The shortage of cadaveric donor organs has led to worldwide acceptance of living donor liver transplantation (LDLT) in adult patients. For each patient, there are usually a very limited number of available living donor candidates. Many of them may not be optimal due to inappropriate interlobular volume, excessive hepatic steatosis, or other medical conditions.1, 2 Although various innovative surgical techniques have been devised to overcome the anatomical variations of living donor livers, in a previous report only a small proportion of volunteers who had undergone living donor workup actually donated partial liver grafts.3
Among the first-line screening tests to exclude inappropriate liver donors are assays of serum hepatitis B surface antigen (HBsAg). Transplantation of an HBsAg-positive liver graft always induces intractable hepatitis B virus (HBV) reactivation or de novo hepatitis, both of which may lead to early graft failure. Prior to 2000, there was only 1 report of transplantation of an HBsAg-positive cadaveric donor liver graft, and it was performed in the United States.4 Recently, 3 similar cases were reported from Italy.5 All 4 recipients of HBsAg-positive donor liver grafts were followed up for 10 months to 2 yr and were alive at the time of the reports. These small studies with interim outcomes are not sufficient, however, to draw any definite conclusions.6
Although donor HBsAg positivity has been an absolute contraindication for liver donation in our institution, 1 such liver was used for LDLT in 2000. The recipient is still alive to date, despite the recurrence of HBV. The living donor is also doing well, without any clinical problems except HBsAg positivity. Here we describe the full 5-yr posttransplantation sequences of this recipient, focusing on viral marker status, such as response to antiviral therapies.
A 43-yr-old male patient with acute exacerbation of HBV-associated liver cirrhosis was transferred to our institution in 2000. He had been diagnosed with hepatitis B 13 yr previously. He revealed evidence of massive ascites and acute renal failure, with hepatorenal syndrome. His viral marker status is summarized in Table 1. He was put on the waiting list for a cadaveric donor liver with the highest priority for 14 days, but no cadaveric donor was available through the Korean Network for Organ Sharing. Despite intensive supportive care, the patient's condition worsened, but there was no living donor candidate who could meet the general selection criteria of our institution.7
Table 1. Preoperative HBV Viral Marker Status of the Recipient and Living Donor
Abbreviations: HBsAg, hepatis B surface antigen; anti-HBs, antibody to HBsAg; anti-HBc IgG, hepatitis B core antibody immunoglobulin G; HBeAg, HBV e antigen; HBV, hepatitis B virus.
Anti-HBs titer was 21.9 IU/L.
Checked using hybridization capture assay: quantitative value was not available.
A 27-yr-old cousin of the patient who underwent living donor workup was excluded as a donor candidate due to concurrent positivity of HBsAg and antibody to HBsAg (anti-HBs). Donor viral marker status is also summarized in Table 1. Since the patient could not survive without immediate liver transplantation (LT), this cousin was considered again as a donor candidate. Liver imaging studies using dynamic computed tomography and Doppler ultrasonography showed no significant anatomical variations or abnormalities. Right lobe volume was estimated as 61% of the whole liver volume on computed tomography volumetry. Preoperative liver needle biopsy did not show any noticeable pathologic change. His liver function profiles were within the normal range (serum aspartate transaminase 16 IU/L, alanine transaminase 12 IU/L, total bilirubin 0.9 mg/dL, and prothrombin time 1.1 international normalized ratio). The donor candidate was diagnosed as an HBV carrier, and concurrent positivity for HBsAg and anti-HBs was thought to result from coinfection with different HBV subtypes or HBV S mutants.8, 9
After informed consent on potential donor risk and poor recipient prognosis was obtained, LDLT of the right lobe was performed in October 2000. During mini-laparotomy at the initiation of the donor operation, the liver appeared grossly normal. Intraoperative liver wedge biopsy revealed no evidence of steatosis or cholestasis and only mild portal inflammation. Aside from HBsAg positivity, there was no evidence of overt HBV infection. Routine surgical procedure was applied for procurement of the right lobe graft. After harvesting, the right lobe graft weighed 590 gm, and the graft-to-recipient weight ratio was 0.9. Middle hepatic vein branches were reconstructed using autologous saphenous vein grafts. Duct-to-duct reconstruction was performed.
Following LDLT, the recipient recovered slowly but progressively. Renal failure was managed by continuous veno-venous hemodialysis and avoidance of nephrotoxic drugs. Steroid and mycophenolate mofetil were administered until the patient's renal function recovered.
During the anhepatic phase, 40,000 IU of hepatitis B immunoglobulin (HBIG) was infused. During the first week, the patient was infused with 20,000 IU/day HBIG, but the anti-HBs titer was not increased to 100 IU/L and serum HBsAg levels became positive. The HBIG dose was increased to 40,000 IU/day, and lamivudine was added after the second week, but the patient still remained HBsAg-positive. Famciclovir was added and the dose of HBIG was reduced to 2,000 IU/day. HBIG was continued only for the first 6 months. HBsAg and hepatitis B e antigen were continuously positive, but HBV deoxyribonucleic acid (DNA) remained negative on hybridization assay (lower detection limit is known as 105 copies/mL). After 15 months, biopsy-proven acute cellular rejection occurred, so immunosuppression using cyclosporine was augmented. The biopsy showed equivocal evidence of pathologic changes resulting from hepatitis B infection. The patient's serum became positive for HBV DNA, so interferon alpha therapy was begun (Fig. 1). The concentration of serum HBV DNA decreased, but remained positive for a while. At 28 months, his liver function profile again deteriorated, and a liver biopsy was performed under suspicion of acute rejection. Pathologic examination revealed chronic HBV infection with severe periportal activity, moderate lobular activity, and septal fibrosis, with the condition close to precirrhosis. The patient was subsequently treated with low immunosuppression without a change in antiviral agents (lamivudine and famciclovir). After that, his HBV DNA became negative again and liver function profiles became stabilized. At 44 months posttransplantation, adefovir dipivoxil was added according to the guideline approved by American Association for the Study of Liver Diseases.10, 11 This agent was also proven to be very effective for HBV recurrence in our preliminary study.12 After 3 months' use of lamivudine and adefovir, his hepatitis B e antigen status converted to seronegative. After that, the viral markers of HBsAg-positive, hepatitis B e antigen-negative, and HBV DNA-negative status continued for 17 months to date. Recent checkups using the polymerase chain reaction method revealed HBV DNA-negative results. The course of these treatments is summarized in Figure 1. The recipient remains alive 64 months after LDLT.
The donor viral markers remained unchanged at the 1-yr routine follow-up. During a recent follow-up, he showed no evidence of active hepatitis B, but his viral marker status remained HBsAg-positive. Serum anti-HBs status was not examined incidentally during follow-up. We had intended to follow the donor on a lifelong basis, but his lack of compliance to clinic visits made it difficult. His latest follow-ups were done through telephone interviews and local clinic visits.
LT, liver transplantation; LDLT, living donor liver transplantation; HBsAg, hepatitis B surface antigen; anti-HBs, antibody to HBsAg; HBV, hepatitis B virus; HBIG, hepatitis B immunoglobulin; DNA, deoxyribonucleic acid.
Extreme scarcity of cadaveric organ donors has made LDLT the primary type of LT in Korea. Only 42 cadaveric donor LTs were performed nationwide in Korea during the year of 2000, making the likelihood that our patient would have received one of these livers quite low considering the blood group compatibility.13
The prevalence of HBV in the general Korean population is high, with 40% of living liver donors in our institution being hepatitis B core antibody-positive.14 Most of hepatitis B core antibody-positive grafts were implanted into HBV-positive recipients, but some were implanted into HBV-negative recipients due to the limited availability of living donors. The risk of de novo hepatitis from an hepatitis B core antibody-positive liver graft was effectively prevented by treatment with HBIG or antiviral agents.15 Anti-HBs positivity of the recipient itself, however, did not prevent occurrence of de novo hepatitis from hepatitis B core antibody-positive liver graft.16
The risk to a recipient of an HBsAg-positive liver graft is definitely much higher than to a recipient of an hepatitis B core antibody-positive liver. Thus, implantation of an HBsAg-positive graft has been historically prohibited. The recent development of potent antiviral agents that suppress HBV replication may reduce the risks associated with an HBsAg-positive liver graft. The favorable outcome observed in the first reported recipient of an HBsAg-positive liver graft may have been exceptional because the patient spontaneously became negative for HBsAg and HBV DNA.4 In contrast, the clinical progression in the 3 Italian patients was very similar to that of our patient.5
We utilized every available anti-HBV treatment, including high-dose HBIG, lamivudine, famciclovir, interferon alpha, and adefovir dipivoxil, to prevent progression of HBV infection in our patient. At first, we used high-dose HBIG monotherapy because it had been very effective for HBsAg-positive recipients and, at that time, lamivudine was used only for recurred HBV recipients in our institution. However, high-dose HBIG monotherapy was ineffective,4, 5 with a dosage of 20,000-40,000 IU per day unable to increase the serum anti-HBs titer to over 100 IU/L and unable to prevent the patient from becoming serum HBsAg-positive. The addition of lamivudine stabilized the serum concentrations of aspartate and alanine transaminases. During the third stage of treatment, after seroconversion to hepatitis B e antigen positivity, we added famciclovir, which has anti-HBV activity.10, 17 The patient's serum became positive for HBV DNA after strong immunosuppression therapy to control acute rejection, after which he was treated with interferon alpha.17 Finally, this patient was treated with a combination of adefovir dipivoxil and lamivudine,11, 18 after which his liver function stabilized, a condition that has lasted for at least 20 months. The clinical progression of this patient seems to be very similar to that of HBV-positive recipients of HBsAg-negative liver grafts who experience HBV recurrence despite HBV prophylaxis. In our series of 486 HBV-associated LTs up to the end of 2003, 17 patients revealed HBV recurrence despite high-dose HBIG prophylaxis (our unpublished data). As the effect of lamivudine was not uniformly reliable, a few patients died from progression of fibrosing cholestatic hepatitis. Following the introduction of adefovir dipivoxil, we have not experienced any further deaths.12, 19 Our result provides further evidence that combined prophylaxis with lamivudine and adefovir may be the best way to manage escape mutants and hepatitis recurrence.5
Concurrent positivity for HBsAg and anti-HBs has been observed in the uncommon condition of coinfection with different HBV subtypes, HBV S mutants, or “a” epitope variants.8, 20, 21 Low titers of heterotypic antibody, however, are not associated with changes in the clinical course of HBV infection.20 HBV subtypes or gene mutations were not studied in the living donor of this case.
Before deciding whether to perform this operation, we were very anxious about the safety of the living donor. We would have canceled the donor operation if there had been any clinical evidence of HBV infection during preoperative workup or mini-laparotomy. As the right-left liver volume proportion of the donor was favorable, the size of the remnant left lobe appeared to be sufficiently large to not affect donor safety. The natural course of disease in HBV carriers could not exclude the possibility that this individual will progress to active hepatitis in the future.10 Thus, we had a serious ethical dilemma between the possible future risk to the donor after liver donation and our wish to save the recipient. To date, LDLT has prolonged the life of the patient for at least 5 yr, and there was no detrimental consequence to the donor. We emphasize again that present case is definitely a very unusual situation not to be generalized at all because life-long donor safety is not fully guaranteed. Contrary to LDLT, there is no necessity to worry about donor safety in cadaveric donor LT. We think that further attempts using an HBsAg-positive liver graft will be confined to only cadaveric donor LT.
In conclusion, our result implicates that the recipient of an HBsAg-positive liver graft may survive for a long period following combined therapy with lamivudine and adefovir. It is still better to avoid the use of HBsAg-positive liver grafts until there is more evidence on patient prognosis. At the present time, it is a challenge to use an HBsAg-positive cadaveric liver graft when no other donor is available.