Hmmm... I wonder if this is what happened to my first transplant. :( Very interesting!
Hepatitis C and Liver Transplantation
Thomas Shaw-Stiffel, MD
End-stage liver disease (cirrhosis) due to chronic hepatitis C viral
(HCV) infection has become the leading indication for liver
transplantation (LTx) in the United States. Unfortunately, LTx does not
cure HCV, a common misconception. Instead, recurrent HCV infection of
the new liver occurs in almost all instances and some form of liver
damage is noted histologically (seen under the microscope in a liver
biopsy specimen) in the vast majority of cases.
Furthermore, the natural history of recurrent HCV following LTx appears
to be significantly accelerated compared to that in non-LTx cases.
Rather than the 20% figure quoted for non-LTx cases who may develop
cirrhosis after 20-30 years, anywhere from 10 to 30% of LTx recipients
with recurrent HCV have advanced fibrosis (scarring) or full-blown
cirrhosis within only 5 years. Another problem is that, once cirrhosis
develops post-LTx, complications occur more rapidly than in non-LTx
cases. If another LTx is required, the outcome is usually not as
favorable and some liver transplant centers refuse to offer a second
LTx on this account.
In
some instances, a particularly aggressive form of recurrent HCV
develops within only a few months post-LTx and this condition has been
labelled “fibrosing cholestatic hepatitis” (FCH). It also occurs in
some cases of recurrent hepatitis B post-LTx where it was first
described. FCH is characterized by progressive jaundice (yellowing of
the skin and whites of the eyes) with a rapid decline in liver function
leading to liver failure, most often associated with markedly elevated
viral levels detected in the bloodstream (more than 20 times pre-LTx
levels) and in the liver tissue as well. In these cases, the virus
itself appears to be the major cause of liver damage (cytopathic),
whereas in most other cases of recurrent HCV post-LTx (as discussed
below) the liver damage is thought to be immunologically related, due
to “innocent bystander” injury to the liver cells as the immune cells
try to kill off the virus, albeit unsuccessfully. In FCH, loss of the
new liver is common within 3-6 months post-LTx and retransplantation is
invariably a failure. The aggressive nature of FCH suggests that these
cases may be infected with a more virulent form of HCV which in some
way contributes to the poor outcome, perhaps aggravated by the use of
higher doses of immunosuppression early following LTx. Fortunately,
this type of recurrent HCV is uncommon.
On the other hand, a sizeable number (30-50%) of patients with
recurrent HCV post-LTx follow a more indolent course with moderately
high viral levels (10-20 times pre-LTx levels) but minimal damage
histologically despite a slow but significant progression to cirrhosis
after 10-15 years. The ability to predict how a given patient with
recurrent HCV will do post-LTx remains an intense area of research
since it might then differentiate between patients who need anti-HCV
treatment versus those who do not, thereby reducing side effects and
costs. Certain factors have been identified as being important. These
include: viral levels in the bloodstream pre-LTx or early post-LTx,
viral genotype, age of the liver donor, degree of immunosuppression
post-LTx, timing of the HCV recurrence post-LTx, early histologic
findings post-LTx, and failure to respond to interferon-based therapies
prior to LTx. More often than not, however, these are too variable to
help in predicting the outcome in a particular individual.
The events associated with HCV infection of the new liver post-LTx are
now becoming clearer. One recent study assessed viral levels in the
bloodstream (via serial sampling and mathematical time-plots called
“kinetics”) during and shortly after LTx. The investigators found that
for a brief period after the old liver is removed, HCV is not
detectable, and infection of the new liver occurs quite early, in fact
at the time of reperfusion (restoration of blood flow by the surgeons)
during the final stages of the LTx operation itself. In general,
pre-LTx viral levels are reached within 4 days post-LTx and continue to
rise until 1-4 months when they reach 10-20 times the pre-LTx levels.
At that point, viral levels begin to fall somewhat (as discussed below)
but they remain significantly higher than those prior to the LTx,
except in cases of FCH where the levels continue to rise inexorably. In
the majority of patients with recurrent HCV post-LTx who don’t develop
FCH, liver enzymes remain close to normal or minimally elevated (unless
rejection of the liver occurs, which must be confirmed by a liver
biopsy and treated appropriately), despite relatively high sustained
viral levels in the bloodstream and liver.
Then, around 1-4 months post-LTx, there is often a marked rise in liver
enzymes during the phase of “acute” hepatitis, which is confirmed
histologically (and usually distinct from acute rejection). Of note,
viral levels in the bloodstream start to fall at this time. This is
thought to be due to the body’s immune response to the virus, although
considerably blunted due to the immunosuppressants the patient is on in
order to prevent rejection. If immunosuppression has been particularly
strong (due to prior episodes of rejection), especially with single or
repeated doses of corticosteroids or OKT3 (a potent immunomodulator),
viral replication can be quite high (no counteracting effect of the
immune system) and the patient is then at significant risk to develop
FCH. Fortunately, in most other cases, viral levels fall at this point
as do liver enzymes, and the patient enters the phase of “chronic”
hepatitis, usually starting around 6 months post-LTx and continuing
indefinitely.
In most
cases of chronic hepatitis, liver enzymes (along with viral levels)
remain stable although elevated during the ensuing months or even
years, and serial liver biopsies show some degree damage albeit mild.
The risk of developing fibrosis and/or cirrhosis is unpredictable, but
tends to be infrequent (10-30%, depending on the transplant center).
Viral levels tend to fall steadily depending on the degree to which the
immune response is restored in any given patient post-LTx, in
conjunction with the common practice nowadays to taper and stop
corticosteroids at this time (i.e., 6 months post-LTx). However, in a
sizeable number of cases, the immune “reconstitution” associated with
tapering immunosuppression may paradoxically worsen liver damage,
leading instead to a more rapid progression to cirrhosis, as the immune
cells try to rid the body of HCV but indirectly damage the liver cells
as “innocent bystanders.” The higher viral levels that persist post-LTx
likely play a major role, as perhaps does the alloimmune (organ
rejection) response. Certain genetic factors such as cytokine
(intercellular mediator) response (e.g., TNF-a), liver steatosis (fat),
and body mass index (as measure of excess total body fat) may also
contribute.
Of interest,
the degree of liver damage associated with recurrent HCV post-LTx
appears to be worse now (since 1995 or 1996) than it was a decade or so
ago. The reason(s) for this remain uncertain but may relate to the use
of more potent immunosuppressants nowadays and also to the common
practice of rapidly tapering and stopping corticosteroids soon after
LTx in the hope that this will ameliorate viral replication and,
indirectly, the liver damage thought to be triggered by it. The use of
induction (prior to LTx) immune therapies to reduce the need for
immunosuppression post-LTx may be beneficial although as yet unproven.
In terms of specific immunosuppressants used post-LTx, tacrolimus and
cyclosporine do not seem to differ appreciably in their effects on
viral replication or post-LTx outcomes. Another newer
immunosuppressant, mycophenylate mofetil, showed some promise as an
anti-HCV agent itself in preliminary studies but this has not panned
out. In fact, a recent study showed that when this drug was used in
conjunction with induction therapy such as anti-interleukin-2 receptor
antibody, it was found to be deleterious.
In terms of anti-HCV treatment, ideally it would be best to clear the
body of HCV prior to the LTx in order to minimize the risk associated
with recurrence. Unfortunately, it is usually quite difficult to treat
patients awaiting LTx due to the low blood counts seen in these cases
due to the large spleen (from congestion related to the liver
cirrhosis) that affects these counts. Post-LTx, the situation is also
not ideal since anti-HCV treatment is not well tolerated for a variety
of reasons. The use of growth factors such as G-CSF (white cell
booster) and epoietin (red blood cell booster) to increase cell counts
is helpful. Overall, post-LTx, standard interferon (IFN) and ribavirin
(RBV) together have led to sustained virologic response (cure) rates of
around 25% post-LTx compared to 40% in ideal non-cirrhotic pre-LTx
patients. The recent introduction of the longer-acting pegylated
infererons (PEG-IFN) and RBV should help improve sustained virologic
response rates to 40% or more. Studies are currently underway to
address this. Nevertheless, when best to intervene with anti-HCV
treatment remains uncertain. Some experts treat “pre-emptively”—before
significant HCV recurrence post-LTx. On the other hand, most
authorities recommend waiting first for histologic damage to occur with
evidence of chronic hepatitis and/or progression in fibrosis before
committing the patient to potentially toxic anti-HCV treatment.
In summary, recurrent HCV post-LTx is becoming an all-to-common
problem. Fortunately, most patients do reasonably well although 10-30%
develop cirrhosis after 5 years or more. Very few have the more
aggressive form of FCH related to markedly elevated viral levels.
Intense research should soon shine a light upon the events that occur
in the new liver during viral infection and the immune response to it,
in order to develop more effective treatment protocols once recurrent
infection has occurred and, ultimately, strategies to prevent
reinfection of the new liver to begin with.
REFERENCES
- Berenguer M, Lopez-Labrador FX, Wright Tl. Hepatitis C and liver transplantation. J Hepatol 2002;35:666-678.
- Berenguer M. Natural history of recurrent hepatitis C. Liver Transplant 2002;8(suppl 1):S14-18.
- McCaughan GW, Zekry A. Pathogenesis of hepatitis C virus recurrence in the liver allograft. Liver Transplant 2002;8(suppl 1):S7-13.
- Rakela J, Vargas HE. Hepatitis C: Magnitude of the problem. Liver Transplant 2002;8(suppl 1):S3-6.
- Gane E. Treatment of recurrent hepatitis C. Liver Transplant 2002;8(suppl 1):S29-37.
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