Skin tests predict acute cellular rejection in liver transplantation

Skin tests predict acute cellular rejection in liver transplantation

April 1998 • L0042 THE C282Y MUTATION IS NOT A SIGNIFICANT COFACTOR FOR MORE SEVERE LIVER DISEASE IN A COHORT OF IRISH HEPATITIS C PATIENTS. S. Barre...

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April 1998

• L0042 THE C282Y MUTATION IS NOT A SIGNIFICANT COFACTOR FOR MORE SEVERE LIVER DISEASE IN A COHORT OF IRISH HEPATITIS C PATIENTS. S. Barrett, G.Callagy*, E. Ryan, J.C. O'Keane* P.Mac Mathuna, and J. Crowe. Hepatobiliary Unit and Dept. of Pathology*, Mater Misericordiae Hospital, Dublin, Ireland. Hepatic iron overload in chronic hepatitis C virus (HCV) infection is reported to be associated with increased hepatic inflammation, fibrosis and a negative response to Interferon therapy. The mechanism of iron overload in HCV is not clearly defined. Whether increases in iron occur because of HCV or whether increases in iron predate and predispose to more severe hepatitis is unclear. The involvement of even a single copy of the candidate gene for genetic Hacmochrnmatosis [Cys282Tyr (C282Y) mutation in the HLA-H gene] in the pathogenesis of liver damage in HCV has yielded conflicting results. The purpose of this study was to clarify the role of the C282Y mutation in iron accumulation and severity of liver disease in a cohort of patients with chronic HCV. Seventy six patients (F) mean age 44.1 (SD=7.19) with histologically proven chronic HCV were evaluated. The C282Y mutation was detected by PCR followed by restriction digestion with Rsal. A semiquantitative grading system (0-4) was used for histological assessment of liver iron overload on Perls' stain. Inflammatory activity (0-18, minimal-severe; Desmet, 1994) and fibrosis (0-6, Ishak; 1995) were also evaluated. The C282Y mutation was present in 13/76 (17.1%) patients including 1 homozygous (HH) and 12 heterozygous (Hn) individuals. Liver iron staining was detected in 4/76 (5.3%) patients, 1 was HH (grade III siderosis) 1 was Hn (grade I siderosis) and 2 were heterozygous normal (grade I siderosis). Inflammatory activity was minimal in 26 patients (1/26 HH and 4/26 Ha), mild in 41 (6/41 Hn) and moderate in 9 (2/9 Hn) patients. Fibrosis was absent in 24 patients (5/24 Hn), a fibrosis score of one was seen in 21 patients (1/21 HH and 4/21 Hn) and scores of greater than one were seen in 31 (3/31 Hn) patients. Condusions: Histological evidence of iron overload was seen in only 4•76 patients with the most severe (grade III) siderosis seen in a HH patient with minimal activity. There was no association between the presence of the C282Y mutation and inflammation or fibrosis in this HCV infected cohort. This result suggests that in chronic HCV patients with moderate to severe iron overload should be evaluated for genetic Haemochromatosis. • L0043 RECOMBINANT INTERFERON THERAPY FOR CHRONIC HEPATITIS C IN PATIENTS WITH HIV INFECTION. C.Bartbolomew, PJ Piliero, S. Szebenyi, B. McKenna, B. Stellrecht, C.Ramnes. Albany Medical College, Albany, New York. Studv Design: Prospective sequential open label trial. Study Purpose: To evaluate tolerance and efficacy of recombinant interferon therapy in HIV- infected patients with chronic hepatitis C. METHODS: Patients with HIV and hepatitis C virus (HCV) coinfection who have compensated liver disease, a CD4 count >50 cells/cmm, a positive HCV RNA by PCR, and no other cause of chronic hepatitis were recruited. All patients had serial liver biopsies as out patients. If liver biopsy was consistent with HCV, patients were assigned sequentially to interferon alpha 2b (INF-a) 3 or 5 million (M) units (U) subcutaneously (SQ) three times per week (TIW) for 6 months. Patients who tolerated but did not respond to INF-a 3MU TIW after 6 months could opt for an additional 6 months of INF-a at a dose of 5MU TIW. Response to therapy was determined by 1) serial liver biochemical tests, 2) serial qualitative and quantitative serum HCV RNA by PCR and 3) serial liver biopsies using Knodell and Sheuer scoring. Study duration was 18 months. RESULTS: 28 patients (18 male, 10 female) enrolled: 15 patients in group A (INF-a 3 MUTIW) and 13 patients in group B (INF-a 5 MUTIW). 3 patients from each group (total 6 patients) withdrew due to adverse effects. 12 patients in group A completed 6 months of therapy: 2 patients became HCV RNA PCR negative at 6 months but relapsed to HCV RNA PCR positive at 12 months. 8 of the 12 patients in group A opted for an additional 6 months of IFN-a at 5 MUTIW (group C). All these patients remained HCV RNA PCR positive. Lastly of the 13 patients in group B who completed 6 months of IFN-a 5 MUTIW only 1 patient transiently became HCV RNA PCR negative. No serious study drug toxicity occurred. A total of 47 liver biopsies were performed without complication. 5 patients were cirrhotic by biopsy. No significant improvement in histologic scoring of biopsies was noted. CONCLUSION: IFN-a therapy as a single agent for treatment of chronic hepatitis C in patients with HIV is well tolerated but ineffective. There was no long term loss of viremia and no significant improvement in liver histology. Percutaneous liver biopsies in well compensated HIV patients can be performed without added risk.

AASLD A1209

• L0044 EFFECT OF CISAPRIDE UPON JEJUNAL BACTERIAL FLORA AND BACTERIAL TRANSLOCATION IN ASCITIC CIRRHOTIC RATS. R. Bartolf, A. Pardo, R. Planas, B. Vifiado*, E. Cabr6, M.P. RodrfguezIglesias, V. Ausina*, M.A. Gassull. Departments of Gastroenterology and *Microbiology. Hospital Universitari Germans Trias i Pujol. Badalona. Catalonia. Spain. Intestinal bacterial translocation (BT) to mesenteric lymph nodes is a major pathogenic factor of bacterial infections in experimental, and probably also in human cirrhosis. BT is facilitated by the presence of intestinal bacterial overgrowth which, in turn, is favoured by disturbances in bowel motility. Both bacterial overgrowth and slow intestinal transit occur in cirrhotic patients. Increasing the intestinal motility with prokinetic drugs, such as cisapride, might decrease bacterial overgrowth and thus reduce the risk of BT in cirrhosis. AIM: To assess the effect of cisapride upon the jejunal bacterial flora and the incidence of BT in ascitic cirrhotic rats. METHODS: 24 Sprague-Dawley male rats with orogastric CCl4-induced cirrhosis and ascites were randomized to b e treated with s.c. cisapride (2 mg/Kg/day) (Group A, n=12) or placebo (Group B, n=12) for 7 days. At the end of treatment, animals were laparotomized and samples of jejunal fluid and all the identifiable mesenteric lymph nodes were harvested. Jejunal fluid was cultured in agar-blood plates as well as in MacConkey and CNA media to determine its bacterial content (CFU). Mesenteric lymph nodes were cultured in agar-blood plates and MacConkey medium to assess the presence of BT. Five healthy rats were used as controls. RESULTS: Total jejunal bacterial content was significantly higher in Group B (3.7-0.5x106 CFLI) than in Group A (1.5 ±0.4x106 CFU) and controls (2.0 ± 0.1xl06 CFU) (p=0.027). A significantly greater of E. coli in Group B (7.6 -+ 1.2x105 CFU) mostly accounted for such an increase (3.5 +- 1.3x105 in Group A, 0.01 +0.01xl05 in controls; p=0.004). No animal in Group A developed BT, whereas this occurred in four animals (33%) of Group B (p=0.04). BT was due to E. coli (n=2), Lactobacillus sp (n=l) and Klebsiella sp (n=l). One of the rats with BT also developed spontaneous bacterial peritonitis. The total E. coli jejunal content was significantly higher in rats with than in those without BT (lxl06 vs. 0.4 _ 0.1xl06 CFU; p<0.0005). CONCLUSIONS: The administration of cisapride to ascitic cirrhotic rats results in a decrease of the jejunal bacterial flora, particularly E. coli, which is associated to a decrease in BT to mesenteric lymph nodes. These results suggest that prokinetic agents may be useful in preventing BT in cirrhosis. • L0045 SKIN TESTS PREDICT ACUTE CELLULAR REJECTION IN LIVER TRANSPLANTATION. AJ Bathgate. JN Plevris, MM Dollinger and PC Hayes. Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Edinburgh, Scotland. A_i___m_mDelayed : type hypersensitivity reactions are similar to animal models of acute rejection and this study is assessing the capability of patients with chronic liver disease to mount a cutaneous reponse to a neo antigen pretransplantation and the correlation with acute cellular rejection. Method: Patients on the waiting list for transplantation were sensitised to diphenylcyclopropenone (DPC)for 48 hours. An elicitation test was carried out 14 days later and a score given for each of the 5 concentrations tested (bulla = 3, vesicles =2, erythema = 1). Acute cellular rejection was defined as rejection requiting therapy with high dose steroids. The clinicians deciding on therapy were blinded to skin test results as were the pathologists. The histopathological score was also noted in those who had biopsies at day 7. The nutritional status aetiology and Child's score was also assessed. Results: 15 patients (7 PBC,3 ALD,2 PSC,1 HBV,1 cryptogenic) have been transplanted so far. Eight have had no response while the 7 responders have had scores from 1-7. All reactors had acute rejection while one non-reactor was treated for rejection (p=0.004). The correlation of skin test score and day 7 biopsy score is shown in figure 1. 8, 7.

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There was no correlation of skin test results with either nutritional status or Child's score. Conclusions:The ability to mount a delayed type hypersensitivity reaction pretransplantation predicts those patients who will have acute cellular rejection. This may allow tailoring of immunosuppression on an individual basis.