Recurrent and de novo Diseases in the Allograft Liver
Stefan G. Hübscher
University of Birmingham
With many people now surviving long term following liver transplantation, problems relating to disease
recurrence are becoming increasingly important. The majority of diseases for which liver transplantation
is carried out in the adult population have the potential to recur in the liver allograft. However, the
incidence and clinical impact of disease recurrence varies widely:
| DISEASE RECURRING || INCIDENCE|
|HEPATITIS B ||15 - 85% (much less common in recent years)|
|HEPATITIS C ||>90%|
|PBC ||8 - 75%|
|NEOPLASIA ||HCC : 30 - 50 %|
Cholangiocarcinoma : up to 90%
|AUTOIMMUNE HEPATITIS ||11-83%|
|ALCOHOL ||10 - 30%|
|NASH ("cryptogenic" cirrhosis) ||22 - 37%|
There are two important factors, which influence the histological diagnosis of recurrent disease in
the liver allograft. Firstly, there may be similarities to - and/or interactions with other
complications of liver transplantation. A good example of this is the complex relationship which exists
between hepatitis C and acute cellular rejection. Secondly, the immunosuppressive therapy which is
routinely used in liver transplant patients may modify disease severity - diseases which are thought to
be immune mediated (e.g. autoimmune hepatitis or primary biliary cirrhosis) might be prevented from
recurring or progress more slowly whereas viral infections might be expected to behave in a more
This talk will focus on a number of diseases where liver biopsy assessment plays a particularly
important role in the diagnosis and management of disease recurrence in the liver allograft.
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 . 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  and long-term survival is now comparable to that seen in other indications for
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 . 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 . It is now recognised
that complications of recurrent disease are associated with a significant reduction in graft and patient
survival in HCV-positive patients .
Histological features of HBV and HCV infection in the liver allograft are generally similar to those
seen in the non-transplanted liver . 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
. A case of de novo hepatocellular carcinoma occurring in
association with recurrent HCV cirrhosis, 7 years after transplantation, has also been reported ,
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 . 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 . 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 . 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
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 . Prevalence rates of disease recurrence are in the region of 10-50% for PBC and 10-30%
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
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
Autoimmune hepatitis (AIH)
Approximately 20-30% of patients undergoing liver transplantation for AIH will develop features of
disease recurrence . 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 . 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
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 
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
Autoantibodies arising de novo following liver transplantation have also been noted in association with
episodes of rejection
. 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 . 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
. 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
. 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
Drug toxicity in the liver allograft
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
Liver toxicity related to immunosuppressive agents 
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
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 .
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