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Increased frequency of cirrhosis during hepatitis C infection with cryoglobulinemia
April 1 9 9 5
ALCOHOUSM RECURRENCE DOES NOT INFLUENCE THE CLINICAL OUTCOME OF PATIENTS TRANSPLANTED FOR ALCOHOLIC CIRRHOSIS (~,p, Paaeaux. J.M. Fabre~ P.F. Perrigault, F. Navarre, P. Blanc, B. Souche. P. Poasoz, D. Larrey, J. Domergue, H. Michel. Institut des Maladies de I'Appare[I Digestif, H6pital Salnt-Eloi, Montpellier. France. Many transplant centers ere reluctant to accept alcoholic patients for liver transplantation (L'r), because of their supposed risk of alcoholic recurrence and poor compliance with the required tmmunosuppressive regimen, both resulting in graft failure. The aim of the study was to assess the influence of alcoholic recidivism on clinical outcome of patients transplanted for alcoholic cirrhosis. Mv=thods : from march 1989 to december 1993, 116 LT were performed in 101 patients in our liver transplant unit. Alcoholic cirrhosis was the indication for LT in 44 patients. Thirty-eight patients survive more than 3 months and were studied regarding alcoholic recurrence. Recidivism was proved by quastionning the patient, alcohofuda detection, abnormal biochemical liver tests and liver biopsy excluding others causes of liver failure. Patient survival was calculated by • life table analysis using the Kaplan-Maler method; survival curves were compared by the log-rank test. A probability value of p < 0.05 was considered to be significant. Results : Mean follow-up was 28 months (5 to 66). Alcoholism recidivism was asserted in 10 of the 38 patients (27 %), There were 7 males and 3 females, mean age 42.5 yrs (31 to 49). Mean alcohol intake was 69 g per day (40 to 110). All the 10 patients admitted their alcoholism. One-year, 2-yeers and 3-year actuarial survival rate were respectively 100 %, 80 % and 80 %. Two of the 10 patients died during the follow-up : one from EBV-induced lymphoma and one from traumatic cerebral hematoma directly caused by high alcohol intake. One of these 10 pts had poor compliance with immunosuppressiva drags, responsible for 2 acute rejection episodes successfully treated with corticosteroids. Liver biopsy showed steatosis > 50 % in 8 pts, steatosis < 50 % in 2 10ts. Mallory inclusion bodies in 1 pt. The 10 pts had neither fibrosis nor cirrhosis. For the 28 other patients, 23 males and 5 females, mean age 50 years (33-59), the 1-yr, 2-yrs, and'3-yrs actuarial survival rates were respectively 89 %. 72 % and 66 % (non significative). Conclusion : alcoholism recidivism citer LT for AC does not seem to influence the clinical outcome of patients. Nevertheless, all alcoholic graft recipients must absolutely abstain from consumming alcohol,
• INCREASED FREQUENCY OF CIRRHOSIS DURING HEPATITIS C INFECTION WITH CRYOGLOBULINEMIA P.H. Pagliero, M. Perreard, D. Monges, J. Boucraut, M. Chrestian, J.R. Harlr, P.J. Weiller, A. G6rolami. Depts of Hepatology, Immunology, Pathology, and Internal Medicine, CHU Timone, Marseille, FRANCE. The role of Hepatitis C Virus (HCV) in the induction of mixed cryoglobulinemia (MC) is well known, but the relations between MC and histological lesions are not well established. P a t i e n t s and M e t h o d s : 148 consecutive patients (pts) with chronic hepatitis and anti-HCV antibodies (Riba 2) were studied. 137 pts had a liver biopsy. In the 11 other patients, cirrhosis was ascertained on clinical and biological criteria. Cryoglobulins were isolated from patients sera and characterized by immunoblotting. R e s u l t s : 94 pts (63,5%) with chronic HCV infection had MC (type 2 : 17, type 3 : 59, absence of characterization : 9, not classified : 9). No significant difference was found between pts with MC and without MC for age, sex, alcohol consumption, transmission route, ALAT level, presence of dysthyroi'dia and presence of auto-antibodies. KnodeI1 score was significantly higher (p < 0,05) in the group with MC (8.57 + 3.65) than in the group without MC (7.18 _+ 3.54). Serum Gammaglobulins were increased (p < 0,01) in pts with MC, independently of the presence of cirrhosis. Cirrhosis was significantly more often observed in pts with MC than in pts without MC (39/94 (41,5%) versus 8/54 (14,8%), p < 0,02). So, 83% of the pts with anti-HCV antibodies and cirrhosis had MC. C o n c l u s i o n s : This study confirms the high prevalence (63,5%) of MC in chronic HCV infection. In addition, our work shows a strong association between M C ~ n d cirrhosis in pts with chronic HCV infection.
AASLD
Al141
UVER TRANSPLANTATION FOR ALCOHOUC CIRRHOSIS : A MONOCENTRIC EXPERIENCE ABOUT 44 PATIENTS WITH CONTROL GROUP OVER A FIVEYEAR-PERIOD. (~.P. Paaeaux. J.M. Fabre, P.F. Perrigault, F. Navarre, P. Blanc, B, Souehe, P. Possoz, D. Lerrey, J. Domergue, H. Michel. Institut des Maladies de I'Appareil Dtgestit. H6pital Salnt-Eloi, Montpellier, France. Albeit the most common cause of end-stage liver failure in North America and Europe, aleoholis cirrhosis is often considered as an unlikely indication for liver transplantation (L'r), partly because of the potential risk of alcoholism recurrence after LT and partly because of reports indicating frequent post-operative complications. The aim of the studv was to compare the clinical outcome of patients transplanted for alcoholic and non alcoholic cirrhosis and to assess alcoholism recurrence rate. Patients - Methods : between march 1989 and december 1993, 116 LT were performed in 191 pts in our liver transplant unit. We excluded 14 pts transplanted for fulminant hepatitis or neoplasic disease. The remaining 87 pts were allocated in 2 groups regarding LT indication : group A =alcoholic cirrhosis; 44 pts 36 males and 18 females, mean age 49 yrs (31 to 63). Group B : non alcoholic cirrhosis; 43 pts, 22 males and 21 females. mean age 50 yrs (18 to 66). Indication for LT in group B was : post-necrotic B or C cirrhosis (n=27), primary biliary cirrhosis (n=6), primary sclerosing cholangitis (n=3), miscellaneous (n=7). Kaplan-Meier method, log-rank test, Chi-2 test and t Student test were used for statistical analysis. Flesqlt~ : 27 pts of group A (61 %) and 29 pts of group B (67 %) ere still alive. One year and 3 year actuarial survival were respectively 80 % and 60 % for group A and 80 % and 66 % for group B (ns). Ratransplantation rate was 13.6 % in group A and 13.9 % in group B (NS), Acute rejection was diagnosed in 51% of pts of group A and 46 % of pts of group S (NS). Cytomegalovirus infection was diagnosed in 44 % of pts of group A and 36 % of pts of group B (NS), Bacterial infection was diagnosed in 31 % of pts of group A and 29 % of pts of group B (NS). Mean stay duration in intensive care unit was 31 + 21 days in group A and 23 ± 14 days in group B (p = 0.06). Alcoholism recurrence was diagnosed in 10 of the 38 pts. of group A who survive more than 3 months (26 %) with a mean follow-up of 28 months. Conclusion : patients with alcoholic cirrhosis can be transplanted successfully and achieve good health not significantly different from that of patients transplanted for other causes. Alcoholism recurrence is 26 % but does not influence clinical outcome.
• EXPRESSION OF CHOLESTEROL 7a-HYDROXYLASE IN RESPONSE TO CHOLESTEROL AND BILE ACID FEEDING IN THE HAMSTER AND RAT W.M. Pandal~, M. Doerner ~, D.M. Heuman ~, P.B. Hylemon ~, J.Y.L. Chiang2, andZ.R. Vlahcevid. Depts. of MealJ, McGuire VAMC and Meal. Col. of VA, Richmond, VA, and Dept. of Biochem. 2, N.E. Ohio Univ, Rootstuwn, OH Species differences in regulation of cholesterol 7a-hydroxylase (C7c~H) may determine their propensity toward hypercholesterolemia. To date, most studies on the regulation of this enzyme have been carried out in the rat, an animal which appears to differ in its cholesterol metabolism from man and many other species. Specific aim: To compare the effects of different bile acids and cholesterol on C7c~H in hamsters vs rats. Methods: SD rats and Syrian hamsters were pair fed for 14 days normal chow (controls), cholesterol (Cho]; 2%), cholestyramine (Cst; 5%), cholic acid (CA; 1% rat, .1% hamster), chanodeoxycholic acid" (CDCA; .1%), and deoxycholic acid (DCA; .1%). Hepatic bile was collected prior to sacrifice and analyzed for bile acid composition. Livers were harvested, and specific activities, mRNA levels and transcriptional activities of C7c~H were determined. Results: CA feeding $ C7c~H specific activity, mRNA levels, and transcriptional activity in rat by 62__+14%, 72+3%, and 44+3, and in hamster by 65_-4-18%, 69+2%, and 93%, respectively. Similar changes in C7c~H specific activity occurred in both species following CDCA and DCA feeding. Cst feeding t all three parameters in both species. Chol feeding: % of controls (mean+SE). Species
C7aH spcc.act,
Rat
mRNA
Cholesterol trans, act.
serum
microsomal
~ 188+_58% I'1915:81% f 120±78% ¢33_+20% ¢16%
Hamster ~.65+18% ¢,92+1% $71±13% t65±13% t'49±5% Conclusior -regulated by 1,lie acid feeding at the evel of gene transcription, both in rats and hamsters. Marked differences were observed with the feeding of diets high in cholesterol. In the rat, cholesterol feeding induces C7~rH gene transcription, thus facilitating efficient cholesterol elimination via its conversion to bile acids. In contrast, in the hamster cholesterol feeding represses C7c~H at the transcriptional level. This profound species difference in the regulation of C7~H by cholesterol may explain the resistance of rats to develop hypercholesterolemia, and the propensity toward hypercholesterolemia in hamsters in response to a diet high in cholesterol. In light of humans predisposition to develop hypercholesturolemia, we postulate that human hepatic cholesterol homeostasis is more akin to hamster than rat.
ALCOHOUSM RECURRENCE DOES NOT INFLUENCE THE CLINICAL OUTCOME OF PATIENTS TRANSPLANTED FOR ALCOHOLIC CIRRHOSIS (~,p, Paaeaux. J.M. Fabre~ P.F. Perrigault, F. Navarre, P. Blanc, B. Souche. P. Poasoz, D. Larrey, J. Domergue, H. Michel. Institut des Maladies de I'Appare[I Digestif, H6pital Salnt-Eloi, Montpellier. France. Many transplant centers ere reluctant to accept alcoholic patients for liver transplantation (L'r), because of their supposed risk of alcoholic recurrence and poor compliance with the required tmmunosuppressive regimen, both resulting in graft failure. The aim of the study was to assess the influence of alcoholic recidivism on clinical outcome of patients transplanted for alcoholic cirrhosis. Mv=thods : from march 1989 to december 1993, 116 LT were performed in 101 patients in our liver transplant unit. Alcoholic cirrhosis was the indication for LT in 44 patients. Thirty-eight patients survive more than 3 months and were studied regarding alcoholic recurrence. Recidivism was proved by quastionning the patient, alcohofuda detection, abnormal biochemical liver tests and liver biopsy excluding others causes of liver failure. Patient survival was calculated by • life table analysis using the Kaplan-Maler method; survival curves were compared by the log-rank test. A probability value of p < 0.05 was considered to be significant. Results : Mean follow-up was 28 months (5 to 66). Alcoholism recidivism was asserted in 10 of the 38 patients (27 %), There were 7 males and 3 females, mean age 42.5 yrs (31 to 49). Mean alcohol intake was 69 g per day (40 to 110). All the 10 patients admitted their alcoholism. One-year, 2-yeers and 3-year actuarial survival rate were respectively 100 %, 80 % and 80 %. Two of the 10 patients died during the follow-up : one from EBV-induced lymphoma and one from traumatic cerebral hematoma directly caused by high alcohol intake. One of these 10 pts had poor compliance with immunosuppressiva drags, responsible for 2 acute rejection episodes successfully treated with corticosteroids. Liver biopsy showed steatosis > 50 % in 8 pts, steatosis < 50 % in 2 10ts. Mallory inclusion bodies in 1 pt. The 10 pts had neither fibrosis nor cirrhosis. For the 28 other patients, 23 males and 5 females, mean age 50 years (33-59), the 1-yr, 2-yrs, and'3-yrs actuarial survival rates were respectively 89 %. 72 % and 66 % (non significative). Conclusion : alcoholism recidivism citer LT for AC does not seem to influence the clinical outcome of patients. Nevertheless, all alcoholic graft recipients must absolutely abstain from consumming alcohol,
• INCREASED FREQUENCY OF CIRRHOSIS DURING HEPATITIS C INFECTION WITH CRYOGLOBULINEMIA P.H. Pagliero, M. Perreard, D. Monges, J. Boucraut, M. Chrestian, J.R. Harlr, P.J. Weiller, A. G6rolami. Depts of Hepatology, Immunology, Pathology, and Internal Medicine, CHU Timone, Marseille, FRANCE. The role of Hepatitis C Virus (HCV) in the induction of mixed cryoglobulinemia (MC) is well known, but the relations between MC and histological lesions are not well established. P a t i e n t s and M e t h o d s : 148 consecutive patients (pts) with chronic hepatitis and anti-HCV antibodies (Riba 2) were studied. 137 pts had a liver biopsy. In the 11 other patients, cirrhosis was ascertained on clinical and biological criteria. Cryoglobulins were isolated from patients sera and characterized by immunoblotting. R e s u l t s : 94 pts (63,5%) with chronic HCV infection had MC (type 2 : 17, type 3 : 59, absence of characterization : 9, not classified : 9). No significant difference was found between pts with MC and without MC for age, sex, alcohol consumption, transmission route, ALAT level, presence of dysthyroi'dia and presence of auto-antibodies. KnodeI1 score was significantly higher (p < 0,05) in the group with MC (8.57 + 3.65) than in the group without MC (7.18 _+ 3.54). Serum Gammaglobulins were increased (p < 0,01) in pts with MC, independently of the presence of cirrhosis. Cirrhosis was significantly more often observed in pts with MC than in pts without MC (39/94 (41,5%) versus 8/54 (14,8%), p < 0,02). So, 83% of the pts with anti-HCV antibodies and cirrhosis had MC. C o n c l u s i o n s : This study confirms the high prevalence (63,5%) of MC in chronic HCV infection. In addition, our work shows a strong association between M C ~ n d cirrhosis in pts with chronic HCV infection.
AASLD
Al141
UVER TRANSPLANTATION FOR ALCOHOUC CIRRHOSIS : A MONOCENTRIC EXPERIENCE ABOUT 44 PATIENTS WITH CONTROL GROUP OVER A FIVEYEAR-PERIOD. (~.P. Paaeaux. J.M. Fabre, P.F. Perrigault, F. Navarre, P. Blanc, B, Souehe, P. Possoz, D. Lerrey, J. Domergue, H. Michel. Institut des Maladies de I'Appareil Dtgestit. H6pital Salnt-Eloi, Montpellier, France. Albeit the most common cause of end-stage liver failure in North America and Europe, aleoholis cirrhosis is often considered as an unlikely indication for liver transplantation (L'r), partly because of the potential risk of alcoholism recurrence after LT and partly because of reports indicating frequent post-operative complications. The aim of the studv was to compare the clinical outcome of patients transplanted for alcoholic and non alcoholic cirrhosis and to assess alcoholism recurrence rate. Patients - Methods : between march 1989 and december 1993, 116 LT were performed in 191 pts in our liver transplant unit. We excluded 14 pts transplanted for fulminant hepatitis or neoplasic disease. The remaining 87 pts were allocated in 2 groups regarding LT indication : group A =alcoholic cirrhosis; 44 pts 36 males and 18 females, mean age 49 yrs (31 to 63). Group B : non alcoholic cirrhosis; 43 pts, 22 males and 21 females. mean age 50 yrs (18 to 66). Indication for LT in group B was : post-necrotic B or C cirrhosis (n=27), primary biliary cirrhosis (n=6), primary sclerosing cholangitis (n=3), miscellaneous (n=7). Kaplan-Meier method, log-rank test, Chi-2 test and t Student test were used for statistical analysis. Flesqlt~ : 27 pts of group A (61 %) and 29 pts of group B (67 %) ere still alive. One year and 3 year actuarial survival were respectively 80 % and 60 % for group A and 80 % and 66 % for group B (ns). Ratransplantation rate was 13.6 % in group A and 13.9 % in group B (NS), Acute rejection was diagnosed in 51% of pts of group A and 46 % of pts of group S (NS). Cytomegalovirus infection was diagnosed in 44 % of pts of group A and 36 % of pts of group B (NS), Bacterial infection was diagnosed in 31 % of pts of group A and 29 % of pts of group B (NS). Mean stay duration in intensive care unit was 31 + 21 days in group A and 23 ± 14 days in group B (p = 0.06). Alcoholism recurrence was diagnosed in 10 of the 38 pts. of group A who survive more than 3 months (26 %) with a mean follow-up of 28 months. Conclusion : patients with alcoholic cirrhosis can be transplanted successfully and achieve good health not significantly different from that of patients transplanted for other causes. Alcoholism recurrence is 26 % but does not influence clinical outcome.
• EXPRESSION OF CHOLESTEROL 7a-HYDROXYLASE IN RESPONSE TO CHOLESTEROL AND BILE ACID FEEDING IN THE HAMSTER AND RAT W.M. Pandal~, M. Doerner ~, D.M. Heuman ~, P.B. Hylemon ~, J.Y.L. Chiang2, andZ.R. Vlahcevid. Depts. of MealJ, McGuire VAMC and Meal. Col. of VA, Richmond, VA, and Dept. of Biochem. 2, N.E. Ohio Univ, Rootstuwn, OH Species differences in regulation of cholesterol 7a-hydroxylase (C7c~H) may determine their propensity toward hypercholesterolemia. To date, most studies on the regulation of this enzyme have been carried out in the rat, an animal which appears to differ in its cholesterol metabolism from man and many other species. Specific aim: To compare the effects of different bile acids and cholesterol on C7c~H in hamsters vs rats. Methods: SD rats and Syrian hamsters were pair fed for 14 days normal chow (controls), cholesterol (Cho]; 2%), cholestyramine (Cst; 5%), cholic acid (CA; 1% rat, .1% hamster), chanodeoxycholic acid" (CDCA; .1%), and deoxycholic acid (DCA; .1%). Hepatic bile was collected prior to sacrifice and analyzed for bile acid composition. Livers were harvested, and specific activities, mRNA levels and transcriptional activities of C7c~H were determined. Results: CA feeding $ C7c~H specific activity, mRNA levels, and transcriptional activity in rat by 62__+14%, 72+3%, and 44+3, and in hamster by 65_-4-18%, 69+2%, and 93%, respectively. Similar changes in C7c~H specific activity occurred in both species following CDCA and DCA feeding. Cst feeding t all three parameters in both species. Chol feeding: % of controls (mean+SE). Species
C7aH spcc.act,
Rat
mRNA
Cholesterol trans, act.
serum
microsomal
~ 188+_58% I'1915:81% f 120±78% ¢33_+20% ¢16%
Hamster ~.65+18% ¢,92+1% $71±13% t65±13% t'49±5% Conclusior -regulated by 1,lie acid feeding at the evel of gene transcription, both in rats and hamsters. Marked differences were observed with the feeding of diets high in cholesterol. In the rat, cholesterol feeding induces C7~rH gene transcription, thus facilitating efficient cholesterol elimination via its conversion to bile acids. In contrast, in the hamster cholesterol feeding represses C7c~H at the transcriptional level. This profound species difference in the regulation of C7~H by cholesterol may explain the resistance of rats to develop hypercholesterolemia, and the propensity toward hypercholesterolemia in hamsters in response to a diet high in cholesterol. In light of humans predisposition to develop hypercholesturolemia, we postulate that human hepatic cholesterol homeostasis is more akin to hamster than rat.