De Novo Autoimmune Hepatitis after Liver

Transplantation
Maria Guido, M.D.,1 and Patrizia Burra, M.D.2

ABSTRACT

Allograft dysfunction with clinical, serologic, and histologic features resembling

autoimmune hepatitis (AIH) may develop in pediatric and adult patients who have received
a liver transplant (LT) for end-stage diseases other than AIH. This condition is now
known as de novo AIH, although its pathophysiology is still uncertain and whether it

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represents a specific type of rejection or a genuine form of AIH is under debate. The
occurrence of de novo AIH seems to be unrelated to the etiology of the disease
necessitating liver transplantation, but it has been correlated with antiviral treatment in
cases of hepatitis C virus (HCV) infection recurring after LT. Several investigators have
reported adverse outcome of de novo AIH, including graft failure, particularly in cases with
late diagnosis. Prompt treatment with prednisone, with or without azathioprine (in
addition to the basic immunosuppressive regimen), seems to be the best option. The
histology of de novo AIH is characterized by an infiltrate rich in plasma cells with
significant interface hepatitis and perivenular necro-inflammatory activity. These features
are not specific for autoimmune damage; therefore, other causes of graft dysfunction must
be excluded. The final diagnosis may be a challenge in patients with recurrent hepatitis C,
and requires careful clinical and pathologic assessment.

KEYWORDS: Autoimmune hepatitis, liver transplantation, histology

D e novo autoimmune hepatitis (AIH) is a rare
condition, occurring late after liver transplantation,
characterized by histologic and clinical features indis-
tinguishable from those of classic AIH, and affecting
patients transplanted for end-stage diseases other than
AIH.
The condition was first described in children in
1998 at King’s College Hospital in London, where the
term ‘‘de novo AIH’’ was coined.1 De novo AIH was
found to develop at a median of 24 months after liver
transplant (LT) and to be histologically characterized by
portal lymphocytic and plasma cell inflammation with
interface hepatitis, bridging and perivenular necrosis,
without the typical features of acute or chronic rejection.
All of the children affected had high titers of serum
autoantibodies, including antinuclear (ANA), anti-
smooth muscle (SMA), antigastric parietal cell, and
atypical antiliver/kidney microsome (LKM) antibodies,
associated with elevated serum immunoglobulin G
(IgG); none of the patients had been transplanted for
AIH. The condition was treated successfully with the
protocol therapy for AIH (steroids and azathioprine).
Shortly after that first report, a similar dysfunction was
described in adults2: 7 of 1000 LT patients developed the
complication after a period ranging from 3 months to
7 years; here again, none had been transplanted for AIH,

1
Department of Medical Sciences and Special Therapies - Pathology
Unit; 2Department of Gastroenterological and Surgical Sciences, Uni-
versity of Padova, Padova, Italy.
Address for correspondence and reprint requests: Maria Guido,
M.D., Istituto di Anatomia Patologica, Via Gabelli, 61, 35100 Padova
(e-mail: mguido@unipd.it).
Contemporary Issues in Liver Pathology; Guest Editors, Swan N.
Thung, M.D., and Prodromos Hytiroglou, M.D.
Semin Liver Dis 2011;31:71–81. Copyright # 2011 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0031-1272834.
ISSN 0272-8087.
71
72 SEMINARS IN LIVER DISEASE/VOLUME 31, NUMBER 1 2011
but 1 had primary biliary cirrhosis (PBC) and 2 had
primary sclerosing cholangitis (PSC). As in the pediatric
cases, the adults had high titers of serum autoantibodies
(anti-LKM, ANA, or AMA antibodies at titers > 1/80)
and high IgG levels when the complication developed,
and their liver biopsies showed changes compatible with
an autoimmune-type hepatitis. The patients were
treated by reintroducing steroids (in cases in which
steroids had been withdrawn) and azathioprine, or by
adjusting their basic immunosuppressive regimen; none-
theless, two patients developed cirrhosis and lost their
grafts, requiring retransplantation. Although the authors
of this second report also came from King’s College
Hospital, they did not call this complication de novo
AIH, but used the term ‘‘graft dysfunction mimicking
AIH,’’ suggesting that it might represent a form of
rejection.
Other cases have since been described by vari-
ous groups in both children and adults, and after LT
from either living or cadaveric donors, performed for
end-stage diseases of different etiologies.3–11 In pa-
tients transplanted for hepatitis C virus- (HCV-)
related cirrhosis, the occurrence of de novo AIH has
been associated with the antiviral treatment for re-
current HCV infection.12 All reported series have in
common the finding of histologic lesions consistent
with AIH, namely interface hepatitis and portal in-
flammatory infiltrate rich in plasma cells, with or
without centrilobular necrosis. These lesions are not
specific for autoimmune damage, however, not even in
native livers; a broad spectrum of diseases must be
considered in the differential diagnosis. This spectrum
becomes even broader in the post-LT setting, where
not only unique complications (such as rejection) may
occur, but immunosuppression may alter the type and
severity of liver damage. Combined with the unsolved
question of whether de novo AIH is a true auto-
immune disease or a type of rejection, this makes the
disease difficult to deal with in routine practice.
Because prompt treatment with steroids, with or
without azathioprine or an adjustment of the basic
immunosuppressive regimen have induced a marked
improvement in most cases, it is important to be aware
of the existence of this condition and to make every
effort to diagnose it without delay because this may
save grafts and patients.
PATHOGENESIS
The pathogenesis of de novo AIH is still unclear. The
designation ‘‘autoimmune’’ is based on similarities with
classic AIH, although it has not been demonstrated that
similar phenotypes coincide with the same diseases. The
concept of autoimmunity per se after LT could be (and
has been) considered an oxymoron because autoimmun-
ity implies the immune system attacking normal host
antigens due to the failure of self-tolerance mechanisms.
Because donor livers contain nonmajor histocompatibil-
ity complex antigens that are not expressed in the native
liver, all forms of immune reaction against an allogeneic
organ should be defined as rejections.13 However, Mieli-
Vergani and Vergani14 have correctly pointed out that
the concept of recurrence of AIH after LT is generally
accepted,15,16 as is recurrence of other autoimmune
diseases such as PBC and PSC, and that targets for
liver-specific autoimmunity are species-specific and
shared by recipients and donors.
The mechanisms behind de novo autoimmunity
after LT are presumably similar to those of classic AIH,
which include multiple antigenic stimuli from viruses
and toxins, and a genetic predisposition.17 In chronically
injured organs, inflammation and tissue damage trigger a
cascade of autoreactive T cell specificities, enabling
cryptic or sequestered epitopes to be processed and
presented, a phenomenon known as epitope spreading.18
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Molecular mimicry mechanisms involving the release of
cross-reactive antibodies, have been suggested to explain
how different viruses may trigger self-perpetuating liver
injury in the nontransplant setting, and this mechanism
is considered one of the most likely explanations for
recurrent or de novo autoimmunity after LT, though this
has yet to be demonstrated conclusively.19–23 So far, de
novo AIH has been identified in patients who had
posttransplant Epstein-Barr virus, cytomegalovirus,
and parvovirus infections,24 as well as in cases with
recurrent HCV infection.
In transplanted individuals, immunosuppressive
therapy may affect the ability of the immune system to
preserve self-tolerance. In association with a physiologic
immaturity of the immune system, this may explain why
most cases of de novo AIH have been seen in children.
It has also been suggested that immunosuppres-
sive therapies could have a paradoxical effect in some
individuals: a cyclosporine-induced autoimmune disease
has been demonstrated in experimental models,25,26 and
has been correlated with a defective de novo T cell
development in the thymus favoring the emergence of
autoaggressive T cell clones. Similar T-cell-dependent
autoimmune manifestations have been seen after bone
marrow transplantation in patients treated with cyclo-
sporine, and also in experimental models of bone marrow
transplantation after treatment with tacrolimus.27–30
Further studies are undoubtedly needed to clarify the
pathogenesis of de novo AIH.
DE NOVO AIH AND RECURRENT HEPATITIS
C AFTER LIVER TRANSPLANT
De novo AIH is already a complicated issue with many
questions remaining to be solved, but it becomes a real
challenge when it occurs in the context of post-LT
recurrent HCV infection.
 DE NOVO AUTOIMMUNE HEPATITIS AFTER LIVER TRANSPLANTATION/GUIDO, BURRA
In early reports, there were very few cases of de
novo AIH in patients transplanted for HCV-related
cirrhosis. One was the index case of the first adult series
reported by Heneghan et al.2 This patient developed the
condition 8 months after a third transplant, having lost
the first allograft to severe recurrent hepatitis C, and the
second one to vascular complications. The third trans-
plant was performed when the patient was HCV-RNA-
negative, with no signs of any autoimmune processes
under way. When the dysfunction developed, a high titer
of anti-LKM antibodies was detected along with a
histologic picture of severe hepatitis with a predomi-
nance of plasma cells in the portal infiltrate and no
evidence of rejection or other complications. The patient
remained HCV-RNA-negative and was successfully
treated with steroids. In the series reported by Salcedo
et al,24 three patients who developed de novo AIH had
been transplanted for HCV-related cirrhosis. Two were
treated with steroids. Apparently, no differences
emerged between the HCV-positive and the HCV-
negative cases in terms of the autoantibodies, the histo-
pathologic findings, and the outcome of the allografts.
All transplant centers have lately been experienc-
ing the occurrence of de novo AIH in patients trans-
planted for HCV-related cirrhosis; some reports have
suggested an association with antiviral therapy.12,31,32 In
the case reported by Cholongitas et al, de novo AIH
developed during antiviral therapy with pegylated-inter-
feron and ribavirin in a patient with a low titer of ANA
documented before LT.31 A liver biopsy performed after
abandoning the antiviral therapy (due to a persistent
HCV-RNA positivity in serum) revealed chronic hep-
atitis with a portal infiltrate rich in plasma cells. A
second biopsy performed a month later to seek an
explanation for rising transaminases associated with a
high titer of anti-LKM antibodies showed features
consistent with chronic HCV infection and autoimmune
hepatitis. Prednisolone induced a progressive improve-
ment in the laboratory test findings despite an increase in
serum HCV-RNA.
The case of de novo AIH observed at The Mount
Sinai Medical Center in New York, occurred 11 months
after a patient was started on interferon and ribavirin
therapy, when HCV-RNA had become undetectable.32
Autoantibodies were initially negative, but total serum
immunoglobulins were very high. Histology showed a
picture of severe hepatitis with a dense infiltrate of
plasma cells and parenchymal collapse, but with no
changes consistent with rejection; this was labeled as a
case of ‘‘immune-mediated’’ hepatitis. The condition was
successfully treated with azathioprine, but recurred when
azathioprine was discontinued. A second liver biopsy
showed the same results as the first biopsy; however, by
this time the autoantibodies had become positive. Once
again, the situation was restored to normal by reintro-
ducing azathioprine. Using the International Diagnostic
73
Criteria for the Diagnosis of Autoimmune Hepatitis, a
score of 15 was obtained before treatment, and a score of
18 afterwards, prompting the condition to be interpreted
as ‘‘definite’’ autoimmune hepatitis.
An Italian group has described nine cases of likely
de novo AIH in patients with recurrent HCV hepatitis,
who were treated with pegylated-interferon and riba-
virin.12 The condition developed during or shortly after
stopping this treatment and in the presence of a virologic
response in all but one case. Graft rejection, anastomotic
complications, and concomitant infections were ruled
out in all cases. Liver histology findings were charac-
terized by severe interface hepatitis with plasma cell
infiltration and hepatocyte rosettes. The outcome, fol-
lowing withdrawal of antiviral therapy and administra-
tion of prednisone varied, with five remissions and four
graft failures (with two deaths). It is worth adding that
the autoantibody titers (where ANA and ASMA pre-
vailed) were not particularly high in most cases, and
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ductopenia was histologically confirmed in two patients;
therefore, a concomitant ongoing chronic rejection could
not be ruled out with certainty. Chronic ductopenic
rejection has been reported in patients receiving pegy-
lated-interferon and ribavirin.33 On the other hand,
three patients developed other definite autoimmune
disorders, i.e., overlap AIH-PBC, autoimmune thyroi-
ditis, and systemic lupus erythematosus.
A retrospective analysis performed at our center
showed that, among 71 LT patients treated with pegy-
lated-interferon and ribavirin for recurrent HCV, 10
developed a graft complication during or after the treat-
ment, with histologic findings consistent with autoim-
mune damage (unpublished data). Only four patients
had autoantibodies at the time of the complication; five
patients were HCV-RNA negative. Interestingly, trans-
aminase levels before antiviral therapy were significantly
higher in patients who did develop immune-mediated
liver damage. Four patients were treated with steroids
and azathioprine. Graft loss occurred in one case and two
(HCV-RNA negative) patients died of liver failure
related to the autoimmune disease. The fourth case
responded to the immunosuppressive treatment, but
developed HCV cirrhosis a year later. Of the untreated
cases, three died of liver failure and three recovered and
are still alive.
New insight regarding the meaning of post-LT
autoimmune complications in HCV patients came from
a study conducted by the group at The Mount Sinai
Medical Center.34 Working on the assumption that
plasma-cell-rich inflammation is a hallmark of auto-
immunity, 38 patients were selected from those trans-
planted for HCV-related cirrhosis between 1996 and
2002 based on a high proportion of plasma cells (>30%)
in the inflammatory infiltrate, a condition labeled
‘‘plasma cell hepatitis’’ (PCH). Important data from
this study included (1) PCH developed within 2 years
74 SEMINARS IN LIVER DISEASE/VOLUME 31, NUMBER 1 2011
after LT in 58% of cases, (2) 60% of these patients had a
poor outcome (onset of cirrhosis, graft loss, or death), (3)
82% had recently reduced their immunosuppressive
medication or had subtherapeutic calcineurin inhibitor
levels, (4) autoantibody status was available in 23 cases
and only 14 had a titer > 1:40, and (5) a trend toward a
better outcome was seen in patients treated only by
raising their immunosuppression than in those treated
with steroids. Based on these observations, although
PCH in patients with HCV infection resembles AIH,
it is more likely to represent a specific form of rejection.
A further case-control study conducted by the same
group35 confirmed the worse prognosis associated with
PCH in HCV patients compared with chronic hepatitis
C alone, emphasizing the importance of early identi-
fication of this condition. This study also demonstrated
that plasma cell numbers were often higher in livers
explanted from patients who developed PCH than in
those who did not, suggesting the role of an immuno-
logic predisposition.
In the setting of recurrent hepatitis C, the sce-
nario is further complicated by the fact (known from the
nontransplant model) that chronic hepatitis C can be
associated with the detection of nonorgan-specific auto-
antibodies in
20 to 25% of individuals, as well as
with several extrahepatic immune-mediated manifesta-
tions,36–38 though the risk of autoimmune phenomena
increases after antiviral therapy.39–41 Generally, the
appearance of autoantibodies in chronic hepatitis C
could be explained by the observation that the HCV
E2 region binding CD81 antigen promotes B cell pro-
liferation and clonal expansion, lowering the activation
threshold.42 Although the genesis of autoimmune man-
ifestations in chronic hepatitis C in nontransplanted
patients remains controversial, the most recent experi-
ence indicates that the presence of autoantibodies is
unrelated to any major differences in clinical presenta-
tion, clinical course, or response to antiviral therapy.43–45
In some studies, serum autoantibodies and high IgG
levels have been associated with a more severe histologic
activity and it has been suggested that clinical signs of
autoreactivity in hepatitis C are surrogate markers of
disease severity.46,47
This could be the case in transplanted patients
too, as suggested by Khettry et al,48 who conducted a
clinicopathologic analysis of patients who had been
transplanted for HCV-related cirrhosis and had histo-
logically confirmed recurrent hepatitis C. The authors
were able to identify two patterns of recurrence. A
histologically typical recurrent hepatitis C was observed
in 52 of 92 cases (60.4%), characterized by a variable
(usually mild) degree of chronic lobular, periportal, and
portal inflammation, without a conspicuous plasma cell
infiltrate. The stage of fibrosis increased during follow-
up in a minority of these patients. In 9 of the remaining
40 cases, the histologic picture was described as AIH-
like, characterized by moderate to severe portal, peri-
portal, and lobular necroinflammation with prominent
plasma cells. Fibrosis progressed in most of these cases
and one patient died with a progressive AIH-like con-
dition on histopathologic examination. By analogy with
the non-LT setting, the authors of this study considered
the AIH-like pattern as a severe variant of hepatitis C,
but six of their patients had serum autoantibodies, which
would be consistent with the belief that signs of auto-
immunity may be related to a more severe hepatitis, with
plasma cell infiltrate. Whether AIH-like chronic hep-
atitis, PCH, and de novo AIH are the same disease or
not, what is clear is that in cases of recurrent hepatitis C,
severe necro-inflammation with numerous plasma cells
identifies a distinct condition that is likely to have a poor
outcome.
MAKING A DIAGNOSIS OF DE NOVO
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AUTOIMMUNE HEPATITIS
There are no generally accepted criteria guiding the
diagnosis of de novo AIH, which is hardly surprising
given the uncertainty over many aspects of this condi-
tion. Even in the nontransplant setting, AIH is difficult
to diagnose, demanding careful exclusion of other dis-
eases and detection of characteristic features, including
histologic findings (i.e., abundant plasma cells, interface
hepatitis), as well as clinical and laboratory findings, such
as abnormal serum globulin levels, and one or more
characteristic autoantibodies.49 According to the diag-
nostic scoring system developed by an international
panel in 1993 and revised in 1999,50 patients are classi-
fiable as having ‘‘probable’’ or ‘‘definite’’ AIH. The
system has been recommended for use in diagnostically
challenging cases with few or atypical clinical, laboratory,
and histologic findings. Although it has not been specif-
ically validated in the post-LT setting, this system has
been applied to de novo AIH, and most published cases
were scored as probable or definite AIH. Nevertheless,
the Banff Working Group51 suggested the following
minimal diagnostic criteria for de novo AIH: (1) a
significant titer of autoantibodies associated with hyper-
gammaglobulinemia; and (2) a compatible allograft
histology, after excluding virus-induced or drug-related
hepatitis and late acute or chronic rejection.
Autoantibodies
Serum autoantibodies are one of the main diagnostic
features of AIH, though they are neither pathogno-
monic nor disease-specific.52 In patients with de novo
AIH, the classic autoantibodies (ANA, AMA, and anti-
LKM1) are the most common ones found in the serum,
but atypical autoantibodies have also been observed.
Atypical LKM antibodies have been detected in
both pediatric1 and adult patient series. Some patients in
 DE NOVO AUTOIMMUNE HEPATITIS AFTER LIVER TRANSPLANTATION/GUIDO, BURRA
the study by Salcedo et al24 displayed an atypical anti-
liver/kidney cytosolic antibody (LKC) not reacting to
the microsomal liver fraction containing the classic
molecular target of LKM-1. There was a direct relation-
ship between such titers and the severity of liver damage;
the level of this atypical LKC autoantibody dropped
significantly after steroid treatment.
Aguilera et al53 found cytoplasmic antibodies
directed against glutathione S-transferase T1 (GSTT1)
in the sera of patients with de novo AIH. This enzyme
belongs to a family involved in detoxifying cells from
toxic reactive electrophiles, and is lacking in 20% of the
population. In the original report, four cases of otherwise
‘‘typical’’ de novo AIH were associated with anti-
GSTT1 antibodies, and GSTT1 genotyping demon-
strated that the gene was absent in all of them, suggest-
ing that a GSTT1 donor/recipient genotype mismatch
might be the necessary condition for the appearance of
autoantibodies and the development of de novo AIH. In
this situation, the immune system would recognize the
GSTT1 protein as a nonself antigen and the graft
dysfunction would be the consequence of an alloreactive
immune response. In a further study, 29 of 419 consec-
utive adult LT recipients with a donor/recipient GSTT1
mismatch had anti-GSTT1 autoantibodies and 20 of
them developed de novo AIH after a median 26 months
of follow-up. On multivariate analysis, a high anti-
GSTT1 titer was an independent predictor of de novo
AIH.54
The prevalence of autoantibody positivity after
LT varies among the published studies; only very few
data come from the systematic assessment of autoanti-
bodies before and after LT because most programs do
not routinely screen recipients for autoantibody produc-
tion. Some studies have associated the development of
autoantibodies with the occurrence of rejection55–60 and
most have found that autoantibodies are detected all the
more frequently, the longer the interval after LT.61–64
Among 179 LT patients who were autoantibody-neg-
ative before transplantation, 71% had detectable auto-
antibodies with titers > 1/40 afterwards, and the highest
prevalence (66%) was recorded 36 months after the
transplant.61 In a study by Avitzur et al,63 one or more
autoantibodies were detected after LT in 26% of chil-
dren with no history of autoimmune diseases; anti-SMA
was the most common, and the time elapsing since
transplantation (> 4 years) was the only risk factor for
the detection of autoantibodies.
The presence of autoantibodies has been associ-
ated with a greater risk of developing posttransplant liver
dysfunction. In a study of 158 LT children,62 chronic
hepatitis with progressive fibrosis (leading to cirrhosis in
some cases) was a common finding. The most important
risk factor for this condition was positivity for serum
autoantibodies, which were detected in 72% and 80% of
cases, 5 and 10 years after LT (as opposed to 13% and
75
10%, respectively, among cases with a normal histol-
ogy). However, only four children had other features
suggestive of a diagnosis of de novo AIH. A recent
study64 found autoantibodies in 74% of children after
orthotopic liver transplantation (OLT), but there was
no difference in the prevalence of graft dysfunction
between those with and without autoantibodies; among
the cases with autoantibodies, only four children had
hypergammaglobulinemia associated with graft dys-
function, and none fulfilled the criteria for AIH. Riva
et al65 detected autoantibodies in 60 of 247 trans-
planted children, 22 of whom had graft dysfunction,
such as rejection (n ¼ 13) or consistent with de novo
AIH (n ¼ 9). In a study by Hadzic et al,66 157 (41.6%)
of 377 children transplanted for nonautoimmune dis-
orders were subsequently found positive for autoanti-
bodies, but only 12% of them had graft dysfunction
labeled as de novo AIH.
These data suggest two important practical con-
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siderations:
1. Autoantibodies are often detected after LT, but they
are not invariably a sign of liver dysfunction, or their
mere presence does not necessarily establish a cause-
and-effect relationship. After LT, therefore (as in the
general population), caution is required in interpret-
ing the significance of serum autoantibody positiv-
ity,67 which should be seen as potentially indicative
of—but not as proof of—an autoimmune disorder.
The autoantibody titers should always be taken into
account because high titers (1:160) are unlikely to
be nonspecific.
2. Autoantibodies should be sought more systematically
before and after LT to gain a better understanding of
their clinical significance and improve our knowledge
of the incidence and pathogenesis of de novo AIH.
Histology
As a rule, the histopathologic manifestations of different
liver diseases remain invariable for the most part, regard-
less of whether they occur in native or transplanted
livers. The histologic findings of AIH in native livers
are well defined.68,69 Typical cases are characterized by
portal lymphocytic infiltrate, often with a high propor-
tion of plasma cells, associated with interface hepatitis
and varying degrees of lobular inflammation, and in
severe cases, bridging necrosis, confluent necrosis, or
multiacinar collapse. Emperipolesis and hepatic rosette
formation are also considered typical signs.70 An inflam-
matory infiltrate rich in plasma cells is characteristic, but
not pathognomonic, and a lack of plasma cells does not
preclude the diagnosis. A histologic picture of chronic
hepatitis with lymphocytic infiltrate, but without
the other characteristic lesions, may therefore still be
considered compatible with a diagnosis of AIH.70 Cases
76 SEMINARS IN LIVER DISEASE/VOLUME 31, NUMBER 1 2011

Figure 1 De novo autoimmune hepatitis occurring 2 years after liver transplant in a 51-year-old man transplanted for alcoholic
cirrhosis. Portal tract inflammation with severe interface hepatitis (A; black arrows) and numerous plasma cells representing
more than 30% of the inflammatory infiltrate (B,C). [Hematoxylin and eosin, x40 (A,B) and x60 (C)]

of otherwise typical AIH (in terms of serology, autoanti- addition to the broader spectrum of differential diag-
body profile, and response to treatment), but character- noses to consider, there is also the fact that immuno-
ized by centrilobular inflammation and necrosis sparing suppression may alter the features of some conditions,

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the portal and periportal regions, have also been de-
scribed. This may represent an early stage of the dis-
ease.71–73
De novo AIH is characterized, by definition, by
histologic lesions resembling classical AIH. In partic-
ular, a plasma cell-rich inflammatory infiltrate has
been described in almost all reported cases (Fig. 1),
often associated with centrilobular necrosis (Fig. 2). In
native livers, the main histologic differential diagnoses
of AIH are related to drug-induced and viral chronic
hepatitis. After LT, histologic assessment is compli-
cated not only by conditions unique to allografts, such
as organ preservation injury and rejection, but also by
the fact that transplanted patients are at risk of several
complications and there may be more than one con-
comitant insult contributing to liver dysfunction. In
in terms of the type and severity of the related lesions.
An accurate interpretation of the histologic findings in
light of all available clinical data, including the time
elapsing since LT, is mandatory to reach a definitive
diagnosis. Because de novo AIH is usually a late
complication, occurring with a mean time of 2 years
after LT, the most common problem is to differentiate
it from late acute rejection and from recurrent hep-
atitis C.
Acute rejection is straightforward to diagnose in
the presence of its key features: polymorphic, blast-rich,
portal inflammation, bile duct damage, and venulitis74–76
(Fig. 3). However, late acute rejection may mimic
chronic hepatitis, showing fewer blasts in the portal
inflammatory infiltrate, more interface hepatitis, and
less severe bile duct damage.51 A systematic evaluation

Figure 3 Acute cellular rejection 60 days after liver trans-

Figure 2 Centrilobular necro-inflammation (also known as plant. The inflammatory infiltrate is polymorphic with eosino-
central perivenulitis). Inflammatory infiltrate is composed of phils, some plasma cells and blasts, and it is more evident
mononuclear cells. CV, central vein. (Hematoxylin and around the inflamed bile duct (arrow). Endotheliitis (arrow-
eosin, x60) head) is evident. (Hematoxylin and eosin, x60)
 DE NOVO AUTOIMMUNE HEPATITIS AFTER LIVER TRANSPLANTATION/GUIDO, BURRA
Figure 4 Dense mononuclear portal infiltrate with severe
bile duct injury (arrows) and rupture of basement membrane.
These findings suggest acute rejection rather than hepatitis.
(Hematoxylin and eosin, x100)
of the type, severity, and topography of the lesions
should nonetheless lead to a diagnosis in most cases.
Portal tracts: Portal tract inflammatory infiltrate is
diffuse in rejection, with a tendency to become more
pronounced around bile ducts (Fig. 3). It is usually more
evenly distributed throughout the biopsy specimen in
rejection than in chronic hepatitis. Blasts are usually
found, albeit in smaller numbers, as well as neutrophils
and eosinophils. There may be plasma cells too, but large
numbers (exceeding 30%) are not characteristic of re-
jection. Generally, even late, portal inflammation is more
polymorphic in rejection than in AIH.
Bile ducts: In nontransplant AIH patients, bile
duct injury in the form of lymphocytic or mixed cellular
cholangitis has been described as a transient feature in a
minority of cases,77 but overt bile duct destruction with
rupture of the basement membrane (Fig. 4) is not a
genuine feature of AIH. Damage involving the majority
of the bile ducts consequently points to a diagnosis of
rejection.
Periportal zone: It is important to evaluate the
prevalence and severity of periportal necro-inflammation
because diffuse and severe interface hepatitis is not a
feature of early or late rejection.
Lobules: Pan-lobular hepatitis is part of the histo-
logic spectrum of AIH, and along with extensive paren-
chymal collapse, with bridging necrosis (Fig. 5) and
regenerative features, such as rosettes, has been described
in most cases of de novo AIH, but not in rejection.
Perivenular inflammation and cell dropout can be seen in
both rejection and de novo AIH, and may also be caused
by adverse drug reactions and blood flow obstruction.
However, vascular alterations are more common soon
after LT, are rarely associated with inflammatory infil-
trate, and can be ruled out by clinical investigations. If
77
Figure 5 De novo autoimmune hepatitis occurring
18 months after liver transplant for hepatitis C virus (HCV)
cirrhosis in a 45-year-old woman. At the time of this biopsy,
she was HCV-RNA negative, with a high titer of antinuclear
antibodies. Note severe portal inflammation with many
plasma cells and interface hepatitis, associated with brid-
ging necrosis (arrows). The bile duct (arrowhead) is spared.
Downloaded by: UNIVERSITEIT GENT. Copyrighted material.
(Hematoxylin-eosin, x20)
perivenular necro-inflammation is prominent (i.e., in-
volving the majority of the central zone), this is regarded
as a sign of immune-mediated damage and usually
responds to increased immunosuppression.78–83 When
prominent central perivenulitis is seen in conjunction
with significant portal inflammation, the diagnosis is
based on the prevalence and severity of the bile duct
damage: mild or no bile duct damage points to a
diagnosis of chronic hepatitis, which may be labeled de
novo AIH if the patient’s autoantibody titers and IgG
levels are high.51 Isolated centrilobular injury may be a
sign of late acute rejection or of early AIH,79,80 but it is
impossible to differentiate between the two in the
absence of any other key features. This change responds
to increased immunosuppression, however, regardless of
its pathogenesis.83
In cases of post-LT recurrent hepatitis C, the
scenario is complicated by two main problems. First, any
rejection or de novo AIH that develops is very likely to
co-exist with viral damage, so the main goal is to
establish which process is prevalent and requires treat-
ment. Second, as mentioned previously, features of
autoimmune damage come within the spectrum of
HCV-related hepatitis. An accurate diagnosis is of great
clinical importance because increasing a patient’s immu-
nosuppression may exacerbate the effects of recurrent
hepatitis C, hastening fibrogenesis or inducing fibrosing
cholestatic hepatitis as a consequence of increased HCV
replication. It may help to assess serum HCV-RNA
levels because rejection is usually associated with low
viremia and most cases of de novo AIH have been seen in
the absence of detectable HCV-RNA.84 As in non-
HCV patients, the key histologic features remain the
prevalence and severity of mononuclear inflammatory
bile duct damage and pericentral necro-inflammation
78 SEMINARS IN LIVER DISEASE/VOLUME 31, NUMBER 1 2011
Figure 6 Portal tracts with severe chronic inflammation,
with formation of lymphoid follicles (circles) and interface
hepatitis. The bile duct is spared (arrowhead). Despite serum
antinuclear antibodies (1:40) and low levels of hepatitis C
virus RNA, histologic findings are consistent with recurrent
chronic hepatitis C. (Hematoxylin-eosin, x20)
(Fig. 6).85 Mild bile duct damage is seen in acute or
chronic hepatitis C and in AIH, but extensive lympho-
cytic cholangitis and/or bile duct loss are only apparent
in rejection.84 Prominent perivenulitis, involving the
majority of the central zones, is not a feature of hepatitis
C in native livers or allografts, so its presence rules out
the possibility of HCV being the main culprit behind
allograft dysfunction and points instead, as in non-HCV
patients, to an immune-mediated etiology. The inter-
pretation of severe interface hepatitis and/or prominent
plasma cell infiltrate (>30%) in HCV patients remains
controversial. Whether these cases represent variants of
rejection, chronic hepatitis C (as suggested by Khettry
et al48), or de novo AIH, this kind of histologic pattern
clearly identifies patients at higher risk of a poor out-
come. These histopathologic features should always
arouse the suspicion of concomitant rejection and/or
autoimmune phenomena, the risk becoming worse after
weaning from steroids. Such a pattern must therefore be
sought and highlighted by pathologists. Any therapeutic
decisions should be based on a careful evaluation of all
the other clinical parameters, including markers of auto-
immunity, viral load, and serum levels of immunosup-
pression. Weaning such patients should be delayed or
undertaken only with extreme caution.
THERAPY
De novo AIH responds to changes in immunosuppres-
sive therapy. In most reports, administering steroids
(with or without azathioprine) has proved the best
approach1,2,24 achieving a remission in most, but not
all cases, regardless of whether the immunosuppressive
regimen was based on tacrolimus, cyclosporine, or siro-
limus. Guidelines for the management of AIH recently
approved by the American Association for the Study of
Liver Diseases86 suggest that de novo AIH after LT
should be treated by reintroducing corticosteroids, or
raising their dosage, and optimizing calcineurin inhib-
itor levels. If response is incomplete, azathioprine or
mycophenolate mofetil should be added to the cortico-
steroid and calcineurin inhibitor regimen. Tacrolimus
should be replaced with cyclosporine, or the calcineurin
inhibitor with sirolimus, if response continues to be
incomplete, and retransplantation should be considered
for patients with refractory de novo AIH progressing to
allograft failure.
SUMMARY
De novo AIH is a serious, but rare post-LT complica-
tion that needs to be included in the differential diag-
nosis of late allograft dysfunction. Its pathogenesis is
uncertain; further studies are needed in this regard. The
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diagnosis may be challenging, particularly in patients
with recurrent HCV hepatitis, but a clear diagnosis is
important for appropriate and timely therapy, which
should be based on optimizing immunosuppression.
Combinations of steroids and azathioprine have proved
to be the most successful approach. The diagnosis
depends on the presence of high titers of serum autoanti-
bodies, high levels of IgG, and a liver biopsy demon-
strating an AIH-like picture, with plasma-cell-rich
inflammatory infiltrate, interface hepatitis, and lobular
necro-inflammation, often with central perivenulitis.
These findings are not pathognomonic for de novo
AIH and close clinicopathologic correlation is needed
to exclude other causes of graft dysfunction, namely viral
infections, rejection, and drug toxicity.
ABBREVIATIONS
AIH autoimmune hepatitis
ANA antinuclear antibody
GSTT1 glutathione S-transferase T1
HCV hepatitis C virus
IgG immunoglobulin G
LKM liver/kidney microsome antibodies
LT liver transplant
PBC primary biliary cirrhosis
PSC primary sclerosing cholangitis
SMA smooth muscle antibody
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