A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C.

This randomized, prospective, multicenter trial compared the safety and efficacy of steroid-free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA-positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid-free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid-free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS.

Hepatic and cardiac iron overload among patients with end-stage liver disease referred for liver transplantation.

BACKGROUND: Iron overload is associated with fatal cardiovascular events following liver transplantation. Myocardial iron deposits were observed post-mortem in patients who died of cardiac events after transplantation at our institution. This observation prompted testing to exclude cardiac iron in subsequent transplant candidates. AIMS: To assess the results of testing for iron overload in liver transplant candidates at our institution. METHODS: Ferritin, TIBC, and serum iron were measured in cirrhotics referred for transplantation. Patients with transferrin saturation ≥50% and ferritin ≥250 ng/mL underwent liver biopsy graded for iron. Patients with 3-4+ hepatic iron deposits underwent HFE mutation analysis and endomyocardial biopsy with iron staining. RESULTS: Eight hundred and fifty-six patients were evaluated for liver transplantation between January 1997 and March 2005. Two hundred and eighty-seven patients (34%) had transferrin saturation ≥50% and ferritin ≥250 ng/mL. Patients with markers of iron overload had more advanced liver disease than those with normal iron indices. One hundred and fifty-three patients underwent liver biopsy. Twenty-six patients (17%) had 3-4+ hepatic iron staining. One patient was a C282Y heterozygote. Endomyocardial biopsy was performed in 14 patients of whom nine had cardiac iron deposition. CONCLUSIONS: Non-HFE-related cardiac iron overload can occur in advanced liver disease We therefore recommend screening for cardiac iron prior to liver transplantation.

Hepatitis C infection increases the risk of new-onset diabetes after transplantation in liver allograft recipients.

BACKGROUND: Recent evidence suggests that new-onset diabetes after transplant (NODAT) adversely affects orthotopic liver transplant (OLTX) patient and graft survival. The objective of this study is to evaluate the effect of hepatitis C infection on the natural history of NODAT. METHODS: A retrospective review of 492 OLTX recipients at a single center was conducted from January 1993 to January 2003. Patients were followed for a minimum of 12 months (range 12 months-10 years). The study population consisted of 444 OLTX recipients who were either HCV positive (n = 206) or HCV negative (n = 238). NODAT was defined by the need for antidiabetic medication for at least 7 days starting anytime after OLTX. Statistical analysis was performed by using the Student t test, Kaplan-Meier survival, and chi-square tests. RESULTS: The overall incidence of NODAT was 33% (146/444). There was a significant difference in the development of NODAT between the HCV-positive group (82/206, 40%) and the HCV-negative group (64/238, 27%) (P < .001). Other independent risk factors for development of NODAT were male gender and age >50 years. CONCLUSION: Hepatitis C infection contributes to the development of diabetes mellitus in OLTX recipients. The mechanisms behind HCV infection and associated NODAT in HCV-positive OLTX recipients warrant further investigation.

High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure.

HYPOTHESIS: The use of potentially hepatotoxic herbal and dietary supplements is highly prevalent in the fulminant hepatic failure (FHF) patient population at our institution, and this subgroup of patients has a worse prognosis. DESIGN: Retrospective case series. Settings An adult tertiary care university hospital and a Veterans Affairs hospital in Oregon. PATIENTS: All patients referred to the liver transplantation service for FHF from January 2001 through October 2002 (N = 20). We defined FHF as onset of encephalopathy within 8 weeks of onset of jaundice in the absence of preexisting liver disease. All patients underwent investigation for potential causes of liver injury. Potentially hepatotoxic supplements were defined as those with previously published reports of hepatic injury related to their use. RESULTS: Ten patients (50%) were recent or active users of potentially hepatotoxic supplements or herbs; 10 had no history of supplement use. In the supplement group, 7 patients (35%) had no other identified cause for hepatic failure. Six patients in the supplement group and 2 patients in the nonsupplement group underwent orthotopic liver transplantation. Five patients in each group died. There were no significant differences in transplantation rate (P =.07) or survival (P>.99) between groups. Supplement use alone accounted for the most cases of FHF during this period, exceeding acetaminophen toxicity and viral hepatitis. CONCLUSIONS: Herbal and dietary supplements were potential hepatotoxins in a high proportion of patients with FHF at our institution. Enhanced public awareness of the potential hepatotoxicity of these commonly used agents and increased regulatory oversight of their use is strongly urged.

Adult living donor versus deceased donor liver transplantation: a 6-year single center experience.

No long-term (>3 years) prospective comparison of adult-to-adult living donor liver transplantation (A2ALLTx) to adult deceased donor liver transplantation (ADDLTx) has been reported. This is a prospective, IRB approved, 6-year comparison of A2ALLTx to ADDLTx. Data include: age, gender, ethnicity, primary liver disease, waiting time, pretransplant CTP/MELD score, cold ischemia time (CIT), perioperative mortality, acute and chronic rejection, graft and patient survival, charges and post-transplant complications. In 6 years, 202 ADDLTx (74.5%) and 69 A2ALLTx (25.5%) were performed at VCUHS. Hepatitis C virus (HCV) was the most common reason for transplantation in both groups (48.1% vs. 42%). Data regarding overall patient and graft survival, monetary charges and retransplantation rates were similar. Comparison of patient/graft survivals, retransplantation rates in patients with and without HCV were not statistically different. A2ALLTx patients had less acute rejection (11.5% vs. 23.9%) and more biliary complications (26.1% vs. 11.4%). Overall, A2ALLTx is as durable a liver replacement technique as the ADDLTx. Patients with A2ALLTx were younger, had lower MELD scores, less acute rejection and similar histological HCV recurrence. Biliary complications were more common in A2ALLTx but were not associated with increased graft loss compared to ADDLTx.

Treatment of Hepatocellular Carcinoma.

The incidence of hepatocellular carcinoma (HCC) is increasing in the United States. Several modalities are available for the treatment of HCC, and decisions regarding the optimal choice of therapy are based on tumor burden and severity of liver disease. Classification systems are helpful for prognostic purposes and to guide in the choice of therapy. Surgical resection is a mainstay of therapy for patients with solitary small tumors and preserved liver function (noncirrhotic or Child-Pugh class A cirrhotic patients without portal hypertension). Unfortunately, a minority of patients is eligible for resection, and postoperative recurrence or de novo HCC is common. Liver transplantation offers the best chance of curing HCC in cirrhotic patients. Patients with a solitary tumor less than 5 cm or no more than three tumors each 3 cm or less have a survival rate of 70% with less than 20% recurrence at 5 years. Access to liver transplantation is limited by organ availability, and tumor progression during the waiting period can lead to ineligibility. Ethanol injection and radiofrequency ablation are effective modalities to ablate small tumors (generally <5 cm) in patients who are not candidates for resection or liver transplantation. These modalities can also be used to treat HCC prior to liver transplantation. Transarterial chemoembolization is used to treat patients with multifocal or large HCC who are ineligible for other therapies. Chemotherapeutic agents are infused into the tumor via the hepatic artery along with embolic material in order to induce tumor necrosis. This technique should be used in selective patients with relatively preserved liver function, absence of portal vein thrombosis, or encephalopathy. Limited data exist to support the use of this modality as a primary treatment option for small HCC. Chemotherapeutic or hormonal therapies have a limited role in the management of patients with HCC. Despite mixed outcomes, we routinely use the somatostatin analog octreotide in advanced, multifocal HCC. Emerging therapies should focus on treatment of small tumors and targeted pharmacologic therapy for advanced disease.