Federica Fabris

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.

Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis

The diagnosis of an underlying chronic myeloproliferative disorder (CMPD) is often problematic in patients with primary extrahepatic portal vein obstruction (EHPVO) or Budd‐Chiari syndrome (BCS); indeed, conventional clinical and hematological parameters usually yield insufficient information. To assess the diagnostic contribution of the gain‐of‐function mutation V617F of the JAK2 gene, 93 patients with EHPVO or BCS were investigated. JAK2 V617F was identified in 35.6% of 73 patients with EHPVO and in 40% of 20 patients with BCS. Taking the JAK2 mutation as a test with the highest positive predictive value for the diagnosis of CMPD, conventional clinical‐hematological parameters had a sensitivity for CMPD lower than 48%. Bone marrow (BM) histology provided a diagnosis of CMPD in 41/74 (55.4%) patients, with a sensitivity of 93.5%. Clonality of hematopoiesis as assessed by granulocyte X‐chromosome inactivation was present in 65.1% of 43 informative female patients, with a sensitivity of 86.6%. By resolving the sensitivity bias of the JAK2 mutation with the results of BM histology and clonality assay, CMPD was diagnosed in 53% of patients with EHPVO or BCS. In conclusion, CMPD is the major cause of primary EHPVO or BCS. JAK2 V617F is a very reliable and noninvasive molecular marker for CMPD and should be used as a first test for diagnosis. (HEPATOLOGY 2006;44:1528–1534.)

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.

Risk factors for thrombophilia in extrahepatic portal vein obstruction

Scant information exists on the role of thrombophilia in extrahepatic portal vein obstruction (EHPVO). We studied 65 patients with EHPVO, 500 with deep vein thrombosis (DVT) of the lower limbs, and 700 healthy controls referred for thrombophilia screening, including the search for gain‐of‐function mutations in genes encoding coagulation factor V (factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocysteinemia. At least one abnormality in the thrombophilia screening was found in 40% of patients with either EHPVO or lower limb DVT and in 13% of controls, for odds ratios of 4.0 (95% CI, 2.3–7.0) and 4.4 (95% CI, 3.3–5.9), respectively. Statistically significant associations with EHPVO were observed for the prothrombin G20210A mutation (odds ratio, 8.1; 95% CI, 3.8–17.5) and the deficiencies of antithrombin, protein C, or protein S taken together (odds ratio, 4.5; 95% CI, 1.1–18.0). The odds ratio for the prothrombin G20210A was approximately twice that for lower limb DVT. Patients with factor V Leiden had an odds ratio for EHPVO of 0.8 (95% CI, 0.1–6.4) and for lower limb DVT of 7.5 (95% CI, 4.4–13.0). The odds ratio for EHPVO in patients with hyperhomocysteinemia was 2.0 (95% CI, 0.9–4.9). At variance with lower limb DVT, oral contraceptive use was not associated with an increased risk of EHPVO. Myeloproliferative disorders were diagnosed in 35% of patients with EHPVO. In conclusion, the risk for EHPVO is increased in the presence of thrombophilia resulting from the prothrombin G20210A mutation and from the deficiencies of the naturally occurring anticoagulant proteins, but not from factor V Leiden. (HEPATOLOGY 2005;41:603–608.)

The international normalized ratio calibrated for cirrhosis (INRliver) normalizes prothrombin time results for model for end‐stage liver disease calculation

The model for end‐stage‐liver‐disease (MELD) is a mathematical score used to prioritize patients for liver transplantation and includes results for creatinine, bilirubin, and prothrombin time (PT) expressed as international normalized ratio (INR). The rationale of using the MELD rests on the assumption that the score would be the same across the country if the methods used to measure the variables yield the same numerical results regardless of the testing laboratory. Evidence was provided that specific methodologies may influence the MELD, and the PT‐INR was identified as the most important. This study was designed to provide information on the between‐thromboplastin variability and to explore alternatives to obviate such variability. Fifty‐seven patients with cirrhosis were selected, and their PTs were measured with 7 thromboplastins. The thromboplastins were previously calibrated by testing plasmas from patients on vitamin K antagonists and healthy subjects to assign the international sensitivity index (ISIvka) needed to convert PT into INR. Each of the thromboplastins was also assigned an ISIliver by substituting in the calibration the plasmas from vitamin K antagonist patients with plasmas from patients with cirrhosis. INR and MELD values for individual patients were calculated by using the ISIvka or the ISIliver. The mean INRvka obtained with the 7 thromboplastins were significantly different (P < 0.001). Conversely, the mean INRliver were not. Similarly, the mean MELDvka were significantly different (P < 0.001), but those differences were abrogated for the MELDliver. Conclusion: The alternative thromboplastin calibration using plasmas from patients with cirrhosis instead of from vitamin K antagonist patients is feasible and may resolve the variability of the MELD to prioritize patients for transplantation. (HEPATOLOGY 2007.)

The coagulopathy of cirrhosis assessed by thromboelastometry and its correlation with conventional coagulation parameters

BACKGROUND Thromboelastometry allows continuous registration of the blood viscoelastic changes upon activation by cephaline or tissue-factor plus calcium-chloride. The technique is used as a near-patient-testing device to guide transfusion in cardiac surgery or liver transplantation and less to investigate hemostasis in acquired or congenital coagulopathies. AIMS (i) Review of the coagulopathy associated with cirrhosis and (ii) report on its investigation by thromboelastometry in comparison with conventional coagulation parameters. METHODS We investigated citrated blood samples from 51 adult cirrhotics for the following thromboelastometry parameters: coagulation-time (CT), clot-formation-time (CFT), maximum-clot-firmness (MCF). RESULTS Relatively few patients [14/51(27%)] were identified as abnormal by CT; in contrast, a greater proportion were identified by the CFT [41/51(80%)] or MCF [39/51(76%)]. CFT and MCF were correlated with the platelet-count, antithrombin and fibrinogen. Prothrombin time (PT) was correlated with CFT and MCF. None of the coagulation parameters were correlated with CT. The correlation of the Child-Pugh-score (taken as index of severity) versus MCF or PT was -0.457(p < 0.001) or 0.484(p < 0.001), suggesting MCF as a suitable prognostic index. CFT and MCF, but not CT obtained ROC curves that were useful to distinguish patients from healthy individuals. CONCLUSIONS Thromboelastometry, currently used to assist liver transplantation is also suitable for investigating stable cirrhosis. CFT and MCF are the most interesting parameters to be considered for future clinical studies needed to assess their value as measures of bleeding-risk and prognosis in this category of patients.

High levels of factor VIII and risk of extra-hepatic portal vein obstruction

BACKGROUND/AIMS High levels of coagulation factor VIII are a risk factor for lower-limb deep vein thrombosis (DVT). Their role in extra-hepatic portal vein obstruction (EHPVO) is not established. METHODS Factor VIII was measured in 85 patients with EHPVO (primary in 58 and complicating liver cirrhosis in 27), in 200 with lower-limb DVT, in 108 with liver cirrhosis without thrombosis and in 200 healthy controls. RESULTS Factor VIII levels were significantly higher in patients with primary EHPVO (138 IU/dL, range 86-366), EHPVO and cirrhosis (147 IU/dL, 95-242), lower-limb DVT (140 IU/dL, 64-400) and cirrhosis alone (160 IU/dL, 43-446) than in controls (112 IU/dL, 62-250, p<0.001). When factor VIII exceeded 129 IU/dL (66th percentile), the odds ratios were 10.5 (95%CI 3.3-33.4) for primary EHPVO, 6.0 (1.2-30.7) for EHPVO and cirrhosis, 5.0 (2.6-9.4) for lower-limb DVT. After exclusion of the effect of the acute phase reaction, the odds ratio for primary EHPVO was 4.2 (0.8-22.7), and was 8.7 (0.9-80.5) after exclusion also of patients with chronic myeloproliferative disorders. CONCLUSIONS High factor VIII levels are independently associated with an increased risk for EHPVO. The risk of EHPVO increased with increasing factor VIII levels and was only partially dependent on the acute phase reaction.

MPL and JAK2 exon 12 mutations in patients with the Budd-Chiari syndrome or extrahepatic portal vein obstruction

To the editor: The Budd-Chiari syndrome (BCS) and extrahepatic portal vein obstruction (EHPVO) are splanchnic vein thromboses (SVT) that may occur as presenting complications of undiagnosed chronic myeloproliferative disorders (CMPD). Diagnosis of the underlying CMPD may be difficult because

Primary prophylaxis of variceal bleeding in cirrhotic patients: A cohort study

BACKGROUND Current guidelines recommend beta-blockers for primary prevention of variceal haemorrhage in cirrhotic patients, and band ligation for patients with contraindications or intolerance to beta-blockers. However, it has been suggested that these patients may respond poorly to band ligation. AIM We evaluated the usefulness of a strategy in which band ligation was used to treat patients with contraindications or intolerance and patients not responding to beta-blockers identified by hepatic vein pressure gradient measurement. Haemodynamic responders and patients refusing hepatic vein pressure gradient measurement were given long-term beta-blockers. METHODS One hundred and thirty-five consecutive patients with high-risk oesophageal varices and no prior bleeding were enrolled. Twenty-five patients with contraindications (group A), 26 with intolerance to beta-blockers (group B) and 25 showing a poor haemodynamic response (Group C) underwent band ligation. Twenty-two haemodynamic responders (Group D) and 37 refusing hepatic vein pressure gradient measurement (Group E) were treated with beta-blockers. RESULTS Median follow-up was 32 months. 12/135 patients (8.9%) bled: 3/25 (12%) in group A, 1/26 (3.8%) in group B, 0/25 (0%) in group C, 0/22 (0%) in group D and 8/37 (22.2%) in group E. Mortality was 8/135 (5.9%). CONCLUSIONS Patients with contraindications, intolerance or not responding to beta-blockers treated with band ligation achieve protection from variceal bleeding comparable to that of good responders to beta-blockers.

Impact of portal vein thrombosis on the efficacy of endoscopic variceal band ligation

BACKGROUND Influence of portal vein thrombosis on efficacy of endoscopic variceal banding in patients with cirrhosis or extrahepatic portal vein obstruction has never been evaluated. Aim of the study was to assess influence of thrombosis on rate and time to eradication in cirrhosis and extrahepatic portal vein obstruction undergoing banding, compared to cirrhotic patients without thrombosis. METHODS Retrospective analysis of 235 consecutive patients (192 with cirrhosis without thrombosis, 22 cirrhosis and thrombosis and 21 extrahepatic portal vein obstruction) who underwent banding. Banding was performed every 2-3 weeks until eradication; endoscopic follow-up was performed at 1, 3, 6 months, then annually. RESULTS Eradication was achieved in 233 patients. Median time to eradication in cirrhotic patients with portal vein thrombosis vs. cirrhotic patients without thrombosis was 50.9 days (12-440) vs. 43.4 days (13-489.4); log-rank: 0.04; patients with extrahepatic portal vein obstruction vs. cirrhotic patients without thrombosis 63.9 days (31-321.6) vs. 43.4 days (13.0-489.4); log-rank: 0.008. Thrombosis was shown to be the only risk factor for longer time to eradication. CONCLUSIONS Portal vein thrombosis per se appears to be the cause of a longer time to achieve eradication of varices but, once eradication is achieved, it does not influence their recurrence.