Pregnancy in women with portal vein thrombosis: results of a multicentric European study on maternal and fetal management and outcome.

BACKGROUND & AIMS: Women of childbearing age account for approximately 25% of patients with non-cirrhotic portal vein thrombosis (PVT). We aimed at assessing maternal and fetal outcome in pregnant women with known PVT. METHODS: We performed a retrospective analysis of the files of women with chronic PVT in three European referral centers between 1986 and 2010. RESULTS: Forty-five pregnancies, 28 (62%) treated with low molecular weight heparin, occurred in 24 women. Nine (20%) were lost before gestation week 20. Preterm birth occurred in 38% of deliveries: there were 3 births at week 24-25, 7 at week 32-36, and 26 after week 37. A term birth with a healthy infant occurred in 58% of pregnancies. Cesarean section was used in 53% of deliveries. Two women developed HELLP syndrome. A favorable outcome happened in 64% of pregnancies. Pregnancies with an unfavorable outcome were associated with a higher platelet count at diagnosis. Bleeding from esophageal varices occurred in 3 patients during pregnancy, all without adequate primary prophylaxis. Genital or parietal bleeding occurred postpartum in 4 patients, only one being on anticoagulation therapy. Thrombotic events occurred in 2 patients, none related to lower limbs or mesenteric veins. There were no maternal deaths. CONCLUSIONS: In pregnant PVT patients treated with anticoagulation on an individual basis, the rate of miscarriage and preterm birth appears to be increased. However, fetal and maternal outcomes are favorable for most pregnancies reaching gestation week 20. High platelet counts appear to increase the risk for unfavorable outcome. Pregnancy should not be contraindicated in stable PVT patients.

Diagnostic performance of Baveno IV criteria in cirrhotic patients with upper gastrointestinal bleeding: analysis of the F7 liver-1288 study population.

BACKGROUND & AIMS: The definition of failure to control bleeding agreed upon at the Baveno IV consensus meeting, included the Adjusted Blood Requirement Index [ABRI: number of blood units/(final-initial hematocrit+0.01)]. ABRI ≥0.75 denotes failure. However, timing for hematocrit measurements was not defined. The aims of this study were: (1) to assess the Baveno IV criteria performance to classify treatment success or failure to control bleeding at 5 days, (2) to determine the appropriate timing for hematocrit. METHODS: Two hundred and forty-two cirrhotic patients with gastrointestinal bleeding were independently classified by three clinical experts according to the Baveno IV criteria, by analysis of the database of a randomized trial. ABRI was calculated by using the closest hematocrit to the 5 day time point from the first trial product administration (ABRI-1) or after the latest transfusion within the 5-day period (ABRI-2). The gold standard for success/failure for 5-day control of bleeding was the clinical judgment of the three independent observers based on all the clinical and follow-up data. RESULTS: Inter-observer agreement for the final outcome assessment was 0.82 and a final consensus was obtained in 236/242 patients. Inter-observer agreement on patient classification with Baveno IV criteria was 0.70 with ABRI-1 and 0.84 with ABRI-2. c-statistics for correct patients classification were 0.86 for ABRI-1, 0.84 for ABRI-2, and 0.88 for Baveno IV criteria without ABRI. ABRI-1 caused misclassification of 27 patients and ABRI-2 of 39. CONCLUSIONS: Baveno IV criteria are accurate to assess outcome of patients with variceal bleeding. There is a substantial observer variability linked to timing of hematocrits for ABRI calculation. With the current definition ABRI does not add to the performance of the other criteria.

ActiTest accuracy for the assessment of histological activity grades in patients with chronic hepatitis C, an overview using Obuchowski measure.

BACKGROUND: ActiTest (AT) is a biomarker of liver necro-inflammatory histological activity validated in patients with chronic hepatitis C (HCV). AIM: The aim was to assess the accuracy of AT in comparison with alanine aminotransferase (ALT) the standard of care. METHODS: Methods used an integrated database of individual data and the new recommended Obuchowski measures. An updated "classical" meta-analysis of AT validation studies was also performed. The main end points were the area under the ROC curves (AUROCs) for the diagnosis of each histological activity grade defined using METAVIR scoring system. To avoid repeated tests and the spectrum effect of activity grades prevalence, the comparison of AT and ALT accuracies used the Obuchowski method. RESULTS: For the individual analysis, a total of 1250 patients were included and for the meta-analysis six studies (2017 patients) were included. The overall accuracy of AT for the diagnosis of any activity grade (Obuchowski measure=0.850) was significantly higher than the accuracy of ALT (Obuchowski measure=0.837; P=0.009). The updated standard meta-analysis confirmed the accuracy of AT (p<0.0001) both in independent AUROC=0.79 (95% CI, 0.73-0.85) and in non independent studies AUROC=0.74 (95% CI, 0.67-0.81). CONCLUSIONS: The accuracy of AT for grading the necro-inflammatory activity of patients with HCV was significantly higher than ALT serum activity alone, the standard biomarker.

Management of liver failure in general intensive care unit.

OBJECTIVE: To produce French guidelines on Management of Liver failure in general Intensive Care Unit (ICU). DESIGN: A consensus committee of 23 experts from the French Society of Anesthesiology and Critical Care Medicine (Société française d'anesthésie et de réanimation, SFAR) and the French Association for the Study of the Liver (Association française pour l'étude du foie, AFEF) was convened. A formal conflict-of-interest (COI) policy was developed at the start of the process and enforced throughout. The entire guideline process was conducted independently of any industrial funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide their assessment of the quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. Some recommendations were ungraded. METHODS: Two fields were defined: acute liver failure (ALF) and cirrhotic patients in general ICU. The panel focused on three questions with respect to ALF: (1) Which etiological examinations should be performed to reduce morbidity and mortality? (2) Which specific treatments should be initiated rapidly to reduce morbidity and mortality? (3) Which symptomatic treatment should be initiated rapidly to reduce morbidity and mortality? Seven questions concerning cirrhotic patients were addressed: (1) Which criteria should be used to guide ICU admission of cirrhotic patients in order to improve their prognosis? (2) Which specific management of kidney injury should be implemented to reduce morbidity and mortality in cirrhotic ICU patients? (3) Which specific measures to manage sepsis in order to reduce morbidity and mortality in cirrhotic ICU patients? (4) In which circumstances, human serum albumin should be administered to reduce morbidity and mortality in cirrhotic ICU patients? (5) How should digestive haemorrhage be treated in order to reduce morbidity and mortality in cirrhotic ICU patients? (6) How should haemostasis be managed in order to reduce morbidity and mortality in cirrhotic ICU patients? And (7) When should advice be obtained from an expert centre in order to reduce morbidity and mortality in cirrhotic ICU patients? Population, intervention, comparison and outcome (PICO) issues were reviewed and updated as required, and evidence profiles were generated. An analysis of the literature and recommendations was then performed in accordance with the GRADE® methodology. RESULTS: The SFAR/AFEF Guidelines panel produced 18 statements on liver failure in general ICU. After two rounds of debate and various amendments, a strong agreement was reached on 100% of the recommendations: six had a high level of evidence (Grade 1 ±), seven had a low level of evidence (Grade 2 ±) and six were expert judgments. Finally, no recommendation was provided with respect to one question. CONCLUSIONS: Substantial agreement exists among experts regarding numerous strong recommendations on the optimum care of patients with liver failure in general ICU.

Impact of interferon-alpha treatment on liver fibrosis in patients with chronic hepatitis B: an overview of published trials.

BACKGROUND: The impact of interferon treatment in patients with hepatitis B virus (HBV) infection on fibrosis progression in comparison with its natural history has yet to be assessed in any large-scale randomized studies. The present report is a review of the evidence-based data published so far. METHODS: Studies were included if they had at least two repeated estimates of liver fibrosis per patient treated with interferon-alpha (whether pegylated or not). Meta-analysis was performed using a random-effects model. RESULTS: Altogether, 13 studies were included in the review, involving a total of 707 HBV patients treated with interferon-alpha-2a or -2b for 12-83 months. Only one study included pegylated interferon as monotherapy. A total of 787 untreated patients were also followed. Only one study used a non-invasive biomarker. There was a significant reduction in the fibrosis progression rate, with a risk reduction of 0.49 (95% CI: -0.64--0.34; chi(2)=119; degrees of freedom [DF]=6; P<0.0001), and significant heterogeneity (Cochran Q=81; P<0.0001). This significant impact was similar for both randomized (reduction of risk: -0.45; 95% CI: -0.64--0.26; P<0.0001) and not-randomized (controlled) studies (reduction of risk: -0.53; 95% CI: -0.79--0.28; P<0.0001). CONCLUSION: According to these findings, the benefit of interferon treatment on fibrosis progression is clinically significant in patients with advanced fibrosis by the reduction of fibrosis progression to cirrhosis. Pegylated interferon now needs to be compared, in terms of benefit-risk factors, with the new generation of HBV treatments (such as entecavir and tenofovir), using non-invasive biomarkers.

[Metabolic encephalopathies]. / Encéphalopathies métaboliques.

Metabolic encephalopathies (ME) are a common cause of admission to emergency rooms, to hospitalization wards or to intensive care units. They could account for 10 to 20% of causes of comatose states in ICU and could be associated to a poor outcome especially in older patients. Nevertheless, they are often reversible and are associated with a favorable outcome when diagnosed and rapidly treated. They correspond to an altered brain functioning secondary to the deficiency of a substance that is mandatory for the normal brain functioning or to the accumulation of a substance that can be either endogenous or exogenous. It preferably occurs in co-morbid patients, complicating its diagnosis and its management. Altered brain functioning, going from mild neuropsychological impairment to coma, movement disorders especially myoclonus and the absence of any obvious differential diagnosis are highly suggestive of the diagnosis. Whereas some biological samplings and brain MRI are essential to rule out differential diagnosis, some others, such as electroencephalogram, may be able to propose important clues in favor of the diagnosis. Once simple symptomatic measures are introduced, the treatment consists mainly in the correction of the cause. Specific treatment options are only seldom available for ME; this is the case for hepatic encephalopathy and some drug-induced encephalopathies. We will successively describe in this review the main pathophysiological mechanisms, the main causes, favoring circumstances of ME, the differential diagnosis to rule out and the etiological work-up for the diagnosis. Finally, a diagnostic and therapeutic strategy for the care of patients with ME will be proposed.

Methodological aspects of the interpretation of non-invasive biomarkers of liver fibrosis: a 2008 update.

This review summarizes the methodological aspects of the interpretation of non-invasive biomarkers in liver fibrosis. A scoring system has been updated to better compare the quality of fibrosis biomarkers. Several methodological issues are related to the classical methodology using biopsy, as this is considered the gold standard. However, from evidence-based data, it appears that the methodology needs to change to prevent flawed conclusions among key opinion leaders as well as in obsolete guidelines. As waiting for the perfect biomarker for the diagnosis of advanced fibrosis to come along is probably a waste of time, in the meantime, methods can be improved. The main proposals for improving the methodology are, to take into account the spectrum bias, to assess accuracy between adjacent stages, to compare biomarkers in the same patient, to assess the cause of failure among discordant cases and to use specific statistical methods adapted for imperfect gold standards.

Continuous infusion of high-dose omeprazole is more effective than standard-dose omeprazole in patients with high-risk peptic ulcer bleeding: a retrospective study.

UNLABELLED: High-dose omeprazole reduces the rate of recurrent bleeding after endoscopic treatment of peptic ulcer bleeding. However, the effectiveness of high-dose vs. standard-dose omeprazole in peptic ulcer bleeding has never been shown. AIM: To compare the benefits of high-dose vs. standard-dose omeprazole in peptic ulcer bleeding. METHODS: We reviewed the medical files of patients admitted between 1997 and 2004 for high-risk peptic ulcer bleeding who had undergone successful endoscopic treatment. We distinguished 2 periods: before 2001, standard-dose omeprazole (40 mg/day intravenously until alimentation was possible, then 40 mg/day orally for 1 week); after 2001, high-dose omeprazole (80 mg bolus injection, then 8 mg/h continuous infusion for 72 h, then 40 mg/day orally for 1 week). During both periods, patients subsequently received omeprazole, 20 mg/day, orally for 3 weeks. RESULTS: We enrolled 114 patients (period 1, n = 45, period 2, n = 69). Therapy with high-dose omeprazole significantly decreased the occurrence of poor outcome (27 vs. 12%, P = 0.04), rebleeding (24 vs. 7%, P = 0.01), mortality due to haemorrhagic shock (11 vs. 0%, P < 0.001) and need for surgery (9 vs. 1%, P = 0.05). CONCLUSIONS: In this retrospective study, high-dose omeprazole reduced the occurrence of rebleeding, need for surgery and mortality due to hemorrhagic shock in patients with high-risk peptic ulcer bleeding, as compared with standard-dose omeprazole.

Relationship between the Fibrotest and portal hypertension in patients with liver disease.

BACKGROUND: The best technique to estimate portal hypertension (PHT) is to measure the hepatic venous pressure gradient (HVPG), which is an invasive method. AIM: To assess the relationship between the Fibrotest (Biopredictive, Paris, France) and the presence and degree of PHT in patients with liver disease, and to determine if the Fibrotest can diagnose severe PHT, defined by HVPG >or= 12 mmHg, in cirrhotic patients. METHODS: Patients who underwent a transjugular liver biopsy were prospectively included. HVPG was measured, and classification of histological lesions assessed. The same day, blood samples for Fibrotest were performed. RESULTS: A total of 130 patients were included (no or minimal fibrosis: 12%, moderate fibrosis 17%, cirrhosis 71%). There was a significant correlation between Fibrotest and HVPG (Pearson correlation coefficient = 0.58, P < 0.0001), also weaker in cirrhotic patients (Pearson correlation coefficient = 0.24, P = 0.02). In cirrhotic patients, Fibrotest was significantly higher when there was a severe PHT (0.87 +/- 0.15 vs. 0.73 +/- 0.14, respectively, P = 0.02). The areas under the receiver operating characteristic curves for the diagnosis of severe PHT was 0.79 +/- 0.07, not different from that of platelets and Child-Pugh score. CONCLUSION: In patients with liver disease or cirrhosis, Fibrotest is correlated with the presence and degree of PHT. Other studies are needed to confirm these results, especially in non-decompensated cirrhotic patients.

Spontaneous ascitic fluid infection and bacteremia due to Yersinia pseudotuberculosis in a liver transplant patient.

We report herein a case of bacteremic ascitic fluid infection in a liver transplant patient caused by a strain of Yersinia pseudotuberculosis serogroup I that lost the yersiniabactin core. The patient's outcome was favorable after a combined therapy with a third-generation cephalosporin and gentamicin.

Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis.

BACKGROUND: Randomized controlled trials testing flumazenil in hepatic encephalopathy have shown conflicting results. AIM: To compare flumazenil and placebo in hepatic encephalopathy in patients with cirrhosis. METHODS: An overview of randomized controlled trials comparing flumazenil and placebo in hepatic encephalopathy in patients with cirrhosis was performed. For each end-point, heterogeneity and treatment efficacy were assessed by Peto and Der Simonian methods. As most trials were crossover in nature, a sensitivity analysis was performed including the two treatment periods. RESULTS: Six double-blind randomized controlled trials, including 641 patients (326 treated with flumazenil and 315 with placebo), were identified. The treatment duration ranged from 5 min to 3 days. Heterogeneity tests between control groups were not significant. The mean percentages of patients with clinical improvement (five trials) were 27% in treated groups and 3% in placebo groups. This difference was significant by both methods (Peto: odds ratio=6.15; 95% confidence interval, 4.0-9.5; P < 0.001; Der Simonian: mean rate difference, 29%; 95% confidence interval, 17-41; P < 0.001). The mean percentages of patients with electroencephalographic improvement were 19% in treated groups and 2% in placebo groups. This difference was significant only with the Peto method (odds ratio=5.8; 95% confidence interval, 3.4-9.7; P < 0.001). The sensitivity analysis showed similar results. CONCLUSIONS: This meta-analysis shows that flumazenil induces clinical and electroencephalographic improvement of hepatic encephalopathy in patients with cirrhosis.

[Cholestatic icterus induced by the administration of fusidic acid in a cirrhotic patient]. / Ictère cholestatique induit par la prise d'acide fucidique chez un patient cirrhotique.

INTRODUCTION: Fucidic acid is an antibiotic essentially used to treat staphylococcal infections. Its chemical structure is very similar to that of bilary acids and hence implies competitive mechanisms between their elimination and metabolization. OBSERVATION: A patient with a past history of alcohol-induced cirrhosis was treated with fucidic acid for a Staphylococci aureus urinary infection. On day 2 of treatment a conjugate bilirubine icterus appeared. There was no argument to suggest a decompensation of the icterus. The icterus disappeared on suspension of fucidic acid. COMMENTS: The occurrence of an icterus in a cirrhotic patient may evoke decompensation of the hepatopathy and an extensive exploration must be made. A thorough survey of all drug administration must be made. Notably, the possibility of the occurrence of a connective bilirubin icterus during treatment with fucidic acid must be known. The icterus always regresses on withdrawal of treatment and this etiology must be evoked before conducting invasive examinations.

Early-TIPSS placement prevents rebleeding in high-risk patients with variceal bleeding, without improving survival.

BACKGROUND: Early-TIPSS (transjugular intrahepatic portosystemic shunt) placement may improve rebleeding and reduce 1-year mortality, compared to standard management in high-risk patients with cirrhosis and variceal bleeding. AIM: To obtain external validation of this therapeutic approach. METHODS: We performed a prospective study including all consecutive patients with Child-Pugh C 10-13 cirrhosis or Child-Pugh B with active bleeding at endoscopy admitted to our ICU between March 2011 and February 2013 for variceal bleeding. TIPSS were placed within 72 h after stabilisation. Patients were matched for gender, age, Child-Pugh score, MELD score and to patients from a historical cohort hospitalised before March 2011. RESULTS: 31/128 patients with cirrhosis (77.4% men, mean age 53.2 ± 9.0 years old, MELD score 20.9 ± 6.9, Child-Pugh C: 77.4%) admitted for acute variceal bleeding between March 2011 and February 2013 (TIPSS+ group) were matched to 31 historical patients (TIPSS- group). Uncontrolled bleeding occurred in 1/31 patients in the TIPSS+ group vs. 2/31 patients in TIPSS- group (P = 0.55). The 1-year probability of being free of rebleeding was higher in the TIPSS+ group (97% vs. 51%, P < 0.001). Actuarial 1-year survival was not different between the two groups (66.8 ± 9.4% vs. 74.2 ± 7.8%, P = 0.78). Acute cardiac failure occurred more frequently in the TIPSS+ group (25.8% vs. 6.4%, P = 0.03). CONCLUSIONS: Early-TIPSS placement effectively prevents rebleeding in high-risk patients with variceal bleeding but does not significantly improve survival. This might be due to the high proportion of patients with Child-Pugh C cirrhosis in our series. Cardiac failure may play a role and must be investigated before the procedure, when possible.

Meta-analysis: the impact of IL28B polymorphisms on rapid and sustained virological response in HCV-2 and -3 patients.

BACKGROUND: Recent studies suggested that IL28B polymorphisms may affect rapid and sustained virological response rates in HCV patients infected with genotype 2 or 3. AIM: To assess the role of IL28B polymorphisms on the virological response in HCV-2 and -3 patients. METHODS: We performed meta-analysis of studies evaluating the impact of rs12979860 and rs8099917 polymorphisms on rapid and sustained virological response in HCV-2 or -3 patients. RESULTS: Twenty-three studies involving 3042 patients were included. The first meta-analysis evaluated the impact of rs12979860 polymorphism and included 1963 patients. When compared with rs12979860 CT/TT patients, CC patients had a higher rapid virological response rate (mean difference: 12.9%, 95% CI: 6.5-19.4%, P < 0.001) and a higher sustained virological response rate (mean difference: 4.9%, 95% CI: 0.1-9.8%, P = 0.046). The second meta-analysis evaluated the impact of rs8099917 polymorphism and included 2246 patients. When compared with rs8099917 TG/GG patients, TT patients had a higher rapid virological response rate (mean difference: 14.8%, 95% CI: 7.2-22.4%, P < 0.001) and a higher sustained virological response rate (mean difference: 5.5%, 95% CI: 0.4-10.6%, P = 0.033). When considering only patients treated for 24 weeks, results were unchanged. No potential sources of between-study heterogeneity were identified. CONCLUSIONS: Favourable IL28B polymorphisms are associated with higher rapid and sustained virological response rates in HCV-2 and -3 patients. However, as the impact on a sustained response is very limited, it is unlikely that IL28B polymorphisms provide additional predictive value when considering other predictors of a sustained response.

Peptic ulcer bleeding in patients with or without cirrhosis: different diseases but the same prognosis?

BACKGROUND: Physiopathology and prognosis of peptic ulcer bleeding (PUB) have never been described in cirrhotic patients. AIM: To assess risk factors and outcome of PUB in two groups of patients with PUB with or without cirrhosis. METHODS: We included prospectively all patients with PUB referred to our ICU of Hepatology and Gastroenterology between January 2008 and March 2011. All patients were treated according to international recommendations. Diagnosis of cirrhosis was based on clinical, biological and morphological exams. Aetiologies, characteristics and outcomes of PUB were compared in cirrhotic vs. noncirrhotic patients. RESULTS: A total of 203 patients with PUB were included prospectively. Twenty-nine patients had cirrhosis (group Cirr+), and 174 patients had no cirrhosis (group Cirr-). Demographic data were similar between the two groups except for age and alcohol consumption. Aetiology of cirrhosis was alcohol in 97% of cirrhotic patients. Characteristics of PUB were not different between the two groups. Ninety-three per cent of patients with cirrhosis had endoscopic portal hypertension. Aetiology of PUB was different between the group Cirr+ and Cirr- (Helicobacter pylori = 10.3% vs. 48.8%, P < 0.0001; NSAID's = 17.2% vs. 54.0%, P < 0.0001; idiopathic PUB = 79.3% vs. 23.8%, P < 0.0001). Outcome was comparable concerning re-bleeding (7.0% vs. 6.9%, P = 0.31), need for arterial embolisation (10.3 vs. 8.6%, P = 0.76), need for salvage surgery (0 vs. 1.7%, P = 0.31) and mortality (3.0% vs. 1.1%, P = 0.87). CONCLUSIONS: Physiopathology of PUB seems to be different in patients with cirrhosis. In cirrhotic patients, PUB occurs almost only in alcoholics. In our series, prognosis was similar to general population. PUB in cirrhosis might be related to portal hypertension and/or alcohol.