Current Concepts in Liver Disease: An Update, Part 2
Moderator: Dr. Linda D. Ferrell
Section 2 -
Pathology of Autoimmune Overlap Syndromes
Stefan G Hübscher
Department of Pathology
University of Birmingham
Birmingham B15 2TT, U.K.
Introduction – Basic Concepts and Diseases Involved
During the past 20 years there has been increasing interest in the concept of "overlap syndromes"
involving three liver diseases that are thought to have an immune-mediated basis – autoimmune hepatitis
(AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Although all three
diseases are often referred to as being autoimmune, only AIH fulfils the criteria for a classical
autoimmune disease. This article will focus on histological aspects of overlap syndromes involving AIH,
PBC and PSC and the role of liver biopsy in the diagnosis and management of this rather poorly-defined
group of conditions.
The term overlap syndrome is applied to describe cases that are difficult to classify within a single
diagnostic category of AIH, PBC or PSC and instead appear to have biochemical, immunological or
histological features of more than one disease process
. Three main types have been recognised:
(i) The "true" overlap syndrome is the commonest form and mostly involves
simultaneous presentation with combined features of AIH and PBC or AIH and PSC. Overlap syndromes
involving combinations of PBC and PSC have also been described, but are much less common
have been infrequent reports of cases that appear to have features of all 3 diseases  . (ii) The "cross-over" or "outlier" syndrome refers to cases where there are some
features suggesting one disease process and others favouring an alternative diagnosis. The best example
is so-called "autoimmune cholangitis" (AIC), which is characterised by biochemical and histological
features favouring PBC and an autoantibody profile more in keeping with AIH. Most people now regard
this as a variant of PBC (AMA-negative PBC), although the precise nature of AIC remains controversial
(see later). (iii) The "sequential" syndrome is an uncommon variant of
overlap syndrome in which patients present initially with classical features of one autoimmune liver
disease and subsequently develop features of another autoimmune liver disease, sometimes after a lag
interval of many years. The commonest examples involve AIH and PSC, with AIH usually presenting first
Less frequently there is progression from PSC to AIH
. A few cases of PBC and AIH
presenting with temporal dissociation have also been reported
The significance of overlap syndromes in terms of classifying autoimmune liver diseases and
understanding the relationship between them is uncertain. A number of possible explanations have been
. The most likely is that AIH, PBC and PSC are three distinct disease processes, which
happen to share overlapping biochemical, serological or histological features. Alternatively they may
represent co-existence of different autoimmune diseases, possibly related to shared genetic
susceptibility. Least likely is the suggestion that autoimmune liver disease forms a continuous disease
spectrum, within which AIH, PBC and PSC are different manifestations.
Although the "outlier syndrome" autoimmune cholangitis is generally regarded to be a variant of PBC,
various other possibilities have been suggested. These include a variant of AIH with biliary features
a small duct variant of PSC  or a distinctive syndrome that has features different from all
three of the other diseases
. The recent use of more sensitive and specific tests to measure
serum anti-mitochondrial antibodies (AMA) has shown that these may be present in some cases previously
classified as AIC  . Fluctuating levels of AMA have also been recognised to occur during different
phases in the evolution of PBC, in some cases becoming undetectable
, which also suggests that
AIC and PBC may be different manifestations of a common disease process. It has been suggested that the
term "autoimmune cholangitis" could be applied to all cases with clinical, biochemical and histological
features compatible with a diagnosis of PBC , irrespective of their AMA status
but this has not
been widely applied.
Overlap syndromes involving AIH with hepatitis C, alcoholic liver disease, non-alcoholic fatty liver
disease and other chronic liver diseases have also been described
. These will not be
considered in further detail here. However, it is worth noting that autoantibodies are commonly present
in low titre in many chronic liver diseases, where they are considered to be a non-specific response to
Incidence and Diagnostic Criteria
The reported incidence of autoimmune overlap syndromes varies widely, most likely due to the use of
different diagnostic criteria. Overall, approximately 20% of people with autoimmune liver disease may be
considered to have features compatible with an overlap syndrome
Although the diagnostic
features of the three main disease involved are well described (see Table 1), the criteria required to
diagnose overlap syndromes have not been clearly defined or standardized.
Table 1. Diagnostic Features of AIH, PBC and PSC
| ||Autoimmune Hepatitis ||Primary Biliary Cirrhosis ||Primary Sclerosing Cholangitis|
|Autoantibodies ||ANA, SMA (type 1) |
SLA/LP (type 3)
(raised Alk Phos)
(raised Alk Phos)
|Immunoglobulins ||Raised IgG ||Raised IgM ||Normal levels or polyclonal elevation|
|Normal ||Normal ||Abnormal|
Bile duct lesions
Bile duct loss
Studies of adult patients with an initial diagnosis of AIH  ,
suggested that approximately 5-10% of cases have additional features supporting a diagnosis of an overlap
syndrome. A higher prevalence of overlap syndromes involving AIH and PSC has been documented in
children, amongst whom 50% with an initial diagnosis of AIH were found to have cholangiographic findings
typical of PSC  .
The term "autoimmune sclerosing cholangitis" (ASC) has been proposed in this
Although the classical histological features of AIH, PBC and PSC are distinctive, areas of
histological overlap exist, even amongst cases which are otherwise typical in terms of their clinical,
biochemical and serological features  . Thus inflammatory bile duct lesions and other biliary
features can be seen in otherwise typical cases of AIH, whilst portal inflammation and interface
hepatitis can be considered as part of the normal histological spectrum of PBC and PSC.
AIH is characterised by a predominantly mononuclear plasma cell rich infiltrate, mainly involving
portal and periportal regions. Interface hepatitis is an important feature in establishing a diagnosis
of AIH  and is also likely to be important in determining disease progression - it is often
associated with ballooning, rosetting and fibrous entrapment of periportal hepatocytes and thus forms a
potential pathway for the development of progressive periportal fibrosis. Parenchymal inflammatory
changes are also seen in AIH and typically mainly involve centrilobular regions. More severe cases may
be involved with bridging necrosis or panacinar necrosis, which are adverse prognostic features
associated with disease progression and poor response to immunosuppressive therapy  .
Inflammatory bile duct lesions are also recognised to occur in otherwise typical cases of AIH
. The changes seen are usually mild, with focal lymphocytic infiltration of bile ducts that are otherwise
well preserved. Less commonly there are more severe changes with biliary epithelial cell damage or
disruption, in some instances associated with bile duct loss. Cases of AIH with destructive cholangitis
or ductopenia tend to have higher alkaline phosphatase levels than those without biliary changes, but are
otherwise similar in terms of disease behaviour and response to immunosuppression
favouring an alternative or additional diagnosis of autoimmune biliary disease include extensive bile
duct loss and features of chronic cholestasis (marginal ductular reaction, cholate stasis and
accumulation of copper-associated protein). However, ductular reaction can also be seen in cases of AIH
with an acute presentation and/or prominent lobular inflammatory component and as part of the spectrum of
progressive disease with the development of bridging fibrosis or cirrhosis.
Primary biliary cirrhosis and primary sclerosing cholangitis
The initial targets for damage in these diseases are bile ducts. PBC is characterised by inflammatory
lesions involving small (interlobular) ducts, whereas PSC is associated with lesions affecting bile ducts
of all sizes. Typical bile duct lesions are only seen in approximately 30% of liver biopsies from
patients with PBC and 10% of those with PSC, so that a definite diagnosis is rarely possible on
histological grounds  . Most cases of PBC and PSC are now diagnosed on the basis of serological and
radiological findings respectively and liver biopsy is not used routinely in many centres. However,
histological assessment may still carried out in cases with unusual features or an uncertain diagnosis,
including those with a suspected overlap syndrome.
The bile duct lesions in PBC comprise a histological spectrum including lymphocytic and granulomatous
cholangitis. Although lymphocytic cholangitis can also be seen in AIH, the presence of florid duct
lesions with duct disruption should still suggest a diagnosis of PBC. Likewise granulomatous duct
lesions are not recognised to be a feature of AIH. The classical fibrosing bile duct lesions in PSC tend
mainly to affect medium-sized ducts, which explains why these are rarely seen in needle biopsy specimens.
Other biliary features occur in PBC and PSC as a consequence of bile duct loss. They include marginal
ductular reaction, features of cholate stasis in periportal hepatocytes (feathery degeneration,
ballooning and Mallory's hyaline formation) and the accumulation of copper and copper-associated protein.
These changes are associated with the development of progressive periportal fibrosis and enable a
diagnosis of chronic biliary disease to be made, even if typical bile duct lesions are not present.
Inflammatory changes are also recognised to occur as part of the histological spectrum of autoimmune
biliary disease. They are generally more prominent in PBC than PSC. In common with the changes seen in
AIH, inflammation mainly involves portal and periportal regions. PBC is characterised by a mixed
population of cells including lymphocytes, plasma cells, neutrophils and eosinophils. Interface
hepatitis is also a common finding and appears to be important in the development of fibrosis in PBC 
. Inflammatory changes also occur in the liver parenchyma and may include granulomatous foci. They are
typically mild, but again appear to be involved in the development of fibrosis  . The presence of
unusually prominent interface hepatitis, with hepatocyte ballooning and rosetting, should raise the
possible of an additional or alternative diagnosis of AIH. Confluent and bridging necrosis are also
distinctly uncommon in PBC or PSC and again suggest another diagnosis.
Autoimmune cholangitis is associated with histological features closely resembling those occurring in
PBC, including foci of granulomatous cholangitis and bile duct loss
. Subtle differences in the
composition of portal inflammatory infiltrates have been described, including larger numbers of T
and plasma cells  in AIC compared with AMA-positive PBC. However, other aspects of
inflammatory activity in cases of AIC are similar to those seen in PBC and do not suggest an additional
diagnosis of AIH
Problems with the Diagnostic Criteria for Autoimmune Overlap Syndromes
Given the intrinsic overlap that appears to exist between AIH, PBC and PSC, it is not surprising that
problems have arisen with trying to establish criteria for the diagnosis of autoimmune overlap syndromes.
A particular problem relates to the lack of a single diagnostic criterion for AIH. Instead the diagnosis
of AIH is based on a constellation of clinical, biochemical, serological and histological findings. The
International Autoimmune Hepatitis Group has devised a scoring system in which points are attributed to a
range of individual diagnostic features – these are then combined to produce an aggregate score, which
can be then interpreted as "definite" or "probable" AIH  . In addition to positive scores for typical
features of AIH, negative scores are given for features considered to be atypical - these include a
cholestatic biochemical profile, the presence of anti-mitochondrial antibodies and biliary features on
liver biopsy, all of which are features one would expect to see in an overlap syndrome. It is not clear
how the AIH scoring system should be applied or modified in cases where these other features are present
. Another approach to the problem is to view it from the perspective of a patient with an
initial diagnosis of PBC or PSC and then try to establish the minimum diagnostic criteria (biochemical,
serological, histological or combinations of all three) required to diagnose an overlap syndrome. Again
no clear agreement exists. Suggested criteria to be applied to patients with an initial diagnosis of PBC
were 2 of 3 of the following : (1) ALT > 5x upper limit of normal (ULN), (2) Serum IgG > 2x ULN or
smooth muscle antibody positivity (3)
liver biopsy showing moderate or severe interface hepatitis
. Although such an approach offers hope for a more standardised approach to future studies, there are
still problems in applying the pathological criteria which are not clearly defined.
Prognostic and Therapeutic Implications
Given the lack of uniformity in the criteria used to diagnose overlap syndromes, it is not surprising
that their prognostic significance and therapeutic implications are also poorly understood. There are no
reports of controlled therapeutic trials in this setting  . A detailed discussion of therapeutic
aspects is beyond the scope of this article, but a few general points will be considered.
The inflammatory changes occurring in classical AIH respond to treatment with corticosteroids and
other immunosuppressive agents
By contrast, ursodeoxycholic acid (UDCA) is increasingly
emerging as the first line medical treatment for the cholestatic problems that occur in PBC and PSC
A similar approach has been advocated for the treatment of autoimmune cholangitis
many overlap syndromes occurring in adults (PBC/AIH and PSC/AIH), the biliary disease is considered to be
the main diagnosis with hepatitic features occurring as a secondary phenomenon. UDCA can still used as
the first line of treatment in such cases
. However, other studies have suggested that some
patients with an overlap syndrome involving PBC and AIH may benefit from combined therapy with UDCA and
. Similar observations have been made for cases with an AIH/PSC overlap
By contrast, the overlap syndrome involving AIH and PSC in children ("autoimmune
sclerosing cholangitis") is considered to lie within the spectrum of AIH and immunosuppression is used
as the first line of treatment, although UDCA may also be used as an adjunct  .
Summary and Conclusions
Although there are still problems with the diagnosis and classification of autoimmune overlap
syndromes, there is increasing evidence to suggest that cases with overlapping features may behave
differently from classical cases of "pure" AIH, PBC and PSC. Histological assessments are important in
the investigation of patients with atypical presentations of autoimmune liver disease, and form an
important component in the diagnosis of overlap syndromes. Mild hepatitic features are commonly present
in PBC and PSC and biliary features can be seen in otherwise typical AIH. Diagnostic criteria for
"overlap syndrome" are therefore difficult to define. Nevertheless, cases of
PBC or PSC with unusually prominent histological inflammatory activity may benefit from
immunosuppression, whereas in a person with an initial diagnosis of AIH, the presence of bile duct
lesions or other biliary features may point to an underlying biliary disease. Liver biopsy can also
help to identify or confirm biliary features in cases of "autoimmune cholangitis" (AMA-negative PBC).
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