Maria Torres

Comparison of tacrolimus with microemulsion cyclosporine as primary immunosuppression in hepatitis C patients after liver transplantation

BACKGROUND Immunosuppression in patients with hepatitis C virus (HCV) following orthotopic liver transplantation can lead to significant increases in serum viral loads. Our aim was to analyze the effect of a randomized study of two immunosuppressive agents (tacrolimus vs. microemulsion cyclosporine) on the outcome of HCV patients following orthotopic liver transplantation. METHODS From December 1995 to September 1996, 50 adult patients transplanted for HCV cirrhosis were randomly assigned to receive tacrolimus (Prograf) (group 1, 25 patients) or microemulsion cyclosporine (Neoral) (group 2, 24 patients). All patients received alpha-interferon after transplantation, and the overall steroid doses were no different between the groups. Serum RNA levels were measured by signal amplification of Chiron. Biopsies were taken when transaminases were greater than 2x base line or when there was an inappropriate response to alterations in immunosuppression regimens. RESULTS There were more episodes of rejection in the Neoral group, but there were no differences in bacterial and viral infections, nor in the rate of HCV recurrence between the two groups. There were seven deaths in group 1 and eight in group 2. Overall patient and graft survival rates in the Prograf and Neoral groups at 18 months were 72 and 68% and 67 and 64%, respectively. CONCLUSIONS (a) Both immunosuppression regimens had similar HCV recurrence rates; (b) there were no differences in bacterial or opportunistic infections; and (c) patient and graft survival was similar between the two groups.

Reconstitution of hepatitis C virus-specific T-cell - Mediated immunity after liver transplantation

Hepatitis C virus (HCV)‐related liver failure is the leading indication for liver transplantation worldwide. After transplantation, virological recurrence is the rule, but the spectrum of histological injury is wide, ranging from the development of allograft cirrhosis within a few years to minimal hepatitis despite long‐term follow‐up. The immunological correlates of this variable natural history are poorly understood. Here, we studied the kinetics of the cellular immune responses, viral replication, and allograft histology in 24 patients who had undergone liver transplantation for HCV‐related liver failure. Using direct ex vivo methodologies (i.e., interferon‐gamma ELISPOT and major histocompatibility complex class I–peptide tetrameric complexes), we found that patients who experienced viral eradication after antiviral therapy showed restoration of HCV‐specific T‐cell responses, whereas patients with progressive HCV recurrence that failed to respond to therapy showed declining frequencies of these viral‐specific effector cells. The cytotoxic T lymphocytes that peripherally reconstituted after transplantation were clonotypically identical to those present within the recipient explant liver, defined at the level of the T‐cell receptor beta chain (one epitope/one clone). Moreover, the subset of patients who spontaneously demonstrated minimal histologic recurrence had more vigorous CD4+ T‐cell responses in the first 3 months, particularly targeting nonstructural proteins. We provide evidence that T‐cell responses emerge after liver transplantation, and their presence correlates with improved histological and clinical outcomes. In conclusion, these results may help identify patients more likely to develop severe HCV recurrence and therefore benefit from current antiviral therapy, as well as provide a rationale for the future use of novel immunotherapeutic approaches. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2005;41:72–81.)

Does the heterozygous state of alpha-1 antitrypsin deficiency have a role in chronic liver diseases? Interim results of a large case-control study.

Background: The role of the heterozygous PiZ state of alpha-1 antitrypsin deficiency (&agr;1ATD) in the pathogenesis of chronic liver disease (LD) is still a matter of controversy. Aim: To determine the prevalence of &agr;1ATD heterozygote states in a large population of patients with established LD compared with individuals with no LD, and to determine whether the prevalence of PiZ is increased in patients with more severe LD. Methods: A cross sectional case-control study among patients with and without LD. Blood samples were tested for &agr;1AT levels and &agr;1AT phenotype. The severity of LD was determined by clinical evaluation, lab tests, imaging studies and histopathology. Results: In total, 1405 patients were enrolled; 651 with, and 754 without LD. Out of them, 173 patients had decompensated cirrhosis requiring liver transplantation. PiMZ was significantly more prevalent in White patients (3.5%) compared with Hispanics (1.7%; P = 0.029). There was no difference in PiMZ prevalence between the total LD group and the group with no LD (2.1% vs. 1.7%; P = 0.64). Within the LD group, 5.7% of 173 patients with decompensated LD, listed for liver transplantation, had PiMZ, compared with 2.1% of 478 patients with less severe LD (P = 0.016). Similarly, there was a disproportionately higher prevalence of PiZ among hepatitis C virus (HCV) patients (5.6%) and patients with nonalcoholic fatty liver disease (NAFLD) (5.0%) with decompensated LD, compared with HCV patients (1.2%) and NAFLD patients (1.9%) with less severe LD (P = 0.044 and 0.017, respectively). Patients with cryptogenic cirrhosis, who were not considered NAFLD patients, did not have a higher prevalence of PiMZ compared with patients with LD of known etiologies (1.9% vs. 2.3%; P = 0.12). Conclusions: We found no association between the heterozygous PiZ state of &agr;1ATD and the presence of chronic LD in-general or the presence of cryptogenic cirrhosis. In contrast, patients with decompensated LD of any etiology had a significantly higher prevalence of PiMZ compared with patients with compensated LD. Furthermore, in patients with chronic LD due to HCV or NAFLD there was a significant association between the PiMZ heterozygous state and increased severity of LD and the need for liver transplantation. These interim results suggest that the PiMZ &agr;1ATD heterozygous state may have a role in worsening LD due to HCV or NAFLD.

Prevalence of hla antigens and haplotypes in noncaucasian transplant patients with autoimmune hepatitis

Background: Autoimmune hepatitis (AIH) is a chronic necroinflammmatory liver disease that affects mainly young caucasian women. HLA antigens AI, B8, DR3 and DR4 have been associated with different clinical presentations of AIH in caucasian (C) patients. The prevalence of these antigens is unknown in other ethnic groups with AIR. Aim: Evaluate the prevalence of HLA antigens AI, B8, DR3 and DR4 in noncaucasian (NC) patients with autoimmune hepatitis. Methods:We reviewed the records of 37 patients undergoing liver transplantation (OLT) for AIH between June 1994 and March 1999. HLA antigens were determined serologically by Standard Lymphocytotoxicity Method (one Lambda Canuga Park LA). The HLA of these patients were compared to 115 liver transplant donors as controls. Results: Out of the 37 AIH patients who underwent OLT, 20 were C and 17 were NC. NC patients included: 5 Hispanics (H) and 12 Blacks (B).Among donors, 46 were C and 69 were NC. NC donors included: 58 H, 10 Band 1 Asian. The prevalence of HLA antigens AI, B8, DR3 and DR4 in AIH patients was not different between C and NC. However 6 of 20 C had haplotype AIB8DR3 or AIB8DR4 vs none of 17 NC (p=0.014). When C patients were compared with C controls the prevalence of B8 (8120 vs 4/46) and DR3 (7/20 vs 2/46) was statistically significant (p=0.0047 and 0.0023 respectively). No other known or expected HLA antigens or haplotypes were significantly increased in C pts when compared to C controls. In NC pts however, the prevalence of AI, B8, DR3 and DR4 were not different than NC controls. The prevalence of A30 (6/17 vs 7/69, p=0.018), A31 (2/17 vs 0/69, p=0.037), and B42 (3/17 vs 1/68, p=0.02) was increased in NC patients when compared to NC controls. 4 out of 6 patients wiht A30, both patients with A31, and 2 out of 3 patients with B42 were black, which is a common finding. Conclusion: The increased prevalence of HLA B8, and DR3 antigens, and HLA AIB8DR3 and HLA AIB8DR4 haplotypes in caucasian patients was in agreement with previous reports. In noncaucasian patients with AIH there was no increase in these HLA antigens or haplotypes. HLA A30, A31 and B42 were more prevalent in noncaucasian patients with AIR.