Hepatitis C Virus Reinfection in Allografts After Orthotopic Liver Transplantation VOLKER KONIG,~ JURGEN BAUDITZ,'HARTMUT LO BECK,^ RAINER LUSEBRINK,3 PETER NEUHAUS,3 GERHARD BLUMI~LU~DT,~ WOLF OTTO BECHSTEIN,3 RUTHNEUHAUS,3 RUDOLFSTEFFEN3 AND UWE HOPF'

'Department of Internal Medicine, 2Department of Pathology and 3Department of Surgery, Universitiitsklinikum Rudolf Virchow-Charlottenburg, Freie Universitat Berlin, W-lo00 Berlin 19, Germany

From September 1988 to May 1991, 160 orthotopic liver transplantationswere performed in our hospital. Twentyfour patients had end-stagecirrhosis caused by chronic non-A,non-B hepatitis. Antibodies against hepati* C virus were documented before and after orthotopic liver transplantation in 13patients. Studies ueing the polymerase chain reaction demonstrated hepatitis C virus RNA in the serum and liver t h e of 17 patients (10of whom tested positive for hepatitis C virus antibodies) before orthotopic liver transplantation. " h u e samples taken from liver grafts during the operation were hepatitis C Virus RNA negative in eveq case. Ten of these 17 patients had positive hepatitis C virus RNA findings in serum and liver biopy specimens within the firet month after surgery. One patient died of M u m r sepsis 2 mo after orthotopic liver tramplantation. Another patient died of multiorgan failure 3 mo after a retransplantation. Two patients underwent r e t r q l a n t a t i o n for graft rejeetion at 2 and 3 mo, respectively. One year after orthotopicliver transplantation,hepatitis C virus RNA waa demomkrated in allograft biopsy specimensin 13 of 16 patients. Two patients remained hepatitie C virua RNA negative in repeated biopsies up to 12 mo. Mild portal andlobular hepatitis developed within 6 months of orthotopic liver transplantation in four patients and within 1 yr in five additional patients. The data suggest that panhtent hepatitis C Virus reinfects the allograft in moet cases, but the risk of acute organ damage caused by hepatitis C virus reinfection is low. (=Al Y l u M Y lSB~161137-1143.)

TABLE1. Major hietological criteria for hepatitie reinfection VB. acute rejection Hietological cllaugea ~~~

Portal inflammation Portal vein endotheliitis Acute cholangitis Piecemeal necroses Eosinophilic changes Focal necrosea Central vein endotheliitis

Hepetitis reinfection

Acate rejection

+

+ + +

~~

-

-

+ +

(

i-

( + )"

+ )" -

+

-

"Mainly indicative of hepatitis reinfection but may also occur in acute rejection.

TABLE2. Frequency of anti-HCVand HCV ELNA in eera h m 24 patienta who subsequently undewwent OLT for end-stage cirrhoeia c a d by NANB hepatitis Markers

hti-HCV podtive

HCV RNA positive HCV RNA negative

10 (42%)" 3 (13%)

hti-HCV UelptiVe

7 (29%) 4 (16%)

"Data expressed as no. of patients (percentage of whole).

immune globulin might reduce damage to the gr& caused by HBV reinfection (4). Recent developments have provided dmgnostic tests End-stage cirrhosis is one of the major indications for for infection with hepatitis C virus (HCV) (5). A orthotopic liver transplantation (OLT) (1).Most pa- first-generation test has documented antibody activity tients have chronic viral hepatitis, and reinfection of the against HCV in 70% to 80% of patients with chronic gn& is a potential complication in these cases. Previous non-A, non-B (NANB) hepatitis (6, 7).Additionally, the studies of virus reinfection after OLT were composed of polymerase chain reaction (PCR), with specific primers patients with HBV and hepatitis delta virus infections for HCV, has allowed direct demonstration of the virus (2, 3). Prompt treatment with HBs antibody hyper- (8-11). Results with this technique have shown that HCV infection is present in approximately 90% of patients with chronic NANB hepatitis (12). It has become apparent that positive HCV antibody Recsived February 7, 1992; accepted July 7, 1992. This work was supported by the Forschungeschwerpunkt"Hepatitis" of the (anti-HCV) findings do not necessarily imply a chronic me Univwnit&tJ3erh. HCV-carrier state because first-generation anti-HCV Addma5 reprint requeeta to: Volker Kijnig, M.D., Department of Internal Medicine,Univensit(itsl*' '' RudoVVihow, Spandauer D m m 130,W-1000 tests may produce false-positive results (13-16). Available data are few on clinical parameters, morBerlin 19, Garmany. 31/1/phological findings and results of anti-HCV and HCV 1137

1138

KONIG ET AL.

HEPATOLOGY

TABLE 3. Follow-upof serum ALT levels after OLT Months Ptter OLT

Patients

No.

AmW)

Sex

1

2

3

4

5

8

7

8

9

10

11

12

~~

1 2 3 40 5 6 7 8

sb 10 11 12 13 14 15 16 17

57 57 64 47 30 60 28 63 51 49 59 54 64 64 33 58 41

M F M F F M F F F F F F M F M F F

58 146 140 120 24 156 ND 32 180 20 159 24 32 34 172 40 94

40 26 20

36 20 18

26 22 30

36 66 26

24 36 28

22 32 26

24 56 34

28 44 24

24 44 32

26 40 34

28 40 30

22 40 108 196 ND 24

24 88 104 76

28 158 74 94

36 246 48 70

32 74 68 62

28 128 154 64

26 120 88 72

26 94 34 70

24 70 40 72

22 52 154 90

28 58 40 66

TR

TR

40 12 32

28 22 14 32 20 28 28 ND

36 68 10 36 10 28 24 178

24 38 16 32 12 74 36 86

60 36 20 24 20 60 44 60

94 46 22 34 14 44 38 D

ND 26 14 28 20 68 34 50

36 34 56 30 36 ND

84

24 22 24

162 76 74 22 40 24 22 22 16 26 28 26 14 14 12 44 80 50 44 48 40 N D N D 5 2 N

ND = No data available; TR = retransplantation was required because of severe graft rejection. Serum ALT levels are expressed as international units per liter. A normal ALT value is less than 50 IUL. OPatient died of sepsis caused by a Mucor infection 2 mo after OLT. *Patient died after retransplantation as a result of mdtiorgan failure.

PCR in cases of chronic HCV infection after OLT (3, 17-19). This study reports data from 24 patients undergoing OLT as treatment for end-stage cirrhosis induced by chronic viral hepatitis NANB. The PCR demonstrated preoperative HCV infection in 17 of these 24

patients (nos. 10 and 11)suffered severe graft rejection and underwent retransplantation at 2 and 3 mo, respectively. Serological Tests. Virus markers were assayed by commercial tests. Anti-HCV were determined with secondgeneration kits (Ortho Diagnostic Systems, Inc., Raritan,NJ), according to the manufacturer's instructions. c88eS. RNA Prepamtion and Rerterse knscription. HCV RNA was prepared by single-step isolation with a modification of PATIENTS AND METHODS acid guanidinium thiocyanate phenol chloroform extraction Patient Population. From September 1988 to May 1991, according to Chomczynski and Sacchi (20). Five microliters of 160 OLTs were performed in 155 patients at the Rudolf HCV RNA was preincubated with 0.6 pl (60 pmol) of Virchow University Hospital in Berlin. One-year survival is downstream primer NCR2, 2.0 pl of EDTA 0.2 mmoVL (pH currently 92%. In 55 cases OLT was performed for end-stage 8.01, 2.0 p1 of HEPES-HCl 10 mmol/L (pH 6.9) and 0.4 p1 Of cirrhosis associated with viral infection; 24 of these patients H,O for 2 min at 70" C. Reverse transcription was performed had chronic NANB hepatitis. The diagnosis was established by at 45" C for 90 min with 200 units (1 pl) of Moloney murine exclusion of HBV and other viral infections, of metabolic leukemia virus reverse transcriptase (M-MLV H- RT [superscript]; Bethesda Research Laboratories Life Technologies disorders and of autoimmune types of cirrhosis. All patients in this series were of German origin except for Inc., Gaithersburg, MD), 4 p1 of 5 x reverse transcriptase one who was Italian (no. 6). None of the patients had histories buffer consisting of Tris-HC1 50 mmol/L (pH 8.31, KC1 75 of transfusions, intravenous drug abuse, hemodialysis, hemo- mmol/L, M&l, 3 mmol/L, 2 pl of dithiothreitol10 mmol/L, 20 philia A or B, homosexual contacta or prostitution. The mode units RNasin (0.5 pl), 1p1 of dNTP-Mix 20 mmoVL (Promega of transmission of hepatitis NANB on the basis of patient Corp., Madison, WI)and 1.5 pl of H,O. All buffers except for history was classified as sporadic in all cases. the Tris and EDTA solutions used for RNA preparation were Patients received a standard immunosuppressive regimen made with diethyl pyrocarbonat+treated distilled H,O to including corticosteroids, cyclosporine, azathioprine and lym- inhibit RNase activity. All glassware used in the RNA phocytic antibodies. One patient (no. 17) participated in the preparation process was autoclaved and washed in diethyl European multicenter trial of FK 506 and received FK 506 and pyrocarbonate-treated water. PCR. After transcription of HCV RNA in HCV complesteroids. Follow-up in this report ranges from 6 to 24 mo. The first biopsy specimen was obtained during surgery after mentary DNA, two amplificationswere performed accordingto reperfusion of the graft (baseline biopsy). Serial biopsies were the nested primer principle (8). The oligonucleotide primers performed at 1wk and at intervals of 2 to 4 mo in most cases. NCR1, NCR2, NCR3 and NCR4 were derived from the highly Three patients (nos. 6 and 10 at 5 mo and no. 7 at 7 mo) conserved ( >99%) 5' noncoding region (9). Primer NCRl received additional immunosuppressive therapy because graft (sense),corresponding to the position 1-20, and primer NCR2 (anti-sense), corresponding to position 304-332 in the revised rejection was suspected. One patient (no. 4) died of sepsis caused by Mucor infection numbering system of Okamoto (lo), were used for the first 2 mo after OLT. Another patient (no. 9) died of multiorgan PCR directing the amplification of a 341 bp product. NCR3 failure 3 mo after OLT and after retransplantation. Two (sense), corresponding to position 10-31, and NCR4 (anti-

Vol. 16,No.5, 1992

HCV IN LIVER ALLOGRAFTS

1139

lil~1 . . Detection of HCV RNA in liver allografts by PCR. (A) Lane 1, 123 bp ladder; lanes 2 and 3, patient no. 1, 1 and 12 mo after transplantation; lanes 4 to 6,patient no. 6,1,3and 5 mo after transplantation; Lanes 7 to 9, patient no. 8,1,2and 3 mo after tranaphtation; lanes 10 to 12,patient no. 10,1,2and 6 mo after transplantation; lanes 13 and 14,patient no. 15, 1 and 3 m o after transplantation. (B)Lanes 1to 3,patient no. 16,1,2and 4 mo aRer transplantation; lane 4, H,O (control);lane 5,123bp ladder; and lanes 6 to 14,HCV RNA-negative control samples.

entire follow-up period. The remaining 11 patients demonstrated consistently negative findings in the anti-HCV test before and after OLT. Seventeen patients (71%)tested positive for HCV RNA before OLT, and 10 of 24 patients (42%) tested anti-HCV positive (Table 2). Ten of the 17 patients mentioned above (59%) were HCV RNA positive within 1 mo after OLT. Twelve of 17 patients (70.5%) were positive for HCV RNA at 4 mo, and 13 of 15 patients followed (87%) had positive findings 1 yr after OLT. Seven patients with negative findings for HCV RNA before OLT had consistently negative hdings during the entire follow-up period; three of these patients were anti-HCV positive. HCV PCR in the serum yielded the same results as liver graft HCV PCR in all m e s . Aminotransferase levels ranged between 10 and 246 IUL after OLT (Table 31, but no patient had clinical evidence of jaundice. RCVRNA in Liver Biopsy SampZes. Tissue samples from explanted livers were positive for HCV RNA in 17 of 24 cases (71%), confirming the results of mrum tests RESULTS in these patients. Tissue samples taken from a l l o g d b serologirel Data. Thirteen of 24 patients (54.5%) during the transplantation were HCV RNA negative in were anti-HCV positive before OLT and during the every case. HCV RNA was demonstrated in biopsy

sense),corresponding to position 271-296, were used for the second PCR a m p w n g a 287 bp product. Detection of amplification products was achieved by ethidium bromide staining in a 3% agarose gel (NuSieve 2% @?MC BioProducts, Rockland, ME] and agarose 1%). Throughout the whole study false-positive PCR results were avoided by strict application of the contamination prevention measures of Kwok and Higuchi (21). Hiatolqgiwl conditions. Routinely stained biopsy specimens were obtained from explanted livers, and additional biopsies were performed at follow-up examination for up to 24 mo. P d n - e m b e d d e d , coded specimens were stained with hematoqlin and eoain, Masson-Goldner, iron and a periodic acid4cMT reagent. For quantitation of histological changes, we used the numerical scoring system according to Knodell et al. (22) in biopsy samples with "hepatitis-like changes" (Table 1). The criteria for acute rejection were lymphohistioqhc infiltration with endothelial inflammation in portal and central veins, occasional piecemeal necrosis and lesions in bile duct epithelia (acutecholangitis) (Table 1).Acute rejection was not scored additionally.

KONIG ET AL.

1140

HEPATOLOGY

TABLE4. Follow-upof HCV RNA in allografts after OLT in 17 patients with chronic HCV infection and HCV RNA in the explanted liver Patients

NO. 1 2 3 4" 5 6 7 8

P ! 10 11 12 13 14 15 16 17

Month after OLT

m(~r) Sex

57 57

64 47 30 60 28 63 51 49 59 54 64

64 33 58 41

1

2

3

+

M F M F F M F F F F

-

+ + + + + + + + +

F F M

F M F F

TR

+ + +

+

TR

+

+

9

10

+ + +

+

+

+ + +

+

+

+

+

-

+ +

+ +

+

+ + +

-

+

+

12

+ +

-

+

11

+

-

+ +

8

t

-

+ + + +

7

6

+

-

-

5

4

TR = Retransplantation was required because of severe graft rejection; - = liver tissue sample from patient was negative for HCV RNA. "Patient died of sepsis c a d by a M m r infection 2 mo after OLT.

+ +

+ = liver tissue sample from patient was positive for HCV RNA,

bPatient died after retransplantation as a result of mdtiorgan failure.

TABLES. HAI (22) of liver tissue in 17 HCV RNA-positive patients before and after OLT." Patients

No.

Age*)

1 2 3 46 5 6 7 8

57 57 64 47 30 60 28 63 51 49 59 54 64

9" 10 11 12 13 14 15 16 17

64 33 58 41

Month after OLT Explanted liver t h e

12 16 13 13 14 14 21 13 21 9 14 13 13 15 13 16 21

1

4

3

2

AR 1 9 AR A R A R 1 A R A

6

6

A

8

9

10

11

12

1

7

6

8

6 1

R

1

l

A

R

2

CA 2

7

R

1

1

1 5 A R A R 1 A R A R A R A R 1 1 A R 8

1 8

1 4 1 3

2

1

6 2 3

3 3

7

9

3 6

CA 1 1

3

6

10

13

16

17

1

1

2 8

4 8 7

3

AR = Acute graft rejection; CA = acute cholangitis without rejection. Patients no. 10 and no. 11required retransplantation after severe graft rejection.

"Samples from the explanted livers and biopsy samples taken after OLT were both indexed. bPatient died of sepsis caused by a Mucor infection. 'Patient died aRer retransplantation as a reault of multiorgan failure. See Table 1for the histologid criteria of each group.

specimens from the graft within 1 mo in 10 of these 17 patients (59%) with positive HCV hdings (Fig. 1). Twelve of 17 patients (71%) tested positive at 4 mo, and 13 of 15 patients (87%) had HCV RNA in their grafts 1 yr after OLT (Table 4). Two of 15 patients (13%) (nos. 7

and 12)remained HCV RNA negative in multiple biopsy samples up to 1 yr after OLT. All patients with HCV reinfection of the graft remained HCV RNA positive during the entire observation period. Biopsy specimens from the graft were HCV RNA

Vol. 16, No. 5, 1992

1141

HCV IN LIVER ALLOGRAFTS

FIG. 2. Liver biopsy specimen from patient no. 2 taken 10 mo after OLT.Specimen shows hepatitis-like lymphocytic and hietiocytic portal and discrete lobular inflammation with peripolesis, piecemeal necroses furrow) and hepatocellular alteration (H& E; original magnification

x 260).

negative in all seven patients with negative HCV RNA findings in the resected liver. Correlation of the results of serum and liver graft HCV PCR did not reveal preferential infection of blood or liver tissue. We were not able to determine whether liver graft PCR became HCV RNA positive later than serum PCR or vice versa. HistologiccrZ Findinge. Pathological and anatomical examination of the explanted liver of 24 patients in this study demonstrated severe CAH with transformation to complete cirrhosis. The histological activity index (HAI) (22) is shown in Table 5 . Acute rejection with or without cholangitis was the only evidence of inflammation in the graft biopsy specimens obtained within the first month after OLT. Mild acute portal and lobular hepatitis with piecemeal necrosis was observed in three patients (nos. 2,11and 17) at 2 mo (Fig. 2). Three patients (nos. 6,10 and 15)had moderate chronic hepatitis of the viral type at 6 mo (Table 5). Subsequent biopsy specimens showed a less pronounced inflammatory reaction. Generally, earlier recurrence of HCV RNA in serum and liver grafts &r transplantation was more likely to be associated with histological iqjuqy, as is shown by the HAI (22) in Table 5 (nos. 5, 7, 12 and 15). Most patients (10 of 17; 59%) had early recurrence of HCV disease. Statistical analysis of HCV PCR results was not performed because the small number of patients did not permit statistical interpretation. Additionad Immunoeuppreseive Thempy. Three patients (nos.6 and 10 at 5 mo and no. 7 at 7 mo) received additional immunosuppressive therapy administered as prednisolone or methylprednisolone bolus for treatment of suspected graft rejection. Patients no. 6 and no. 7

received steroids because elevated aminotransferase levels suggested acute rejection. Patient no. 10 required retransplantation because of acute rejection 3 mo after the first OLT. Therefore steroid therapy was instituted promptly, after a slight increase in aminotransferases indicative of acute rejection. Additional steroid therapy led to a temporary decrease in the levels of aminotransferases and to an increase in the HAI wore (Table 5). As a consequence, liver histologid studies indicated HCV reinfection of the liver graft. Liver function tests ranged within normal limits throughout the entire observation period. Therefore HCV reinfection of the graft, rather than rejection, was the most likely cause of elevated liver enzyme levels. HCV reinfection probably was facilitated by steroid therapy. These considerations are valid for all three patients because both the HAI and HCV RNA were indicative of recurrent HCV disease. DISCUSSION

Data obtained with PCR documented infection of the graft after OLT in patients with persistent HCV infection. This finding concurs with the conclusions of other authors who have stated that HCV is a major cause of posttransplantation chronic hepatitis and that many of these infections may represent recurrent HCV disease (23). Reinfection was apparent within a few weeks in most cases, although definitive evidence appeared after several months in some patienta. At present it is unclear whether demonstration of the HCV genome in the graft by means of PCR represents viral replication in liver cells. Active viral replication within the graft cannot be differentiated from contamination of the graft with blood or blood cells. It is possible that latent HCV

1142

KONIG ET AL.

infection was present in some cases because hepatitis did not develop in some patients even though HCV RNA was found in the graft. The viral genome amplified from liver biopsy specimens might have originated in serum or in blood cells but not in hepatocytes. On the other hand, it is highly probable that patients with HCV genome in their blood also harbor HCV in their liver grafts, especially under immunosuppressive therapy after OLT. Tissue samples obtained immediately after implantation and reperfusion of the graft were HCV RNA negative in every case. Therefore we have no evidence that demonstration of HCV RNA in liver biopsy specimens during follow-up after OLT might be a result of contamination with HCV-infected blood. An in situ hybridization technique might be an approach to the whole question. Recently, Aria et al. (24)used in situ hybridization to show that the HCV genome was located predominantly in the nuclei of hepatocytes, mononuclear cells and sinusoidal cells in patients with chronic liver disease. HCV reinfection was accompanied by mild portal and lobular hepatitis in most patients. Severe acute hepatitis was not observed in a single case. These findings are in agreement with data reported by Martin et al. (3),who used first-generation anti-HCV tests as diagnostic markers of HCV infection. Our data indicate that persistent HCV infection is associated with chronic inflammation in most allografts, but progression seems to be slow. Blood transfusions during the operation are another potential cause of graft infection with HCV. However, we have not observed seroconversion from negative preoperative anti-HCV status to postoperative positive findings, which has been confirmed by other studies (3, 25). Specific screening for HCV with the anti-HCV ELISA test was introduced by our blood bank in January 1990.In addition to this measure, a careful blood donor recruiting procedure might be responsible for the much lower acquisition rate of HCV than that reported in other studies. In general, German blood donors are not paid for their donations. A recent study screening a total of 116,700 German blood donors with the anti-HCV ELISA showed that German blood donors constitute a group with low prevalence of HCV (26).After transplantation, loss of anti-HCV is frequent and acquisition is rare (25). Moreover, the amount of blood product exposure has not been identified as a risk factor predisposing patients to the development of hepatitis in the posttransplant period (27).More reliable data on this question will require follow-up studies after OLT in patients with negative preoperative HCV findings by PCR, in situ hybridization and anti-HCV tests of the second generation. The possibility of chronic virus infection in the donor has to be considered as a possible mode of HCV transmission. Pereira et al. (28)performed a retrospective study in 716 organ donors and found 13 who were positive for anti-HCV (1.8%). NANB hepatitis developed in 14 of 29 organ recipients (48%). HCV was the cause of posttransplantation liver disease in 12 of the 13 recipients (92%) for whom serum samples were

HEPATOLOGY

available. No apparent relation existed between the type of transplantation procedure and the risk of hepatitis, which was documented in two of the four liver graft recipients in the study. In our series we found no evidence of preoperative HCV infection of the donor organ. This aspect of transplantation will require more precise documentation in the future. Recent studies give some evidence that HCV is able to replicate in lymphocytes. Negative-stranded HCV RNA within lymphocytes of patients with chronic type C hepatitis has been demonstrated by PCR, indicating that transcription of the positive-stranded HCV RNA was under way in these cells (29).Therefore the cellular source of recurrent HCV disease after OLT is most likely represented by lymphocytes and mononuclear blood cells. Even though HCV reinfection rarely causes severe acute inflammation in the liver graft, evidence shows that chronic hepatitis will develop in most patients. Therefore it will be important to test potential prophylactic and therapeutic approaches to graft infection. In analogy to HBV reinfection, protective antibodies might be a valuable component of future treatment schedules. However, neutralizing anti-HCV have yet to be defined. Most patients are viremic when undergoing OLT. As a consequence,the liver graft is reinfected with HCV right from the start. For the future, steps have to be taken to reduce viremia to the lowest level possible before transplantation. Extrahepatic sites of infection might gain significance if it becomes possible to eradicate viremia successfully before transplantation. This procedure has not been attempted in the past, primarily because of the increased risk of leukopenia and severe infection in patients with advanced liver disease. Interferon (1FN)-a given at normal dose levels to these patients could further suppress the levels of leukocytes and thrombocytes, but the levels of IFN that could safely be given to patients at this time would be unlikely to suppress viremia. A way around this problem in the future might be to combine IFN-a with immunostimulatory drugs, such as granulocyte colony-stimulating factor. This combination would enable increased doses of IFN-a to be administered both to patients with advanced liver disease before OLT and to liver graft recipients given lifelong immunosuppressive treatment after OLT and thus decisively reducing the risks of leukopenia or infection. A recent study demonstrated a high rate of partial responses of chronic viral hepatitis by administration of IFN-a after successful liver transplantation (30).Further trials will be necessary to evaluate this problem. Acknowledgment: We thank Mr. K. H. Friedrich for his excellent technical assistance. REFERENCES 1. Van Thiel DH, Schade RR,Gavaler JS, Shaw BW Jr, Iwatsuki S, Starzl TE. Medical aspects of liver transplantation. HEPATOLOGY 1984;4(s~ppl):79-83. 2. Portmann B, O’GradyJ, Williams R. Disease recurrencefollowing

Vol. 16,No. 5, 1992

HCV IN LIVER ALLOGRAFTS

1143

hepatitis: pathogenetic factor or false-positive result? Lancet orthotopic liver transplantation. Transplant Proc 1986;18(suppl 1990;335:754-757. 4):136-143. 3. Martin P, Munoz SJ, Di Bisceglie AM, Rubin R, Waggoner JG, 17. Feray C, Samuel D, Thiers V, Gigou M, Pichon F, Bismuth A, Reynes M, et al. Reinfection of liver graft by hepatitis C Armenti VT, Moritz MJ, et al. Recurrence of hepatitis C virus virus (HCV) after liver transplantation. Analysis through PCR. infection after orthotopic liver transplantation. HEPATOLOGY 1991; J Hepatol 1991;13(suppl2):S27. 13:719-721. 4. Samuel D, Bismuth A, Serres C, Arulnaden JL, Reynes M, 18. Konig V, Bauditz J , Neuhaus P, Blumhardt G, Steffen R, Bechstein WO, Neuhaus R, et al. Follow-up of hepatitis C virus Benhamou JP, Brechot C, et al. HBV infection after liver (HCV) reinfection in liver allograft recipients. J Hepatol 1991; transplantation in HBsAg positive patients: experience with long 13(suppl2):S40. term immunoprophylaxis. Transplant Proc 1991;23:1492-1494. 5. Kuo G, Choo QL, Alter HJ, Gitnick GL, W e k e r AG, Purcell RH, 19. Poterucha J J , Rakela J , Lumeng L, Lee C-H, Taswell HF, Wieener RH. Diagnosis of chronic hepatitis C after liver tramplantation by Miyamura T, et al. An assay for circulating antibodies to a major the detection of viral sequences with polymerase chain reaction. etiologic virus of human non-A, non-B hepatitis. Science 1989; HEPATOLOGY 1992;15:42-45. 244:362-364. 6. Alter HJ,Purcell RH, Shih JW, Melpolder JC, Houghton M, Choo 20. Chomczynski P, Sacchi N.Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroformextraction. Anal QL, Kuo G, et al. Detection of antibody to hepatitis C virus in Biochem 1987;162:156-159. prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989;321:1494- 21. Kwok S,Higuchi R. Avoiding false positives with PCR. Nature 1500. 1989;339:237-238. 7. Tremolada F, Casarin C, Tagger A, Ribero ML, Realdi G, A lhrti 22. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW,et al. Formulation and application of a numerical A, Ruol A, et al. Antibody to hepatitis C virus in post-transfusion hepatitis. Ann Intern Med 1991;114:277-289. scoring system for assessing histological activity in asymptomatic 8. Garson JA, Tedder RS,B r i m M, Tuke P, Glazebrook JA, Trute chronic active hepatitis. HEPATOLOGY 1981;1:431-435. A, Parker D, et al. Detection of hepatitis C viral sequences in blood 23. Poterucha JJ, Rakela J , Ludwig J, Taswell HF, Wiesner RH. donations by "nested" polymerase chain reaction and prediction of Hepatitis C antibodies in patients with chronic hepatitis of unknown etiology after orthotopic liver transplantation. Transinfectivitg. Lancet 1990;335:1419-1422. plant Proc 1991;23(1 Pt 2):1495-1497. 9. Garson JA, Ring C, Tuke P, Tedder RS.Enhanced detection by PCR of hepatitis C virus RNA [letter]. Lancet 1990;336:878-879. 24. Nouri Aria KT, W e R, Alexander GJM,Byrne J , Portmann B, Eddleston ALWF, Williams R. Detection of HCV genome in the 10. Okamoto H, Okada S, Sugiyama Y, Yotsumoto S, Tanaka T, Yoshizawa H, Tsuda F, et al. The 5'-terminal sequence of the liver tissue using an in situ hybridisation technique. J Hepatol 1991;13(suppl2):S56. hepatitis C virus genome. Jpn J Exp Med 1990;60:167-177. 11. Ulrich PP, Romeo JM, Lane PK, Kelly I, Daniel LJ, Vyas GN. 25. Read AE, Donegan E, Lake J, Ferrell L, Galbraith C, Kuramoto IK, Zeldis JB, et al. Hepatitis C in patients undergoing liver Detection, mmiquantitation, and genetic variation in hepatitis C virus sequences amplified from the plasma of blood donors with transplantation. Ann Intern Med 1991;114282-284. 1609- 26. Caspari G, Beyer J, Richter K, Gerlich WH,Schmitt H. Prevalence elevated alanine aminotransferase. J Clin Invest 1990;86: of antibodies to recombinant hepatitis C virus protein C100-3and 1614. 12. Enomoto N, Takada N, Takase S, Takada A, Date T. Hepatitis C of elevated transaminase levels in blood donors from Northern Germany. Med Microbiol Immunol (Earl) 1991;180:261-272. virus RNA genome in plasma of patients with non-A, non-B hepatitis. Gastroenterol Jpn 1991;26:42-46. 27. Read AE, Donegan E, Lake J, Ferrell L, Galbraith C, Kuramoto 13. Ikeda Y, Toda G, Hashimoto N, Kurokawa K. Antibody to IK, Zeldis JB, et al. Hepatitis C in liver transplant recipients. superoxide dismutase, autoimmune hepatitis and antibody tests Transplant Proc 1991;23(1 Pt 2):1504-1505. 28. Pereira BJG, Milford EL, Kirkman RL, Levy AS. Transmission of for hepatitis C. Lancet 1990;335:1345-1346. 14. Theilmann L, Blazek M, Goeser T, Gmelin K, Kommerell B, Fiehn hepatitis C virus by organ transplantation. N Engl J Med W. False positive anti-HCV tests in rheumatoid arthritis. Lancet 1991;325:454-460. 29: Goeser T, Miiller H, Padron G, Pfaff E, Hoffman WJ, Kommerell 1990;335: 1346. 15. Boudart D, Lucas JC, Muller JY, Le Carrer D, Planchon B, B, Theilmann L. Hepatitis C virus replication [letter]. N Engl J Harouweau JL. False positive hepatitis C virus antibody tests in Med 1992;326:65-66. 30. Wright HI, Gavaler JS, Van Thiel DH. Preliminary experience paraproteinaemia. Lancet 1990;336:63. 16. McFarlane IG, Smith HM, Johnson PJ, Bray GP, Vergani D, with alpha-2binterferon therapy of viral hepatitis in liver Williams R. Hepatitis C virus antibodies in chronic active allograft recipients. Transplantation 1992;53:121-124.

Hepatitis C virus reinfection in allografts after orthotopic liver transplantation.

From September 1988 to May 1991, 160 orthotopic liver transplantations were performed in our hospital. Twenty-four patients had end-stage cirrhosis ca...
720KB Sizes 0 Downloads 0 Views