THE SPECTRUM OF RECURRENT HCV AFTER LIVER TRANSPLANTATION

S. G. Hübscher

From the Department of Pathology, The Medical School, University of Birmingham, Birmingham B15 2TT, UK

Incidence and Risk Factors
The great majority (more than 90%) of patients with chronic hepatitis C virus infection who undergo liver transplantation have virological markers of recurrent infection post-transplant (1). HCV RNA can be detected in serum within a few days of transplantation and may reach levels up to 100 times those present pre-transplant during the first 2-3 months post-transplant (2). Many patients remain asymptomatic with good graft function during the first 12 months post-transplant, but most eventually develop features of recurrent disease.
Three main risk factors predisposing to more severe liver disease have been identified: HCV genotype (type 1b); number and severity of acute rejection episodes and the amount and type of immunosuppression used to treat them; and levels of viraemia (3-6).
A number of histological features seen in early post-transplant biopsies may also be predictive of more aggressive disease behaviour. These include severity of necro-inflammatory activity (periportal and/or lobular), presence and/or severity of macrovesicular steatosis and the presence of prominent hepatocyte ballooning and/or cholestasis (3,6-9)

Histopathological Features and Natural History
Typical features of HCV infection, as seen in the non-transplanted liver, occur in the majority of cases. Three main phases can again be identified. During the early phase of re-infection (1-3 months), when viral RNA levels are already high, inflammatory changes attributable to HCV are rarely present. However fatty change and scattered acidophil bodies are commonly seen and may be a manifestation of early HCV re-infection (8,10). HCV antigens have also been detected immunohistologically within the first month of transplantation (3). The next phase is one of a mild lobular hepatitis,typically occurring two to four months post transplant. (1,3,7). The third phase of chronic hepatitis is typically seen more than 6 months post-transplant and is associated with histological features resembling those seen in chronic HCV infection of the non-transplanted liver.
There is increasing evidence to suggest that HCV infection also behaves more aggressively in the liver allograft than in the non-transplanted liver. More severe degrees of necroinflammatory activity have been noted, including cases with confluent and bridging necrosis, which are very uncommonly seen in the non-transplant setting. There is also more rapid progression to fibrosis and cirrhosis. The actuarial risk of developing cirrhosis in 3 large series ranged from 8-28% at 5 years (3,5,6). A case of de novo hepatocellular carcinoma occurring in association with recurrent HCV cirrhosis, 7 years after transplantation, has also been reported (11).
A number of atypical histological manifestations of recurrent HCV infection have been recognised. These include diffuse hepatocyte ballooning without a conspicuous inflammatory reaction and an aggressive cholestatic syndrome resembling fibrosing cholestatic hepatitis B infection (12-15). These atypical patterns are also likely to reflect uncontrolled viral replication occurring in an immunocompromised individual resulting in direct cytopathic damage to liver cells. The associated findings of high serum titres of HCV RNA (15) and diffuse cytoplasmic expression of HCV RNA (16) further support this hypothesis.

Hepatitis C Infection and Rejection
An overlap exists between the histological changes seen in recurrent HCV infection and acute cellular rejection and distinction between these two processes is a common problem in the assessment of post-transplant biopsies from patients transplanted for HCV-related liver disease. Some of the features that may be helpful in distinguishing recurrent HCV hepatitis from acute cellular rejection are summarised in the Table below. TABLE : Comparison of histological changes occurring in hepatitis C infection and acute cellular rejection of the liver allograft

(A) PORTAL AND PERIPORTAL CHANGES

	HEPATITIS C	REJECTION
PORTAL INFLAMMATION	MONONUCLEAR CELLS (lymphoid aggregates)	MIXED INFILTRATE (lymphocytes, macrophages, blast cells neutrophils, eosinophils)
INTERFACE HEPATITIS	VARIABLE	MILD
BILE DUCT INFLAMMATION	MILD (lymphocytes)	PROMINENT (mixed infiltrate)
BILE DUCT LOSS	MINIMAL/NONE	VARIABLE (in cases progressing to chronic rejection)
VENOUS ENDOTHELIAL INFLAMMATION	NONE/MILD	YES
FIBROSIS	YES	NO

(B) PARENCHYMAL CHANGES

	HEPATITIS C	REJECTION
PARENCHYMAL INFLAMMATION pattern distribution associated features	GENERALLY MILD spotty random lobular disarray	GENERALLY MILD confluent zonal (acinar zone 3) hepatic vein endothelial inflammation
CHOLESTASIS	RARE (except FCH-like cases)	COMMON
FATTY CHANGE	YES (macrovesicular)	NO
ACIDOPHIL BODIES	COMMON	LESS COMMON
OTHER FEATURES	sinusoidal dilatation

The timing of events is probably most helpful in deciding if cellular infiltrates in the liver are due to rejection or hepatitis C. The majority of acute rejection episodes (approximately 90%) occur in the first month post transplant, a time at which HCV-related inflammatory changes are unlikely to be present. Conversely, in the majority of biopsies taken more than 6 months post-transplant, portal inflammatory changes can be ascribed to recurrent HCV infection. In some cases where distinction between cellular rejection and HCV hepatitis proves to be difficult histologically, it is likely that both conditions are present simultaneously.
A higher than expected incidence of chronic (ductopenic) rejection has been reported in some studies of recurrent HCV infection (17-20). However, the precise relationship between these two processes is unclear .
Histological Grading and Staging
The scoring systems which are used in the histological assessment of chronic hepatitis C in the non-transplanted liver can also be applied to post-transplant liver biopsies. However, because there are other potential causes of inflammation in the liver allograft, particularly rejection, histological scoring of necroinflammatory activity and fibrosis in post-transplant biopsies should only be done when changes present can be attributed to recurrent HCV infection alone.
Other Causes of Post-transplant Chronic Hepatitis
Approximately 20-40% of patients biopsied more than 12 months following transplantation have histological features of chronic hepatitis, not obviously related to recurrent viral disease (21-24). A number of possible aetiological factors have been considered including viral agents (acquired hepatitis B or C, hepatitis G, Epstein -Barr virus), autoimmune disease (recurrent or acquired) or a drug reaction. However, in the absence of any other obvious identifiable cause, the possibility that "idiopathic" chronic hepatitis represents a modified form of rejection has also been considered. In support of this hypothesis, previous studies have suggested that late cellular rejection may have different histological findings to those typically seen in early acute rejection (25,26). These include less conspicuous bile duct inflammation and venular endothelial inflammation, more prominent interface hepatitis, and more prominent lobular hepatitis with spotty necrosis. If a chronic hepatitic form of rejection does exist this has important diagnostic implications for HCV positive patients, in whom distinction from recurrent infection may be difficult or impossible.
Further Points for Consideration
A number of problems that occur in the assessment of post-transplant biopsies from HCV positive patients would benefit from further investigation. These include the following:
(1) Early diagnosis of recurrent HCV infection, including features predictive of more aggressive behaviour (e.g. fatty change)
(2) Distinction between recurrent HCV and cellular rejection in biopsies taken during the first few months following liver transplantation. Recognition and management of cases in which a dual pathology exists.
(3) Use of immunohistochemistry for detecting HCV antigens in routinely processed tissues;
(a) as a diagnostic and prognostic marker in cases of "typical" recurrent HCV infection
(b) in the identification of atypical patterns related to uncontrolled viral replication
(4) Investigating the relationship between typical hepatitic changes and atypical cytopathic changes in recurrent HCV infection. Recognition and management of cases in which a component of both patterns appears to be present.
(5) Distinction between recurrent HCV and rejection-related chronic hepatitic changes in biopsies taken more than 6-12 months following liver transplantation.

References
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  University of Pittsburgh.