Hemda Schmilovitz-Weiss

Improved Immunogenicity of a Novel Third-Generation Recombinant Hepatitis B Vaccine in Patients with End-Stage Renal Disease

Hepatitis B (HBV) infection remains a significant epidemiological problem in the end-stage renal disease (ESRD) population. Vaccination programs using second-generation vaccines lead to effective seroprotection in only 50–60% of these patients. The purpose of this case series was to describe our experience with a novel third-generation vaccine, Bio-Hep-B®, in ESRD patients who had not developed protective anti-HBs titers following a second-generation HBV vaccination protocol. Twenty-nine ESRD patients who had not responded in the past to a standard second-generation HBV vaccination protocol were included in this series. Each patient received 10 µg of Bio-Hep-B® intramuscularly at 0, 1 and 6 months. A month after completion of the vaccination protocol, anti-HBs antibody levels were measured. Following immunization, 25 of 29 patients (86%) developed seroprotective anti-HBs levels ≧10 mIU/ml. There was a significant difference in the titers of anti-HBs antibodies prior to and following vaccination (p < 0.0001). Statistical analysis of the variables age, gender, diagnosis, dialysis mode, weight, hemoglobin, albumin, and KT/V failed to detect predictors of antibody response. A retrospective analysis of the results of a second-generation vaccination program for the years 1999–2001 in our department showed that 19 of 36 (56.4%) ESRD patients developed seroprotection. In conclusion, the results of this study show that the third-generation HBV vaccine Bio-Hep-B® is highly immunogenic in the population of ESRD patients who did not respond in the past to a second-generation vaccine. This enhanced seroprotection offers hope that the new vaccine will reduce the rate of non-responders and help to eliminate HBV infection from dialysis centers.

Does a colonoscopy after acute diverticulitis affect its management?: a single center experience.

Background/Goals: Clinical diagnosis of acute diverticulitis is currently confirmed by an abdominal computerized tomography (CT). Common practice has been to perform a colonoscopy after the event to exclude other diagnoses, mainly colon cancer. Our aim was to evaluate the yield of an early colonoscopy. Methods: Medical records of 220 patients hospitalized for acute diverticulitis between June 1, 2002 and September 1, 2009 were reviewed. Acute diverticulitis was diagnosed by clinical criteria and characteristic CT findings. Fifteen patients were excluded either because of questionable CT or hematochezia. Mean age was 61.8±14.3 years (61% females). Clinical parameters, laboratory results, imaging, endoscopic and histopathological reports, and long-term patients’ outcome were analyzed. Results: One hundred patients (aged 61.8±13.3 y, 54.1% females), underwent an early (4 to 6 wk) colonoscopy after hospital discharge. There were no significant differences in patients’ characteristics or survival between those with or without colonoscopy (4±1.9 vs. 4.2±2.1 y, P=0.62). No colonic malignancy was detected. However, in 32 patients (32%) at least 1 polyp was found. Only 1 was determined as an advanced adenoma. No new or different diagnosis was made after colonoscopy. Conclusions: Our results suggest that colonoscopy does not affect the management of patients with acute diverticulitis nor alter the outcome. The current practice of a routine colonoscopy after acute diverticulitis, diagnosed by typical clinical symptoms and CT needs to be reevaluated.

Tissue expression of squamous cellular carcinoma antigen and Ki67 in hepatocellular carcinoma-correlation with prognosis: A historical prospective study

BackgroundSquamous cellular carcinoma antigen (SCCA) is overexpressed in hepatocellular carcinoma (HCC) tissue and in sera of HCC patients. Our aim was to assess hepatic SCCA immunostaining in a series of HCCs and to correlate its presence with cell proliferation, apoptosis and clinical outcome.MethodsSixty-one HCC patients were included. Liver specimens were obtained either by biopsy (n = 17) or surgically (resection 27, transplantation 17). Immunostaining for AFP, Ki-67, SCCA and TUNEL assay were performed.ResultsSCCA staining was detected in 83.6% of specimens. A statistical significant correlation was found between negative SCCA staining and mortality (p = 0.026) and a higher immunostaining score for Ki67 (p = 0.017). Positive SCCA staining was associated with well and moderate differentiated tumors (p = 0.022). Using multiple logistic regression analysis, Ki67 and TUNEL assay were found to be significant independent predictors of negative SCCA immunostaining. The area under the receiver operator characteristic curve was 0.87. Kaplan-Meier survival analysis revealed a significant difference between the patient group with positive versus negative SCCA immunostaining relating to survival time (p = 0.0106). Cox proportional hazard regression analysis demonstrated that Ki67 immunostaining and liver transplantation or resection were independently associated with mortality.ConclusionsSCCA is overexpressed in HCC. SCCA status is associated with cell proliferation, apoptosis and survival. SCCA and Ki67 staining can predict survival. Our study results support a potential association of negative SCCA expression with other markers of poor outcome in HCC. More studies are needed to clarify the role of SCCA in HCC and expand the knowledge of the SCCA antigen in HCC patients.

Excellent outcome of Lamivudine treatment in patients with chronic renal failure and hepatitis B virus infection.

Chronic hepatitis B virus (HBV) is associated with increased morbidity and mortality in patients with chronic renal failure (CRF) and renal transplant recipients. Lamivudine (3TC) has been shown to be a potent inhibitor of HBV replication. It appears to be safe and effective in patients with CRF, though experience is still limited. We describe 4 patients with CRF on hemodialysis who showed a rapid and full response to 3TC, administered for a median of 10 months. All patients had serum alanine transferase (ALT) levels 3 to 6 times the upper limit of normal prior to treatment, and different degrees of histologic inflammatory activity (Knodell score 4 to 8, median 6). All were serum HBsAg- and HBeAg-positive, with serum HBV DNA 1–3.9 × 107 copies/mL (median 1 × 107 copies/mL). Within 4 to 8 weeks of initiation of therapy, HBV DNA became undetectable and serum ALT normalized. Serum HBeAg disappeared in all 4 patients, with the emergence of anti-HBeAb in 3 of them. Three patients also lost HBsAg with the evolution of a protective anti-HBsAb titer. One patient has already undergone successful kidney transplantation with no evidence of HBV recurrence (serum HBV DNA negative) 16 months postoperatively. Although our study sample is small, these data suggest that 3TC can induce a complete biochemical, virological and serological response in patients with CRF and HBV infection. Its use may enable safe kidney transplantation in selected patients.

Hepatic Effects of Rosiglitazone in Rats with the Metabolic Syndrome

Rats given fructose-enriched diet develop many characteristics of the human metabolic syndrome and non-alcoholic fatty liver disease. In this study, we characterized the hepatic effects of rosiglitazone in fructose-enriched diet rats. Rats were randomly divided into three groups. One group was maintained on standard rat chow diet for 6 weeks, whereas the other two groups were given fructose-enriched diet for 6 weeks. Four weeks after the initiation of fructose-enriched diet, one of the fructose-enriched diet groups was also given rosiglitazone (10 mg/kg/day) for an additional 2 weeks. Rosiglitazone administration to the fructose-enriched diet rats was associated with decreases in the following parameters: blood pressure (-17%), plasma triglycerides (-62%), hepatic total lipids (-19%), hepatic triglycerides (-61%), hepatic malondialdehyde (-88%), glutathione reductase activity (-84%). An increase in adiponectin plasma levels (+329%), hepatic phospholipids (+46%), hepatic alpha-tocopherol concentrations (+24%) and hepatic paraoxonase activity (+68%) was observed. Rosiglitazone caused a decrease in hepatic macrovesicular steatosis score but no change in hepatic fibrosis. Administration of rosiglitazone, to rats with the metabolic syndrome has limited hepatic favourable effects: it improves hepatic lipid metabolism, decreases macrovesicular steatosis and improves some of the hepatic oxidative-anti-oxidative milieu but has no effect on hepatic fibrosis.

Ischemia and Reperfusion Liver Injury is Reduced in the Absence of Toll-like Receptor 4

Background/Aims: Toll-like receptor 4 (TLR4) is expressed on hepatic non-parenchymal cells and hepatocytes. Hepatic signaling through TLR4 is critical in the pathogenesis of ischemia reperfusion injury (IRI) and leads to the release of cytokines. The role of bone marrow-derived TLR4 in the early reperfusion stage is unclear. Methods: We used wild type mice (WT), TLR4deficient (TLR4ko) mice and chimeras to dissociate between the role of TLR4 expression in the liver (TLR4ko/WT) and in the immuno-hematopoietic system (WT/TLR4ko) in mouse hepatic IR injury model. Mice were subjected to in vivo partial IRI (70% for 60 min). Results: Compared with WT IR livers, TLR4ko IRI mice (4 hours) showed a significant reduction in serum liver enzyme, hepatic TNF-α and interleukin-1β levels. Fewer apoptotic hepatocytes cells were identified by morphological criteria and immunohistochemistry for caspase-3. In TLR4ko mice, decreased hepatic CJUN and NF-ĸB expression during IRI was noted compared with WT mice. Chimeric mice having either TLR4 bone-marrow or non-bone marrow derived cells following IRI exhibited almost similar hepatic injury as WT mice in the immediate reperfusion stage. Conclusion: Both TLR4 bone marrow-derived and non-bone marrow-derived cells are necessary in the initial process of hepatic injury. Activating TLR4-dependent signaling is required for IRI. The absence of the TLR4 gene plays a pivotal role in reducing hepatic IR injury.

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.

The 13C-caffeine breath test detects significant fibrosis in patients with nonalcoholic steatohepatitis.

Background The 13C-caffeine breath test (CBT) is a noninvasive tool for the evaluation of the cytochrome P450 system, implicated in the development of nonalcoholic steatohepatitis. Goal To apply the CBT to assess the extent of hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Methods Twenty-six consecutive patients (mean age 56.1±6.85 y, 69.2% women) with NAFLD underwent the CBT, in addition to the clinical and laboratory evaluations and liver biopsy. Ten healthy individuals matched for age served as controls. Results Mean delta over baseline values differed significantly between patients and controls (1.51±0.9 vs. 2.37±0.8 Δ‰/mg, respectively) (P=0.01) and were significantly higher in patients with fibrosis stage <2 (Brunts system) (2.0±0.77 vs. 1.3±0.9 for stage ≥2, P=0.05). Mean delta over baseline values correlated highly with fibrosis stage (P=0.01), albumin (P=0.007), international normalized ratio (P=0.04), bilirubin (P=0.0008), and platelet count (P=0.0001). On multivariate stepwise logistic regression analysis, CBT was the best predictor of severe fibrosis (stage ≥2) (odds ratio 0.274, 95% confidence interval 0.086-0.872, P=0.028), with an area under the curve of 0.788. Conclusions The CBT is safe and easy to perform. It can reliably predict severe hepatic fibrosis in patients with NAFLD. Further large-scale studies are still needed.

Serum globulin levels in predicting the extent of hepatic fibrosis in patients with recurrent post-transplant hepatitis C infection

Abstract:  The progression of HCV‐related disease is particularly aggressive in the post‐transplantation setting. Recipients with recurrent HCV infection undergo repeated liver biopsies in order to estimate disease progression. A strong association was found between serum immunoglobulins levels and hepatic fibrosis in non‐transplanted patients with chronic HCV infection. The aim of this study was to determine if serum globulin and immunoglobulins levels can predict the extent of fibrosis in patients with recurrent HCV infection. The records of 45 patients (mean age 51.6 ± 10.5 yr; 53.3% men) with biochemical, serologic, virologic, and histological evidence of recurrent HCV infection were reviewed. Recurrence developed after a median interval of 11.7 months (range: 3–106); in 14 patients (31.1%), the recurrent infection was severe. The mean duration of follow‐up was 51.4 ± 35.4 months. A total of 96 liver biopsies were performed. The mean fibrosis score increased significantly with an increase in the number of biopsies (p < 0.0001, r = 0.44). On multivariate analysis, the only predictors of severe fibrosis were serum levels of globulin (OR: 5.97, 95% CI: 1.82–19.53; p = 0.0004) and IgG (OR: 1.003, 95% CI: 1.001–1.006; p = 0.018). On linear regression analysis, for each 0.5‐g/dL increase in serum globulin level, there was a 0.22‐point increase in fibrosis stage. In conclusion, serum levels of globulin and IgG can serve as a noninvasive marker of the extent of hepatic fibrosis in patients with post‐transplant recurrent HCV infection, thus avoiding the need for repeated liver biopsies. These findings, if confirmed, have important implications for the prevention and treatment of fibrosis in this patient group.

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.