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Antiviral Therapy Has Long-Term Benefits for
Liver Recipients With Recurrent HCV
NEW YORK (Reuters Health) Feb 20 - Combination therapy with interferon
and ribavirin provides persistent suppression of hepatitis C virus (HCV) in
selected patients after liver transplantation, French investigators have
found. An absence of detectable HCV RNA in the graft at the end of antiviral
therapy is a favorable prognostic indicator.
Dr. Thierry Bizollon, of Hotel-Dieu in Lyon, and colleagues reviewed the
records of 54 patients who underwent liver transplantation for HCV
cirrhosis. Serum HCV RNA, intrahepatic HCV RNA, and elevated serum alanine
aminotransferase (ALT) levels were measured at least 6 months later. The
patients received interferon plus ribavirin induction therapy for 6 months,
then 12 months of ribavirin.
Ten men and four women had a sustained response to antiviral therapy, the
group reports in the February issue of Gut. A sustained response was defined
as normal serum ALT levels each month for the first 6 months after therapy
ended, as well as no serum HCV RNA at 6 months.
The research team followed these 14 patients for 3 years after withdrawal
of antiviral combination therapy. In 13 of the 14 patients, no serum HCV RNA
and no HCV RNA on the graft was detected at any time. The mean Knodell score
for fibrosis remained relatively stable, and five patients had normal or
near-normal scores.
These findings "very likely indicated eradication of the chronic HCV
infection and subsequent interruption of the disease progression, with a low
risk of further relapse of development of cirrhosis on the graft," Dr.
Bizollon's group infers.
The patient who relapsed developed serum HCV RNA 7 months after the end
of antiviral therapy and exhibited an increased serum ALT level at 22
months. He was the only patient of the 14 who exhibited positivity for HCV
RNA on the graft at study entry.
"This case may suggest that the treatment does not completely suppress
viral replication and very low replication rates remain in the compartment
of replication-competent cells (mainly hepatocytes)," the investigators
write.
They note that the patient had serum and graft HCV RNA, but no hepatitis,
for 15 months. "This observation of late relapse raises the question of the
cytopathogenicity of HCV for hepatocytes and suggests that mechanisms other
than direct cytotoxicity may be implicated in HCV-induced graft damage."
Gut 2003;52:283-287.
http://www.askemilyss.com/bites/bite0203/recurr.htm
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SourceURL:http://www.gastrohep.com/news/news.asp?id=2186
Outcome of liver
transplantation for patients infected by hepatitis C
More severe fibrosis and rapid fibrosis progression occurs following
transplantation in patients infected with hepatitis C virus genotype 4,
determine researchers in the August issue of Liver Transplantation.
The predictors of post-transplantation hepatitis C virus (HCV)-related
liver disease remain unclear.
In addition, the impact of HCV genotype on the outcome of transplantation
has not been established.
In this study, a team of physicians from Birmingham, England, examined the
outcome of liver transplantation in patients with infected with HCV
genotype 4.
The team assessed 128 patients who underwent transplantation for HCV
infection. Of these, 28 patients were infected with genotype 1, 11 with
genotype 2, 19 with genotype 3, and 32 with genotype 4.
The team determined that the median interval from transplantation to biopsy
was 1.92 years.
5-year survival rates were similar for the different genotypes.
Liver Transplantation
They found that 26% of HCV genotype 4 patients developed either severe
fibrosis or cirrhosis, compared with 7% of patients with other genotypes.
Furthermore, a greater fibrosis progression rate was observed in patients
with genotype 4.
Univariate and multivariate analysis found that rapid liver fibrosis was
associated with the presence of HCV genotype 4 infection.
Donor and recipient age, and graft warm ischemic time also were associated
with the rate of fibrosis progression.
The investigators established that the 5-year cumulative rate for the
development of cirrhosis or severe fibrosis was 84% in genotype 4 patients,
and 24% in other genotypes.
In addition, the 5-year survival rates for patients with genotypes 1, 2 and
3, and 4 were 72%, 80%, and 79%, respectively.
Dr Mohamed Wali's team concluded, "5-year survival for patients who
underwent transplantation for HCV genotype-4 infection was similar to that
of genotype non-4 patients".
"However, more severe fibrosis and rapid fibrosis progression was observed
after transplantation in patients with genotype-4 infection".
Liver Transpl 2003; 9: 796-804
31 July 2003
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Immune System Drug May Increase Availability of
Liver Transplants |
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Animal research at The Johns
Hopkins University School of Medicine has found that a drug already
approved by the FDA for testing in people might one day dramatically
expand the number of livers useable for human transplantation. July 30,
2003
Studying rats with fatty livers, the
researchers discovered that bathing the livers in a human immune system
protein called interleukin-6 (IL-6) rescues them from failure when
transplanted into other rats. The findings appear in the July issue of
Gastroenterology.
Roughly 40 percent of adults in the United States have so-called
"fatty" livers, which frequently fail to function at all or fail quickly
when transplanted.
"IL-6 really works," says Zhaoli Sun, M.D., Ph.D., a scientist in the
department of surgery. Sun cautions that IL-6's ability to "rescue"
fatty livers for transplantation needs to be tested in larger animals,
such as pigs, before human studies are undertaken.
"IL-6 is already approved for use in humans, but it has many negative
effects when injected," says Sun. "Fortunately, our technique stores the
liver in IL-6 before it's transplanted, rather than giving IL-6 to the
organ recipient, so side effects should be minimized."
For his experiments, Sun developed two special rat colonies while an
instructor in the laboratory of Andrew Klein, M.D., in collaboration
with Anna Mae Diehl, M.D., a professor of gastroenterology whose
research has focused on regeneration -- rather than transplantation --
of fatty liver. In humans, fatty livers generally stem from either diet
or alcohol consumption, and the two rat models developed fatty livers
under equivalent conditions.
After removing a fatty liver from one animal, and before
transplanting it into another, Sun bathed the liver in a soup of
nutrients that either did or did not include IL-6. Livers soaked in IL-6
had better blood flow and better function and allowed recipients to
live, while fatty livers never exposed to IL-6 succumbed quickly to
damage and never worked well enough to save their new hosts.
Sun says it's not known yet how IL-6 protects the fatty livers from
damage or how it improves so-called "microcirculation," which helps
prevent large chunks of the liver from dying. But while those questions
are interesting scientifically, Klein, director of the Johns Hopkins
Comprehensive Transplant Center, says clinical trials won't need to wait
for those answers.
"Eventual clinical trials, if approved, would probably begin by
looking for reduced damage or improved function in organs we would
already use for transplant," says Klein, who notes that that a generally
acceptable cutoff is a liver with no more than 30 percent of cells
containing big droplets of fat. "Moving toward livers that currently
would be borderline would be a gradual process."
Roughly 17,500 people are awaiting liver transplants in the United
States, and 5,327 liver transplantations were performed last year across
the country, according to statistics kept by the United Network for
Organ Sharing. IL-6 has been administered to people as part of early
phase clinical trials in adults and children with various cancers, but
was limited by its toxicity.
The studies were funded by the National Institutes of Health,
including the National Institute on Alcohol Abuse and Alcoholism, and
the Johns Hopkins Department of Surgery.
Authors on the paper are Sun, Klein, Diehl and Sumito Hoshino of
Johns Hopkins; Svetlana Radaeva, Osama El-Assal, Hong-Na Pan, Barbara
Jaruga, Sandor Batkai, George Kunos and Bin Gao of the National
Institute on Alcohol Abuse and Alcoholism; and Zhigang Tian, of the
University of Science and Technology of China.
Reproduced with permission of Englemed.com
http://www.hepquest.com/ |
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Gastroenterology, July 2003 Journal Scan
From
Hepatology
July 2003 (Volume 38, Number 1)
Chronic hepatitis C-related cirrhosis is one of the
leading indications for orthotopic liver transplantation throughout
the world. Recurrence of hepatitis C virus (HCV) infection is
essentially universal in the posttransplantation setting, and although
disease progression is increased in this patient population compared
with the immunocompetent population (before and after development of
HCV-related cirrhosis), the natural history of posttransplantation
hepatitis C is quite variable. Thus significant reductions in graft
and patient survival are observed among the population of patients
undergoing liver transplantation for HCV-related disease.
The incidence of posttransplantation hepatitis C
recurrence is increasing. There is currently no discrete or
combination of variables predictive of which individual will progress
to serious HCV-related disease in the posttransplantation setting.
Clearly, it would be therapeutically advantageous to identify those
patients at high risk for progression to severe forms of disease
recurrence so that specific interventions may be implemented, such as
preemptive antiviral treatment. Therefore, efforts should be directed
at defining the presence of specific variables in either the
pretransplant or early posttransplant setting that may then serve as
accurate predictors of those patients likely to progress to severe
disease.
Berenguer and colleagues developed a model based on
pre- and/or early posttransplantation variables that might help
predict progression to severe disease. This study involved 554
patients with posttransplantation HCV-related disease. Clinical and
histologic outcomes were assessed, and a total of 1353 biopsy
specimens obtained after 1 year were scored. Outcome measures used
included cumulative probability of developing severe disease (defined
as fibrosis stage 3 and 4) within 5 years and actual progression to
severe disease within 2 years of liver transplantation. Cox
proportional hazard survival analysis was used for the entire cohort,
and parameters analyzed included HCV genotype and recipient, donor,
and transplant-related variables.
Overall, these findings confirm those of previous
studies suggesting that immunosuppression (induction with
mycophenolate, duration of azathioprine, etc.), old age of the donor,
and HCV genotype (1b) have an adverse effect on HCV-related disease
progression in liver transplant recipients. The model used early
posttransplantation variables to predict the recurrence of severe
HCV-related disease in post-liver transplant patients. The estimated
probability of a patient being considered at high risk for severe
HCV-related disease recurrence was calculated from a formula that
included the age of the donor and the recipient's therapy as critical
parameters (variables). The cumulative risk of progressing to severe
disease (ie, fibrosis stage 3 and 4) was significantly greater among
patients transplanted recently (P < .001) and was present in
all centers.
Therefore, these findings suggest that the increase in
HCV-related disease seen in the posttransplant setting in recent years
is likely attributable to alterations in patient care over time --
such as the use of different immunosuppressive regimens and the use of
livers from older donors. In line with the latter, it follows that the
use of younger organ donors, most especially in the setting of
patients with HCV-related cirrhosis, and implementation of
less-intensive immunosuppressive strategies in the early
posttransplant period may warrant consideration. However, such
interventive strategies for improving the outcomes of patients with
HCV-related disease undergoing liver transplantation require
prospective evaluation to determine the relative risks and benefits.
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IL-6: A magic potion for liver transplantation?
Markus Selznera
[MEDLINE LOOKUP]
Rolf Grafa
[MEDLINE LOOKUP]
Pierre-Alain Clavien*
a
[MEDLINE LOOKUP
Liver transplantation has become a routine procedure in many centers over
the past decade and is currently the only hope for many patients with end
stage liver disease. The success of liver transplantation has created an
increasing imbalance between organs available for transplantation and the
number of patients awaiting an organ. The ensuing shortage has triggered
interest to use marginal organs such as those containing fat. Currently,
these organs are used with great caution because mild steatosis (<30% of
hepatocytes containing fat) is associated with graft dysfunction,
particularly when additional risk factors are present,1,2
and moderate (30%–60%) and severe (>60%) steatosis are major risk factors
for graft failure.3–6
The wide use of steatotic livers for transplantation would significantly
increase the organ pool because the prevalence of steatosis is high in the
general population and increases with age. Although only about 11% of young
people have steatosis, the prevalence exceeds 40% in people over 60 years of
age.7–9
Fatty livers poorly tolerate cold9,10
and warm11
ischemia/reperfusion injury and have impaired ability to regenerate.12,13
New insights into mechanisms of injury related to steatosis are needed to
develop protective strategies and thereby allow the safe use of fatty livers
for transplantation. An incompletely answered question is whether lean and
fatty livers share similar pathways of injury or whether they are
independent. Recent evidence suggested that different pathways are active in
fatty and non-fatty livers because different types of cell death occur
following the ischemic period.11
Thus, fatty livers not only poorly tolerate long periods of ischemia but
also develop different types of injury than those observed in lean organs.
Similarly, strategies improving regeneration in lean livers are ineffective
in the presence of fat deposits in hepatocytes.14
Thus, it seems that specific strategies will be needed to use fatty liver
for transplantation.
Two central issues remain the subject of controversies in clinical
transplantation, namely, how to identify fat deposits in potential grafts
and how macro- vs. microvesicular steatosis impacts the outcome of
transplantation. In the situation of evaluating a potential organ for
transplantation, the presence of fat deposits is assessed in H&E-stained
frozen biopsy specimens. However, it was recently shown that H&E staining
underestimates micro- and macrovesicular steatosis.15
Therefore, specific fat staining techniques on frozen sections, such as
Red-oil-O or Sudan red staining, should be used, however, always in
conjunction with an H&E stain to avoid misinterpretation.6,15
In addition, conventional paraffin sections should be routinely obtained to
later confirm the result of the frozen biopsy specimen postoperatively.
Next, the debate remains active on whether only macrovesicular steatosis
puts the organ at risk, or whether microvesicular steatosis may also
contribute to poor outcome.10,16,17
In macrovesicular steatosis, the hepatocytes contain one large fat droplet,
whereas in microvesicular steatosis, the hepatocytes are filled with
numerous small fat droplets leaving the nucleus in the cell center. While no
definite study is available, most clinical data suggest that increased risk
is related to the presence of macrovesicular steatosis.18,19
Thus, studies in animal models of macrovesicular steatosis are important to
perform, such as with obese animals (e.g., Ob/ob mice or Zucker rats).
In this issue of GASTROENTEROLOGY, Sun et al.20
evaluated whether interleukin (IL)-6, a widely studied hepato-protective
cytokine, confers protection in a liver transplantation model in Zucker
rats.20
Homozygous Zucker rats lack the leptin receptor and develop an overeating
syndrome resulting in obesity and steatosis by the age of 8 weeks.21
Sun et al. convincingly show in this model that IL-6 application to the
fatty liver during preservation reduces liver injury and increases animal
survival after transplantation. This finding is important because it
indicates a clinically relevant effect of the cytokine to protect the
steatotic organ against reperfusion injury. In an attempt to further
evaluate the pathway of protection, Sun et al. investigated the type of
sinusoidal endothelial (SEC) cell death after reperfusion. They found that
SEC death occurs through pathways leading to both apoptosis and necrosis,
called “necrapotosis.”22
This type of injury was prevented by IL-6 treatment. The protection of SEC
was associated with an activation of STAT3, and Bcl-XL. In
addition, IL-6 treatment improved hepatic microcirculation after
transplantation.
IL-6 is a cytokine with numerous effects. In a human study, we recognized
that high IL-6 levels after liver resection in humans correlate with low
postoperative transaminase levels and beneficial outcome.23
Animal experiments confirmed this clinical observation as mice lacking IL-6
have impaired ability to regenerate and increase injury after liver
resection, an effect that exogenous IL-6 before surgery corrected.24,25
Further studies showed that IL-6 is necessary for the induction of liver
regeneration in vivo, and its effect is dependent on TNF- ,
which acts as an upstream mediator.24,26–28
The impaired regeneration in TNF receptor-1 knockout mice is corrected by
IL-6, but IL-6-lacking mice exhibited impaired regeneration even in presence
of TNF-.
IL-6 acts directly on hepatocytes inducing the translocation of STAT3 to the
nucleus causing early gene activation and mitosis.24
In addition to this signaling effect on hepatocyte proliferation, IL-6 also
protects the liver against various forms of liver injury, such as ischemia
and reperfusion,25
toxins,29
and cell death mediated by Fas activation.30
IL-6-deficient mice have increased caspase 3 and 8 activities and reduced Bcl-2
and Bcl-xL levels.29,30
Administration of IL-6 results in the activation of the antiapoptotic
mediators Bcl-2 and Bcl-xL indicating that IL-6
might be an important regulatory cytokine of the apoptotic pathway in normal
hepatocytes.
These broad protective effects of IL-6 in lean livers suggest that this
cytokine might become the ideal drug to apply in patients undergoing liver
surgery involving ischemia and the need for regeneration (e.g., liver
resection performed under inflow occlusion). Unfortunately, this use in
patients may not be appropriate because of potential side effects, such as
fever, fatigue, arthralgias, hyperbilirubinemia, and thrombocytosis.31,32
In contrast, liver transplantation may offer a unique opportunity to use
IL-6 because the cytokine can be given exclusively to the graft (cadaveric
or living related) without directly exposing the recipient. Indeed, Sun et
al. show that IL-6 administration solely to the graft does protect the fatty
liver graft after transplantation.20
Whether IL-6 is also protective in the cold preserved liver and whether
protective mechanisms other than those observed in the lean organ are
involved is unknown. Sun et al. convincingly show protection and potential
clinically relevant effects, and suggest novel mechanisms. In lean animals,
cold ischemia and reperfusion injury related to transplantation induces SEC
apoptosis, whereas hepatocytes undergo a predominantly nonapoptotic cell
death.33–35
It is still unclear whether rapid SEC death after reperfusion triggers the
hepatocyte injury or whether the injuries to these 2 types of cells are
unconnected. We have favored the first hypothesis because blocking apoptosis
of SEC by various antiapoptotic strategies improves hepatocyte injury and
animal survival following liver transplantation.33,34,36,37
Sun et al.20
identified “necrapoptosis,” a mixed form of necrosis and apoptosis, as the
typical injury of SEC in fatty liver after transplantation. The prevention
of “necrapoptosis” of SEC by IL-6 suggests that the main target of
protection may involve STAT3 activation in these cells. They further
speculate that the protective function of IL-6/STAT3 is likely mediated via
the induction of the antiapoptotic gene Bcl-2 and Bcl-xL,
as previously described.20,29,30
However, as SEC death in fatty livers discloses features of necrosis, one
wonders whether other types of protection might be involved. The use of
antiapoptotic drugs concomitant to the administration of IL-6 might have
helped to sort out the antiapoptotic vs. antinecrotic effects of IL-6. The
study does not exclude that IL-6 protects SEC through other pathways.
Another central finding of the study by Sun et al. is the dramatic
beneficial effect of IL-6 on the hepatic microcirculation after
transplantation in fatty liver. Impaired microcirculation upon reperfusion
of fatty liver is a major cause of graft injury38
and might be the single most important factor for poor outcome. Protective
strategies, which improved microcirculation in steatotic livers, such as
ischemic preconditioning, have revealed to be the most effective.39,40
Thus, the main effect of IL-6 might well rely on microcirculation, but
whether this effect is linked to protection of SEC or other mechanisms
remains unclear. The observation by Sun et al. that microcirculation was
improved by IL-6 already 10 minutes after reperfusion, whereas the
protection of sinusoidal endothelial cells was noted 1 hour after
transplantation suggests that improved microcirculation through IL-6
application may contribute to preservation of SEC.
Another important line of investigation in the fatty liver lies in the
energy status of hepatocytes. Recent data suggests that steatosis is
associated with decreased intrahepatic ATP levels and increased necrosis
following the reperfusion injury of normothermic ischemia.40,41
Strategies improving ATP levels in fatty livers, such as ischemic
preconditioning, were protective against normothermic ischemia. A link
between IL-6 and ATP generation has been shown in colonic epithelial cells.
IL-6 administration to colonic cell lines resulted in increased ATP
generation by mitochondrial phosphorylation.42
IL-6 might also protect through preservation and restoration of ATP levels
in hepatocytes.
Thus, how IL-6 protects the fatty liver after transplantation requires
further investigation. The study by Sun et al. is important and should
motivate future investigations of the hepato-protective effects of IL-6.
From a clinical perspective, the study is important because protection by
direct exposure of grafts to IL-6 avoids the negative systemic side effects
of systemic IL-6 exposure to the recipient patient. Another important issue
before clinical application is how the same treatment affects lean donor
livers. Depending on dosing and timing, IL-6 may have a negative impact on
lean grafts. Thus, the safety of IL-6 in lean grafts is important because
assessment of hepatic fat in clinical practice is often inaccurate.
This study in the fatty liver opens new avenues for further research and
holds the promise for the development of a new strategy in humans to protect
the fatty organ and extend the donor pool.
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Conference Report
Highlights of the 9th Meeting of the International Liver Transplantation
Society (ILTS) and the 13th Meeting of the Liver Intensive Care Group of
Europe (LICAGE)
June 18-21, 2003; Barcelona, Spain
Olivier Detry, MD, PhD
Medscape Transplantation 4(2), 2003. © 2003 Medscape
Posted 07/09/2003
Hepatocellular Carcinoma (HCC): HCC is the fifth most common malignant
disease in the world, causing almost 1 million deaths annually.[1] HCC has
a heterogeneous geographical distribution that is related to differences
in the prevalence of risk factors on various continents; HCC is one of the
most frequent neoplasms in Asia and in Africa. In Japan, the incidence has
been reported at 15 cases per 100,000 population per year.[2] The
incidence of HCC is considered intermediate in the Mediterranean
countries. In the Western world, the incidence has historically been low,
but in the United States where the incidence of hepatitis C and B virus (HCV
and HBV) infection has increased, the incidence of HCC has risen to 2.8
cases per 100,000 population per year.[3] The incidence and mortality
rates for HCC are nearly equal.
HCC usually develops in a diseased liver
involving a chronic inflammatory process whose final expression is
cirrhosis (Figure 1). Cirrhosis should be considered a premalignant state
for HCC; the incidence of HCC is 1.5% per year in cirrhotic livers. As HCC
remains asymptomatic for a long time, most patients are diagnosed at an
advanced stage and cannot benefit from curative treatment. Therefore,
patients with cirrhosis should undergo early detection using serum
alpha-fetoprotein levels and imaging of the liver parenchyma by echography
every 6 months. This strategy facilitates early diagnosis of small,
asymptomatic tumors, which can be cured.
Treatment of cirrhotic patients with HCC is
difficult because of their underlying liver disease. The evolution of HCC
in these patients is often complicated by hepatocellular insufficiency,
gastrointestinal hemorrhage, and/or ascites. Moreover, recurrence of HCC
or metachronous development of a second HCC is frequent in cirrhotic
livers. Sensitivity of HCC to nonsurgical therapies is low and prognosis
is poor. In fact, only patients with small (stage 1 and 2) tumors can be
cured by surgical therapies.
Liver Transplantation (LT) for HCC: In a
comprehensive review, Professor J Bruix, MD, of Catalonia, Spain,[4]
presented a state-of-the-art lecture on LT for HCC. Curative options for
HCC include: percutaneous ethanol injection, radiofrequency ablation,
resection, and LT. Percutaneous ethanol injection (Figure 2) is accepted
as an attractive alternative to surgery in patients with small-size HCC
and has been widely performed,[5] but the recurrence rate is high with
this modality. Percutaneous ethanol injection is indicated for small-size
HCC in patients with a contraindication to resection or LT. Radiofrequency
ablation produces thermal ablation via an electric current that passes
through the tumor via an electrode tip, resulting in heat regeneration and
coagulation necrosis (Figure 3). Radiofrequency ablation has been used to
treat hepatocarcinoma in large series,[6] but further clinical trials are
needed to assess long-term results. Resection of HCC in cirrhotic livers
may be done with acceptable operative risks in patients with good hepatic
reserve (Child's Class A), normal serum bilirubin level, and low portal
hypertension (< 10 mm Hg).[7] Figures 4A-4C show a peripheral 4-cm HCC in
hepatic segment 5 in a patient with Child's Class A cirrhosis due to HCV,
treated by resection of segment 5. However, the postresection recurrence
rate is high.[8-10] Risk factors for recurrence have been extensively
studied, but not definitely determined: grade of the tumor,
differentiation, number of nodules, preoperative alpha-fetoprotein levels,
and DNA-ploidy.
Among the curative therapies for HCC, LT has
gained wider acceptance as improvements in crude survival and
recurrence-free survival have been demonstrated in selected cases.[8,11]
LT has the advantage of resecting the whole liver, including the HCC, and
potentially removing undiagnosed synchronous HCC, daughter HCC, and
hepatic micro-invasion. Moreover, LT treats cirrhosis and therefore
protects the patient against future complications of cirrhosis and
development of a second HCC. The main drawbacks of LT are the high
incidence of posttransplant recurrence, which is enhanced by
immunosuppressive agents,[12] and the shortage of liver grafts, which
leads to long waiting times on the LT list. The doubling time of HCC is
approximately 6 months; thus, a significant number of patients become
nontransplantable during the interval between evaluation and acceptance
for LT and availability of a graft, leading to a significant drop-out rate
(due to death) that is variable across centers and responsible for
variable management strategies across centers. This factor should be
included in all studies comparing results of LT to liver resection for HCC
(intent-to-treat analysis).
To date, no randomized study has been done to
compare results of resection vs LT for HCC and, therefore, no definite
conclusion about which treatment offers the best outcome can be made. Such
a study is unlikely, however, because recent, good retrospective papers
have reported better results for LT compared with resection in selected
cases.[8,11]
Mazzafero and colleagues[11] prospectively
demonstrated in 1996 that small HCC (1 nodule < 5 cm, 3 nodules < 3 cm)
has a very good chance of recurrence-free long-term survival after LT.[11]
These criteria, known as "the Milan criteria," are widely accepted. This
paper confirmed previous retrospective reports comparing results of
resection with LT for small HCC in cirrhotic livers,[13,14] even in
Child's Class A patients.[8] Liver transplantation seems, therefore, to be
the best available treatment for small HCC in the patient with cirrhosis
(even Child's Class A) and should be performed as soon as possible after
diagnosis to limit drop-out due to death. Surgical resection should be
reserved for Child's Class A cases with contraindications to LT such as
psychiatric problems, advanced age, high-grade tumor, extrahepatic spread
of the tumor, or nonavailability of LT (ie, in some Asian countries).
Incidental Hepatocarcinoma: Making a
pretransplant diagnosis of HCC in the cirrhotic liver is not always easy,
even with the advent of spiral computed tomography (CT) and magnetic
resonance imaging. In many cases, a small HCC may be found in a liver
pathology specimen and called an incidental hepatocarcinoma. It has been
suggested that these incidental hepatocarcinomas have a very good
prognosis if their size is small.[15] This finding was further confirmed
by Cosme Manzarbeitia, MD,[16] and colleagues, of Philadelphia,
Pennsylvania, who reported their experience of 12 incidental
hepatocarcinomas with 91% of survival at 33 months.
Stage 1 and Stage 2 HCC: Patients with stage 1
and stage 2 HCC are good candidates for LT, and it is important to offer
them access to a liver graft in a timely manner. Several alternatives in
this regard have been proposed.
Increase Access of Patients With HCC to the
Cadaveric Donor Pool. In the United States, the United Network for Organ
Sharing (UNOS) implemented a new liver allocation system in February 2002.
This system allocates liver grafts according to an index of severity of
liver disease, the MELD score.[17] To increase access to LT by patients
with HCC, additional points corresponding to Milan criteria are given to
patients with HCC (24 points for stage 1 and 29 points for stage 2
patients), in order to decrease their waiting time and their drop-out
rate. This policy has resulted in a marked increase in patients with HCC
undergoing LT within the United States. Richard B. Freeman, MD,[18] of
Boston, Massachusetts, reported that between February 2002 and February
2003, 23% of cadaveric LT performed in the United States was for HCC,
representing a 6-fold increase compared with the pre-MELD (Model for
End-Stage Liver Disease) allocation era. Most patients were transplanted
within 3 months of the HCC diagnosis, and the drop-out rate nearly
disappeared. However, because the mortality risk for non-HCC patients was
significant, it was recently decided to reduce the priority points given
for HCC to 20 for stage 1 and 24 for stage 2 HCC. The impact of this
policy modification needs further evaluation.
Living-related Donor LT. Living-related LT (LRLT)
in adults was pioneered during the late 1990s to decrease waiting list
mortality.[19] This procedure requires the procurement of enough liver
mass (ideally, 0.8% to 1% of the recipient weight) to provide efficient
liver function; thus, most donors undergo right hepatic lobectomy. This
procedure is considered a major resection of liver tissue and is
associated with a mortality risk of 0.2% to 0.5%. Several donor deaths
have been reported in the United States and in Europe.[20,21] LRLT
decreases the recipient waiting time and increases the whole donor liver
pool and is particularly attractive for stage 1 and stage 2 HCC patients
whose posttransplant prognosis is excellent.[22]
Marginal Donors. Since short waiting time is a
key factor for patients with HCC, it seems acceptable to transplant them
with suboptimal or marginal liver grafts (ie, steatotic, from
non-heart-beating donors [NHBD], donors with hypernatremia, or older
donors), according to Han Grewal, MD, of Jacksonville, Florida.[23]
Marginal cadaveric grafts present several risk factors for posttransplant
graft dysfunction or nonfunction, often leading to refusal by multiple
centers before being accepted by centers willing to use them for HCC
patients. However, livers from marginal donors can have good long-term
function, according to Cosme Manzarbeitia, MD,[24] and colleagues of
Philadelphia, Pennsylvania, who presented his center's experience with
outcomes of 19 NHBD livers transplanted between 1995 and 2002. In this
series, the rates of primary nonfunction graft and bile duct stenosis were
not different from the rates in cadaveric livers.
Expanding the Criteria of LT for Advanced HCC:
Patients suffering from advanced HCC in excess of the Milan criteria have
a significantly lower chance of cure after LT and should not routinely be
considered as LT candidates. However, some patients may be cured if there
is no extrahepatic spread. If liver grafts were not in short supply, many
patients with more advanced HCC might benefit from LT.
LRLT has been proposed as a means of giving
access to LT by patients with advanced HCC without extrahepatic
spread.[25,26] However, LRLT for advanced HCC patients poses the ethical
problem of putting the life of a healthy donor at risk, with the
possibility of early posttransplant recurrence and recipient death. J.M.
Llovet, MD,[27] and colleagues, of Catalonia, Spain, presented their
experience with LRLT for extended criteria donors (single HCC </= 7 cm, 3
nodules </= 5 cm, or 5 nodules </= 3 cm). Eight patients with these
criteria underwent LRLT, and all are alive and recurrence-free at
follow-up. Another possibility for patients with advanced, intrahepatic
HCC is the use of livers from NHBD donors.[23] However, the evolution of
these patients needs to be determined by longer follow-up studies.
Even in patients with good prognosis according
to the Milan criteria, early and aggressive recurrence may be observed
and, conversely, some patients with high-grade tumors have not experienced
recurrence. Risk factors for recurrence after resection and LT have been
studied: tumor size, number of nodules, macroscopic or microscopic
vascular invasion, differentiation, and alpha-fetoprotein level.
Guido Schumacher, MD, [28] of Berlin, Germany,
retrospectively studied the DNA ploidy of 87 patients transplanted for HCC.
Ten-year survival was strongly dependent on DNA ploidy; survival was 98%
with diploid cells, 83% with polyploid cells, and 18% with aneuploid
cells. Tumors were aneuploid in 36% of stage pT1, in 52% of stage pT2, and
70% of stage pT3 patients. The exact role of DNA ploidy needs further
study, but could be used to select patients with advanced tumor stage
whose recurrent risk might be low after LT. Another new prognostic
criterion that should be further evaluated is the total tumor volume,
according to Matteo M. Ravaioli, MD,[29] and colleagues of Bologna, Italy;
use of a cut-off point of 30 cm3 seems to be promising.
Neoadjuvant Therapies: Marginal donor and LRLT
will not provide enough grafts to all patients with HCC awaiting LT. To
avoid tumor progression during this waiting period, chemoembolization has
been performed and is of great interest, as reported by several
investigators at this meeting.[30-32] Chemoembolization limits the
drop-out rate and, therefore, improves the intent-to-treat results of LT
for HCC. Figures 5A-5C show a central 3-cm HCC in a cirrhotic liver due to
HCV treated by LT after neoadjuvant chemoembolization.
Radiofrequency ablation has been recently
developed and proposed as a treatment for liver metastases and primary
tumors.[6] Radiofrequency ablation has also been proposed for control of
HCC before LT with good results.[33]
Surgical resection may also be offered as a
first-line therapy in selected patients with HCC, with the possibility of
LT as a second-line therapy if the histology shows a high risk of
intrahepatic recurrence.[34,35]
Conclusion: In conclusion, LT is the best
available curative option for small (Milan criteria, stage 1 and stage 2)
HCC in the cirrhotic liver, even in the case of Child's Class A cirrhosis,
and should be discussed with the patients and performed as soon as
possible after the diagnosis. Surgical resection should be reserved for
patients with contraindications to LT or without access to LT (ie, Asian
countries). LRLT may be a good alternative to cadaveric transplantation in
patients with early-stage HCC. Marginal and NHBD livers may also be used
to decrease waiting time. Caution is required before offering LT to
patients with advanced (stage 3 and stage 4) intrahepatic HCC, especially
if LRLT is considered.
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