DISEASE RECURRING	INCIDENCE
HEPATITIS B	15 - 85% (much less common in recent years)
HEPATITIS C	>90%
PBC	8 - 75%
PSC	8-27%
NEOPLASIA	HCC : 30 - 50 % Cholangiocarcinoma : up to 90%
AUTOIMMUNE HEPATITIS	11-83%
ALCOHOL	10 - 30%
NASH ("cryptogenic" cirrhosis)	22 - 37%

Chronic viral hepatitis (HBV and HCV)
In early post-transplant series the incidence of recurrent HBV infection was approximately 50%, resulting in a significant reduction in graft and patient survival [2]. The main risk factor for disease recurrence was the presence of active viral replication at the time of transplantation. The use of effective anti-viral therapies pre-and post-transplant has greatly reduced the impact of HBV infection in the liver allograft [3] and long-term survival is now comparable to that seen in other indications for liver transplantation.

Chronic HCV is now the commonest indication for liver transplantation in many centres. Re-infection is universal and in the majority of cases is associated with graft inflammation [4]. Risk factors for more severe disease in the liver allograft include high viral titres (pre- and post-transplant), acute rejection, amount and type of immunosuppression given and viral genotype 1b [5]. It is now recognised that complications of recurrent disease are associated with a significant reduction in graft and patient survival in HCV-positive patients [6].

Histological features of HBV and HCV infection in the liver allograft are generally similar to those seen in the non-transplanted liver [7]. However, disease severity is considerably greater in the liver allograft than in the native liver, presumably related to effects of immunosuppression. Histologically, more severe degrees of necroinflammatory activity are frequently present, including areas of confluent and bridging necrosis. There is also more rapid progression to fibrosis and cirrhosis. Occasional cases progress to cirrhosis within 1-2 years of transplantation , 10-30% of cases are cirrhotic 5 years post transplant, and 50% by 10 years [8, 9] . A case of de novo hepatocellular carcinoma occurring in association with recurrent HCV cirrhosis, 7 years after transplantation, has also been reported [10], again supporting the concept of accelerated disease progression in the liver allograft .

Areas of overlap exist between recurrent HCV infection and acute cellular rejection and the distinction between these two conditions is one of the most common problems in the assessment of post-transplant biopsies [1]. In many cases where the changes present are difficult to interpret histologically, it is likely that a combination of HCV- and rejection-related changes are present. HCV infection has been recognised as a risk factor for chronic (ductopenic) rejection suggesting that HCV may augment immune-mediated bile duct destruction in the liver allograft.

A rare severe cholestatic syndrome – "fibrosing cholestatic hepatitis" – has been described in a small number of cases of recurrent HBV infection [11]. FCH tends to occur in the first few months following transplantation and in most cases has a poor outcome. Similar cholestatic changes have also been reported in some cases of recurrent HCV infection [4]. Histological features include prominent hepatocyte ballooning and cholestasis with generally mild or absent inflammatory changes. These cholestatic syndromes are typically associated with high levels of viral replication and high tissue expression of viral antigens suggesting direct cytopathic injury to hepatocytes in the setting of imunosuppression.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)
It is now generally accepted that both of these chronic cholestatic diseases can recur in the liver allograft [12]. Prevalence rates of disease recurrence are in the region of 10-50% for PBC and 10-30% for PSC.

Most cases of recurrent PBC have been diagnosed on the basis of histological findings in late post-transplant biopsies, many of which have been obtained on a protocol basis. Changes are similar to those seen in the non-transplanted liver and include granulomatous cholangitis, bile duct loss, periportal inflammation and ductular reaction. In cases where inflammatory bile duct lesions are not seen, distinction from other graft complications associated with bile duct loss (e.g. chronic rejection) may occasionally be difficult. Most cases have mild asymptomatic disease, but a few patients have developed progressive fibrosis and in occasional cases this has led to an established cirrhosis and the need for re-transplantation [13, 14] .

The diagnosis of recurrent PSC is difficult as similar radiological and histological features have also been documented as a manifestation of ischaemic cholangitis. However, a number of studies (including some "blinded" to the original diagnosis) have shown that histological and/or radiological features of sclerosing cholangitis are more commonly seen in patients transplanted for PSC than in those transplanted for other diseases [15, 16, 17] .

Autoimmune hepatitis (AIH)
Approximately 20-30% of patients undergoing liver transplantation for AIH will develop features of disease recurrence [18]. The criteria which have been used to diagnose recurrent AIH in the liver allograft are similar to those which have been used in the non-transplanted liver and include, in varying combinations, biochemical changes (raised serum transaminases), serological abnormalities (positive autoantibodies and hypergammaglobulinaemia), histological features ( including portal hepatitis with numerous plasma cells and prominent interface activity] and steroid dependency [19]. However, the sensitivity and specificity of these various criteria for AIH is less in the setting of liver transplantation due to the presence of other factors such as immunosuppression and the alloimmune response to graft antigens. In many cases where recurrent AIH appears to be related to under-immunosuppression, biochemical and histological features rapidly resolve once adequate immunosuppression is restored. However, AIH may be associated with more aggressive behaviour including progression to cirrhosis and graft failure and the need for retransplantation.

Non-alcoholic steatohepatitis (NASH)
In recent years NASH has been recognised as an increasingly important cause of chronic liver disease, in some cases leading to cirrhosis and the need for liver transplantation. Most cases are associated with factors related to insulin resistance, such as obesity and diabetes mellitus. These factors frequently persist following liver transplantation, predisposing to NASH recurring in the liver allograft [20, 21, 22]

De Novo Disease

Acquired viral hepatitis (HBV and HCV)
Infection with these two viruses may be acquired from the donor liver, from blood products or rarely from other sources. Histological features are similar to those seen with recurrent viral infection (discussed earlier], although acquired disease generally behaves less aggressively [1]

Acquired autoimmune hepatitis
Recent studies have shown that classical biochemical, serological and histological features of autoimmune hepatitis may develop in patients transplanted for diseases other than AIH [23, 24] . Autoantibodies arising de novo following liver transplantation have also been noted in association with episodes of rejection [25, 26] . The mechanisms underlying these observations are uncertain, but they raise questions regarding the concept of recurrent autoimmune hepatitis and the utility of autoantibodies as a marker of disease recurrence.

Acquired non-alcoholic steatohepatitis (NASH)
Cases of NASH, apparently arising de novo following liver transplantation have been reported [27]. Some of these, which have developed following liver transplantation for "cryptogenic" cirrhosis, might be better regarded as recurrent rather than acquired disease. The liver transplant operation itself is also associated with risk factors for insulin resistance (e.g.weight gain, diabetogenic properties of some immunosuppressive drugs)

Other changes in late post-transplant biopsies
Changes related to recurrent disease are the commonest diagnosis in late post-transplant biopsies [28, 29, 30] . Other graft complications such as rejection or biliary obstruction may also be seen less frequently. There are also a number of other changes not obviously related to disease recurrence or other recognised graft complications. These include miscellaneous vascular and/or structural abnormalities such as sinsusoidal dilatatation and nodular regenerative hyperplasia and unexplained chronic hepatitic changes, discussed further below.

"Idiopathic" post-transplant chronic hepatitis
Features of chronic hepatitis, for which no obvious cause can be identified have been observed in approximately 20-40% of patients biopsied as part of routine annual review [1, 18, 29, 31, 32] . Most cases are asymptomatic with normal or only mildly deranged liver biochemistry, usually a mild transaminitis. A small number of cases have developed rapidly progressive graft failure associated with histological features of multiacinar necrosis Approximately 5% of patients followed up for a minimum of 10 years have developed progressive fibrosis resulting in an established cirrhosis.

In the absence of any other identifiable cause, the possibility of chronic hepatitis representing a modified form of rejection should be considered. By definition, typical features of acute (cellular) or chronic (ductopenic) rejection are not seen in cases diagnosed as chronic hepatitis. However, some biopsies with predominantly hepatitic features have other changes raising the possibility of rejection. In addition, there is a suggestion that late cellular rejection may be associated with histological changes which are different to those typically seen in early acute rejection and more closely resemble those occurring in chronic viral or autoimmune hepatitis [28, 33] .

Drug toxicity in the liver allograft
General Considerations
A number of the drugs which are routinely administered to people undergoing liver transplantation are potentially hepatotoxic. The diagnosis of drug toxicity in liver allograft recipients is difficult due to problems in distinguishing it from other complications of liver transplantation. Minor degrees of drug-induced liver injury are probably often overlooked in another cause for graft injury is apparent.

In addition to causing hepatotoxic reactions, immunosuppressive drugs may play an important role in modulating disease severity in recurrent viral infection and autoimmune disease (discussed earlier). Some drugs (e.g. Cyclosporin) may predispose to development of 'de novo' AIH

A detailed discussion of all of the drug reactions which may potentially occur in the liver allograft is beyond the scope of this talk. Brief consideration will be given here to liver damage caused by immunosuppressive agents.

Liver toxicity related to immunosuppressive agents [1]
Cyclosporin A has been associated with minor biochemical derangements in patients undergoing renal, bone marrow and cardiac transplantation. Histological manifestations of CyA toxicity are not well documented, but in rare cases where liver biopsies have been obtained, minor abnormalities, predominantly involving centrilobular (zone 3) regions, have been described. These include hepatocyte ballooning, cholestasis and spotty hepatocellular necrosis. CyA has been shown in experimentally to enhance hepatocyte regeneration and has been postulated as a possible cause of otherwise unexplained nodular changes in late post-transplant biopsies .

Azathioprine has been associated with a range of lesions related to vascular and/or sinusoidal endothelial cell injury. These include sinusoidal dilatation and peliosis hepatis, veno-occlusive disease, centrilobular (zone 3) necrosis and nodular regenerative hyperplasia Other liver lesions which have been attributed to azathioprine include cholestasis and mild hepatitic changes

Corticosteroids have been implicated in the pathogenesis of NRH occurring in the liver and in other allograft .

Tacrolimus (FK506) has hepatotrophic effects and has been suggested as a possible cause of nodular changes in late post-transplant biopsies. It has also been implicated in the pathology of centrilobular necrosis in the liver allograft .

References

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