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The purpose of this study was to evaluate whether there was a difference in mortality following orthotopic liver transplantation (OLT) in a US veteran (VA) population (n = 149) compared to a non-VA (university) population (n = 285) and what factors could explain this difference. Survival following OLT for 149 VA patients was compared with that of 285 university patients. By Kaplan-Meier survival analysis, VA patients had higher mortality than university patients with respective 1-year, 3-year, and 5-year survival of 82%, 75%, and 68% vs. 87%, 82%, and 78% (p = 0.006). Gender, etiology of end-stage liver disease (ESLD) and donor age (i.e. older than 34 years) also significantly influenced survival. However, when donor and recipient age, gender, model for end-stage liver disease (MELD) score, and etiology of liver disease were included with hospital status in a multivariate Cox proportional hazards model, the VA population did not have higher mortality. A final model to predict mortality following transplantation was derived for all 434 patients where individuals were assigned risk scores based on the equation R = 0.219 (gender) + 0.018 (donor age) + 0.032 (recipient age) + 0.021 (MELD), where recipient age, donor age, and MELD score are the respective continuous variables and gender = 1 (men) and 0 for women (c-statistic = 0.71).

After orthotopic liver transplantation (OLT), allograft rejection remains an important problem and is the major reason that immunosuppressive therapy must be administered. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory mediator that is central to the immune response, and intragraft expression of this cytokine is increased during acute cellular rejection (ACR). Polymorphisms within the TNF promoter have been identified and correlated with alterations in production. The aims of this study were to determine if an individual patient's propensity to develop ACR is related to the presence of these genetic polymorphisms (either alone or in combination) within donor and recipient tissue and to determine if these polymorphisms affect patient survival after OLT. The study group consisted of 210 patients who underwent OLT between 1989 and 1999 with at least 6 months survival, including 42 cases who had evidence of acute cellular rejection (biopsy-proven, elevated enzymes, and response to increased immunosuppression) and were matched 4:1 to controls (n = 168) with similar age, gender, underlying liver disease, date of transplant, and baseline immunosuppression. The underlying liver diseases were hepatisis C virus (HCV)/alcohol (70), HCV alone (50), alcohol (30), primary biliary cirrhosis (15), primary sclerosing cholangitis (15), autoimmune hepatitis/cirrhosis (10), cryptogenic (15), and hepatitis B virus (HBV) (5). DNA was extracted from paraffin-embedded donor and recipient liver tissue (total 420 samples), amplified, and sequenced for TNF single-nucleotide polymorphisms (TNFA-308 A/G and TNFA-238 A/G). We found no differences between the TNF allelic distributions among donors without liver disease (presumably representative of a normal control population) and patients with end-stage liver disease undergoing OLT. Multivariate analysis revealed no association with TNF polymorphisms (within donor or recipient tissue) and rejection risk or patient survival after transplantation. In this large case control analysis of patients undergoing liver transplantation for diverse etiologies, TNF promoter polymorphisms were not independently associated with rejection or survival.

Hepatitis C virus-related liver failure is the single leading indication for liver transplantation, and the study of HCV in the transplant setting has enhanced the understanding of the natural history of disease and putative mechanisms by which HCV causes liver injury. In a subset of patients, allograft cirrhosis develops within a few years after transplantation, and recent findings suggest these individuals are immunologically impaired compared with individuals with mild HCV recurrence at long-term follow-up. Fig. 9 shows a conceptual paradigm of mechanisms potentially involved in shaping HCV outcome after transplantation. It is possible that relative antiviral control by innate and adaptive immune responses (to maintain HCV replication below a certain threshold) prevents direct cytopathic injury and induction of oxidative stress and apoptosis of cells. Additional phenomena that may contribute to induction of apoptosis (eg, genetic polymorphisms within the donor organ. CMV coinfection, and ischemic-preservation injury) may augment the initial cascade of liver injury. Recruitment to the allograft of nonspecific cells may decrease viral replication by way of noncytolytic mechanisms or augment viral replication (eg, Th2 phenotype) and direct cytopathic injury. The immune response is likely insufficiently vigorous to keep viral replication under control, but may maintain chronic liver injury. The liver transplant model is unique in that distinct phenotypic outcomes can be observed over a short period of time. A consideration of the temporal evolution of different mechanisms is also important, because mechanisms that initially predominate may become less important over time, and conversely, as suggested with the inverse correlation between viral load at 5 years and allograft fibrosis, new immune responses may emerge that modify the host-virus interaction. Prospective characterization of the immunoregulatory and virologic mechanisms involved in the liver transplantation model hopefully will help unravel the causal basis of reported associations, lead to the development of highly specific therapeutic strategies, and ultimately diminish the rate of graft loss from recurrent disease.

Progressive liver allograft injury related to hepatitis C virus (HCV) recurrence occurs in 20% to 30% of liver transplant recipients within the first 5 years. In particular, the subset of patients who develop the severe cholestatic variant has an extremely high mortality. We report our center's experience with 7 cholestatic patients who were treated with interferon alfa-2b (3 million IU three times per week initially) in combination with ribavirin. In 4 of the 7 patients, HCV-RNA in serum became undetectable, and in an additional patient, normalization of serum bilirubin was achieved despite persistent viremia. Discontinuation of antiviral therapy by patient choice, intolerance of side effects, or occurrence of infection were followed temporally by rapid relapses of the cholestatic syndrome, allograft failure, and death. The only 2 patients alive in remission of this syndrome have been maintained on antiviral therapy for an average of 32 months. Thus, based on our experience, we recommend that duration of antiviral therapy in the subset of patients with cholestatic HCV recurrence should be indefinite.

Spontaneous resolution of hepatitis C virus (HCV) infection is a relatively infrequent event, and these individuals provide a unique opportunity to characterize correlates of protective immunity as an important first step in the development of vaccine candidates. The aim of this study was to directly and comprehensively enumerate HCV-nonstructural protein 3 (NS3) specific CD4+ and CD8+ T cells ex vivo from HLA diverse individuals who had been successful in spontaneously resolving HCV infection. We measured interferon gamma (IFN-γ) production with an ELISPOT assay using magnetic bead-separated CD4+ or CD8+ T cells in response to autologous DCs that had been pulsed with 15mer per peptides overlapping by 11 amino acids and spanning all of the NS3 protein (150 total peptides). All subjects with spontaneously recovered HCV infection demonstrated vigorous and multispecific CD4+ T-cell responses to NS3 peptides, and 6 of 10 subjects demonstrated CD8+ T-cell responses. More importantly, we identified novel, previously unpredicted antigenic regions, which in most cases elicited high frequencies within a given individual. In conclusion, subjects who have spontaneously eradicated HCV infection up to 35 years earlier demonstrate persistent CD4+ and CD8+ T-cell responses specific to NS3. By providing a comprehensive screening of all potential T-cell epitopes contained in the NS3 region, our strategy defines the breadth of the T-cell response and identifies novel, unpredicted specificities. (HEPATOLOGY 2003;37:577-589.)

Hepatitis C virus (HCV)-related liver disease is the leading indication for orthotopic liver transplantation worldwide. Recurrent HCV infection as defined by viremia after transplantation is nearly universal, with histologic evidence of recurrent hepatitis present in the majority. Although short-term survival appears to be similar to that in other causes of liver failure, it has recently been demonstrated that approximately 20-30% of HCV-positive patients develop allograft cirrhosis by 5 years. Therefore, it is possible to define disease outcomes within a relatively short period of follow-up. Identification of patients who are likely to develop progressive HCV-related allograft injury is important to optimize results of current antiviral therapy.

Interferon (IFN) and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection yields a sustained response rate of only approximately 40%. Previous studies have linked IFN responsiveness to viral sequence variation in parts of the E2 and NS5A genes, but this remains controversial. We studied pretreatment sera from 28 subjects (23 with HCV genotype 1a) who received high-dose IFN induction followed by IFN-ribavirin combination therapy. Serum HCV sequences were amplified and compared from 14 responders with undetectable HCV RNA 24 weeks after therapy and 11 nonresponders (excluding three who dropped out of the study). Analysis included the E2 PKR eIF-2alpha phosphorylation homology domain (PePHD, codons 659-670), where the sequence was well conserved, and codons 2001-2420 of NS5A. In NS5A, the proposed PKR binding domain (codons 2209-2274), containing the putative IFN sensitivity determining region (ISDR, codons 2209-2248), showed too little variation among subjects to differentiate responders and nonresponders. NS5A codons 2356-2385 (which includes the V3 region) exhibited more variation. Here, six of 12 genotype 1a responders showed four or more amino acid changes from the prototype HCV-1 sequence, as compared with one of eight nonresponders, but this fell short of statistical significance (P = 0.16). NS5A sequences from posttreatment sera were examined in six nonresponders to look for selection of treatment-resistant viral subpopulations, but no consistent change was detected. In conclusion, our results indicate that the sequences of the ISDR, the PKR-binding domain, and the PePHD are unlikely to have predictive value for IFN treatment success in those infected with HCV genotype 1a. However, the finding of greater variability among treatment responders in the carboxy end of NS5A suggests that the V3 region merits further investigation.

Background: With current early transplant patient and allograft survivals nearly optimized, long-term medical complications have become a significant focus for potential improvement in patient outcomes. Cardiovascular disease and associated risk factors have been shown in renal transplant patients to be related to the pharmacologic immunosuppression employed. Objective: The objective of this study is to investigate at 3 years postliver transplant (OLTx) the incidence of hypertension (HTN), hyperlipidemia (HLIP), diabetes mellitus (DM), nephrotoxicity (NTX), and cardiovascular disease (MI, angioplasty, CHF, CVA, and seborth) as well as rejection in two cohorts of liver transplant recipients who received either tacrolimus (FK-506) or cyclosporine (CSA) and to analyze the consequences of these complications on mortality following transplantation. Methods: Eighty-seven sequential patients (CSA: n = 50, mean age 48 years, M/F 32/18; and FK-506: n = 37, mean age 45 years, M/F 22/15) who underwent OLTx between 1994 and 1998, were ≥18 years, and had a minimum of 3 years of complete follow-up were included in the analysis. All OLTx candidates over age 50, who had a history of alcoholic cirrhosis, or had a history of cardiac conditions/events underwent complete cardiac consultation including an echocardiogram with additional cardiac investigation as indicated prior to OLTx. Results: At 3 years following OLTx, the incidence of acute rejection (40% versus 19%, P < 0.05), HTN (62% versus 38%, P < 0.05), HLIP (14% versus 5%, P = 0.08), and cardiovascular disease (18% versus 0%, P < 0.001), were significantly greater for the CSA patients compared with the FK-506 patients. Eight (20%) of the CSA patients who died before 3 years had their death attributed to cardiovascular events versus none in the FK-506 group. Conclusion: Compared with CSA, FK-506 was associated with significantly less rejection and a reduced incidence of HTN and cardiovascular disease.

Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, affecting approximately 2% of the world's population. The immune mechanisms responsible for the highly variable natural history in a given individual are unknown. We used a multiparameter flow cytometric technique to functionally and phenotypically characterize HCV-specific effector T cells in the peripheral blood of 32 individuals with different stages of hepatitis C disease (resolved, mild chronic, advanced chronic) and normal controls. We found the highest frequencies of virus-specific effector cells with an activated memory phenotype (CD45RO+CD69+) in subjects who had resolved HCV infection, either spontaneously or with antiviral therapy. Effector cells from patients with resolved infection produced Th1 type cytokines following stimulation with nonstructural antigens (NS3 and NS4), whereas effector cells from chronically infected patients produced Th1 type cytokines predominantly following stimulation with the HCV core antigen. Stimulation with superantigen staphylococcal enterotoxin (SEB) induced the same levels of cytokine production in the different patient groups. Among the HCV-seropositive patients, viral load inversely correlated with the Th1 effector cell response to NS3. Interleukin (IL)-4 was produced only in response to the control antigens, but not in response to the HCV recombinant proteins. Taken together, these findings suggest that a vigorous HCV-specific CD4+ Th1 response, particularly against the nonstructural proteins of the virus, may be associated with viral clearance and protection from disease progression. Prospective studies using this new flow cytometric assay will be required to determine whether antiviral therapy modifies the frequency, specificity, and function of these virus-specific effector cells.

Liver tissue from hepatitis C virus (HCV)-related end-stage disease contains T-cell infiltrates. The goal of this study is to determine whether CD4 T-cell clones established in vitro using an antigen-independent technique from explanted liver tissue (n = 3) are representative of dominant clones present in vivo. T-cell receptor (TCR) use by intrahepatic CD4 T cells was assessed by spectratype analysis. Clones were established from single CD4 T cells by culturing in vitro with anti-CD3 and interleukin-2 (n > 25 per patient). TCR genes expressed by each clone were identified by sequencing. When identical clones were isolated, the original spectratype was analyzed further to determine whether the clone was a dominant T-cell expansion in vivo. Evidence for clonal expansions was found in all patients by spectratyping. T cells expressing the same TCRBV genes used for spectratyping were cloned in vitro. Duplicate clones expressing the same TCR genes were observed in 2 patients. Confirmation that clones established in vitro matched those present in vivo was obtained for 2 clones. Many dominant clones identified by spectratyping did not proliferate in vitro. Although spectratyping suggested the widespread accumulation of clonal expansions in HCV-related end-stage liver disease, clones established in vitro using anti-CD3 were poorly representative of dominant clones present in vivo. Although cloning with anti-CD3 has the advantage of generating T-cell clones not biased a priori toward a specific antigen, modified cloning strategies will need to be developed to expand those clones that appear dominant in end-stage organs.

Background: Mortality within the first year after orthotopic liver transplantation (OLTx) is usually due to infection or allograft failure. Late complications leading to death after OLTx have not been extensively evaluated. The aim of this study was to determine the incidence of late mortality and to identify the most common causes and risk factors associated with late mortality after OLTx. Methods: A total of 479 OLTx were performed in 459 patients (320 males, 139 females; mean age 47 years, range 13 to 69) between September 1991 and April 2000. All patient deaths among liver transplant recipients who survived more than 1 year after transplantation (follow-up mean 3.4 years, median 3, range 1 to 8.6) were reviewed. Results: In all, 122 allografts (24%) were lost in 109 patients during the study period (24%). Seventy-five allografts were lost in 69 patients by 1 year (15%). Forty-seven allografts were lost in 40 patients who survived at least 1 year (9.6%). Actuarial survivals at 2 years, 5 years, and 9 years were 95%, 85%, and 80%, respectively (based on 100% survival at 1 year). The causes of the late mortality were malignancy (9 patients), disease recurrence (8), late infection (6), renal failure complications (5), cardiovascular complications (4), chronic rejection (3), gastrointestinal hemorrhage (2), medication noncompliance (1), and unknown (2). Conclusions: Malignancy and disease recurrence are the major causes of late mortality among adult OLTx recipients. Pharmacologic immunosuppression is associated with many of the causes of late mortality. Advances in immunosuppression with less toxicity may improve long-term survival after OLTx.

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is common, although the majority of cases are mild. A subset of transplant recipients develops progressive allograft injury, including cirrhosis and allograft failure. Minimal data are available on the safety and efficacy of antiviral treatment in this group of patients. The aim of this study is to review our experience in the treatment of moderate to severe HCV recurrence with combination interferon-α2b and ribavirin (IFN/RIB). Between October 1993 and October 1999, a total of 197 patients underwent OLT for HCV-related liver failure. This study describes 12 transplant recipients with moderate to severe recurrence treated with IFN/RIB. All patients met at least 1 of the following inclusion criteria: (1) moderate to severe inflammation (grade III to IV) on allograft biopsy, (2) bridging fibrosis on allograft biopsy, or (3) severe cholestasis attributable solely to HCV recurrence. Two patients had undergone re-OLT for allograft cirrhosis secondary to HCV recurrence and now had evidence of progressive HCV in their second allografts. Appropriate dose reductions of both IFN and RIB, as well as initiation of granulocyte colony-stimulating factor (G-CSF), for marked leukopenia were recorded. IFN/RIB therapy was started 60 to 647 days post-OLT, and duration of therapy ranged from 39 to 515 days. Seven patients were administered G-CSF to successfully treat leukopenia. Six of the 12 patients (50%) became HCV RNA negative by polymerase chain reaction. One of these 6 patients (no. 1) was HCV RNA negative at 6 months but chose to discontinue therapy because of intolerable side effects, experienced a relapse, and was HCV RNA positive at 12 months. Two of the remaining 5 patients were HCV RNA negative at 2 and 9 months off therapy. For the entire group, there was a statistically significant decrease in serum biochemical indices assessed at initiation of therapy and 1, 3, and 6 months into therapy. Most patients required dose reductions of both IFN and RIB. Five patients died; 3 patients died of liver-related complications that included severe intrahepatic biliary cholestasis, severe HCV recurrence, and chronic rejection with profound cholestasis. In the subset of HCV-positive liver transplant recipients with moderate to severe recurrence, combination IFN/RIB therapy resulted in complete virological response (serum RNA negative) in 6 of 12 patients (∼50%). However, only 1 of 12 patients (8.3%) had sustained virological clearance after cessation of IFN/RIB therapy. Dose reductions of both IFN and RIB were required in most patients. The use of G-CSF (sometimes preemptively) allowed correction of leukopenia and full-dose antiviral therapy. Multicenter trials using combination therapy to identify factors predictive of response are needed in the subset of patients with progressive allograft injury. (Liver Transpl 2001;7:181-190.)

Key Points 1. Approximately 20% of hepatitis C virus (HCV)-positive liver transplant recipients develop evidence of allograft cirrhosis by year 5. 2. The prevalence of HCV infection in patients undergoing retransplantation has significantly increased since 1990. 3. Retransplantation for recurrent HCV is associated with poor long-term survival. 4. Preoperative hyperbilirubinemia (billirubin ≥5 mg/dL) and renal failure predict poor outcome after retransplantation. 5. Retransplantation is the only viable option for patients in whom allografts fail because of recurrent HCV disease.

Endoscopic ultrasound (EUS) was used to evaluate cirrhotic patients with and without prior variceal hemorrhage. The findings were compared with those of EUS in noncirrhotic control subjects to determine EUS features indicative of cirrhosis and of a risk for variceal hemorrhage.Patients with cirrhosis undergoing indicated endoscopic screening for varices or surveillance after endoscopic therapy for variceal hemorrhage were studied and compared with healthy noncirrhotic control patients undergoing EUS for benign conditions.Sixty-six cirrhotic patients (31 with prior hemorrhage) and 32 control patients were studied. Nonhemorrhage cirrhotic patients had more severe liver disease by Child's class (p = 0.02) and less beta-adrenergic blocker usage (p0.0001). Paraesophageal varices were detected in 97% of cirrhotic patients and 3% of control patients (p0.001) and were a more sensitive predictor of cirrhosis than varices at endoscopy (74%, p0.0001). Azygos vein and thoracic duct diameters, and gastric mucosa and submucosa thickness were greater for cirrhotic than control patients (p0.001). More hemorrhage patients had large (5 mm or greater) paraesophageal varices (odds ratio 3.1: 95% CI [1.1, 8.3]; p0.05) and paragastric varices (odds ratio 3.7: 95% CI [1.3, 10.2]; p = 0.01). Paraesophageal varix size correlated with ascites (p = 0.03) and, for nonhemorrhage patients, with Child's class (p0.01).Paraesophageal and paragastric varices correlate with the presence and severity of liver disease and portal hypertension. These data support the hypothesis that large paraesophageal and paragastric varices (5 mm or greater) may be risk factors for variceal hemorrhage, an observation that merits further prospective study. Cirrhosis causes dilation of the azygos vein and thoracic duct and thickening of gastric mucosa and submucosa.

The immune control of infection with hepatitis C virus (HCV) is poorly understood; vigorous antibody responses to viral proteins seem to coexist with the virus and thus whether they are neutralizing remains controversial. HCV-related liver failure is the leading indication for orthotopic liver transplantation (OLT) worldwide. Attenuated antibody responses in immunosuppressed patients and decreased reliability compared to assessment of HCV RNA has hampered the use of antibody testing post-OLT. The goals of this current analysis were twofold: to determine the sensitivity of a prototype strip immunoblot assay (RIBA 3.0, Chiron Diagnostics) for the diagnosis of HCV post-OLT; to determine if there was a correlation between antibody response and severity of histological recurrence.The study was comprised of 76 HCV-positive individuals divided into three patient groups: liver allograft recipients with evidence of mild or no histological recurrence (n = 52), liver allograft recipients with evidence of severe HCV recurrence and allograft cirrhosis (n = 12), and nontransplant patients being enrolled in an induction interferon trial (n = 12). All transplant patients had histological follow-up of at least 1 yr.Sixty of the 64 (94%) HCV-positive OLT recipients had 1+ reactivity to two or more recombinant antigens; three of the patients who lacked a detectable response had minimal histological recurrence and one had severe recurrence. All nontransplant patients demonstrated 4+ reactivity to at least two antigens, and 55/64 (86%) OLT recipients demonstrated this same level of reactivity. Seven of the nine patients lacking this high level of reactivity had evidence of minimal recurrence. Furthermore, the mean (+/- SEM) level of antibody reactivity for c100 (p = 0.04) and NS5 (p = 0.01) were significantly lower for patients with mild recurrence after OLT, compared to the other groups. The level of antibody reactivity was unrelated to HCV genotype or viral load.The recently developed RIBA 3.0 assay for detection of antibodies to HCV appears to be highly sensitive for the diagnosis of HCV post-OLT. In general, the level of antibody reactivity was comparable in the transplant patients and in nonimmunosuppressed controls. The pathogenic implications of the relatively diminished humoral response in patients with mild recurrence post-OLT are discussed.

Evaluating abnormal liver test results requires careful attention to the corresponding clinical data obtained during history taking and physical examination. Generally, it is helpful to separate liver tests into three categories: tests that assess synthetic function, tests that assess hepatocellular necrosis (hepatocellular enzymes), and tests that assess cholestasis. The clinical setting together with the specific pattern of liver function abnormalities can narrow differential diagnosis and provide a cost-effective approach to assessing patients and identifying those who need liver biopsy.

Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide and the leading indication for liver transplantation. The hallmark of the disease is its propensity to evolve into chronicity, probably because viral heterogeneity allows the virus to escape immune-mediated neutralization. Treatment with interferon alpha (IFN-alpha) has been disappointing, but higher and more frequent doses, and combination therapies, including nucleoside analogs, might lead to improved suppression of HCV RNA levels. Molecular analysis of HCV before and during treatment has indicated that high viral RNA levels and the presence of HCV genotype 1 are independent predictors of poor treatment outcome. New antiviral agents in development include inhibitors of HCV replicative enzymes, such as protease, helicase and polymerase, as well as several genetic approaches, such as ribozymes and antisense oligonucleotides. The main hindrance to drug development for hepatitis C is the lack of a small animal model or a productive tissue culture system for assessing drug action.

Vancomycin-resistant Enterococcus (VRE) infection is emerging in the transplant population, and there is no effective antibiotic therapy available. The aims of this retrospective review were to (1) investigate the outcome of and (2) identify common characteristics associated with VRE infection and colonization in orthotopic liver transplant (OLTx) candidates.From October 1994 through September 1998, 126 isolates of VRE were identified in 42 of 234 OLTx recipients and 5 OLTx candidates who did not proceed to transplantation. Data were collected by patient chart review or from a computerized hospital database.The 1-year mortality rate with VRE infection was 82%, and with VRE colonization, 7%. This mortality rate contrasts with a 14% 1-year mortality for non-VRE transplant patients (P0.01, infected patients and colonized patients). Characteristics of VRE colonized and infected patients included recent prior vancomycin (87%), coinfection by other microbial pathogens (74%), recent prior susceptible enterococcal infection (72%), concurrent fungal infection (62%), additional post-OLTx laparotomies (47%), and renal failure (Cr2.5 mg/dL or need for dialysis; 43%). Biliary complications were seen in 52% of post-OLTx VRE-infected or VRE-colonized patients (versus 22% in non-VRE transplant patients, P0.05).VRE infection is associated with a very high mortality rate after liver transplantation. The incidence of biliary complications prior to VRE isolation is very high in VRE-infected and VRE-colonized patients. The most common characteristics of VRE patients were recent prior vancomycin use, recent prior susceptible enterococcal infection, coinfection with other microbial pathogens, and concurrent fungal infection. With no proven effective antimicrobial therapy for VRE, stringent infection control measures, including strict and limited use of vancomycin, must be practiced.

To determine the outcome of orthotopic liver transplantation (OLT) for end-stage liver disease caused by hepatitis C virus (HCV).HCV has become the leading cause of cirrhosis and hepatic failure leading to OLT. Recurrent HCV after OLT is associated with significant complications and may lead to graft loss that requires retransplantation (re-OLT). The authors studied the outcome of transplantation for HCV, the effect of primary immunotherapy, and causes of retransplantation.The authors conducted a retrospective review of their experience during an 8-year period (1990-1997), during which 374 patients underwent transplants for HCV (298 [79.6%] received one OLT; 76 [20.4%] required re-OLT). Median follow-up was 2 years (range 0 to 8.3). Immunosuppression was based on cyclosporine in 190 patients and tacrolimus in 132 patients. In a third group of patients, therapy was switched from cyclosporine to tacrolimus or from tacrolimus to cyclosporine (cyclosporine/tacrolimus group).Overall, 1-, 2-, and 5-year actuarial patient survival rates were 86%, 82%, and 76%, respectively. The 2-year patient survival rate was 81 % in the cyclosporine group, 85% in the tacrolimus group, and 82% in the cyclosporine/tacrolimus group. In patients receiving one OLT, overall 1-, 2-, and 5-year patient survival rates were 85%, 81%, and 75%, respectively. The 2-year patient survival rate was 79% in the cyclosporine group, 84% in the tacrolimus group, and 80% in the cyclosporine/tacrolimus group. The overall graft survival rates were 70%, 65%, and 60% at 1, 2, and 5 years, respectively. The graft survival rate at 2 years was similar under cyclosporine (68.5%), tacrolimus (64%), or cyclosporine/tacrolimus (60%) therapy. Re-OLT was required in 42 (11.2%) patients for graft dysfunction in the initial 30 days after OLT. Other causes for re-OLT included hepatic artery thrombosis in 10 (2.6%), chronic rejection in 8 (2.1%), and recurrent HCV in 13 (3.4%) patients. The overall survival rates after re-OLT were 63% and 58% at 1 and 2 years. The 1-year survival rate after re-OLT was 61 % for graft dysfunction, 50% for chronic rejection, 60% for hepatic artery thrombosis, and 60% for recurrent HCV. At re-OLT, 85.3% of the patients were critically ill (United Network for Organ Sharing [UNOS] status 1); only 14.7% of the patients were UNOS status 2 and 3. In re-OLT for chronic rejection and recurrent HCV, the 1-year survival rate of UNOS 1 patients was 38.4%, compared with 87.5% for UNOS 2 and 3 patients. In patients requiring re-OLT, there was no difference in the 1-year patient survival rate after re-OLT when cyclosporine (60%), tacrolimus (63%), or cyclosporine/tacrolimus (56%) was used for primary therapy. With cyclosporine, three patients (1.5%) required re-OLT for chronic rejection versus one patient (0.7%) with tacrolimus. Re-OLT for recurrent HCV was required in four (3%) and seven (3.6%) patients with tacrolimus and cyclosporine therapy, respectively.Orthotopic liver transplantation for HCV is performed with excellent results. There are no distinct advantages to the use of cyclosporine versus tacrolimus immunosuppression when patient and graft survival are considered. Re-OLT is an important option in the treatment of recurrent HCV and should be performed early in the course of recurrent disease. Survival after re-OLT is not distinctively affected by cyclosporine or tacrolimus primary immunotherapy. The incidence of re-OLT for recurrent HCV or chronic rejection is low after either tacrolimus or cyclosporine therapy.

Background Intrahepatic abscess (IA) is an uncommon complication after liver transplantation (OLTx) usually found in the setting of hepatic arterial thrombosis (HAT) often with associated biliary tree necrosis and/or stricture. Conventional treatment of IA in this setting has required retransplantation. Methods A retrospective review of 274 patients (287 OLTx) from September 1991 through September 1996 was performed. Median follow-up was 3.6 years. Diagnosis of HAT was confirmed by arteriography and IA was documented by computerized tomography. Percutaneous drainage of the abscess and stenting of biliary strictures, if present, was achieved using conventional interventional radiology techniques. Results The diagnosis of hepatic artery complication was made in 14 patients (5.1%), 2 of whom required retransplantation. Hepatic artery thrombosis associated with solitary IA was found in 3 patients (1%) who were transplanted in our center and in 1 additional patient followed up at our center but transplanted elsewhere. All 4 patients had complete resolution of IA using this approach. Three of the 4 patients are alive and well, with the fourth patient succumbing to recurrent hepatitis B infection resulting in allograft failure. Conclusions Solitary hepatic allograft abscesses associated with HAT respond to percutaneous drainage and antibiotics, obviating the need for retransplantation in this setting.

Silymarin, derived from the milk thistle plant, Silybum marianum, has been used for centuries as a natural remedy for diseases of the liver and biliary tract. As interest in alternative therapy has emerged in the United States, gastroenterologists have encountered increasing numbers of patients taking silymarin with little understanding of its purported properties. Silymarin and its active constituent, silybin, have been reported to work as antioxidants scavenging free radicals and inhibiting lipid peroxidation. Studies also suggest that they protect against genomic injury, increase hepatocyte protein synthesis, decrease the activity of tumor promoters, stabilize mast cells, chelate iron, and slow calcium metabolism. In this article we review silymarin's history, pharmacology, and properties, and the clinical trials pertaining to patients with acute and chronic liver disease.

Bone marrow transplantation (BMT) is a highly successful and curative therapy for many primary hematologic malignancies. However, hepatic dysfunction and failure are important causes of morbidity and mortality in this patient group after BMT. Hepatic failure can occur as a result of involvement by graft-versus-host disease (GVHD) or as a result of veno-occlusive disease (VOD). Therapies for these complications are often ineffective, especially for VOD, as approximately one fourth of patients develop irreversible liver disease and die of multiorgan failure. Accordingly, we have reviewed our center's experience with orthotopic liver transplantation (OLT) to manage the hepatic complications of BMT. We describe two patients who were treated with OLT after developing hepatic failure post-BMT. One patient had VOD with mild cutaneous and gastrointestinal GVHD; in the other patient, the pathophysiologic process affecting the liver was severe GVHD. Based on our center's experience and review of the literature, we believe OLT should be considered in patients with severe hepatic dysfunction post-BMT.

Background & Aims The factors associated with adverse outcome from hepatitis C virus (HCV) infection are incompletely understood. To determine the incidence and risk factors associated with the development of end-stage liver disease (ESLD) and liver-related death (LRD), we conducted a retrospective/prospective population-based study in a cohort of Alaska Native persons chronically infected with HCV from 1994 to 2005. Methods We followed 960 persons prospectively for an average of 7.2 years and retrospectively for 12.1 years with data from medical records and serum samples. We compared data from subjects that were chronically infected with those who recovered from HCV infection, stratified by alcohol use. Survival models were used to examine factors associated with ESLD and LRD in chronically infected patients. Results During prospective follow-up, 80 (8.8%) and 47 (5.2%) patients developed ESLD and LRD, respectively. In examining incidence per 100 person-years, no difference was found among heavy alcohol users in the incidence of LRD (2.28 versus 3.50; P = .34) or ESLD (3.21 versus 5.69; P = .13) in persons with chronic HCV compared with those recovered from HCV infection. In subjects that consumed P = .01) and of ESLD were 1.58 versus 0.36 ( P = .002), respectively, in subjects with chronic infection versus those that recovered. Multivariate analysis showed that older age, heavy alcohol use, and HCV genotype 3 were associated with ESLD. Conclusions A history of heavy alcohol use is associated with the highest incidence of LRD and ESLD, regardless of whether patients are chronically infected or recover from HCV infection.

Fulminant hepatitis is a rare but potentially fatal adverse reaction that may occur after the use of disulfiram. A patient without a known history of liver disease was transplanted for fulminant hepatic failure secondary to disulfiram. A high index of suspicion and aggressive therapeutic approaches are essential for the prompt diagnosis and treatment of disulfiram-induced hepatic failure. The clinical presentation, histopathology, treatment, and all cases of disulfiram-induced hepatic failure reported in the English literature are reviewed. The role of orthotopic liver transplantation in a case of disulfiram-induced hepatic failure is discussed.