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Poor outcome following orthotopic liver transplantation for cryptogenic cirrhosis
H E P A T O L O G Y V o l . 22, N o . 4, P t .
185
2, 1 9 9 5
AASLD
TREATMENT OF CHRONIC NANB AND C HEPATITIS WITH (x-INTERFERON: A META-ANALYSIS OF DOSE AND DURATION. C Niederau, T Heint.qes, and D H&ussin.qer. Dept. of Medicine, Division of Gastroenterology and Hepatology, University DQsseldorf, Germany.
ABSTRACTS
186
POOR OUTCOME FOLLOWING ORTHOTOPIC LIVER T R A N S P L A N T A T I O N FOR C R Y P T O G E N I C CIRRHOSIS. M_RR C harlton. M. Kondo, R. Gomez. SK Roberts. AJ Czaia. JL Steers. RAF Krom and RH Wiesner. Mayo Clinic and Foundation; Rochester, MN, USA.
Background. End-stage liver disease secondary to cryptogenic cirrhosis is a frequent indication for orthotopic liver transplantation (OLT). There are, however, no published reports documenting the outcome of OLT for this indication. Aims. To determine 1) survival and 2) incidence of histologic recurrence of cryptogenic cirrhosis following OLT. Methods. Between March 1985 and December 1994, 560 OLT's were carried out at our institution. Of these, 39 patients transplanted for cryptogenic cirrhosis met the following criteria: ANA < 1:40, neg ASMA, AMA, HCV PCR and HBsAg, normal Ceruloplasmin and c~-I AT phenotype, transferrin saturation < 65%, a liver biopsy excluding hemochromatusis and other hepatologic disorders. Post-OLT survival was analyzed in these 39 patients. Histological recurrence was assessed with protocol liver biopsies in all patients surviving more than six months. Results. There were 2l female and 18 male recipients with cryptogenic cirrhosis, a mean age of 40.6 years (range 3-63). Median Child's score at time of OLT was 10 (.@_2.25 SEM). Actuarial one year survival was 72% ~_ 0.07 SEM) and five year survival was 50% (+ 0.08 SEM). Actuarial survival in our non-cryptogenic recipients was 89% at one and 80% at five years. This actuarial survival was significantly decreased in patients undergoing liver transplant for cryptogenic cirrhosis (p<0.001) at both one and five years. Amongst *.he 27 patients surviving more than six months (mean follow-up 5.5 years) six patients have persistent hepatitis histologically without apparent infectious, vascular, biliary or drug etiologies. Four patients (15%) chronic active hepatitis and two (7%) have steatohepatitis. No patient had evidence of recurrence of cryptogenic cirrhosis. Conclusions. 1) OLT for cryptogenic cirrhosis is associated with a poor outcome compared to other indications. Most of the mortality in this patient group occurs early (10/18 by four months). The etiology for the excess mortality remains unclear. 2) Hepatitis of uncertain etiology occurred in 22% of recipients. 3) No evidence of recurrence of cryptogenic cirrhosis was seen thus far in the follow-up.
AUXILIARY LIVER TRANSPLANTATION FOR FULMINANT LIVER FAILURE : LIMITS OF AN ATTRACTIVE CONCEPT. Belghiti J, Zinzindohoue F, Durand F*, Noun R, Sauvanet A, Bemuan J*. Departments of Digestive Surgery & *Hepatology, Hrpital Beaujon, 92110 Clichy-FRANCE Auxiliary liver transplantation (ALT) theoretically bridges the period of acute liver failure until the native liver (NL) recovers and immunosuppression can be discontinued. However, this attractive concept is burdened by technical problems and by the selectiort of candidates. We report oar experience of ALT with special references to early graft function, factors of technical failure and thus, circumstances that may Contraindicate an ALT. Patients: From April 1993 to April 1994, among the 24 adults who were candidates for emergency liver transplantation, we decided to perform OLT in 15 because of poor quality graft, age>60 years, pre-existing chronic liver disease, haemodynamic instability, and poor neurological status in 1,2, 3, 4 and 5 patients respectively. ALT was performed in the remaining 9 patients. At the time of transplantation, coma was present in 5 patients and severe confusion in 4. Results : Graft function, postoperative course and outcome are listed as follows: Patients Graft Vessel Prothr. time Vascular Causal Outcome (sex/age) size graft Day 1/3/10 complications disease M/33 FG P 10/62/67 none DT Al(24months)*** I::/57 FG P 9/46/PT DT Dd (day 6) F/21 FG P+A 13/41/49 PT+AR HBV Dd (day 10) M/55 FG P+A 21/51/35 none DT Dd (day 16) F/24 PG(II-IV) none 6/38/69 PT* HBV AI**(14 months) M/16 PG(V-VIlI) none 29/53/72 none M3d AI (8 months) F/20 PG(I-IV) none 34/54/71 none HBV AI (6 months)*** F/27 PG(II-1V) none 21/36/60 none DT AI (4 months)*** H/30 PG(V-VIII) none 25/41/65 none DT AI (2 months) *successful thrombectomy, **graft removal at 7 months, ***regeneration with fibrosis. FG=full-size graft, PG=partial graft, D=donor, R=recipient, P=portal, A=arterial, T=thrombosis, R=mpture, DT=drug toxicity, HBV=hepatitis B virus, MH=major hepatectomy, Al--~ive, Dd=dead. Conclusion: These results indicate that in selected patients, ALT can provide a rapid liv~ function and may enable native liver recovery if the use of full-size graft and/or vascular graft is avoided. However, fibrosis in the native liver occured postoperatively in half o~ our surviving patients. The development of methods improving native liver regeneratioa could optimize results of ALT.
The optimal dose and duration of (x-interferon therapy remain illdefined because the sample size of most previous studies was too small to allow definite conclusions. The present meta-analysis therefore evaluates the influence of dose and duration of co-interferon therapy on its response. Methods: The meta-analysis analyzed 52 randomized trials of e-interferon in chronic NANB and C hepatitis enrolling 3749 patients. In these studies, published between 1986 and 1994, 2927 patients had been treated with various doses of interferon for various periods, and 822 patients had either not been treated or had received placebo. The analysis included randomized studies which did not have a control group of untreated patients but compared different doses and durations of interferon therapy. Results: Interferon initially (3 months after begin of therapy) induced ALT normalization in 1499/2927 patients (51.2%); only 482/2218 patients (21.7%) still had normal ALl" values 3-6 months after interferon had been stopped (defined as tong-term response). Nevertheless, long-term response was increased more than 8-fold by interferon (21.7%) when compared with untreated controls (2.7%) (X2 =156.1; p sl 0-~s). The long-term response to weekly doses 2 12 M.U. (31.3%) was doubled when compared with 9 M.U. (16.7%) and tripled when compared with doses 6 M.U. (9.2%) (X2=59.9; p=0,95.10~3). Treatment for > 9 months doubled the response when compared with periods of < 6 months (29.4% vs. 14.6%; X2=64.0; p=0.12.10 -~4 ). Total interferon doses ;a 240 M,U. resulted in a threefold higher response as compared with doses < 240 M.U. (30.6% vs. 10.8%; X2=103.3; p=0.99.10ls). Regression analyses corroborated that the tong-term response was significantly correlated with dose and duration of interferon therapy and most closely with the total interferon dose given. Conclusions: The meta-analysis suggests that widely used therapy schedules such as 3 M.U. ~t-interferon given thrice weekly for 6 months (or even lower doses and shorter durations) result in insufficient long-term responses. Thus, future studies should focus on long-term treatment and weekly doses exceeding 9 M.U. a-interferon.
187
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188
OUTCOME OF LIVER RETRANSPLANTATION (ReOLTx) FOR RECURRENT HEPATITIS C INFECTION. Casavilla FA,* Lee R; Lira J, Kramer D, Irish W, Rakela J, and Fun.q JJ. Pittsburgh Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Viral hepatitis frequently recurs after OLTx for either hepatitis R (HBV') or hepatitis C (HCV), and ReOLTx for recurrent HBV is known to lead to poor results. Aim: To examine the outcome of ReOLTx in patients with allograft failure due to recurrent HCV infection. Patients and Methods: Between January, 1990 and July, 1994,27 adult patients underwent ReOLTx for recurrent HCV (excluding those with concurrent HBV or malignancy). All had (+) serology and/or PCR for HCV and chronic hepatitis (+/- cirrhosis) was confirmed histologically. At ReOLTx, 17 had coexisting pathologic findings: chronic rejection (n= 12), hepatic artery or portal vein stenosis/thrombosis (n=3), and ACR (n=l). Nine patients required >1 ReOLTx, with recurrent HCV being the indication for 2nd ReOLTx in 3 patients, for 3rd ReOLTx in 4, and for both 1st and 2nd ReOLTx in the remaining 2. Results: The patients were predominantly male (67%) with a mean age of 40.6 years (range 21.9-59.0); 14 (52%) were ICU-bound. ReOLTx for recurrent HCV was performed between 87 and 4262 days (median 759) following prior OLT)dReOLTx. After a median follow-up period of 120 days (0-1810), mortality was 67% (18/27) overall, and was greater in those requiring >1 ReOLTx (89%(8/9) vs 56%(10/18), p=0.189, (Fisher's exact test); ReOLTx->I incurred a relative risk of mortality of 2.0 (Cox regression) when compared to those undergoing only 1 ReOLTx.. The most common causes of death were bacterial sepsis (n=6) and fungal infection (n=4) followed by cardiac failure (n=2), multisystem organ failure (n=2) and others (n=4). Conclusions: ReOLTx for recurrent end-stage liver disease due to HCV infection is associated with a high mortality rate; this risk is even higher when >1 ReOLTX. Recurrent HCV infection is a controversial indication for ReOLTx. Careful selection of patients and new therapeutic strategies are needed.
185
2, 1 9 9 5
AASLD
TREATMENT OF CHRONIC NANB AND C HEPATITIS WITH (x-INTERFERON: A META-ANALYSIS OF DOSE AND DURATION. C Niederau, T Heint.qes, and D H&ussin.qer. Dept. of Medicine, Division of Gastroenterology and Hepatology, University DQsseldorf, Germany.
ABSTRACTS
186
POOR OUTCOME FOLLOWING ORTHOTOPIC LIVER T R A N S P L A N T A T I O N FOR C R Y P T O G E N I C CIRRHOSIS. M_RR C harlton. M. Kondo, R. Gomez. SK Roberts. AJ Czaia. JL Steers. RAF Krom and RH Wiesner. Mayo Clinic and Foundation; Rochester, MN, USA.
Background. End-stage liver disease secondary to cryptogenic cirrhosis is a frequent indication for orthotopic liver transplantation (OLT). There are, however, no published reports documenting the outcome of OLT for this indication. Aims. To determine 1) survival and 2) incidence of histologic recurrence of cryptogenic cirrhosis following OLT. Methods. Between March 1985 and December 1994, 560 OLT's were carried out at our institution. Of these, 39 patients transplanted for cryptogenic cirrhosis met the following criteria: ANA < 1:40, neg ASMA, AMA, HCV PCR and HBsAg, normal Ceruloplasmin and c~-I AT phenotype, transferrin saturation < 65%, a liver biopsy excluding hemochromatusis and other hepatologic disorders. Post-OLT survival was analyzed in these 39 patients. Histological recurrence was assessed with protocol liver biopsies in all patients surviving more than six months. Results. There were 2l female and 18 male recipients with cryptogenic cirrhosis, a mean age of 40.6 years (range 3-63). Median Child's score at time of OLT was 10 (.@_2.25 SEM). Actuarial one year survival was 72% ~_ 0.07 SEM) and five year survival was 50% (+ 0.08 SEM). Actuarial survival in our non-cryptogenic recipients was 89% at one and 80% at five years. This actuarial survival was significantly decreased in patients undergoing liver transplant for cryptogenic cirrhosis (p<0.001) at both one and five years. Amongst *.he 27 patients surviving more than six months (mean follow-up 5.5 years) six patients have persistent hepatitis histologically without apparent infectious, vascular, biliary or drug etiologies. Four patients (15%) chronic active hepatitis and two (7%) have steatohepatitis. No patient had evidence of recurrence of cryptogenic cirrhosis. Conclusions. 1) OLT for cryptogenic cirrhosis is associated with a poor outcome compared to other indications. Most of the mortality in this patient group occurs early (10/18 by four months). The etiology for the excess mortality remains unclear. 2) Hepatitis of uncertain etiology occurred in 22% of recipients. 3) No evidence of recurrence of cryptogenic cirrhosis was seen thus far in the follow-up.
AUXILIARY LIVER TRANSPLANTATION FOR FULMINANT LIVER FAILURE : LIMITS OF AN ATTRACTIVE CONCEPT. Belghiti J, Zinzindohoue F, Durand F*, Noun R, Sauvanet A, Bemuan J*. Departments of Digestive Surgery & *Hepatology, Hrpital Beaujon, 92110 Clichy-FRANCE Auxiliary liver transplantation (ALT) theoretically bridges the period of acute liver failure until the native liver (NL) recovers and immunosuppression can be discontinued. However, this attractive concept is burdened by technical problems and by the selectiort of candidates. We report oar experience of ALT with special references to early graft function, factors of technical failure and thus, circumstances that may Contraindicate an ALT. Patients: From April 1993 to April 1994, among the 24 adults who were candidates for emergency liver transplantation, we decided to perform OLT in 15 because of poor quality graft, age>60 years, pre-existing chronic liver disease, haemodynamic instability, and poor neurological status in 1,2, 3, 4 and 5 patients respectively. ALT was performed in the remaining 9 patients. At the time of transplantation, coma was present in 5 patients and severe confusion in 4. Results : Graft function, postoperative course and outcome are listed as follows: Patients Graft Vessel Prothr. time Vascular Causal Outcome (sex/age) size graft Day 1/3/10 complications disease M/33 FG P 10/62/67 none DT Al(24months)*** I::/57 FG P 9/46/PT DT Dd (day 6) F/21 FG P+A 13/41/49 PT+AR HBV Dd (day 10) M/55 FG P+A 21/51/35 none DT Dd (day 16) F/24 PG(II-IV) none 6/38/69 PT* HBV AI**(14 months) M/16 PG(V-VIlI) none 29/53/72 none M3d AI (8 months) F/20 PG(I-IV) none 34/54/71 none HBV AI (6 months)*** F/27 PG(II-1V) none 21/36/60 none DT AI (4 months)*** H/30 PG(V-VIII) none 25/41/65 none DT AI (2 months) *successful thrombectomy, **graft removal at 7 months, ***regeneration with fibrosis. FG=full-size graft, PG=partial graft, D=donor, R=recipient, P=portal, A=arterial, T=thrombosis, R=mpture, DT=drug toxicity, HBV=hepatitis B virus, MH=major hepatectomy, Al--~ive, Dd=dead. Conclusion: These results indicate that in selected patients, ALT can provide a rapid liv~ function and may enable native liver recovery if the use of full-size graft and/or vascular graft is avoided. However, fibrosis in the native liver occured postoperatively in half o~ our surviving patients. The development of methods improving native liver regeneratioa could optimize results of ALT.
The optimal dose and duration of (x-interferon therapy remain illdefined because the sample size of most previous studies was too small to allow definite conclusions. The present meta-analysis therefore evaluates the influence of dose and duration of co-interferon therapy on its response. Methods: The meta-analysis analyzed 52 randomized trials of e-interferon in chronic NANB and C hepatitis enrolling 3749 patients. In these studies, published between 1986 and 1994, 2927 patients had been treated with various doses of interferon for various periods, and 822 patients had either not been treated or had received placebo. The analysis included randomized studies which did not have a control group of untreated patients but compared different doses and durations of interferon therapy. Results: Interferon initially (3 months after begin of therapy) induced ALT normalization in 1499/2927 patients (51.2%); only 482/2218 patients (21.7%) still had normal ALl" values 3-6 months after interferon had been stopped (defined as tong-term response). Nevertheless, long-term response was increased more than 8-fold by interferon (21.7%) when compared with untreated controls (2.7%) (X2 =156.1; p sl 0-~s). The long-term response to weekly doses 2 12 M.U. (31.3%) was doubled when compared with 9 M.U. (16.7%) and tripled when compared with doses 6 M.U. (9.2%) (X2=59.9; p=0,95.10~3). Treatment for > 9 months doubled the response when compared with periods of < 6 months (29.4% vs. 14.6%; X2=64.0; p=0.12.10 -~4 ). Total interferon doses ;a 240 M,U. resulted in a threefold higher response as compared with doses < 240 M.U. (30.6% vs. 10.8%; X2=103.3; p=0.99.10ls). Regression analyses corroborated that the tong-term response was significantly correlated with dose and duration of interferon therapy and most closely with the total interferon dose given. Conclusions: The meta-analysis suggests that widely used therapy schedules such as 3 M.U. ~t-interferon given thrice weekly for 6 months (or even lower doses and shorter durations) result in insufficient long-term responses. Thus, future studies should focus on long-term treatment and weekly doses exceeding 9 M.U. a-interferon.
187
153A
188
OUTCOME OF LIVER RETRANSPLANTATION (ReOLTx) FOR RECURRENT HEPATITIS C INFECTION. Casavilla FA,* Lee R; Lira J, Kramer D, Irish W, Rakela J, and Fun.q JJ. Pittsburgh Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Viral hepatitis frequently recurs after OLTx for either hepatitis R (HBV') or hepatitis C (HCV), and ReOLTx for recurrent HBV is known to lead to poor results. Aim: To examine the outcome of ReOLTx in patients with allograft failure due to recurrent HCV infection. Patients and Methods: Between January, 1990 and July, 1994,27 adult patients underwent ReOLTx for recurrent HCV (excluding those with concurrent HBV or malignancy). All had (+) serology and/or PCR for HCV and chronic hepatitis (+/- cirrhosis) was confirmed histologically. At ReOLTx, 17 had coexisting pathologic findings: chronic rejection (n= 12), hepatic artery or portal vein stenosis/thrombosis (n=3), and ACR (n=l). Nine patients required >1 ReOLTx, with recurrent HCV being the indication for 2nd ReOLTx in 3 patients, for 3rd ReOLTx in 4, and for both 1st and 2nd ReOLTx in the remaining 2. Results: The patients were predominantly male (67%) with a mean age of 40.6 years (range 21.9-59.0); 14 (52%) were ICU-bound. ReOLTx for recurrent HCV was performed between 87 and 4262 days (median 759) following prior OLT)dReOLTx. After a median follow-up period of 120 days (0-1810), mortality was 67% (18/27) overall, and was greater in those requiring >1 ReOLTx (89%(8/9) vs 56%(10/18), p=0.189, (Fisher's exact test); ReOLTx->I incurred a relative risk of mortality of 2.0 (Cox regression) when compared to those undergoing only 1 ReOLTx.. The most common causes of death were bacterial sepsis (n=6) and fungal infection (n=4) followed by cardiac failure (n=2), multisystem organ failure (n=2) and others (n=4). Conclusions: ReOLTx for recurrent end-stage liver disease due to HCV infection is associated with a high mortality rate; this risk is even higher when >1 ReOLTX. Recurrent HCV infection is a controversial indication for ReOLTx. Careful selection of patients and new therapeutic strategies are needed.