R Tur-Kaspa

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.

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.

Experience with lamivudine therapy for hepatitis B virus infection before and after liver transplantation, and review of the literature

Abstract.  Ben‐Ari Z, Mor E, Tur‐Kaspa R (Beilinson Campus, Petah Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel). Experience with lamivudine therapy for hepatitis B virus infection before and after liver transplantation, and review of the literature. J Intern Med 2003; 253: 544–552.

Combination hepatitis B immune globulin and lamivudine versus hepatitis B immune globulin monotherapy in preventing recurrent hepatitis B virus infection in liver transplant recipients.

UNTIL RECENTLY, liver transplantation in patients infected with the hepatitis B virus (HBV) was associated with a high rate of graft loss and poor survival because of viral recurrence. With the use of hepatitis B immune globulin (HBIG), allograft rejection rates have decreased (15% to 50%). However, recurrences still occur due to the saturation of the antibody-binding capacity of HBIG by the high viral load or by mutations in the hepatitis B surface antigen (HBsAg) molecule that render HBIG ineffective. Lamivudine, a purine nucleoside analog that serves as a reverse transcriptase inhibitor, is known to be a potent inhibitor of HBV replication. Lamivudine, administered before and after liver transplantation to prevent graft reinfection, was found to produce a complete and sustained suppression of viral replication. However, lamivudine escape mutations in the YMDD locus of the HBV DNA polymerase have been reported more frequently. Following 52 weeks of therapy post–liver transplantation, Perrillo et al documented a mutation rate of 27%. Our long-term study showed that 62.5% of patients developed lamivudine resistance. The aim of the present study was to determine the efficacy of the combination of HBIG and lamivudine compared with that of HBIG monotherapy to prevent recurrent HBV infection in patients undergoing orthotopic liver transplantation (OLT).

De novo tumors after liver transplantation: A single-center experience

ORGAN transplant recipients are considered to be at increased risk of malignancy because of prolonged immunosuppression therapy. Reported incidence rates range between 3% and 15%, twice that of the general population. De novo nonlymphoid solid tumors are an important cause of late allograft morbidity and patient mortality. The aim of the present study was to characterize the incidence and types of malignancies associated with liver transplantation in a single center. The analysis assessed the risk factors, clinical characteristics, and outcome of de novo malignancies particularly tumor-specific mortality.

Role of circulating soluble CD40 as an apoptotic marker in liver disease

AbstractObjectives: To measure levels of soluble CD40, a laboratory marker of apoptosis in patients with liver disease, determine its origin, and correlate the findings with disease activity and histology. Design: Laboratory research study with comparison group. Setting: Liver Institute, Laboratory of HLA Typing and Histopathology Department, Rabin Medical Center, Israel. Subjects: One hundred ten patients with liver disease and 20 healthy controls. Methods: Serum samples were collected from all patients; in addition, paired hepatic and portal vein samples were collected from 23 patients, and bile samples from 5 patients. Soluble CD40 was measured with an enzyme-linked immunosorbent assay. Apoptotic cells in liver tissue were identified by morphological criteria and quantified with the TUNEL assay. Results: Soluble CD40 concentration was significantly higher in patients with liver disease than controls (mean 112.9 ± 197.2 pg/ml vs. 24.2 ± 9.1 pg/ml, p = 0.0001), with highest levels in the chronic viral hepatitis group (mean 131.7 ± 137.5 pg/ml, p = 0.0001). Levels of sCD40 were correlated with serum creatinine, alkaline phosphatase, alpha-feto protein, and the apoptotic index. In the 23 paired samples, CD40 level was higher in the hepatic vein (mean 74.9 ± 114.5 pg/ml) than the portal vein (mean 51.6 ± 67.9 pg/ml); it was highly detectable in bile (mean 115.6 ± 119.6 pg/ml, p = 0.0123). Untreated patients with chronic viral hepatitis (B and C) had higher levels (mean 106.2 ± 76.5 pg/ml) than treated patients (mean 59.3 ± 68.6 pg/ml, p = 0.049). Conclusions: Levels of soluble CD40 increase in different types of liver disease. It probably derives from the liver and is secreted into the bile. Levels correlate with the apoptotic index and are affected by antiviral treatment. Soluble CD40 may serve as a serum marker of apoptosis in liver disease.

Association of post-liver transplantation diabetes mellitus with hepatitis C virus infection

DDIABETES mellitus is a common complication of orthotopic liver transplantation, with an incidence of 5% to 27%. Although the disorder is generally attributed to the long-term use of immunosuppression agents, diabetes mellitus has been associated in recipients who undergo transplantation for hepatitis C virus (HCV) infection. The aim of the present study was to assess the prevalence and predictive factors for posttransplant diabetes mellitus (PTDM).

Cholestasis and hypoalbuminemia as predictors of outcome after liver transplantation

WITH THE SEVERE organ shortage worldwide there has been a trend in recent years toward an increased use of liver allografts from older and otherwise suboptimal donors. The main disadvantage of this donor pool is the increased risk for primary graft non-function (PNF) on initial poor graft function (IPF) after transplantation. Whereas the criteria for retransplantation are well established for patients with PNF recipients with IPF, because of the possibility of full recovery often experience a delay in retransplantatation, which may explain the relatively high mortality rates among recipients with IPF. Several parameters have been proposed as potential prognostic markers for graft survival. Because transplant outcome depends on multiple donor, operative, and recipient factors, most predictive models lack accuracy. For patients with PNF, coagulation function and biochemical parameters are helpful to indicate the need for retransplantation. Severe preservation injury is characterized by cholestasis with rising bilirubin, alkaline phosphatase (AP), and gamma-glutamyl transpeptidase (GGT) levels that peak at the 10th day posttransplantation. We hypothesized that persistence of abnormalities of these cholestatic parameters beyond day 10 after transplantation may predict subsequent graft loss in patients with IPF.