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Cyclosporin A in the treatment of chronic hepatitis C refractory to interferon
HEPATOLOGY Vol. 22, No. 4, Pt. 2, 1995
AASLD ABSTRACTS
1 3 1 3 THE EFFECT OF RENAL DYSFUNCTION ON O~UTCOME IN HEPATIC TRANSPLANTATION. MW lohnson, IA Powelson. H Au(hincloss. lr.. EL Delmonico. and AB Cosimi. The Transplantation
Unit and the Department of Surgery, the Massachusetts General Hospital, Boston, Massachusetts. Renal dysfunction has been applied as an indicator of critical illness in the intensive care patient and as a criterion for the high risk patient preoperatively. We reviewed the records of 150 adult primary orthotopic liver aUograft recipients transplanted at Massachusetts General Hospital from January 1984 to December 1994 to assess the affect of renal dysfunction on liver transplantation outcomes. The actuarial survivals for the entire patient population are 71%, 63% and 61% at 1 year, 2 years, and 3 years respectively. Demographic data, UNOS status, and diagnoses are similar in all comparative groups. Eighteen patients (12%) had evidence of pre-operative renal dysfunction as defined as a serum creatinine level > 2.0 m g / d l (measured the day of surgery). One patient underwent simultaneous liver/kidney transplant and was excluded from analysis. He is alive with functioning allografts > 2 years out. Actuarial survival for the remaining 17 patients is 29.4% at 6 months as compared to 6 month survivals of 80% in patients with pro-operative serum creatinine levels < 2,0 m g / d l (p<0.001). The renal dysfunction group also suffered a significant difference in intra-operative PRBC requirements (p<0.05), peak and discharge serum creatinine levels (p<0.001 and p<0.05, respectively), and length of stay (p=0.05) when compared to patients with a baseline serum creatinine level < 2.0 mg/dl. Four of the 17 patients (24%) with serum creatinine levels > 2.0 mg/dl pre-operatively required hernodialysis post-transplant, while only six of the 132 (4.5%) patients with pre-operative serum creatinine levels < 2.0 m g / d l required hemodialysis post-transplant (p<0.05). All ten of the patients requiring post-transplant hemodialysis have died (p<0.001, as compared to patients not requiring post-transplant hemodialysis). Acute versus chronic renal dysfunction did not significantly alter survivals. In conclusion, pre-operative renal dysfixncti0n adversely effects the outcomes in orthotopic liver allograft transplantation and perhaps could be a criterion used to identify patients who should either undergo simultaneous liver/kidney transplant or be disqualified for organ transplantation. Hemodialysis post-transplant is a harbinger of poor outcome in the liver transplant patient.
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435A
HISTOLOGICALCONSEQUENCESOF CHRQNIC HEPATITISC -HISTOMETRGAL STUDYON REPEATEDLIVER BIOPSIESM.Kage ". K.Shimamatsu , M.Kojiro h. O.Inoue 2~. M.Yano 2 1. The First Department of Pathology, Kurume Univ. School of Medicine 2. Institute tot Clinical Research. Nagasaki Chu~3 National Hospital A i m : We conducted histometricaJ analysis to clarify the chronological changes of fibrosis in chronic hepatitis C which progressed to cirrhosis. Material:
We exammeta repeated liver biopsies obtained from 40 cases cff chronic
hepatitis C and those lrom 30 cases of chronic hepatitis B a.~;controls. The 3 were continuously follo,,~ed tor 5 to 21 years with an average of 7.7 years. Each case had two to ten biopsies w~m an average ot 4: the interval from the first liver biopsy to the last ranged t~'om I m 26 ) :ars. Methods:
1 Staging (scoring for stage): Chronic hepatitis was classified into four
stages according co evolusion of fibrosis: stage 1 {mild portal fibrosis), stage 2 (periportal fibrosisl, stage 3 (portal fibroisis with lobular distortion), stage 4 (liver cirrhosis' 2. Histometrical analysis: We determined area of fibrosis by sassing whole liver tissue of each specimen, using the computer image-analysis system. Degree of fibrosis was defined as the ratio of fibrosis to whole area or hepatic tissue (FR). Results:
[. Stage and FR were well correlated, stage/FR (~h, averagel:
stage I/2.7. stage 2/3.9. stage 3/4,4, stage4/10.5. 2. High FR over 10% was the most frequent m cases over 5{) years old. while FR below 10% was frequent in cases under 50, Especially in the cases over 55 years old, the speed with which chronic hepatitis progressed to cirrhosis was accelerated.
3, Priests with stage 3 in the first biopsy all progress [o
cirrhosis within 10 yeares. 4. In chronic hepatitis B, high FR was found in any age group, Out of eight cases with high FR of more than 10%. 6 cases were younger than 40. Chronic hepatitis B in younger patients had a trend to progress to cirrhosis rapidly. Conclusion
Our histometrica] analysis clarified natural consequences of ~hronic
hepatitis C which progressed to cirrhosis
CYCLOSPORIN A IN THE TREATMENT OF CHRONIC HEPATITIS C REFRACTORY TO INTERFERON. S Kakumu. M Takavanaei T Aivama. K Iwata. A Okumura. K Yoshioka. and M. N-adai~. Third Department of Internal Medicine and Department of Hospital Pharmacy*, Nagoya University School of Medicine, Nagoya, Japan.
1316 SERUM CRYOGLOBULINS AND CHRONIC HEPATITIS C
Interferon therapy is of proven efficacy in chronic hepatitis C, but it is not universally effective and often limited by side effects. Cyclosporin A (CyA) is a potent immune-suppressant widely used in organ transplantation. We conducted a pilot study of CyA therapy in 10 patients (mean age of 59 yr, M/F=9/1) with chronic active hepatitis C who failed interferon therapy previously and had elevated ALT values for at least 6 me. All patients were positive for HCV RNA by RT-PCR with genotype lb. Their mean duration of hepatitis was 15 yr. Oral CyA was given for 3 me in a dose that was increased at 1-me interval, from 1.5-2.0 mg to 2.0-3,0 mg to 3.0-4.0 mg/kg/day. All completed treatment schedule, although two had mild nonsymptomatic dse of blood pressure. Serum ALT levels gradually decreased in all patients but one; the mean percentage decrease was 57.5% (from 153 + 82 IU/L to 65 + 44 IU/L, p<0.01) at the end of therapy. The enzyme levels fell to the normal range in 5 patients. Serum AST and gammaglutamyltransferase levels similarly fell HCV RNA titer (mean 105.3 + 100.8 copies/50 ILl by competitive RT-PCR at start) did not change in any patient throughout the study. There were no appreciable alterations in the other laboratory findings such as serum creatinine levels and lymphocyte subsets (including CD4+ T cell number). These findings suggest that CyA, even in a relatively low dose, has a beneficial effect on the improvement of serum aminotransferase levels without significant side effects, although antiviral effect was not noted in patients with chronic hepatitis C.
Hepatitis C virus (HCV)-associated mixed cryoglobulins (CGs) appear to be frequently detected in hepatitis C related chronic liver disease. To date, no descdption of HCVassociated CGs has appeared in patients indigenous Asia. Thus serum levels of total hemolytic complement (CH50) and anti-C3d-binding immune complex, and the prevalence of CGs were studied in Japanese patients with chronic liver disease (hepatitis C, 155 cases and hepatitis B, 58 cases). CH50 activity was significantly lower in patients with hepatitis C than those with hepatitis B except in responders to interferon who showed sustained loss of HCV RNA. CGs were detected in 24 (37%) of 65 patients with hepatitis C; they generally composed of polyclonal Igs but one. CGs were more frequently observed in cirrhotic patients and in those with a longer duration of disease. CGs-related clinical signs such as vasculitis occurred in only three cases. Patients with CGs had lower CH50 activity and higher immune complex values than those without CGs. Serum HCV RNA levels were lower in CGs-positive patients (p<0.05) than in CGs-negative patients, although distribution of the viral genotype did not differ between the groups. HCV Ab and HCV RNA were detected in all cryoprecipitates tested, respectively. These findings suggest that HCV is a major cause of CGs and advanced liver damage. However, less frequencies of CGs with only polyclonal Igs and less appearance of CGs-related clinical signs among Japanese patients differ compared with those studied in Western countries.
VIRUS DISEASE AMONG JAPANESE PATIENTS. S Kakumu. K Tanaka. T Aivama. J Imai. Y Morishita. and T Fukatsu. Third Dept. of Medicine, Nagoya Univ. Sch. of Medicine and Dept. of Clinical Lab. Nagoya Univ. Hospital, Nagoya, Japan.
AASLD ABSTRACTS
1 3 1 3 THE EFFECT OF RENAL DYSFUNCTION ON O~UTCOME IN HEPATIC TRANSPLANTATION. MW lohnson, IA Powelson. H Au(hincloss. lr.. EL Delmonico. and AB Cosimi. The Transplantation
Unit and the Department of Surgery, the Massachusetts General Hospital, Boston, Massachusetts. Renal dysfunction has been applied as an indicator of critical illness in the intensive care patient and as a criterion for the high risk patient preoperatively. We reviewed the records of 150 adult primary orthotopic liver aUograft recipients transplanted at Massachusetts General Hospital from January 1984 to December 1994 to assess the affect of renal dysfunction on liver transplantation outcomes. The actuarial survivals for the entire patient population are 71%, 63% and 61% at 1 year, 2 years, and 3 years respectively. Demographic data, UNOS status, and diagnoses are similar in all comparative groups. Eighteen patients (12%) had evidence of pre-operative renal dysfunction as defined as a serum creatinine level > 2.0 m g / d l (measured the day of surgery). One patient underwent simultaneous liver/kidney transplant and was excluded from analysis. He is alive with functioning allografts > 2 years out. Actuarial survival for the remaining 17 patients is 29.4% at 6 months as compared to 6 month survivals of 80% in patients with pro-operative serum creatinine levels < 2,0 m g / d l (p<0.001). The renal dysfunction group also suffered a significant difference in intra-operative PRBC requirements (p<0.05), peak and discharge serum creatinine levels (p<0.001 and p<0.05, respectively), and length of stay (p=0.05) when compared to patients with a baseline serum creatinine level < 2.0 mg/dl. Four of the 17 patients (24%) with serum creatinine levels > 2.0 mg/dl pre-operatively required hernodialysis post-transplant, while only six of the 132 (4.5%) patients with pre-operative serum creatinine levels < 2.0 m g / d l required hemodialysis post-transplant (p<0.05). All ten of the patients requiring post-transplant hemodialysis have died (p<0.001, as compared to patients not requiring post-transplant hemodialysis). Acute versus chronic renal dysfunction did not significantly alter survivals. In conclusion, pre-operative renal dysfixncti0n adversely effects the outcomes in orthotopic liver allograft transplantation and perhaps could be a criterion used to identify patients who should either undergo simultaneous liver/kidney transplant or be disqualified for organ transplantation. Hemodialysis post-transplant is a harbinger of poor outcome in the liver transplant patient.
1315
1314
435A
HISTOLOGICALCONSEQUENCESOF CHRQNIC HEPATITISC -HISTOMETRGAL STUDYON REPEATEDLIVER BIOPSIESM.Kage ". K.Shimamatsu , M.Kojiro h. O.Inoue 2~. M.Yano 2 1. The First Department of Pathology, Kurume Univ. School of Medicine 2. Institute tot Clinical Research. Nagasaki Chu~3 National Hospital A i m : We conducted histometricaJ analysis to clarify the chronological changes of fibrosis in chronic hepatitis C which progressed to cirrhosis. Material:
We exammeta repeated liver biopsies obtained from 40 cases cff chronic
hepatitis C and those lrom 30 cases of chronic hepatitis B a.~;controls. The 3 were continuously follo,,~ed tor 5 to 21 years with an average of 7.7 years. Each case had two to ten biopsies w~m an average ot 4: the interval from the first liver biopsy to the last ranged t~'om I m 26 ) :ars. Methods:
1 Staging (scoring for stage): Chronic hepatitis was classified into four
stages according co evolusion of fibrosis: stage 1 {mild portal fibrosis), stage 2 (periportal fibrosisl, stage 3 (portal fibroisis with lobular distortion), stage 4 (liver cirrhosis' 2. Histometrical analysis: We determined area of fibrosis by sassing whole liver tissue of each specimen, using the computer image-analysis system. Degree of fibrosis was defined as the ratio of fibrosis to whole area or hepatic tissue (FR). Results:
[. Stage and FR were well correlated, stage/FR (~h, averagel:
stage I/2.7. stage 2/3.9. stage 3/4,4, stage4/10.5. 2. High FR over 10% was the most frequent m cases over 5{) years old. while FR below 10% was frequent in cases under 50, Especially in the cases over 55 years old, the speed with which chronic hepatitis progressed to cirrhosis was accelerated.
3, Priests with stage 3 in the first biopsy all progress [o
cirrhosis within 10 yeares. 4. In chronic hepatitis B, high FR was found in any age group, Out of eight cases with high FR of more than 10%. 6 cases were younger than 40. Chronic hepatitis B in younger patients had a trend to progress to cirrhosis rapidly. Conclusion
Our histometrica] analysis clarified natural consequences of ~hronic
hepatitis C which progressed to cirrhosis
CYCLOSPORIN A IN THE TREATMENT OF CHRONIC HEPATITIS C REFRACTORY TO INTERFERON. S Kakumu. M Takavanaei T Aivama. K Iwata. A Okumura. K Yoshioka. and M. N-adai~. Third Department of Internal Medicine and Department of Hospital Pharmacy*, Nagoya University School of Medicine, Nagoya, Japan.
1316 SERUM CRYOGLOBULINS AND CHRONIC HEPATITIS C
Interferon therapy is of proven efficacy in chronic hepatitis C, but it is not universally effective and often limited by side effects. Cyclosporin A (CyA) is a potent immune-suppressant widely used in organ transplantation. We conducted a pilot study of CyA therapy in 10 patients (mean age of 59 yr, M/F=9/1) with chronic active hepatitis C who failed interferon therapy previously and had elevated ALT values for at least 6 me. All patients were positive for HCV RNA by RT-PCR with genotype lb. Their mean duration of hepatitis was 15 yr. Oral CyA was given for 3 me in a dose that was increased at 1-me interval, from 1.5-2.0 mg to 2.0-3,0 mg to 3.0-4.0 mg/kg/day. All completed treatment schedule, although two had mild nonsymptomatic dse of blood pressure. Serum ALT levels gradually decreased in all patients but one; the mean percentage decrease was 57.5% (from 153 + 82 IU/L to 65 + 44 IU/L, p<0.01) at the end of therapy. The enzyme levels fell to the normal range in 5 patients. Serum AST and gammaglutamyltransferase levels similarly fell HCV RNA titer (mean 105.3 + 100.8 copies/50 ILl by competitive RT-PCR at start) did not change in any patient throughout the study. There were no appreciable alterations in the other laboratory findings such as serum creatinine levels and lymphocyte subsets (including CD4+ T cell number). These findings suggest that CyA, even in a relatively low dose, has a beneficial effect on the improvement of serum aminotransferase levels without significant side effects, although antiviral effect was not noted in patients with chronic hepatitis C.
Hepatitis C virus (HCV)-associated mixed cryoglobulins (CGs) appear to be frequently detected in hepatitis C related chronic liver disease. To date, no descdption of HCVassociated CGs has appeared in patients indigenous Asia. Thus serum levels of total hemolytic complement (CH50) and anti-C3d-binding immune complex, and the prevalence of CGs were studied in Japanese patients with chronic liver disease (hepatitis C, 155 cases and hepatitis B, 58 cases). CH50 activity was significantly lower in patients with hepatitis C than those with hepatitis B except in responders to interferon who showed sustained loss of HCV RNA. CGs were detected in 24 (37%) of 65 patients with hepatitis C; they generally composed of polyclonal Igs but one. CGs were more frequently observed in cirrhotic patients and in those with a longer duration of disease. CGs-related clinical signs such as vasculitis occurred in only three cases. Patients with CGs had lower CH50 activity and higher immune complex values than those without CGs. Serum HCV RNA levels were lower in CGs-positive patients (p<0.05) than in CGs-negative patients, although distribution of the viral genotype did not differ between the groups. HCV Ab and HCV RNA were detected in all cryoprecipitates tested, respectively. These findings suggest that HCV is a major cause of CGs and advanced liver damage. However, less frequencies of CGs with only polyclonal Igs and less appearance of CGs-related clinical signs among Japanese patients differ compared with those studied in Western countries.
VIRUS DISEASE AMONG JAPANESE PATIENTS. S Kakumu. K Tanaka. T Aivama. J Imai. Y Morishita. and T Fukatsu. Third Dept. of Medicine, Nagoya Univ. Sch. of Medicine and Dept. of Clinical Lab. Nagoya Univ. Hospital, Nagoya, Japan.