肝移植的最新发展

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Liver Transplantation -- New Developments
Tram T. Tran, MD


Introduction
Since the first orthotopic liver transplant (OLT) performed in 1963,
improvements in immunosuppression and surgical techniques have resulted in
OLT becoming the definitive treatment for acute and chronic liver failure.
Liver transplantation has achieved successful 5-year patient survival rates
ranging from 59% for those transplanted for malignancy to 81% for those
transplanted for cholestatic liver diseases.[1] The limiting factor in OLT
remains the disparity between available deceased donors and the increasing
number of potential recipient candidates. Living donor liver transplantation
(LDLT) remains an important, yet somewhat controversial, option to increase
access to transplantation. However, outcomes in LDLT, as well as selection
of ideal recipients and donors, remains an active area of study. Recurrent
disease, especially hepatitis C, is widely recognized as an important cause
of posttransplant graft impairment. Research into what host or viral factors
predict recurrence, the impact of immunosuppression regimens, and treatment
once disease recurs is ongoing. The success of transplantation has led to
further study into groups that were previously thought to be poor transplant
candidates, including patients with more advanced hepatocellular carcinoma
(HCC) and those infected with HIV. These and other important topics in liver
transplantation were the focus of key presentations at this year's meeting
of the American Association for the Study of Liver Diseases.

Living Donor Liver Transplantation
Despite changes in the allocation strategy and efforts to improve donor
awareness, the disparity between the number of available deceased donors and
the number of potential recipients remains fairly constant. In 2002, only
5292 deceased donor liver transplants were performed, whereas the waiting
list had more than 17,000 potential candidates. LDLT first evolved from
performance of adult-to-pediatric left lateral segment transplantation; for
most adult-to-adult transplants, right lobe segments 5-8 are resected. Since
the first cases were performed in the mid 1990s, LDLT has been increasingly
used as a means of bridging the disparity between available donors and the
waiting recipients. In 2001, 506 LDLTs were performed in the United States.
In 2002, a highly publicized donor death and concerns about donor safety and
outcomes resulted in a marked decrease by 30% in the number of LDLTs
performed.

Selection of candidate recipients for LDLT follows the same criteria as for
deceased donor liver transplants. However, in some clinical scenarios, such
as in those patients with known HCC, where more expedited transplantation is
critical, timely transplant may prove to be of more benefit. Additionally,
in cases such as polycystic liver disease where hepatic function is well
preserved despite symptoms, and the MELD (Model for End-Stage Liver Disease)
score is low, LDLT may be the only reasonable option. Once listed for
transplantation, only 50% of eligible recipients are able to identify a
potential donor[2] due to family and personal circumstances or clear medical
contraindications. Once identified, donor selection is of utmost importance
in ensuring, first and foremost, donor safety, and second, the adequacy of
the graft for the recipient.

The Adult-to-Adult Living Donor Liver Transplantation Cohort Study, led by
Dr. Carl Berg, studied the overall mortality in 785 candidates for
transplantation.[3] In this cohort, 371 patients received LDLT, 221
underwent deceased donor liver transplant, and 181 patients died.
Experienced centers performing more than 10 LDLTs showed decreased total
mortality associated with LDLT compared with waiting for deceased donor
liver transplant.

Issues regarding steatotic graft outcome in LDLT are not well defined. Cho
and colleagues[4] prospectively biopsied 55 recipients of LDLT at day 10
posttransplantation to compare outcomes and histologic changes in degree of
steatosis with pre-LDLT liver biopsies. Markers of regeneration were
evaluated as well. They reported that macrovesicular steatosis decreased
post-LDLT and hepatic regeneration did not appear to be impaired, even with
moderate (30%) degrees of steatosis.

Liver allografts taken from donors with hepatitis B infection carry the risk
of transmission of the infection to the immunosuppressed recipient. However,
in those countries where hepatitis B virus (HBV) infection is endemic,
exclusion of donor candidates previously exposed to the virus is not
feasible. Celebi and colleagues[5] reported their findings regarding safety
and outcome in LDLT using healthy donors previously exposed to hepatitis B
in Turkey. They performed 152 LDLTs, 37% of which involved anticore antibody
HBV-positive donors with normal liver biochemistries and histology. Standard
hepatitis B prophylaxis with lamivudine was given after transplantation for
those recipients who were hepatitis B naive (hepatitis B surface antigen
[HBsAg] negative); none of these HBsAg-negative patients developed hepatitis
B after a mean 17-month follow-up.

Commentary: LDLT continues to be an option for increasing access to
transplantation in the setting of an ongoing lack of deceased donor
availability. Expansion of donor selection, increased transplant center
experience, and good outcomes seem promising.

Hepatitis B and Transplantation

HBV-related liver disease has accounted for approximately 5% of all
transplants performed in the United States over the last several years.
Prior to development of effective posttransplant prophylactic regimens,
survival was considerably lower due to recurrent HBV infection after liver
transplant than it was for other major causes of cirrhosis. HBV is now a
successful indication for liver transplantation, and this will likely
continue to be the case with the development of newer nucleoside or
nucleotide analog-based treatment regimens

Starkel and colleagues[6] examined the role of an experimental adjuvant
vaccine, HBsAg/AS04,* in patients transplanted for HBV infection, used as a
modality to potentially allow for the discontinuation of the expensive and
inconvenient hepatitis B immunoglobulin. Ten stable patients received the
vaccine at 0, 1, 2, 6, and 12 months, and 7 of 10 developed some response to
the vaccine, either developing high (> 1000 IU/mL) anti-HBs titers or
reduced hepatitis B immunoglobulin requirements.

What is the association among HBV genotypes, core promotor and precore
variants, and indications for liver transplantation in patients with HBV
infection in the United States? Lok and colleagues,[7] in an ongoing
multicenter study of hepatitis B patients undergoing liver transplantation,
studied the prevalence of genotypes and precore or core promoter variants in
82 patients transplanted for HBV-related disease. HBV genotype C was the
most common (35%), followed by genotype A (31%), and then genotype B (15%).
Forty percent of the patients listed for liver transplant in the United
States were Asian. These Asian patients were more likely to be younger, have
genotype C disease, and have HCC when placed on the transplant waiting list.
Six patients transplanted for acute liver failure secondary to hepatitis B
were all HBV genotype A and not Asian. There was no association found among
HBV genotype, precore and core promotor variants, and HCC as an indication
for transplantation among Asians or non-Asians.

Commentary: With the success of transplantation for hepatitis B-related
disease using hepatitis B immunoglobulin and oral nucleoside and nucleotide
analogs, research focus on streamlining immunoprophylaxis to more convenient
and less costly options is ongoing.