OPV than in cirrhosis: extrahepatic portal vein thrombosis (18 [43%] of 42 vs five [12%] of 42); intrahepatic portal abnormalities (18 [58%] of 31 vs one [2%] of 42) such as reduced caliber, occlusive thrombosis, and lack of visibility; focal nodular hyperplasia-like nodules (six [14%] of 42 vs 0 [0%] of 42); and perfusion disorders (15 [36%] of 42 vs six [14%] of 42). Conversely, the combination of hypertrophy of the caudate lobe and atrophy of segment IV (27 [64%] of 42 vs 10 [24%] of 42) and nodular surface (37 [88%] of 42 vs seven [17%] of 42) were seen significantly more often in cirrhosis. CONCLUSION: Characteristic CT findings in patients with OPV that differ from those in patients with cirrhosis were shown, the most common being the presence of intra- or extrahepatic portal abnormalities.

Idiopathic noncirrhotic portal hypertension.

Idiopathic noncirrhotic portal hypertension (INCPH) is characterized by an increased portal venous pressure gradient in the absence of a known cause of liver disease and portal vein thrombosis. In contrast to the high prevalence of this disorder in India, INCPH is a rare disease in the Western world. The etiology of INCPH can be divided in five categories: chronic infections, exposure to medication or toxins, thrombophilia, immunological disorders, and genetic disorders. Multifactorial etiology can also be encountered. Chronic abdominal infection is incriminated as the most important etiological factor in Eastern patients and thrombophilia in Western patients. The majority of patients with INCPH initially present with signs or complications of portal hypertension (mainly variceal bleeding and splenomegaly). These patients usually have preserved liver function. Liver function impairment occurs mainly in the context of intercurrent conditions. Patients with INCPH are often clinically and radiologically misdiagnosed as liver cirrhosis, so that a liver biopsy is indispensable to discriminate cirrhosis from INCPH. Histopathological characteristics of INCPH are heterogeneous, demonstrating overlap between several pathological entities (e.g., hepatoportal sclerosis, nodular regenerative hyperplasia, and incomplete septal cirrhosis). Even though hemodynamical changes in INCPH patients are not comparable to those in cirrhotics, prophylaxis and treatment of variceal bleeding are recommended to be similar. Anticoagulation therapy must be considered only in patients who develop portal vein thrombosis. INCPH has been considered a disorder with a relatively benign disease course. However, liver failure, hepatic encephalopathy, and hepatopulmonary syndrome can occur and are considered indications for liver transplantation.

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.

Obliterative portal venopathy: portal hypertension is not always present at diagnosis.

BACKGROUND & AIMS: Previous studies on obliterative portal venopathy (OPV) have been biased due to the selection of patients with non-cirrhotic portal hypertension. The aim of this study was to clarify the characteristics of OVP diagnosed by liver biopsy. METHODS: Fifty-nine consecutive patients with OPV were retrospectively selected on strict histological criteria. Clinical, laboratory, portal vein patency, and associated disorders potentially involving vascular alterations were analyzed. The occurrence of complications was recorded during follow-up. RESULTS: Mean age at diagnosis was 38.5±15 years old. Initial presentation was portal hypertension (64% of patients) and/or extrahepatic portal vein thrombosis (EHPVT) (22%) or isolated abnormal laboratory tests (20%). Associated diseases found at diagnosis were: prothrombotic disorders (30% of patients) and immune-mediated disorders (17%); 53% of patients had no causal factor (idiopathic OPV). During follow-up (median 8.6 years, range 1-23 years), features of portal hypertension worsened in 46% of patients; EHPVT and portal hypertension were finally found in 44% and 88% of patients. Anti-coagulation and beta-blockers were administered in 47% and 59% of patients, respectively. Severe complications (liver transplantation and/or death) occurred in 11 (19%) patients, 8 had idiopathic OPV. Patients with prothrombotic disorders received earlier anticoagulation therapy; all survived without transplantation. CONCLUSIONS: A confident diagnosis of OPV can be done by biopsy and is conceivable in patients under 40 years without clinically significant portal hypertension. Poor outcome was noted in 19% of patients, most of them affected with idiopathic OPV. Patients with prothrombotic disorders received early anticoagulation and appeared to have a better outcome despite a high proportion of EHPVT.

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.

The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases.

Myeloproliferative diseases (MPDs) represent the commonest cause of splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT), but their diagnosis is hampered by changes secondary to portal hypertension, while their influence in the outcome of SVT remains unclear. We assessed the diagnostic and prognostic value of JAK2 and MPL515 mutations in 241 SVT patients (104 BCS, 137 PVT). JAK2V617F was found in 45% of BCS and 34% of PVT, while JAK2 exon 12 and MPL515 mutations were not detected. JAK2V617F was found in 96.5% of patients with bone marrow (BM) changes specific for MPD and endogenous erythoid colonies, but also in 58% of those with only one feature and in 7% of those with neither feature. Stratifying MPD diagnosis first on JAK2V617F detection would have avoided BM investigations in 40% of the patients. In BCS, presence of MPD carried significantly poorer baseline prognostic features, required hepatic decompression procedures earlier, but had no impact on 5-year survival. Our results suggest that JAK2V617F testing should replace BM investigations as initial test for MPD in patients with SVT. Underlying MPD is associated with severe forms of BCS, but current therapy appears to offset deleterious effects of MPD on the medium-term outcome.

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.