Ziv Ben-Ari

Cytokine gene polymorphisms in patients infected with hepatitis B virus.

OBJECTIVE:Cytokines play a key role in the regulation of the immune response. The maximal capacity of cytokine production varies among individuals and correlates with the polymorphism in the cytokine gene promoters. The aim of this study was to characterize gene polymorphism in patients with chronic hepatitis B virus (HBV) infection and to determine the different patterns in patient subgroups.METHODS:The study population consisted of 77 patients with chronic HBV infection (23 low-level HBV replicative carriers, 23 compensated high-level HBV replicative carriers, 21 decompensated liver transplant candidates, and 10 patients with documented hepatocellular carcinoma). The genetic profile of five cytokines was analyzed by polymerase chain reaction–sequence-specific primer (SSP), and subjects were genotyped as high or low producers of tumor necrosis factor-α and interleukin (IL)-6, and as high, intermediate, or low producers of transforming growth factor-β1, interferon (IFN)-γ, and IL-10 based on single nucleotide substitutions. The control group included 10 healthy individuals who recovered from HBV infection and 48 healthy controls.RESULTS:A highly statistically significant difference in the distribution of the IFN-γ gene polymorphism (at position +879) was observed between patients with chronic HBV infection and controls. The majority of the patients (65.2%) exhibited the potential to produce low levels of IFN-γ (A/A genotype) compared with 37.5% of the control group (p = 0.003). Healthy individuals who recovered from HBV infection had a similar distribution of IFN-γ gene polymorphism as the healthy controls. No statistically significant difference in IFN-γ production was found between patients with low- and high-level HBV replication and between compensated and decompensated patients. There was also no statistically significant difference in the genetic ability to produce tumor necrosis factor-α (at position −308), IL-6 (at position −174), IL-10 (at position −1082, −819, and −592), and transforming growth factor-β1 (at position +10 and +25).CONCLUSION:These findings suggest an association between the genetic ability to produce low levels of IFN-γ and the susceptibility to develop chronic HBV infection.

A predictive model for failure to control bleeding during acute variceal haemorrhage

BACKGROUND/AIMS Variceal bleeding is a frequent complication of cirrhosis and is associated with a high risk of early rebleeding. In patients with peptic ulcers, continued bleeding or early rebleeding are risk factors for mortality and can be predicted by statistical models; however, no such models exist for acute variceal bleeding. METHODS We prospectively evaluated failure to control bleeding in 695 consecutive patients with cirrhosis, admitted for haematemesis and/or melaena. Criteria were defined for failure to control bleeding, which comprised both continued bleeding or early rebleeding within 5 days of admission. There were 2 sequential groups of patients: (i) those with variceal bleeding initially treated with blood transfusion and vasoactive drugs, and if these failed followed by sclerotherapy (n = 385); (ii) those with variceal bleeding treated with injection sclerotherapy at diagnostic endoscopy (n = 144). The third group was those with bleeding from other sources related to portal hypertension (n = 166). RESULTS Failure to control bleeding was noted in 169 (44%) patients in group 1, 55 (38%) in group 2 and 44 (25%) in group 3. Twenty variables that were evaluable within 6 h of admission, pertaining to severity of bleeding, severity of type of liver disease, mode of admission, and time of diagnostic endoscopy, were entered into a multivariate Cox model. Independent predictors of early rebleeding in group 1 were: active bleeding at endoscopy (irrespective of interval from admission) (p<0.0001), encephalopathy (p = 0.007), platelet count (p = 0.002), history of alcoholism (p = 0.002), presentation with haematemesis (p = 0.02), log urea (p = 0.03) and (shorter) interval to admission (p = 0.007). The variables predictive of 30-day mortality were: early bleeding (p<0.0007), bilirubin (p = 0.0006), encephalopathy (p<0.0001), (shorter) interval to admission (p<0.0001), and log urea (p = 0.004); a model based on these variables was also a good predictor of mortality in the other 2 groups. However, the model derived from group 1 for failure to control variceal bleeding was different in group 2, despite similar patient characteristics and a similar failure rate (following a single injection). This could suggest that sclerotherapy may induce bleeding in some patients independently of the baseline risk for failure to control bleeding. CONCLUSIONS In cirrhotic patients who present with haematemesis or melaena, active variceal bleeding at diagnostic endoscopy is predictive of failure to control bleeding (continued bleeding or early rebleeding within 5 days of admission), and this failure is predictive of 30-day mortality.

Effectiveness of Simeprevir Plus Sofosbuvir, with or Without Ribavirin, in Real-World Patients with HCV Genotype 1 Infection

BACKGROUND & AIMS The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. METHODS We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET--a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment--a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. RESULTS The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%-87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. CONCLUSIONS In a large prospective observational cohort study, a 12-week regimen of simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811.

Disseminated intravascular coagulation in liver cirrhosis: fact or fiction?

Objective:Cirrhosis is commonly associated with haemostatic dysfunction. The similarities of laboratory tests of disseminated intravascular coagulation (DIC) to those found in cirrhosis has led to the belief that DIC is a feature of the haemostatic failure of cirrhosis.Methods:The aim of this study was to determine whether DIC is part of the coagulopathy of cirrhosis by applying quantitative tests for prothrombin fragment 1 + 2, antithrombin III, thrombin-antithrombin complex, and specific fribrinogen degradation products levels (XDP), as well as the thrombelastograph for detecting the Clot Lysis Index.Results:Fifty-two stable cirrhotic patients (33 men, 19 women; mean age, 58.8 yr; range, 24–72 yr) with differing etiologies were studied. On tests of thrombin generation: thrombin-antithrombin complexes, fibrin(ogen) degradation products, and prothrombin fragments 1 + 2 were not found to be significantly different from an age- and gender-matched control group (p= 0.18, 0.3, and 0.67, respectively), whereas albumin, Factor V, fibrinogen, antithrombin III, and α2-antiplasmin were all significantly low (p= 0.0004, 0.002, 0.06, 0.004, and 0.004, respectively), reflecting reduced synthetic function and correlation in ascitic and nonascitic patients. There was no correlation between impaired synthesis (antithrombin III and α2-antiplasmin) and indices of DIC (prothrombin fragment 1 + 2, thrombin-antithrombin complexes, and XDP) (p= not significant). The percentage of patients with high prothrombin fragments 1 + 2 and thrombin antithrombin levels in each Child grade group was similar. Thrombin time was significantly elevated in the cirrhotic group (a manifestation of low fibrinogen levels). The Clot Lysis Index as measured by thrombelastography was significantly abnormal, indicating mild hyperfibrinolysis.Conclusion:We conclude that DIC is not part of the coagulopathy in stable liver cirrhosis without recent complications.

Lamivudine treatment for acute severe hepatitis B: a pilot study.

Abstract: Background: Experience with lamivudine treatment of immunocompetent patients with acute hepatitis B is limited.

Role of cytokine gene polymorphism in hepatitis C recurrence and allograft rejection among liver transplant recipients.

Background. Cytokines play a key role in the regulation of immuneresponses. The maximal capacity of cytokine production varies betweenindividuals and was shown to correlate with polymorphism in cytokine genepromoters. The objective of this study was to analyze the role of cytokineallelic variations in susceptibility to early graft rejection episodes andrecurrence of hepatitis C infection in liver transplant (LTx)recipients. Methods. The genetic profile of five cytokines was studied in 68 LTxrecipients and 49 controls using polymerase chain reaction sequence specificprimers. All individuals were genotyped as high or low producers of TNF-&agr;and IL-6 and high, intermediate, or low producers of transforming growthfactor &bgr; (TGF-&bgr;), interferon &ggr; (IFN-&ggr;), and interleukin 10(IL-10) based on single nucleotidesubstitutions. Results. No statistically significant differences were observedbetween patients with or without early rejection episodes. A significantproportion of patients more prone to rejection were genotyped as having a lowproduction profile of IL-10 compared with the control population(P =0.04). These data are inaccordance with reports regarding other solid-organ transplant recipients.Patients with no recurrence of hepatitis C had the inherent ability to producehigher TGF-&bgr; levels than did patients with recurrent disease(P =0.042). Among nonrecurrentpatients, the percentage of genetically low IL-10 producers was higher thanamong recurrent patients(P =0.07). Furthermore, agenetic tendency to produce higher levels of IFN-&ggr; was noted among LTxrecipients with nonrecurrent hepatitis C than among those with recurrenthepatitis C. Conclusions. While no significant correlation was detected betweenparticular cytokine profile and early rejection episodes, our data stronglysuggest an association between cytokine gene polymorphism of TGF-&bgr;, IL-10,and INF-&ggr; and recurrence of hepatitis C in LTxrecipients.

Role of anti-tumor necrosis factor-alpha in ischemia/reperfusion injury in isolated rat liver in a blood-free environment.

BACKGROUND Warm ischemia/reperfusion injury during liver transplantation is the most important cause of primary nonfunction of liver allografts. Tumor-necrosis factor (TNF)-alpha apparently mediates tissue damage by inducing apoptosis and/or necrosis in liver transplants. The aim of the study was to determine, using an isolated rat liver model, if pretreatment with anti-TNF-alpha monoclonal antibodies can attenuate ischemia/reperfusion liver injury. Specifically, its effect on liver cell apoptosis through the modulation of caspase activity was examined in a blood-free environment. METHODS Isolated rat livers were perfused with Krebs-Henseleit solution and randomly divided into three groups: (1) continuous perfusion for 165 min (control); (2) perfusion for 90 min, break for 60 min (ischemia), and reperfusion for 15 min; (3) as with group 2, but with administration of monoclonal mouse anti-rat TNF-alpha monoclonal antibodies before induction of ischemia. Caspase-3- and -9-like activity was measured by fluorometric assay, and apoptotic cells were identified by morphological criteria and application of the terminal deoxnucleotidyl transferase-mediated dUTP nick-end-labeling (Tunel) assay. RESULTS Portal pressure increased significantly in group 2 (14.8+/-2.3 mm Hg) compared to group 3, which showed no change (P<0.05). Significant amounts of TNF-alpha were detected in the effluent in group 2 at 1 min of reperfusion (147+/-8.9 pg/ml) compared to group 3 (30+/-6.7 pg/ml, P<0.05). Statistically significant reductions in liver enzyme levels were also noted in the animals pretreated with TNF-alpha antibodies (P<0.02). Caspase-3 and -9 activity was significantly decreased (270 and 160%, respectively) in group 3 compared to group 2 (P<0.005 and <0.05, respectively). A significant reduction in postischemic hepatic injury was noted on Tunel assay: many apoptotic hepatocyte cells were detected in group 2 but not in livers pretreated with monoclonal mouse anti-TNF-alpha antibodies (group 3). CONCLUSIONS Neutralization with specific monoclonal antibodies against TNF before ischemia induction can attenuate postischemic hepatic injury. Apoptotic injury seems to be ameliorated through modulation of caspase-3- and -9-like activity.

Liver transplantation in exertional heat stroke: a medical dilemma.

BackgroundExertional heat stroke (EHS) is a life-threatening condition caused by an extreme elevation in core body temperature. Hepatic involvement is one of the hallmarks of heat stroke, affecting nearly all heat stroke patients. It is usually manifested by increased serum levels of liver enzymes, but acute liver failure has also been reported. Liver transplantation has been proposed as a potential treatment in cases of severe liver failure, but there are no unanimous criteria pointing to the right stage in which to conduct the transplantation.Case presentationWe report a case of an 18-year old patient who suffered heat-induced liver failure. The patient was referred for orthotopic liver transplantation (OLT) but spontaneously recovered completely with conservative treatment.ConclusionsThis case demonstrates the complexity of the decision for liver transplantation in EHS. The various prognostic criteria of acute hepatic failure and their relevance to EHS are critically reviewed, with an aim to assess their application for such a condition.

Circulating soluble cytochrome c in liver disease as a marker of apoptosis.

Abstract. Ben‐Ari Z, Schmilovotz‐Weiss H, Belinki A, Pappo O, Sulkes J, Neuman MG, Kaganovsky E, Kfir B, Tur‐Kaspa R, Klein T (Beilinson and Golda Campuses, Rabin Medical Center, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, and In Vitro Toxicology Laboratory, Sunnybrook Womens College, Toronto, Canada) Circulating soluble cytochrome c in liver disease as a marker of apoptosis. J Intern Med 2003; 254: 168–175.

Serum cholestasis markers as predictors of early outcome after liver transplantation

Abstract:  Background:  Early cholestasis is not uncommon after liver transplantation and usually signifies graft dysfunction. The aim of this study was to determine if serum synthetic and cholestatic parameters measured at various time points after transplantation can predict early patient outcome, and graft function.