Kidney and Liver Transplant - Update and Issues
Case 5 -
Recurrent Disease after Liver Transplantation
Arthur H. Cohen, Juan Lechago and Cynthia C. Nast
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The histologic parameters of this biopsy of Case #5 are entirely consistent with recurrent chronic
hepatitis C. The portal infiltrate can also be found in acute cellular rejection, but it lacks the mixed
character that is typical of the rejection mechanism. The lack of significant bile duct damage and
endotheliitis, on the other hand, fails to support the existence of a significant rejection component.
Recurrence of primary disease following liver transplantation is a growing field since, as a result of
significant improvements in both surgical technology and anti-rejection regimes, patient survival has
improved very significantly in the last few years. Obviously, the frequency of recurrent disease varies
with the nature of the primary disease of the recipient. However, detection of such recurrent disease is
often related to the presence of specific markers or histologic features and, in the absence of such
specificity, complex differential diagnosis situations may arise.
Hepatitis B or C?
It is currently accepted that both hepatitis B and C invariably recur in the donor liver as soon as
this is perfused with the recipient's blood. In the case of hepatitis B, the appearance of both core and
surface antigens in hepatocytes is generally accompanied bythe development of acute hepatitis B, followed
by chronic hepatitis and, ultimately, cirrhosis. This process may be slow in some cases and take an
accelerated pace in others, sometimes complicated by hepatocellular carcinoma. A relatively rare and
rapidly progressing form of liver dysfunction after transplantation for hepatitis B has been described.
This entity, which appears 3 to 12 months after transplantation, has been termed fibrosing cholestatic
hepatitis and courses with ballooning and ground glass change of the hepatocytes, marked cholestasis with
canalicular and ductal bile plugs, and periportal fibrosis followed by septal fibrosis and cirrhosis.
These generally unfavorable clinical courses have determined that many authors seriously question the
role of liver transplantation in chronic hepatitis B.
Hepatitis C, by contrast, has a much more protracted course and only about 50% of transplanted livers
present histologic evidence of recurrent hepatitis C. End-stage liver disease associated with HCV
infection is currently the most common indication for liver transplantation in adults. Whereas, in most
instances hepatitis C and even cirrhosis develop eventually, this progression is comparatively slow, the
degree of hepatitis C tends to be mild, and long survivals with good quality of life are increasingly
achieved. In a recent study, it has been noted that HCV genotype 4 is associated with unfavorable
outcomes more frequently whereas HCV genotype 3b portends a more favorable outcome.
Whereas typical, full-blown histologic findings of acute rejection and chronic hepatitis C can be
readily differentiated from each other, mild degrees of either, or coexistence of both, may present
serious problems of differential diagnosis. These difficulties may be compounded by the fact that
anti-rejection therapy may modify the early histopathological features of recurrent hepatitis C. Overt
endotheliitis, specially of terminal hepatic veins, and widespread bile duct damage are indicative of
acute rejection, as has been discussed. However, minor degrees of portal branch endotheliitis and
moderate damage and distortion of bile ducts is also seen in chronic hepatitis C, whereupon the question
of mild rejection may arise in some instances. Likewise, mixed portal infiltrates with eosinophils are
commonly seen in allograft rejection, but can also be present in recurring hepatitis C. The main
parameters of the differential diagnosis between acute rejection and recurrent hepatitis C are tabulated
Differential Diagnosis: Acute Rejection vs. Recurrent HCV
| Findings || Acute Rejection || Recurrent Hcv|
|Mixed portal inflammation, including eos & PMNs ||+/++ ||+/±|
|Predominantly portal mononuclear cells + eos ||-/± ||+/++|
|Bile duct damage ||+/++ ||-/±|
|Endotheliitis (pericentral) ||+/++ ||-/±|
|Centrilobular hepatocyte necrosis & mononuclears ||±/++ ||-/±|
Unusual histologic presentations in recurring hepatitis C include a rare form of fibrosing
cholestatic hepatitis similar to that seen in hepatitis B, and a cholestatic variant, with hepatocellular
necrosis, cholestasis, and bile ductular proliferation, but without widespread fibrosis. Both these
entities also present differential diagnostic problems with bile duct obstruction, as well as chronic
rejection with bile duct destruction.
Liver transplantation for autoimmune hepatitis has been followed by recurrent disease in 30% to 40%
of the cases 35 to 280 days after the transplant. High-grade inflammation in the native liver appears to
be a strong predictor of recurrence. An interesting problem of differential diagnosis has been brought
to light in the last few years, namely the appearance of de novo autoimmune
hepatitis in the liver of patients transplanted for other etiologies. The first report of such
occurrence deals with two adults transplanted because of primary biliary cirrhosis. However, further
data have accrued on the appearance of autoimmune hepatitis in pediatric patients who were given
orthotopic liver transplants for a variety of conditions and who did not have a previous history of
autoimmune hepatitis. It is important to keep this possibility in mind and to look for the parameters
of autoimmune hepatitis because, in pediatric patients, the hepatitis does not respond to the more
commonly used tracrolimus or even cyclosporin and requires treatment with steroids and azathioprine.
Cryptogenic Cirrhosis and NASH
The so-called cryptogenic cirrhosis behaves variously after liver transplantation, probably reflecting
a variety of etiologies. Approximately 20% of such cases of cryptogenic cirrhosis have been associated
with autoimmune hepatitis. Interestingly, another 33% of such cryptogenic cirrhosis cases have been
associated with non-alcoholic steatohepatitis (NASH) and have shown a 22% recurrence rate. Risk factors
for recurrence are obesity, type2 diabetes mellitus and hyperlipidemia.
A subject of considerable controversy is the use of liver transplantation in cases of malignancy of
the liver. The most common malignancy present at the time of transplantation tends to be hepatocellular
carcinoma (HCC). In most cases, the existence of the neoplasm is known at the time of the operation, but
in a few instances, a small HCC is found, somewhat "incidentally," in the explanted liver that had
cirrhosis for another reason. With the exception of the fibrolamellar variant, which has a relatively
favorable evolution, most HCCs that are large and known to be present recur soon after transplantation
and cause the death of the patient between 3 and 36 months from the operation. A study carried out at
the Mayo Clinic several years ago found that the best prognosis in terms of survival applies to patients
with elevated alpha-fetoprotein (AFP) in circulation, but with no visible mass: 80% 2-year disease-free
survival. By contrast, patients with incidental HCC at the time of operation presented 68% 2-year
disease-free survival, and those with a visible mass lesion, the 2-year disease-free survival was only
50%. In patients with known HCC, it has been recently determined that non-resective
ablation therapies are
safe and effective means of reducing the progression of the neoplasm while awaiting transplantation.
Other Examples of Primary Disease Recurrence
Other examples of primary disease recurrence are primary biliary cirrhosis and primary sclerosing
cholangitis. Because of their histopathological and temporal presentation, these entities will be
discussed in Case #6.
Recipient and Donor Factors in Graft Survival
A number of parameters have been identified in an effort to predict the outcome of a liver
transplantation which relate to both, recipient and donor. For example, a recipient who has end stage
liver disease because of alcoholic liver disease poses an interesting ethical problem inasmuch as
persistence of alcohol abuse will surely doom the precious transplanted organ. Whereas alcoholic liver
disease is by itself an excellent indication for liver transplantation, recent studies reveal that the
period of documented alcohol abstinence prior to the operation is very significant. Patients who were
abstinent for less than 6 months had a recurrence rate of 65% accompanied by significant mortality. By
contrast, when abstinence was for 6-12 months the recurrence rate was 11.8% and 2 year-plus abstinence
resulted in a recurrence rate of 5.5%.
Other factors related to the recipient that portend unfavorable outcomes, particularly when more than
two such factors are present in the same patient, include Child classification of liver insufficiency,
preoperative gastrointestinal bleeding, mechanical ventilation, hemodialysis, and requirement for
catecholamines. All of these have been found to be significant in the rate of development of the so
called multiple organ dysfunction syndrome (MODS), a quantitable parameter
with prognostic value. The Model of End-Stage Liver Disease (MELD) score, an accurate predictor of
survival in patients awaiting liver transplantation, has also been applied to the assessment of
progression after transplantation. It has been found that the survival without bridging fibrosis in the
allograft at one year post transplantation is significantly lower in patients with higher MELD scores.
Regarding the donor, the status of the transplanted liver has proven to be significant in the
development of the so-called primary non-function (PNF). After some debate,
it seems reasonably established that, in the absence of active hepatitis or other obvious disqualifiers,
the degree and type of steatosis is a highly reliable predictor for the occurrence of PNF.
Interestingly, it has been determined that microvesicular steatosis by itself is of little significance,
a fortunate fact since this is sometimes a feature very difficult to demonstrate using routine stains
during an intraoperative consultation. Macrovesicular steatosis has proven to be a defining parameter:
whereas low degrees of macrovesicular steatosis in the donor liver (up to an estimated 30% of hepatocytes
involved) did not result in the development of PNF to a significant degree, moderate (30-60% involvement)
and severe (over 60%) macrovesicular steatosis resulted in poor outcomes. Other factors, such as
advanced age of the donor, length of time in intensive care prior to death, and others appear to have
some influence, but have not been accurately assessed as independent predictors.
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