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Followup after liver transplantation for protoporphyric liver disease
150A
AASLD ABSTRACTS
173 F O L L O W U P
AFTER LIVER TRANSPLANTATION FOR P R O T O P O R P H Y R I C L I V E R DISEASE. J Bloomer. J Rank. R Zwiener. and R Carithers. Dept. of Pediatrics at Children's Medical Center of Dallas, Dept. of Medicine at U of Washington, Seattle, and Dept. of Medicine at U of Minnesota, Minneapolis, MN Protoporphyda is a genetic disorder in which there is excessive accumulation and excretion of protoporphyrin (pp), Some patients develop serious liver damage due to pp deposition in the liver and require liver transplantation. Because protoporphyria causes unique p r o b l e m s in the perioperative period, and because bone marrow production of excess pp continues after transplantation, the efficacy of transplantation is uncertain. We present our experience with foUowup of 9 patients who underwent transplantation for protoporphyric liver disease. Two patients died within 2 months of transplantation, one of complications from massive abdominal bleeding and the other from sepsis after small bowel perforations. The remaining 7 patients (3F, 4M with age range of 13 yrs to 38 yrs at transplantation) are alive at followup (14 mos to 8 yrs, mean 3.6 yrs). Two patients had skin burns as a result of exposure to operating room lights, and 3 had severe axona! neuropathies in the postoperative period requiring mechanical ventilation for 2.5 to 14 wks. Five had episodes of acute rejection which responded to therapy, and 4 had biliary tract complications. Five patients have returned to a good functional state, with liver chemistries normal at followup, and liver biopsies normal or showing only mild portal triad abnormalities. Red cell pp levels remain significantly elevated (1765 + 365 meg/dL, normal <65), but are markedly decreased compared to levels at the time of transplantation (5128 + 1655). The other 2 patients, both of whom had episodes of rejection, CMV infection, and biliary tract obstruction requiring endoscopic therapy, have had a recurrence of protoporphyric liver disease documented by abnormal chemistries and characteristic biopsy features 3 yrs and 5 yrs after transplantation. Thus liver transplantation can be done successfully in patients with protoporphyric liver disease, despite unique and serious postoperative complications, with survival rates comparable to those in the general transplant population. However, disease may recur in the new liver, particularly if there are several complications which cause cholestasis after transplantation.
175 HCV REINFECTION IN LIVER TRANSPLANTED RECIPIENTS ASSESSED BY HCV-AG EXPRF~SION IN LIVER CELLS. V Vary,as. K Krawczvnski. N Martfnez~ L Castells. H Allende. D Carson. R. Esteban J Guardia.Hospital Universitari Vail d "Hebron, Barcelona, Spain and Hepatitis Branch, DVRD/NICD, C.D.C and Prevention, Atlanta. Objective: This study was to evaluate the timing and the clinico- pathological significance of HCV-Ag expression in liver cells and to correlate with liver histology and HCV-RNA levels. Methods: Liver biopsy specimens were obtained from 42 HCV positive liver transplant (LT) recipients. Patients were divided into three groups: group A, 12 patients studied in the first month; group B, 13 patients studied between 1 and 6 months; group C, 17 patients studied between 6 and 18 months after LT. Expression of HCVAg was assessed by direct IF testing of frozen specimens and graded from 1 + (< 5% positive ceils) to 3 + ( > 20% positive cells). HCV RNA levels were measured by PCR teenique (Monitor-Roche). Liver lesions were classified into 3 groups: acute hepatitis, chronic hepatitis, and non-viral lesions. Results: In group A, HCVAg was found in 6 of 13 specimens (46%), and its expression was graded 1+ in 3, 2+ in 2 and 3+ in 1. Mean HCV-RNA level was 41,2 X 104 genomic copies/ml. In group B, HCVAg was found in 13 of 13 specimans(100%), and was graded 1+ in 1, 2+ in 1 and 3+ in 11. Mean HCV-RNA level was 418,8 x 104 genomic copies/mL In group C, HCV-Ag was found in 17 of 17 specimens (100%), and was graded 1+ in 5, 2+ in I and 3+ in 11. Mean HCV-RNA level was 448,3 x 104 ganomic eopies/ml. The differences in number of HCV-Ag positive cases, the mean intensity of HCvAg expression and the mean HCV-RNA levels between groups A and B (p=0.0008, p=0.0001, p=0.0036 respectively) and A and C (p=0.0008, p=0.005, pffi0.02 respectively) were statistically significant. Patients with acute or chronic hepatitis had significantly more HCVAg expression (13=0.007) and more HCV-RNA levels (p=0.02) than did patients with nonviral lesions. There were no differences in the intensity of HCVAg expression between acute hepatitis and those with chronic hepatitis. Conclusions: HCVAg is expressed in one-half of the patients in the first month after LT and its universally present thereafter in correlation with serum HCV-RNA levels.
HEPATOLOGYOctober 1995
174 S GENE ESCAPE MUTANTS AS A CAUSE OF HBV REINFECTION IN PATIENTS WHO RECEIVED HBIG POST-OLT. MG Ghanv. B Avola. FG Villamil*. R Gish#. S Roiter*. IM Vierlln~*. ASF Lok. Tulane Univ a n d VA Med Ctr, New Orleans; Cedars-Sinal/UCLA*, Los Angeles; Pacific Med Ctr#, San Francisco. Mutations involving the 'a' d e t e r m i n a n t of the HBV S gene resulting in loss of binding to anti-'a' has been reported in OLT patients (pt) who developed HBV reinfection after p r o p h y l a c t i c t h e r a p y with monoclonal anti-HBs. The occurrence of S 'escape' m u t a n t s in OLT pt who received polyclonal anti-HBs (HBIG) irnmunoprophylaxis has not b e e n examined. A/m : To d e t e r m i n e the p r e v a l e n c e of m u t a t i o n s in the 'a' d e t e r m i n a n t of the S gene in OLT p t who d e v e l o p e d HBV reinfection despite prophylaxis with HBIG. M e t h o d s : 5 pt who u n d e r w e n t OLT for HBV+, HDV- cirrhosis were studied. All received long-term HBIG. Paired sera pre- a n d post- OLT were analyzed by PCR amplification and direct s e q u e n c i n g of p a r t of the HBV S gene that encompasses the 'a' determinant. R e s u l t s : 4 (8096) pt h a d m u t a t i o n s that could potentially a l t e r the antigenicity of the 'a' d e t e r m i n a n t a n d 1 (20%) h a d wild-type sequence in the post-OLT samples. All pt h a d wild-type sequence pre-OLT. All 5 pt were reinfected while they were still on HBIG. Patient Nueleotide change Amino acid change 1 A-G, 342 thr-ser, 114 T-A, 401 phe-tyr, 134 2 ins AGG between ins of arg between nt 360 & 361 codon 120 & 121 3 C-T, 424 pro-ser, 142 A-C, 431 asp-ala, 144 4 T-G, 432 asp-flu, 144 5 nil nil C o n t u s i o n s : We found a high rate of m u t a t i o n s in the 'a' d e t e r m i n a n t of the HBV S gene in OLT pt who were r e i n f e c t e d while receiving HBIG suggesting that the b r e a k t h r o u g h infection was caused b y escape mutants. Further studies are ongoing to d e t e r m i n e if S escape m u t a n t s are also detected in pt who developed HBV reinfection after discontinuation of HBIG.
176 EFFECT OF DONOR HEPATITIS C SEROPOSITIVITY ON ALLOGRAFT INFECTION IN ORTHOTOPIC LIVER TRANSPLANTATION. P Martin. J Melinek. AB Shaked. C Shackleton, C Holt. K Olthoff. D Imagawa. RW Busuttil. Dumont = UCLA Liver Transplant Program, UCLA School of Medicine, Los Angeles, California The shortage of organ donors in a critical factor limiting access to orthotopic liver transplantation: Thus, it had been our policy to accept liver grafts from hepatitis C antibody positive (HCV+) donors. These grafts were transplanted in recipients suffering from end stage liver disease secondary to hepatitis C. Under extreme circumstances HCV+ organ donors had been accepted in rapidly deteriorating UNOS status IV candidates. The aim of this study was to examine the consequences of use of HCV+ donors in recipients with and without prior HCV infection. METHODS: The pattern of hepatitis C graft infection and disease was studied in 73 recipients undergoing OLT for HCV related end stage liver disease between 10/90= 12/93. These recipients received their grafts from HCV- donors (Group 1, n = 37), 0r HCV+ donors (Group 2, n = 17). The pattern of recurrence in these recipients was compared to the development of hepatitis C in previously non-infected recipients receiving a HCV+ graft (Group 3, n = 19). Active hepatitis C in long term survivors was diagnosed by persistently elevated liver enzymes and repeat liver biopsies showing features consistent with graft hepatitis. RESULTS: The incidence and time to the diagnosis of graft HCV were not different between groups (Table). Recurrence HCV Status Incidence days -4-SD Group 1: - donors, + recipients n = 37 9 (24%) 250 ± 182 Group 2: + donors, + recipients n = 17 5 (29%) 228 ± 159 Group 3: + donors, - recipients n = 19 3 (16%) 221 ± 170 p =0.67 Only one patient (Group 1) died of graft failure due to hepatitis C. The severity and pattern of de novo HCV infection in Group 3 was similar to that in patients with recurrent graft infection. CONCLUSIONS: I. In recipients with prior HCV infection receipt of a HCV+ donor did not alter the rate, onset or severity of graft reinfection compared to recipients of seronegative grafts. 2. In recipients without prior HCV infection transmission of HCV occurs leading to graft injury in a minority of such recipients. This data support the utilization of hepatitis C positive donor livers for hepatitis C+ recipients. However, transplantation of these grafts in the previously non-infeCted recipients should be avoided in non=critical circumstances.
AASLD ABSTRACTS
173 F O L L O W U P
AFTER LIVER TRANSPLANTATION FOR P R O T O P O R P H Y R I C L I V E R DISEASE. J Bloomer. J Rank. R Zwiener. and R Carithers. Dept. of Pediatrics at Children's Medical Center of Dallas, Dept. of Medicine at U of Washington, Seattle, and Dept. of Medicine at U of Minnesota, Minneapolis, MN Protoporphyda is a genetic disorder in which there is excessive accumulation and excretion of protoporphyrin (pp), Some patients develop serious liver damage due to pp deposition in the liver and require liver transplantation. Because protoporphyria causes unique p r o b l e m s in the perioperative period, and because bone marrow production of excess pp continues after transplantation, the efficacy of transplantation is uncertain. We present our experience with foUowup of 9 patients who underwent transplantation for protoporphyric liver disease. Two patients died within 2 months of transplantation, one of complications from massive abdominal bleeding and the other from sepsis after small bowel perforations. The remaining 7 patients (3F, 4M with age range of 13 yrs to 38 yrs at transplantation) are alive at followup (14 mos to 8 yrs, mean 3.6 yrs). Two patients had skin burns as a result of exposure to operating room lights, and 3 had severe axona! neuropathies in the postoperative period requiring mechanical ventilation for 2.5 to 14 wks. Five had episodes of acute rejection which responded to therapy, and 4 had biliary tract complications. Five patients have returned to a good functional state, with liver chemistries normal at followup, and liver biopsies normal or showing only mild portal triad abnormalities. Red cell pp levels remain significantly elevated (1765 + 365 meg/dL, normal <65), but are markedly decreased compared to levels at the time of transplantation (5128 + 1655). The other 2 patients, both of whom had episodes of rejection, CMV infection, and biliary tract obstruction requiring endoscopic therapy, have had a recurrence of protoporphyric liver disease documented by abnormal chemistries and characteristic biopsy features 3 yrs and 5 yrs after transplantation. Thus liver transplantation can be done successfully in patients with protoporphyric liver disease, despite unique and serious postoperative complications, with survival rates comparable to those in the general transplant population. However, disease may recur in the new liver, particularly if there are several complications which cause cholestasis after transplantation.
175 HCV REINFECTION IN LIVER TRANSPLANTED RECIPIENTS ASSESSED BY HCV-AG EXPRF~SION IN LIVER CELLS. V Vary,as. K Krawczvnski. N Martfnez~ L Castells. H Allende. D Carson. R. Esteban J Guardia.Hospital Universitari Vail d "Hebron, Barcelona, Spain and Hepatitis Branch, DVRD/NICD, C.D.C and Prevention, Atlanta. Objective: This study was to evaluate the timing and the clinico- pathological significance of HCV-Ag expression in liver cells and to correlate with liver histology and HCV-RNA levels. Methods: Liver biopsy specimens were obtained from 42 HCV positive liver transplant (LT) recipients. Patients were divided into three groups: group A, 12 patients studied in the first month; group B, 13 patients studied between 1 and 6 months; group C, 17 patients studied between 6 and 18 months after LT. Expression of HCVAg was assessed by direct IF testing of frozen specimens and graded from 1 + (< 5% positive ceils) to 3 + ( > 20% positive cells). HCV RNA levels were measured by PCR teenique (Monitor-Roche). Liver lesions were classified into 3 groups: acute hepatitis, chronic hepatitis, and non-viral lesions. Results: In group A, HCVAg was found in 6 of 13 specimens (46%), and its expression was graded 1+ in 3, 2+ in 2 and 3+ in 1. Mean HCV-RNA level was 41,2 X 104 genomic copies/ml. In group B, HCVAg was found in 13 of 13 specimans(100%), and was graded 1+ in 1, 2+ in 1 and 3+ in 11. Mean HCV-RNA level was 418,8 x 104 genomic copies/mL In group C, HCV-Ag was found in 17 of 17 specimens (100%), and was graded 1+ in 5, 2+ in I and 3+ in 11. Mean HCV-RNA level was 448,3 x 104 ganomic eopies/ml. The differences in number of HCV-Ag positive cases, the mean intensity of HCvAg expression and the mean HCV-RNA levels between groups A and B (p=0.0008, p=0.0001, p=0.0036 respectively) and A and C (p=0.0008, p=0.005, pffi0.02 respectively) were statistically significant. Patients with acute or chronic hepatitis had significantly more HCVAg expression (13=0.007) and more HCV-RNA levels (p=0.02) than did patients with nonviral lesions. There were no differences in the intensity of HCVAg expression between acute hepatitis and those with chronic hepatitis. Conclusions: HCVAg is expressed in one-half of the patients in the first month after LT and its universally present thereafter in correlation with serum HCV-RNA levels.
HEPATOLOGYOctober 1995
174 S GENE ESCAPE MUTANTS AS A CAUSE OF HBV REINFECTION IN PATIENTS WHO RECEIVED HBIG POST-OLT. MG Ghanv. B Avola. FG Villamil*. R Gish#. S Roiter*. IM Vierlln~*. ASF Lok. Tulane Univ a n d VA Med Ctr, New Orleans; Cedars-Sinal/UCLA*, Los Angeles; Pacific Med Ctr#, San Francisco. Mutations involving the 'a' d e t e r m i n a n t of the HBV S gene resulting in loss of binding to anti-'a' has been reported in OLT patients (pt) who developed HBV reinfection after p r o p h y l a c t i c t h e r a p y with monoclonal anti-HBs. The occurrence of S 'escape' m u t a n t s in OLT pt who received polyclonal anti-HBs (HBIG) irnmunoprophylaxis has not b e e n examined. A/m : To d e t e r m i n e the p r e v a l e n c e of m u t a t i o n s in the 'a' d e t e r m i n a n t of the S gene in OLT p t who d e v e l o p e d HBV reinfection despite prophylaxis with HBIG. M e t h o d s : 5 pt who u n d e r w e n t OLT for HBV+, HDV- cirrhosis were studied. All received long-term HBIG. Paired sera pre- a n d post- OLT were analyzed by PCR amplification and direct s e q u e n c i n g of p a r t of the HBV S gene that encompasses the 'a' determinant. R e s u l t s : 4 (8096) pt h a d m u t a t i o n s that could potentially a l t e r the antigenicity of the 'a' d e t e r m i n a n t a n d 1 (20%) h a d wild-type sequence in the post-OLT samples. All pt h a d wild-type sequence pre-OLT. All 5 pt were reinfected while they were still on HBIG. Patient Nueleotide change Amino acid change 1 A-G, 342 thr-ser, 114 T-A, 401 phe-tyr, 134 2 ins AGG between ins of arg between nt 360 & 361 codon 120 & 121 3 C-T, 424 pro-ser, 142 A-C, 431 asp-ala, 144 4 T-G, 432 asp-flu, 144 5 nil nil C o n t u s i o n s : We found a high rate of m u t a t i o n s in the 'a' d e t e r m i n a n t of the HBV S gene in OLT pt who were r e i n f e c t e d while receiving HBIG suggesting that the b r e a k t h r o u g h infection was caused b y escape mutants. Further studies are ongoing to d e t e r m i n e if S escape m u t a n t s are also detected in pt who developed HBV reinfection after discontinuation of HBIG.
176 EFFECT OF DONOR HEPATITIS C SEROPOSITIVITY ON ALLOGRAFT INFECTION IN ORTHOTOPIC LIVER TRANSPLANTATION. P Martin. J Melinek. AB Shaked. C Shackleton, C Holt. K Olthoff. D Imagawa. RW Busuttil. Dumont = UCLA Liver Transplant Program, UCLA School of Medicine, Los Angeles, California The shortage of organ donors in a critical factor limiting access to orthotopic liver transplantation: Thus, it had been our policy to accept liver grafts from hepatitis C antibody positive (HCV+) donors. These grafts were transplanted in recipients suffering from end stage liver disease secondary to hepatitis C. Under extreme circumstances HCV+ organ donors had been accepted in rapidly deteriorating UNOS status IV candidates. The aim of this study was to examine the consequences of use of HCV+ donors in recipients with and without prior HCV infection. METHODS: The pattern of hepatitis C graft infection and disease was studied in 73 recipients undergoing OLT for HCV related end stage liver disease between 10/90= 12/93. These recipients received their grafts from HCV- donors (Group 1, n = 37), 0r HCV+ donors (Group 2, n = 17). The pattern of recurrence in these recipients was compared to the development of hepatitis C in previously non-infected recipients receiving a HCV+ graft (Group 3, n = 19). Active hepatitis C in long term survivors was diagnosed by persistently elevated liver enzymes and repeat liver biopsies showing features consistent with graft hepatitis. RESULTS: The incidence and time to the diagnosis of graft HCV were not different between groups (Table). Recurrence HCV Status Incidence days -4-SD Group 1: - donors, + recipients n = 37 9 (24%) 250 ± 182 Group 2: + donors, + recipients n = 17 5 (29%) 228 ± 159 Group 3: + donors, - recipients n = 19 3 (16%) 221 ± 170 p =0.67 Only one patient (Group 1) died of graft failure due to hepatitis C. The severity and pattern of de novo HCV infection in Group 3 was similar to that in patients with recurrent graft infection. CONCLUSIONS: I. In recipients with prior HCV infection receipt of a HCV+ donor did not alter the rate, onset or severity of graft reinfection compared to recipients of seronegative grafts. 2. In recipients without prior HCV infection transmission of HCV occurs leading to graft injury in a minority of such recipients. This data support the utilization of hepatitis C positive donor livers for hepatitis C+ recipients. However, transplantation of these grafts in the previously non-infeCted recipients should be avoided in non=critical circumstances.