Hepatitis: Cameron AM

Cameron AM, Busuttil RW. · Dumont-UCLA Liver Transplant Center, David Geffen School of Medicine at UCLA, Department of Surgery, 10833 LeConte Ave, 77-132 CHS, Los Angeles, CA 90095, USA. · Expert Opin Biol Ther. · Pubmed #16989581 No free full text.

Abstract: The hepatitis C virus (HCV) infects 3% of the world's population, or approximately 170 million people. Most of those acutely infected progress to chronic infection and are unresponsive to existing antiviral treatment. Over a 20-year period, chronic HCV infection leads to cirrhosis and the sequelae of end-stage liver disease, including hepatic encephalopathy, ascites, variceal haemorrhage and hepatocellular carcinoma. Orthotopic liver transplantation (OLT) is the optimal treatment for decompensated HCV cirrhosis, but is limited by organ availability and universal graft reinfection. This review discusses the results with OLT for HCV from the Dumont-UCLA Liver Transplant Center and discusses future directions in the management of HCV.

Hoffmann CJ, Subramanian AK, Cameron AM, Engels EA. · Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Transplantation. · Pubmed #18813102 No free full text.

Abstract: BACKGROUND: Solid organ transplant recipients commonly are infected with hepatitis viruses, are immunosuppressed, and have other potential hepatocellular carcinoma (HCC) risk factors. METHODS: We studied de novo HCC incidence arising after transplant using U.S. registry data (223,660 recipients, 1987-2005). We used proportional hazards regression to identify HCC risk factors and calculated standardized incidence ratios (SIRs) to compare HCC risk with that in the general population. RESULTS: Based on 74 cases reported by transplant centers to the registry, HCC incidence was 6.5 per 100,000 person-years among kidney, heart, and lung (non-liver) recipients and 25 per 100,000 person-years among liver recipients. Hepatocellular carcinoma incidence among non-liver recipients was independently associated with hepatitis B surface antigenemia (hazard ratio [HR] 9.7, 95% confidence interval [CI] 2.8-33), hepatitis C virus (HCV) infection (HR 6.9, 95% CI 2.5-19), and diabetes mellitus (HR 2.8, 95% CI 1.2-6.6). Among liver recipients, HCC incidence was associated with advancing age (P<0.001), male sex (HR 4.6, 95% CI 1.4-16), HCV infection (HR 3.1, 95% CI 1.3-7.2), and diabetes mellitus (HR 2.7, 95% CI 1.2-6.2). Among non-liver recipients, overall HCC incidence was similar to the general population (SIR 0.8) but elevated among those with HCV (3.4) or hepatitis B surface antigenemia (6.5). Hepatocellular carcinoma incidence among liver transplant recipients was elevated overall (SIR 3.4) and especially among those with HCV (5.0) or diabetes mellitus (6.2). CONCLUSIONS: Hepatocellular carcinoma incidence is elevated among liver transplant recipients and subsets of non-liver recipients. These risk factors indicate the need for improved control of viral hepatitis after solid organ transplantation.

Locke JE, Sun Z, Warren DS, Sheets TP, Holzer H, Shamblott MJ, Montgomery RA, Cameron AM. · Division of Transplantation, Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA. · Ann Surg. · Pubmed #18791369 No free full text.

Abstract: OBJECTIVE: Animal organs engineered to be chimeric for human cells could contribute significantly to the field of transplantation, including studies of human-specific diseases such as hepatitis-C, as treatment for in-born errors of metabolism, and for development of a renewable source of transplantable organs via modified xenotransplantation. We sought to use human embryoid body-derived stem cells (EBDs) to populate livers in animals for applications in transplant surgery. METHODS: SCID mice and rats underwent liver injury with carbon tetrachloride exposure or partial hepatectomy. Animals received intrasplenic injection of fluorescently labeled human stem cells. Spleen and liver were assessed at 2, 7, 15, and 30 days after transplant for the presence of EBDs and markers of human hepatocyte differentiation. RESULTS: EBDs migrate to and engraft in animal liver after splenic injection under conditions of hepatic injury. EBDs are detectable at 2 days and are in abundance at 1 week after transplant. EBDs persist in rodent liver long term (>1 month), and once engrafted differentiate into functional human hepatocytes as assessed by production of human alpha-feto-protein (AFP) and human albumin. CONCLUSIONS: We developed a novel animal model in which hepatic injury and stem cell transplantation lead to the generation of humanized animal organs. We are currently using our model to study recurrent hepatitis-C after liver transplantation, and as an alternative to whole organ transplantation for treatment of in-born errors of metabolism.

Segev DL, Sozio SM, Shin EJ, Nazarian SM, Nathan H, Thuluvath PJ, Montgomery RA, Cameron AM, Maley WR. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Liver Transpl. · Pubmed #18383081 links to  free full text

Abstract: Steroid use after liver transplantation (LT) has been associated with diabetes, hypertension, hyperlipidemia, obesity, and hepatitis C (HCV) recurrence. We performed meta-analysis and meta-regression of 30 publications representing 19 randomized trials that compared steroid-free with steroid-based immunosuppression (IS). There were no differences in death, graft loss, and infection. Steroid-free recipients demonstrated a trend toward reduced hypertension [relative risk (RR) 0.84, P = 0.08], and statistically significant decreases in cholesterol (standard mean difference -0.41, P < 0.001) and cytomegalovirus (RR 0.52, P = 0.001). In studies where steroids were replaced by another IS agent, the risks of diabetes (RR 0.29, P < 0.001), rejection (RR 0.68, P = 0.03), and severe rejection (RR 0.37, P = 0.001) were markedly lower in steroid-free arms. In studies in which steroids were not replaced, rejection rates were higher in steroid-free arms (RR 1.31, P = 0.02) and reduction of diabetes was attenuated (RR 0.74, P = 0.2). HCV recurrence was lower with steroid avoidance and, although no individual trial reached statistical significance, meta-analysis demonstrated this important effect (RR 0.90, P = 0.03). However, we emphasize the heterogeneity of trials performed to date and, as such, do not recommend basing clinical guidelines on our conclusions. We believe that a large, multicenter trial will better define the role of steroid-free regimens in LT.

Zimmerman MA, Ghobrial RM, Tong MJ, Hiatt JR, Cameron AM, Busuttil RW. · Department of Surgery, Division of Liver and Pancreas Transplantation, The Pfleger Liver Institute, The Dumont-UCLA Transplant Center, The David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California 90095-7054, USA. · Transplant Proc. · Pubmed #18089370 No free full text.

Abstract: BACKGROUND: Orthotopic liver transplantation (OLT) is a viable treatment option for patients with hepatitis B (HBV) and concomitant hepatocellular carcinoma (HCC). However, cancer recurrence following transplantation approaches 20%. This study sought to identify the clinical and pathological factors associated with post-OLT survival. METHODS: Univariate and multivariate analyses considered the following variables: combination viral prophylaxis, HBV recurrence, tumor stage, vascular invasion, distribution, nodularity, pre- and post-OLT tumor size, pre-OLT alpha-fetoprotein (AFP), Milan and UCSF criteria, and Asian race. RESULTS: Cumulatively, HCC recurrence-free survival was 77%, 62%, and 53% at 1, 3, and 5 years, respectively, and was significantly better in patients who were free of viral recurrence post-OLT. Similarly, patients treated with combination prophylaxis had a significantly lower mortality than those who were not. CONCLUSIONS: Multivariate analysis revealed that AFP>500 ng/mL, presence of vascular invasion by explant, HBV recurrence, and combination prophylaxis were independent predictors of HCC recurrence-free survival.

Cameron AM, Ghobrial RM, Hiatt JR, Carmody IC, Gordon SA, Farmer DG, Yersiz H, Zimmerman MA, Durazo F, Han SH, Saab S, Gornbein J, Busuttil RW. · Department of Surgery, Dumont-UCLA Liver Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. · Ann Surg. · Pubmed #16998365 links to  free full text

Abstract: OBJECTIVE: Hepatitis C (HCV) is now the most common indication for orthotopic liver transplantation (OLT). While graft reinfection remains universal, progression to graft cirrhosis is highly variable. This study examined donor, recipient, and operative variables to identify factors that affect recurrence of HCV post-OLT to facilitate graft-recipient matching. METHODS: Retrospective review of 307 patients who underwent OLT for HCV over a 10-year period at our center. Recurrence of HCV was identified by the presence of biochemical graft dysfunction and concurrent liver biopsy showing diagnostic pathologic features. Time to recurrence was the endpoint for statistical analysis. Five donor, 6 recipient, and 2 operative variables that may affect recurrence were analyzed by univariate comparison and Cox proportional hazard regression models. RESULTS: Recurrence-free survival in the 307 study patients was 69% and 34% at 1 and 5 years, respectively. Four predictive variables related to either donor or recipient characteristics were identified. Advanced donor age, prolonged donor hospitalization, increasing recipient age, and elevated recipient MELD scores were found to increase the relative risk of HCV recurrence. Examination of HLA disparity between donors and recipients demonstrated no correlation between class I or class II mismatches and recurrence-free survival. CONCLUSIONS: We have identified donor and recipient characteristics that significantly predict hepatitis C recurrence following liver transplantation. These factors are identifiable before transplant and, if considered when matching donors to HCV recipients, may decrease the incidence of HCV recurrence after OLT. A change in the current national liver allocation system would be needed to realize the full value of this benefit.