De novo hepatitis B infection acquired during liver transplantation

Transcription

1 Q JMed 2001; 94:271±275 De novo hepatitis B infection acquired during liver transplantation P.J. GOW and D.J. MUTIMER From the Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, UK Received 8 January 2001 and in revised form 15 March 2001 Summary Although the use of donor organs from patients negative for hepatitis B surface antigen HBsAg) but positive for hepatitis B core antibody HBcAb) is well known to have the potential to transmit hepatitis B to the recipient, routine screening of organ donors for HBcAb is not yet implemented in the UK. We investigated whether current organ donor screening for hepatitis B infection is effective in preventing de novo hepatitis B infection after liver transplantation. The database of the liver transplant unit at the Queen Elizabeth Hospital, Birmingham, was searched for all cases of de novo hepatitis B after liver transplantation between January 1982 and July Four cases were identified from a population of %) adult liver transplant recipients. In all cases, the likely source of hepatitis B in the recipient was the donated organ. De novo acquisition of hepatitis B after liver transplantation occurs within the UK. This problem is likely to be resolved by the institution of HBcAb testing in all liver donors. Continuing the current practice in the UKof incomplete donor hepatitis B testing HBsAg serology only) can no longer be justified. De novo acquired infection has potentially life-threatening implications to the liver recipient and their contacts. Introduction Fortunately, de novo acquisition of hepatitis B associated with liver transplantation is an uncommon occurrence. Most reported cases have resulted from the use of hepatitis B surface antigen HBsAg) negative, hepatitis B core antibody HBcAb)- positive liver donors for HBsAg-negative, HBcAbnegative recipients. 1,2 As the risk of transmission of hepatitis B from these liver donors is now well recognized, it has become practice in many countries to use these livers only for selected recipients. Suitable recipients include HBsAg-positive patients who will receive prophylaxis against hepatitis B reinfection), recipients with natural immunity HBsAg-negative, HBcAb-positive), and recipients with urgent and immediate need for transplantation usually fulminant hepatic failure). In the UK, routine screening of organ donors for hepatitis B involves testing for HBsAg only. Donor hospitals may be requested to check the HBcAb status of the donor, but many are unable to comply with this request during unsocial hours. Donors that are HBsAg-negative but HBcAbpositive may not be identified, and the donor liver poses a potential infectious threat to the recipient. Compared with most countries, the population prevalence of natural immunity to hepatitis B in the UK is low. The scale of the problem of de novo acquisition of hepatitis B following liver transplantation in the UK has not previously been examined. We therefore undertook a retrospective study of adult patients undergoing liver transplantation at the Queen Elizabeth Hospital, Birmingham, between 1982 and We aimed to identify patients with de novo hepatitis B infection, its likely source and the clinical consequences. Address correspondence to Dr D.J. Mutimer, Liver and Hepatobiliary Unit, Third Floor, Nuffield House, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH. david.mutimer@university-b.wmids.nhs.uk ß Association of Physicians 2001

2 272 P.J. Gow and D.J. Mutimer Methods The database of the liver transplant unit at the Queen Elizabeth Hospital, Birmingham, was searched to identify adult patients suffering from de novo hepatitis B infection after transplantation from January 1982 until July The database of the liver transplant unit holds the results of pre-transplant hepatitis B serology and post-transplant liver histology reports on all transplanted patients. Prior to transplantation all potential recipients are screened for hepatitis B with serological testing for HBsAg and HBcAb. In addition, from January 1982 until January 1996, all liver transplant recipients underwent a protocol annual liver biopsy. From January 1996, this protocol was modified to the following: all patients transplanted for viral hepatitis and seronegative fulminant hepatic failure continue to undergo annual liver biopsy. Patients transplanted for alcohol-related liver disease, primary biliary cirrhosis and primary sclerosing cholangitis undergo liver biopsy 1, 3, 5 and 8 years after transplantation. Patients transplanted for other indications undergo liver biopsies on years 1 and 3, and then every 3 years. All liver biopsy specimens are stained with orcein and immunoperoxidase to detect HBsAg. Specimens in which HBsAg is detected are also stained with immunoperoxidase to identify HBcAg. In addition, routine investigations for unexplained abnormalities of liver function tests in posttransplant patients include testing for antibodies to hepatitis C, hepatitis C virus RNA, HBsAg, autoantibodies, liver ultrasound and liver biopsy. Although the protocols described may not detect all cases of de novo hepatitis B infection, it seems likely that few cases would escape detection. Organ donor screening for hepatitis B infection requires testing for HBsAg only. Since 1997, it has been the practice of local organ procurement co-ordinators to request donor hospitals to supply the HBcAb status of organ donors. However, the test is not mandatory, and is not available during unsocial hours in many hospitals. At present July 2000) the HBcAb status is known prior to transplantation of the donor liver in approximately 40% of cases personal communication, donor liver transplant co-ordinators, Queen Elizabeth Hospital). Results In total, 1354 adults received one or more liver transplants at the Queen Elizabeth Hospital between January 1982 and July Sixty-three HBsAg-positive recipients were detected during our search, and have been excluded from further analysis. Four patients with de novo hepatitis B infection after liver transplantation were identified. The clinical details of the individual cases are summarized below. Patient 1 In 1990, a 48-year-old lady underwent liver transplantation for cirrhosis secondary to hepatitis C. Prior to transplantation, serological testing for HBsAg and HBcAb were both negative. Liver biopsy performed in 1993 for mildly abnormal liver function tests revealed widespread staining for HBsAg and HBcAg. Serology subsequently confirmed chronic hepatitis B infection in the patient with positive HBsAg and hepatitis B e antigen HBeAg). The donor was known to be HBsAgnegative. There was no stored donor serum to assay for HBcAb. Apart from organ transplantation, the patient had no identified risk factors for acquisition of hepatitis B infection. In 1993, and with subsequent annual biopsies, liver histology showed no significant inflammatory activity. Therefore, no hepatitis B treatment was initiated. In August 1998, the patient presented with severe abdominal pain. Laparotomy was performed to exclude appendicitis. Intraoperatively, a caecal carcinoma was discovered in addition to multiple hepatic metastasis. A right hemicolectomy was performed. The patient subsequently died of metastatic colonic carcinoma. Patient 2 In 1993, a 28-year-old man was transplanted for fulminant seronegative hepatitis non-a, non-b, non-c hepatitis). A second transplant was performed 3 weeks later for refractory acute cellular rejection. The recipient's pre-transplant serology was negative for HBsAg and HBcAb. In late 1994, 9 months after his second transplant, the patient became jaundiced and a liver biopsy was performed. This revealed severe ductopenia consistent with chronic rejection, normal architecture, no inflammatory activity and strong staining for HBcAg and HBsAg. Serology confirmed chronic hepatitis B infection in the patient. Hepatitis B DNA titre was 439 pg/ml Genostics, Abbott). No anti-viral treatment was initiated. The donor of the first liver was negative for HBsAg at the time of donation, but was not screened for HBcAb. Subsequent testing of stored serum revealed the donor to be HBcAb and HBsAb-positive. The second liver donor was negative for HBsAg; no stored serum was available to assay for HBcAb.

3 De novo hepatitis B from liver transplantation 273 A third transplant was performed in February 1995 for chronic rejection. Unfortunately the patient died, due to primary non-function of the graft. Patient 3 In 1994, a 25-year-old male developed ascites and encephalopathy on a background of cirrhosis secondary to autoimmune hepatitis. In late 1994, the patient underwent a liver transplant and made an uneventful recovery. Prior to transplantation the patient was HBsAg and HBcAb-negative. The organ donor was tested at the time of transplantation, and was known to be negative for HBsAg but positive for HBcAb; despite this serology, the organ was used. In late 1997 and early 1998, the patient developed recurrent cholangitis secondary to an anastamotic biliary stricture. Therefore, in June 1998, a biliary reconstruction was performed. Liver biopsy at the time of the procedure revealed cirrhosis with biliary features and strong staining for HBcAg and HBsAg. Subsequent serology confirmed the diagnosis of hepatitis B in the patient HBsAgand HBeAg-positive). He had high levels of viral replication with hepatitis B DNA titre 407 pg/ml Genostics, Abbott). Postoperatively, liver biochemistry returned to normal. Repeat liver biopsy in January 1999 revealed some improvement with only moderate hepatic fibrosis and minimal inflammatory activity. Further biopsy performed in April 2000 revealed advanced fibrosis and moderate inflammatory activity. The progression was attributed to hepatitis B infection, and treatment with lamivudine was commenced. Patient 4 In March 1999, a 52-year-old farmer underwent liver transplantation for primary sclerosing cholangitis. His liver disease had presented 12 months earlier, with life-threatening variceal haemorrhage requiring a TIPS shunt. Pre-transplant serology confirmed that he had never suffered from hepatitis B infection: HBsAg and HBcAb were negative. In May 2000, the patient's wife presented to her General Practitioner with jaundice, and was found to be suffering from acute hepatitis B. Subsequent serology revealed that her husband, the liver transplant recipient, was a carrier of hepatitis B. The liver donor was negative for HBsAg at the time of donation, but was not screened for HBcAb. Subsequent testing of stored serum confirmed that the donor was HBcAb-positive. During brief follow-up, liver biochemistry of the patient has remained normal. Liver biopsy has yet to be performed. Discussion These four cases describe the de novo acquisition of hepatitis B during liver transplantation in the UK. In all cases, the likely source is unrecognized hepatitis B infection of the donor liver, documented in donor serum in three patients but not available in the fourth. In one case the organ donor was known to be HBsAg-negative but HBcAb-positive. This organ was transplanted into a hepatitis-bnegative recipient without prophylaxis, as in 1994 the infectious risk of such donors was not appreciated. In patients transplanted for hepatitis-b-related liver disease, reinfection of the graft is almost universal if prophylactic therapy is not commenced. 3,4 Frequently, significant liver dysfunction ensues and rapid progression to graft failure may occur. It has been suggested that the outcome of de novo hepatitis B is more benign than that observed for patients with recurrent hepatitis B infection. 2,5 This may reflect differences in the immune response to infected cells in patients with de novo versus recurrent graft infection, although that hypothesis has not been examined. Follow-upfor two of our four patients was brief one died because of chronic rejection during limited follow-up, the other was infected recently). For the other two patients, rapid progression to graft failure was not observed, though antiviral therapy was commenced for one patient. De novo infection may, however, still result in severe graft damage. 2 The four cases described are taken out of a population of 1354 adult patients transplanted in our unit since These cases therefore comprise 0.3% of the transplanted population. Although the database search for patients with de novo hepatitis B is likely to be complete, the disease may be clinically quiescent, and it is quite possible that there are further undetected hepatitis-binfected patients within our post-transplant population. It seems likely that other UK liver transplant units will have experienced a similar incidence of de novo hepatitis B infection. The testing of donor serum for HBsAb, in addition to HBcAb, is not helpful in determining the risk of de novo transmission of hepatitis B to liver recipients. Donors who are HBsAg-negative and HBcAb may transmit hepatitis B regardless of the donor's HBsAb status. 2,6 It seems possible that the acquisition of hepatitis B from donor livers might be prevented by vaccination of potential recipients. Unfortunately, vaccination against hepatitis B of patients with advanced liver disease is usually unsuccessful. In one study, 57 liver failure patients were given three doses of recombinant hepatitis B vaccine, but only nine 16%) developed

4 274 P.J. Gow and D.J. Mutimer a significant antibody response. 7 Also, patients who have received full courses of vaccination against hepatitis B and who are HBsAb-positive but HBcAb-negative) prior to transplantation have been among those that have acquired de novo hepatitis B infection from a HBcAb-positive donor. 5 Thus vaccine-induced HBsAb may provide protection from hepatitis B infection by an innoculum of virus particles in the immunocompetent patient, but may not protect against reactivation of hepatitis B virus from a transplanted liver. Due to shortages in the number of donor organs, living related liver transplants are accounting for an increasing number of transplants throughout the world. Historically, the difficulties in obtaining full donor hepatitis B serology from cadaveric donors can be appreciated, due to the limitations in performing tests `out of hours'. This constraint should not apply to donor screening of living related transplants. Uemoto et al. described their experience with de novo acquisition of hepatitis B in living related donors. 8 From 1990 to 1995, HBcAb-positive donors were not excluded as candidates. Of 171 transplants performed, 16 were from HBcAb-positive donors, and 14 recipients became HBsAg-positive. This experience gives a good idea of the magnitude of the risk associated with the use of HBcAb-positive livers. From 1995 to 1996, the same groupexcluded HBcAb-positive donors unless they were the only possible donor candidates. Of 56 transplants performed in this period, three were from HBcAb-positive donors. With the addition of prophylactic treatment with hepatitis B immunoglobulin, significant infection was prevented. Concern that donor testing for HBcAb will result in wastage of organs is unfounded. When a HBsAg-negative, HBcAb-positive donor is identified, the liver could be used for a hepatitis-binfected recipient, for a naturally-immune recipient, or for an urgent patient not previously exposed to hepatitis B. Thus it is extremely unlikely that the liver from a HBcAb-positive donor would ever be wasted. In the instance where the liver was used by an urgent hepatitis-b-negative recipient, an appropriate prophylactic strategy lamivudine and/or hepatitis B immunoglobulin) 8,9 would be implemented to prevent clinically significant hepatitis B reactivation and infection. Transplant teams should be supplied with more detailed hepatitis B serology from all liver donors. If donor HBcAb status cannot be checked before the liver is used for transplantation, then it must be checked for HBcAb when routine laboratory work resumes the next day. In the instance when a liver from a HBcAb-positive donor is transplanted into a HBcAb-negative recipient, appropriate prophylaxis can be commenced to prevent reactivation of hepatitis B. The risk of hepatitis B acquisition from HBcAbpositive organ donors varies with the type of organ that is used in transplantation. The risk of transmission of hepatitis B to a liver transplant recipient is high, between 60% and 80%. 10 Rates of transmission to kidney transplant recipients are much lower. In one study, only one of 42 renal transplant recipients from HBsAg-negative HBcAb-positive donors became infected with hepatitis B, 6 and none of 27 in a second series. 11 The risk to cardiac transplant recipients also appears low, with none of seven patients infected in one small published experience. 6 Thus, the risk of transmission of hepatitis B from a HBsAg-negative HBcAb-positive kidney or heart donor to a recipient appears small. Therefore the use of these organs is justified for non-immune non-liver recipients without the need for post-transplant prophylaxis. The risk of de novo hepatitis B infection in liver transplant recipients who receive organs from HBsAg-negative, HBcAb-positive donors is now well recognized. Testing donors for HBcAb is likely to resolve this problem. De novo acquired infection has potentially life-threatening implications to the liver recipient and their contacts. References 1. Radomski JS, Moritz MJ, Armenti VT, Munoz SJ. Hepatitis B transmission from a liver donor who tested negative for hepatitis B surface antigen and positive for hepatitis B core antibody. Liver Transpl Surg 1996; 2:130±1. 2. Douglas DD, Rakela J, Wright TL, Krom RA, Wiesner RH. The clinical course of transplantation-associated de novo hepatitis B infection in the liver transplant recipient. Liver Transpl Surg 1997; 3:105± Todo S, Demetris AJ, Van Thiel D, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease. Hepatology 1991; 13:619± O'Grady JG, Smith HM, Davies SE, Daniels HM, Donaldson PT, Tan KC, Portmann B, Alexander GJ, Williams R. Hepatitis B virus reinfection after orthotopic liver transplantation. Serological and clinical implications. JHepatol 1992; 14:104± Fabia R, Levy ME, Crippin J, Tillery W, Netto GJ, Aguanno J, Dysert P, Goldstein RM, Husberg BS, Gonwa TA, Klintmalm GB. De novo hepatitis B infection after liver transplantation: source of disease, incidence, and impact. Liver Transpl Surg 1998; 4:119± Wachs ME, Amend WJ, Ascher NL, Bretan PN, Emond J, Lake JR, Melzer JS, Roberts JP, Tomlanovich SJ, Vincenti F. The risk of transmission of hepatitis B from HBsAg ), HBcAb q), HBIgM ) organ donors. Transplantation 1995; 59:230±4. 7. Chalasani N, Smallwood G, Halcomb J, Fried MW, Boyer TD. Is vaccination against hepatitis B infection

5 De novo hepatitis B from liver transplantation 275 indicated in patients waiting for or after orthotopic liver transplantation? Liver Transpl Surg 1998; 4:128± Uemoto S, Sugiyama K, Marusawa H, Inomata Y, Asonuma K, Egawa H, Kiuchi T, Miyake Y, Tanaka K, Chiba T. Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living related liver transplants. Transplantation 1998; 65:494±9. 9. Dodson SF, Bonham CA, Geller DA, Cacciarelli TV, Rakela J, Fung JJ. Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-hbc positive donors. Transplantation 1999; 68:1058± Dickson RC, Everhart JE, Lake JR, Wei Y, Seaberg EC, Wiesner RH, Zetterman RK, Pruett TL, Ishitani MB, Hoofnagle JH. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Gastroenterology 1997; 113:1668± Satterthwaite R, Ozgu I, Shidban H, Aswad S, Sunga V, Zapanta R Jr, Asai P, Bogaard T, Khetan U, Mendez RG, Mendez R. Risks of transplanting kidneys from hepatitis B surface antigen-negative, hepatitis B core antibody-positive donors. Transplantation 1997; 64:432±5.