Controversies in Liver Transplantation

January 4, 2006

Medscape coverage of: 56th Annual Meeting of the American Association for

the Study of Liver Diseases | Complications of Cirrhosis

Tram T. Tran, MD

Introduction

Current controversies in liver transplantation continue to revolve around

the disparity between available deceased donor organs and maximizing the

available donor pool, difficult clinical scenarios of patient selection

given limited donor resources, management strategies for hepatocellular

carcinoma, and the treatment of long-term complications, including disease

recurrence and other comorbidities. Many of these topics as well as results

of ongoing research were the focus of key presentations during this year's

meeting of the American Association for the Study of Liver Diseases.

Expanding the Donor Pool

Strategies aimed at expansion of the available number of liver grafts

include the use of living donors for both pediatric and adult recipients,

the splitting of 1 cadaveric organ for 2 recipients, and the use of

" extended criteria " donors. These " extended criteria " grafts are those with

risk factors for early or delayed graft dysfunction after transplantation

and may include factors such as advanced-age donor, hemodynamic instability

of donor requiring pressors, steatosis, viral hepatitis positivity, and the

use of non-heart-beating donor (NHBD) grafts.

Barshes and colleagues[1] examined the outcome of 120 NHBD transplants

performed at their center since the implementation of MELD (Model for

End-Stage Liver Disease) scoring as compared with those of recipients of

heart-beating donor (HBD) grafts; subjects were matched for pretransplant

criteria. Results showed 1-year patient survival rates of 80.9% vs 88.3% (P

= ns) for the NHBD and HBD groups, respectively. Graft survival was lower in

the NHBD group (65.3% vs 84.3; P = .02), with 8 retransplants required

compared with 2 retransplants in the HBD cohort.

Therefore, although there appeared to be some increased risk for graft loss

among recipients of grafts from NHBDs requiring retransplantation, overall

patient survival was acceptable.

Hepatocellular Carcinoma -- Where Are We?

Hepatocellular carcinoma (HCC) is an established indication for liver

transplantation, with excellent patient and graft survival and low rates of

recurrence when specific selection criteria are met. The Mazzaferro

criteria[2] are the most widely used guidelines for transplantation for HCC

(1 lesion, no greater than 5 cm, or up to 3 lesions, none greater than 3

cm), with excellent recurrence-free survival. However, recent data reported

by Yao and colleagues[3] suggest that modest expansion of the current

University of California, San Francisco (UCSF) criteria may still yield low

HCC recurrence, while allowing more patients to be transplanted for HCC. The

UCSF criteria propose the following guidelines for transplantation: a single

lesion not exceeding 6.5 cm; or 2-3 lesions, none exceeding 4.5 cm, with

total tumor diameter not greater than 8 cm. Yao and colleagues[4] presented

the long-term follow-up of 23 patients meeting the UCSF criteria

transplanted over a 4-year period and reported 1- and 4-year recurrence-free

rates of 90% -- a finding not statistically different from rates reported

for patients transplanted at earlier stages of tumor.

Living donor liver transplantation (LDLT) is a viable option for patients

experiencing long waiting times for deceased donor liver transplants (DDLT),

and has allowed for expansion of the available donor pool. Patients meeting

criteria for transplantation for HCC are also candidates for LDLT, and the

concern for disease progression in HCC often leads to rapid listing on the

wait list and " fast-track " transplantation. Kulik and colleagues[5]

evaluated the outcomes in 56 LDLT recipients transplanted for HCC vs 31 DDLT

recipients and found that waiting time was significantly shorter for LDLT

(162 vs 471 days, P < .0001). They also found that although tumor stage was

the same for both cohorts, 3-year recurrence-free survival was 46% in the

LDLT group compared with 79% in the DDLT group (P = .08), and a higher

proportion of patients (42% vs 0%; P = .003) in the LDLT group had disease

recurrence at 3 years. These findings suggest that " fast-tracking " patients

with cancer to transplant may include more patients with aggressive tumor

biology who would have otherwise been observed during a longer waiting

period for transplant.

Cirrhosis is a risk factor for the development of HCC. The only treatment

options for HCC with acceptable recurrence-free survival include hepatic

resection or liver transplantation. Given the long waiting times for liver

transplantation, curative resection should be considered in selected

patients. Some studies have suggested that the treatment of hepatitis C

virus (HCV) infection post resection may reduce the risk for late HCC

recurrence.[6] Chen and colleagues[7] reported results of a randomized

multicenter study evaluating the efficacy of interferon* therapy in 264

patients with hepatitis B and C after resection for HCC, with a median

follow-up of 42 months. Although interferon therapy was well tolerated, no

difference in overall survival or recurrence-free survival was noted after

53 weeks of treatment.

Retransplantation

In the setting of lack of donor organ availability, increasing death rates

on the waiting list for primary orthotopic liver transplantation, and the

difficulties with recurrent disease, significant debate continues

surrounding the issue of retransplantation. There is higher associated

morbidity and mortality with retransplantation; however, at present, 4% of

patients listed for liver transplantation are retransplant candidates with

no other option. Pedersen and colleagues[8] assessed the applicability of

the MELD score to assess wait-list mortality in retransplant candidates

compared with primary transplant candidates. They extracted data from the

UNOS (United Network for Organ Sharing) database and found that patients

relisted had higher MELD scores (22 vs 14), but when adjusted for equivalent

MELD scores, short-term wait-list mortality was slightly lower in the

retransplant candidates than in the primary candidates. The study authors

concluded that MELD score is an important determinant of wait-list

mortality, and that patients listed for retransplant have equivalent

wait-list mortality. The continuing controversy will concern not only

predicting how soon a patient needs retransplantation based on the MELD

score but also determining whom we should be transplanting.

Hepatitis C is the leading indication for orthotopic liver transplantation

worldwide, and with nearly universal reinfection of the graft, recurrent HCV

disease is problematic clinically. HCV-related graft cirrhosis has been

reported as high as 30% at 5 years.[9] At present, 40% of liver

retransplants in the United States are due to recurrent HCV disease. Soule

and colleagues[10] assessed outcomes in patients undergoing

retransplantation for HCV-related disease compared with patients receiving a

primary liver transplant. They found a significantly worse survival outcome

at 5 years (60% vs 28%; P < .03) for patients undergoing retransplantation,

with the leading cause of death after retransplant being recurrent HCV

disease leading to liver failure. This study, along with many other reports,

suggests that more strict selection criteria may be required when

considering retransplantation in patients with aggressive HCV recurrence,

although considerable controversy still exists in this arena.

Comorbidities -- Adding to the Problem

In a late-breaking abstract presented during these meeting proceedings,

Foxton and colleagues[11] reported on 163 patients who underwent liver

transplantation for HCV infection at their center between 1990 and 2004.

Biopsies were performed in all subjects, and 33% of recipients were found to

have advanced fibrosis within 6 years after transplantation. Factors

strongly associated with progression to fibrosis included donor age greater

than 55 years (P = .003), pretransplant diabetes (P = .03), and

posttransplant diabetes (P = .00015). The combination of older donor age and

diabetes status resulted in an 8-fold risk of fibrosis progression. This

study yielded useful information regarding potential selection criteria for

donors in HCV-infected individuals who appear at highest risk for severe

recurrence, such as retransplant candidates.

Renal dysfunction is associated with end-stage liver disease due to

multifactorial etiologies, including liver-induced renal ischemia, and

comorbidities such as hepatitis B and C. Hepatorenal syndrome, especially in

the acute setting and requiring dialysis, is a poor prognostic indicator,

with only 35% of patients surviving to liver transplant or discharge.[12]

Dellon and colleagues[13] examined the impact of dialysis and older age on

survival after liver transplantation and reported that in the MELD era, more

recipients are on dialysis and require dual-organ transplantation (liver,

kidney). More important, they found that among patients who were older than

65 years of age and on dialysis at the time of transplant, 1-year survival

in the MELD era was worse for those receiving only a liver transplant (50%)

than for those receiving liver and kidney transplants (67%). Across all

groups, pre- and post MELD era, recipients younger than age 65 years had

better 1-year survival.

Long-term morbidity and mortality in the liver transplant recipient is

affected by many factors, including renal function, disease recurrence, and

cardiovascular comorbidities -- the latter of which may account for 30% to

70% of clinical complications. McAvoy and colleagues[14] performed a

retrospective analysis of 93 patients for 6-12 months post liver

transplantation to assess the validity of the American College of Cardiology

(ACC) guidelines, developed to identify patients at risk for cardiac

disease. Predictors of cardiovascular risk were defined as having either (1)

2 or more of the following factors: obesity, hypertension, smoking, elevated

total cholesterol, family history of premature cardiovascular disease, age

older than 50 years; or (2) 1 of the following: previous myocardial

infarction or cerebral vascular accident; abnormal echocardiogram; or

evidence of an arrhythmia, left bundle branch block, or ST or T wave changes

on ECG. In the follow-up period, 10% of patients had cardiac events, with 2

deaths attributed to cardiovascular disease. Preoperatively, according to

ACC guidelines, 39% of the cohort had been identified as high risk, but only

50% of the cardiovascular events occurred in this group. Therefore, although

a high percentage of transplant recipients have cardiac events in the

posttransplant period, the cause is most likely multifactorial and difficult

to predict based on more traditional risk factors.

Acute liver failure has a high associated mortality, and cerebral edema with

subsequent herniation may occur due to osmotic disturbances in cortical

astrocytes that results in metabolic alterations and oxidative stress,

triggering cerebral blood flow.[15] Thus, predicting which patients have

cerebral edema is important in making the clinical decision to proceed with

liver transplantation, because persistent cerebral edema may portend poor

neurologic recovery post transplant. Bernal and colleagues[16] studied the

role of serum arterial ammonia measurements in acute liver failure as a

predictor of elevated intracranial pressure in 62 patients admitted to their

center. The serum arterial ammonia levels were significantly higher in those

acute liver failure patients with elevated intracranial pressures (155

micromoles/L [263.9 mcg/dL] vs 116; P < .02), and correlated with peak

intracranial pressure -- findings consistent with those from a previous

study suggesting that arterial ammonia level > 200 mcg/dL in patients with

stage III/IV encephalopathy was associated with cerebral herniation.[17]

Hepatitis B continues to be an important indication for liver

transplantation, and with adequate antiviral therapy and the use of

hepatitis B immune globulin (HBIG), survival post liver transplant is

excellent, with low rates of HBV recurrence. Nucleoside and nucleotide

analogues, such as adefovir, are now used in the posttransplant setting. Lok

and colleagues[18] reported on virologic response rates and adefovir

resistance in patients enrolled into the NIH-HBV OLT (National Institutes of

Health-Hepatitis B Virus Orthotopic Liver Transplantation) study. Sixty-one

patients who received adefovir and had at least 6 months of follow-up were

included in their analysis. Of those patients who had prior lamivudine

therapy (57/61), 12 were switched to adefovir monotherapy, and 45 received

combination lamivudine and adefovir. Only 54% of patients achieved an

initial virologic response (HBV DNA < 4 log copies/mL after 6 months of

adefovir treatment), and switching to adefovir monotherapy was significantly

associated with the development of adefovir resistance compared with the

addition of adefovir to existing lamivudine therapy (100% vs 15%; P = .001).

The study authors concluded that combination therapy should be considered in

all liver transplant patients to prevent sequential antiviral resistance.

Recent use of alcohol and drugs is a relative contraindication to liver

transplantation at most transplant centers, and most centers require 6

months of documented abstinence prior to procedure. Compliance with medical

treatment and immunosuppression regimens as well as recidivism are the most

pressing concerns related to nonabstinence. Nuessler and colleagues[19]

retrospectively studied the outcome in 300 patients who underwent liver

transplantation for alcoholic cirrhosis; subjects were followed for a median

of 78 months. Survival rates in this overall cohort were excellent (96% at 1

year, 90% at 3 years, and 73% at 10 years), although long-term survival was

shorter in those who had resumed drinking (54% vs 82%; P = .01). Nineteen

percent of patients had recurrent alcoholism and 52% of those who resumed

drinking developed recurrent cirrhosis. The significant factors leading to

recidivism included abstinence for less than 6 months, poor pretransplant

psychiatric assessment, and weak familial ties. Although mortality may be

high in severe acute alcoholic hepatitis, additional studies are warranted

to justify organ allocation to this controversial population of patients.

Liver biopsy is currently the gold standard for assessing the etiology of

hepatic dysfunction, disease progression, transplant rejection, and for

staging/grading of inflammation and fibrosis. In the transplant recipient,

this assessment is even more critical because changes in treatment or

immunosuppression may ensue. Newer, noninvasive modalities to assess

fibrosis, including transient elastography, are undergoing evaluation for

their potential to yield information without the risk of biopsy. During this

year's meeting, Barrault and colleagues[20] presented their results using

transient elastography to assess fibrosis in a cohort of liver transplant

recipients, 73% of whom were transplanted for HCV infection. The study

authors reported a good correlation between identification of fibrosis by

transient elastography compared with results of liver biopsy performed at

the same time. They suggested that this noninvasive modality may be used to

follow fibrosis progression in the post liver transplant setting. Thus,

transient elastography warrants additional study; however, this tool would

have no applicability in the assessment of other concomitant processes (ie,

rejection), which can be assessed with biopsy.

Concluding Remarks

Liver transplantation is the definitive treatment for acute and chronic

liver failure and over the past 20 years has achieved remarkable success in

patient survival. Current issues surround the maximization of a limited

resource (ie, available donor organs) by the careful assessment of

pretransplant risk of mortality, recurrence of disease, and risk factors for

short-term morbidity and mortality in order to best select recipients. These

studies are especially important in light of the increasing numbers of LDLTs

performed, which put the healthy donor at risk for complications. Once the

liver transplant is performed, clinical focus is shifted to maintaining

long-term graft function and to preventing the need for retransplantation,

particularly crucial in hepatitis C-infected recipients.

*The US Food and Drug Administration has not approved this medication for

this use.

References<snip>

http://www.medscape.com/viewarticle/518703

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January 4, 2006