Clinical History
The patient, a 48-year-old African-American male,
underwent orthotopic liver transplantation for end-stage liver disease due to chronic hepatitis C. The
postoperative course was uneventful except for a single episode of biopsy-documented acute cellular
rejection 20 days after transplantation. Eight months post-transplantation liver function tests
demonstrated mildly increased animotransferases, and a liver biopsy was performed.
Diagnosis: Recurrent Hepatitis C
Pathologic findings: The liver biopsy shows a portal inflammatory
infiltrate, which is composed mainly of small lymphocytes admixed with scattered eosinophils and plasma
cells. There is focal interface activity, and occasional bile ducts demonstrate infiltration by
lymphocytes. In addition, there is scattered lobular lymphocytic inflammation associated with hepatocyte
damage. Endothelialitis is not identified.
Discussion
The majority of causes of primary liver failure may recur in the liver allograft. The
propensity of hepatitis B and hepatitis C to recur is well established, and though somewhat
controversial, convincing recurrence of autoimmune hepatitis, primary biliary cirrhosis, and sclerosing
cholangitis has been documented. In addition, recurrent nonalcoholic steatohepatitis in the liver
allograft has been described. Recurrent disease may cause significant injury and is a major cause of
late liver allograft failure. Accordingly, the possibility of disease recurrence must be part of the
evaluation of all liver allograft biopsies. This is especially challenging because recurrent disease and
many transplant-specific insults share clinical, biochemical, and histologic features. As a practical
point, when evaluating liver allograft biopsies, the pathologist should be aware of the original liver
disease because of this possibility of disease recurrence.
Due to their overlapping histologic features, one of the most difficult diagnostic problems in the
review of liver allograft biopsies is the differentiation of recurrent hepatitis C from acute cellular
rejection (ACR). This is also one of the most common problems, because hepatitis C-related liver failure
is the leading indication for liver transplantation and because ACR and recurrent hepatitis C occur
frequently in the liver allograft. Clinically, the distinction between ACR and recurrent hepatitis C is
particularly important because the treatments are significantly different. As such, recurrent hepatitis
C will be the focus of this discussion.
Recurrence of hepatitis C virus infection in the liver allograft is virtually universal in patients
with pretransplant viremia. Histologic evidence of recurrence occurs in approximately 50% of patients
within the first year after transplantation, and this figure increases to 90% for patients with 5-year
follow-up. The natural history of this re-infection, however, is highly variable. In 20%-30% of these
patients, the degree of injury and histologic progression of the chronic infection is slow, with the
recurrent hepatitis C following a relatively indolent clinical course. At the other end of the disease
spectrum, in 15%-30% of patients, the recurrent hepatitis C progresses to cirrhosis by 5 years
post-transplantation. Accordingly, hepatitis C virus (HCV) infection post-liver transplantation
generally is more aggressive and is associated with a more rapid progression to cirrhosis and subsequent
liver failure in comparison to HCV infection in immunocompetent individuals, where the progression to
cirrhosis often is measured in decades. Furthermore, recent studies have shown that long-term allograft
and patient survival are worse in HCV-infected transplant recipients compared to non-HCV infected
transplant recipients.
The initial round of infection of the allograft by HCV appears to occur during reperfusion of the
liver at the time of transplantation. Serum viral levels reach pre-transplantation levels by
post-operative day 4, and they then increase over the ensuing weeks to reaching a plateau approximately 1
month after transplantation. Neither the levels of viremia nor the liver enzyme levels, however,
correlate with the histologic features. Accordingly, the diagnosis of recurrent hepatitis C is based on
the histologic findings of the allograft biopsy.
Recurrent hepatitis C initially presents as an acute hepatitis, and it subsequently progresses to
chronic hepatitis in the vast majority of patients. Many of the histologic features seen either in the
acute phase or the chronic phase are the same as those of hepatitis C in immunocompetent patients. The
earliest histological evidence of recurrent hepatitis C usually is detected 1 month to 3 months
post-transplantation, but it first may be seen as late as 9 months after transplantation. It typically
presents as a mild acute lobular hepatitis characterized by scattered sinusoidal lymphocytes, spotty,
single cell hepatocyte necrosis, occasional acidophil bodies, and lobular disarray. These finding often
are so subtle as to be overlooked upon microscopic evaluation of the allograft biopsy. Chronic hepatitis
develops an average of 11 months post-transplantation, with a range of 3 months to 40 months after
transplantation. This usually presents as the prototypical portal and lobular lymphocytic hepatitis with
interface activity, scattered lobular hepatocyte necrosis and acidophil bodies. Portal lymphocyte
aggregates are present in up to 75% of cases, especially in cases of longer duration. Atypical
histologic findings that are seen occasionally include centrilobular hepatocyte necrosis and
cholestasis. Of note, a recent study reported that macrovesicular steatosis is a highly sensitive,
though not specific marker for recurrent hepatitis C.
A severe and rapidly progressive form of disease recurrence has been described in 4% to 9% of
patients transplanted for end-stage liver disease due to hepatitis C. Instead of developing chronic
hepatitis, as described above, these patients progress from acute hepatitis to an aggressive, unrelenting
form of cholestatic liver injury. This so-called "cholestatic hepatitis C" is similar to the fibrosing
cholestatic hepatitis seen in some cases of hepatitis B virus recurrence in the liver allograft.
Cholestatic hepatitis C usually begins 1 month after transplantation, and it follows a rapidly
progressive course, with allograft failure occurring within the first 2 years after transplant.
Allograft failure is uniform. Clinically, cholestatic hepatitis C presents as progressive jaundice with
biochemical cholestasis (i.e. elevated bilirubin, alkaline phosphatase, and gammaglutamyltransferase).
Cholestatic hepatitis C histologically is characterized by severe cholestasis (intraheptocytic,
intracanalicular, central bile plugs), extensive periportal fibrosis with progression to bridging
fibrosis, and hepatocyte ballooning and necrosis. A lobular inflammatory infiltrate may be present, but
the portal lymphoplasmacytic infiltrate of typical recurrent chronic hepatitis C often is mild or
absent. Bile ductular proliferation may be present, thereby mimicking large duct obstruction.
Cholestatic hepatitis C consistently is associated with very high viral levels, which are greater than
those seen in routine recurrent chronic hepatitis C. This syndrome appears to reflect "immune escape" by
the virus, and evidence indicates that the HCV may be directly cytopathic in this condition.
Differentiation of recurrent hepatitis C from acute cellular
rejection
The differentiation of recurrent hepatitis C from ACR is a common and challenging problem in liver
allograft biopsy interpretation. Since recurrence of hepatitis C virus infection in the liver allograft
is virtually universal, post-transplantation measurements of serum HCV-RNA do not differentiate recurrent
hepatitis C from ACR. Furthermore, patterns of liver enzyme abnormalities typically cannot distinguish
between these disease processes. Accordingly, the interpretation of the liver allograft biopsy is
crucial in establishing the final diagnosis and guiding clinical management. Unfortunately, histologic
distinction between recurrent hepatitis C and ACR can be quite difficult due to the presence of similar
morphologic features. Of note, while recurrent hepatitis C can manifests as an acute hepatitis, a
chronic hepatitis, or a cholestatic hepatitis, as described above, it is the chronic form of the
recurrent disease that is difficult to distinguish from ACR.
The post-transplantation time interval can provide some information that is useful for making the
distinction between recurrent hepatitis C and ACR. Acute cellular rejection usually occurs much earlier
than the chronic phase of recurrent hepatitis C. Specifically, most cases of ACR occur within the first
2 months post-transplantation, whereas recurrent chronic hepatitis C develops later. As such, a biopsy
with portal tract and bile duct inflammation within the first 2 months post-transplantation is much more
likely to be ACR than recurrent chronic hepatitis C. The acute lobular phase of recurrent hepatitis C
often occurs during this early post-transplant period, but it is not likely to be confused histologically
with ACR. Alternatively, in the absence of evidence of inadequate immunosuppression, the diagnosis of
ACR later than 2 months post-transplantation is less likely, however, exceptions do occur.
Subtle qualitative and quantitative differences in the overlapping histological features of recurrent
hepatitis C and ACR help to distinguish between these two entities. While portal tract inflammation
typically is present in both conditions, in ACR the infiltrates are more polymorphous than those of
recurrent hepatitis C. Specifically, the inflammatory infiltrate in ACR is composed of large, activated
blastic lymphocytes and eosinophils admixed with the small lymphocytes. In HCV infection, however, the
portal infiltrate is composed predominantly of uniform small mature lymphocytes, with only sparse
eosinophils, if they are present at all. Also, portal lymphoid aggregates and lobular inflammation
commonly are present in recurrent hepatitis, but they are not typically seen in ACR. In addition,
depending on the level of disease activity, interface hepatitis may be seen in recurrent hepatitis C, but
is not a typical feature of ACR. While both recurrent hepatitis C and ACR may cause lymphocyte-mediated
bile duct damage, the damage associated with recurrent hepatitis C is milder and focal in comparison to
that due to ACR. Similarly, while endothelialitis may be seen in both conditions, it is more extensive
and more severe in cases due to ACR than those associated with recurrent hepatitis C. Of note, while not
specific for recurrent hepatitis C, macrovesicular steatosis has been reported to be a sensitive marker
for disease recurrence.
References
- Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C and liver transplantation. J Hepatol 2001;35:666-678.
- Baiocchi L, Tisone G, Palmieri G, et al. Hepatic steatosis: A specific sign of hepatitis C reinfection after liver transplantation. Liver Transpl Surg 1998;4:441-447.
- Greenson JK, Svoboda-Newman SM, Merion RM, Frand TS. Histologic progression of recurrent hepatitis C in liver transplant allografts. Am J Surg Pathol 1996;20:731-738.
- McCaughan GW, Zekry A. Pathogenesis of hepatitis C virus recurrence in the liver allograft. Liver Transpl 2002;8:S7-S13.
- Rakela J, Vargas HE. Hepatitis C: Magnitude of the problem. Liver Transpl 2002:8;S3-S6.
- Schluger LK, Sheiner PA, Thung SN, et al. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation. Hepatol 1996;23:971-976.
- Taga SA, Washington MK, Terrault N, et al. Cholestatic hepatitis C in liver allografts. Liver Transpl Surg 1998;4:304-310.
