hepatitis autoinmune y sx de sobrepos

8/2/2019 Hepatitis Autoinmune y Sx de Sobrepos

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Autoimmune hepatitis and overlap syndromes

Hans Peter Dienes, MDa,*, Heike Erberich, MDa,Volker Dries, MDa, Peter Schirmacher, MDa,

Ansgar Lohse, MDb

a

Department of Pathology, Joseph-Stelzmann Str. 9, University of Cologne, 50931 Cologne, GermanybDepartment of Internal Medicine, University of Mainz, Germany

The current understanding of the autoimmune liver disease mechanism

proposes a disorder in the immune tolerance as the main etiolopathology,

possibly influenced by complex and multifactorial predictors.

The liver becomes the target organ if the self-tolerance mechanisms protection

in the liver collapses. The autodestruction can be targeted against different liver cell

populations, such as hepatocytes and/or bile duct epithelia, resulting in auto-immune hepatitis (AIH) or primary biliary cirrhosis (PBC) and possibly primary

sclerosing cholangitis (PSC) [1,2]. In some individuals, the autoimmune disease

seems to affect hepatocytes and biliary cells simultaneously, making diagnosis and

treatment difficult.

Studies show an increase in the simultaneous occurrence of more than one of

these diseases. Various terms for these findings have been used, such as variant

syndrome, overlap syndrome, or cross-over [3,4]. Cross-over is defined as a

diagnostic result that fits one diagnosis but also fits one or two criteria for another

diagnosis. Overlap syndrome is used as a diagnosis when a variation of findingsfor more than one defined diagnosis is observed.

This review concentrates on the histopathology of AIH and overlapping

syndromes to better diagnose these diseases and provides suggestions on their

pathogenesis and development.

Because the diagnosis is composed of clinical, biochemical, serologic,

radiologic, and histologic findings, an overview of characteristic findings in

these fields is also given.

1089-3261/02/$ see front matterD 2002, Elsevier Science (USA). All rights reserved.

PII: S 1 0 8 9 - 3 2 6 1 ( 0 2 ) 0 0 0 0 7 - 7

* Corresponding author.

E-mail address: [email protected] (H.P. Dienes).

Clin Liver Dis 6 (2002) 349362


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Autoantibodies and autoimmune liver diseases

Diagnosis and classification of autoimmune liver diseases is dependent on the

detectable autoantibody profile. Although AIH serology may be complex, diagnosis

of PBC is closely linked to the demonstration of antimitochondrial antibodies (AMA)

with specificity for the E2 subunits of the pyruvate dehydrogenase complex on the

inner mitochondrial membrane, the M2 antigen [58]. Sensitivity and specificity of

anti-M2 AMA for the diagnosis of PBC is more than 95% dependent on the

methodology used for autoantibody testing. Patients positive for AMA, but without

biochemical or histologic disease, usually develop PBC within 5 to 10 years [9].

From these observations, it seems legitimate to suspect an overlap syndrome of PBC

and AIH in all AIH patients with serologic evidence of AMA. If these patients do not

show cholestatic laboratory results, elevated IgM levels, or bile duct lesions on

histology, they should still be closely monitored for these parameters on follow-up,

because they are very likely to develop these features in the course of their disease.

Serologic diagnosis of AIH is more complex because many of the patients do

not necessarily show a diagnostic autoantibody profile. Typical patients with AIH

have high titers of antinuclear antibodies and smooth muscle antibodies. However,

the antibodies also occur in 10% to 15% of patients with chronic viral hepatitis [10].

The presence of both antibodies at high titers, however, can be considered virtually

diagnostic. Highly specific for the diagnosis of AIH are antibodies against a soluble

liver/liver pancreas antigen (SLA/LP), which can be detected in about 20% of AIHpatients [11]. SLA/LP autoantibodies have not been described in any other hepatic

or nonhepatic disease. Some patients with PBC also have SLA/LP autoantibobies,

but these patients appear to suffer from an overlap syndrome with secondary AIH

[12]. In fact, hepatitis appears to be more severe in these SLA/LP-positive PBC

patients than in other PBC/AIH-overlap patients. Antibodies to a liver-kidney mi-

crosomal antigen characterize a small subgroup of patients with AIH that manifests

mostly in childhood [13]. These antibodies are directed against the cytochrome

p-450 isoenzyme 2D6. These antibodies also occur in hepatitis C with a similar

frequency of 1% to 2%, and have been described in a patient following a livertransplant for Wilsons disease and a severe rejection episode [3,14]. Up to 5% of

patients with AIH do not display any of these autoantibodies. Some of these pa-

tients may have antibodies to other antigens, in particular to the asialoglycoprotein

receptor, but these antibodies are not disease specific and therefore of limited

diagnostic value [16]. In addition to autoantibodies, demonstration of the relevant

HLA-susceptibility alleles (B8, DR3, or DR4) and in particular of selective in-

crease of IgG levels are often more helpful in the differential diagnosis of liver

disease [17,18]. The elevation of IgG and IgM is thus a feature of overlap syn-

dromes of AIH and PBC. Table 1 summarizes the main features of autoimmuneliver diseases.

The diagnosis of AIH

There is no pathognomonic marker for the AIH diagnosis. Instead, the diagnosis

has to be established from a combination of several characteristics occurring with

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variable frequency and severity. Therefore, the International Autoimmune Hepa-

titis Group (IAIHG) developed a manual in 1993, revised in 1999, that included

descriptive criteria for definite and probable diagnosis and a numeric scoringsystem [19]. The categories include biochemical and serologic criteria, the absence

of viral markers, history of drug or alcohol abuse, and general aspects of histology

(Table 1).

Histopathology of AIH

According to the IAIHG scoring system from 1999, the diagnostic criteria for

AIH include interface hepatitis of moderate or severe activity with or without

lobular hepatitis or central portal bridging necrosis [19]. The diagnosis of AIHexcludes the finding of biliary lesions, well-defined granulomas, or other

prominent changes suggesting a different etiology. However, these criteria can

be generally applied for all chronic hepatitis.

Recently, more detailed criteria have provided a more characteristic morphol-

ogic description on the histopathology of AIH [1,20,21]. If these criteria are met,

the diagnosis of AIH is more substantially supported.

Hepatocellular necrosis primarily manifests in the liver lobules. Necrosis seems

to be closely associated with the presence of lymphocytes. The infiltration of lym-

phocytes in the portal tract is one other hallmark of AIH. The lymphocytes spillover from the portal tracts into the liver parenchyma. In this context, another im-

portant morphologic feature of AIH is the so-called phenomenon of enperipolesis.

Ballooning degeneration is the primary step for lytic lobular hepatocellular

necrosis caused by lymphocytic infiltration originating in the portal tracts.

In the course of the disease, lytic necrosis lobules become confluent and result

in bridging necrosis. These necroses then extend toward the central lobular areas.

Table 1

Main features of autoimmune liver disease

AIH PBC PSCMean age 20 30 y 50 60 y 30 40 y

Gender Female Female Male

Autoantibody Type 1: ANA;

type 2: SMA;

type 3: LKM, SLA

AMA pANCA

HLA typing B8, DR3, DR4 DR4

Association with

other inflammatory

diseases

Arthritis, thyreoiditis Sjorgen syndrome Inflammatory

bowel disease

Biochemical/serologic

parameter

ALT, g globuline IgM AST, AP, IgG

Histopathology Interface hepatitis,

lobular inflammation,

zone 3 necrosis

Medium-sized bile duct;

nonsuppurative, destructive,

granulomatous cholangitis

All bile ducts,

fibro-obliterative

cholangitis

Abbreviations: AIH, autoimmune hepatitis; ALT, alanine aminotransferase; AMA, antimitochondrial

antibody; ANA, antinuclear antibody; AP, alkaline phosphatase; AST, aspartate aminotransferase;

H.P. Dienes et al. / Clin Liver Dis 6 (2002) 349362 351


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The speed of that development depends on the disease course and its severity. As

a result, periportal hepatocellular regeneration occurs, characterized by pale-

Table 2

IAIHG revised scoring system for diagnosis of autoimmune hepatitis (1999)

Parameters/features Score

Female gender + 2

ALP/AST (or ALP/ALT) ratioa

< 1.5 + 2

1.5 3.0 0

>3.0 2

Serum globulin or IgG above normal

>2.01.52.0

+ 3+ 2

1.0 1.5 + 1

< 1.0 0

ANA, SMA, or LKM-1b

>1:80 + 3

1:80 + 2

1:40 + 1

< 1:40 0

AMA positive 4

Hepatitis viral markers

Positivec 3

Negative + 3

Drug history

Positived 4

Negative + 1

Average alcohol intake

< 25 g/d + 2

> 60 g/d 2

Liver histology

Interface hepatitis + 3

Predominantly lymphoplasmacytic infiltrate + 1

Rosetting of liver cells + 1

None of the above 5

Biliary changese 3

Other changesf 3

Other autoimmune disease(s)g + 2

Optional additional parametersh

Seropositivity for defined autoantibodiesi + 2

HLA DR3 or DR 4 j + 1

Response to therapy

Completek + 2

Relapse + 3Interpretation of aggregate scores

Pretreatment

Definite AIH > 15

Probable AIH 10 15

Post-treatment

Definite AIHl > 17

Probable AIH 12 17



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stained hepatocytes. Necrosis and regeneration of hepatocytes in AIH therefore

show zonal preference with periportal predominance, in contrast to the more focal

pattern of virus-induced liver damage.Apoptosis, seen in many chronic liver diseases, occurs less frequently in AIH.

Eosinophilic shrinkage of hepatocytes appears less obvious, as well. In addition,

the presence of plasma cells is variable and not a constituent feature of AIH. In

some cases, eosinophilic lymphocytes may be present, which simulate AIH at least

as observed in the hypereosinophilic syndrome.In addition to the regeneration

tendency of the hepatic lobula, the portal tract reacts, if inflamed, with expansion

and mononuclear cell infiltration (primarily lymphocytes, accompanied by a

variable degree of monocytes and plasma cells). Genuine lymphoid follicles

may develop; however, they are less frequent than, for example, in chronichepatitis C. Furthermore, the bile duct lesion excludes the diagnosis of AIH

according to the IAIHG scoring system [19]. In some cases, the bile ducts can be

Notes to Table 2:

Abbreviations: AIH, autoimmune hepatis; ALP, alkaline phosphatase, ALT, alanine aminotransferase;

ANA, antinuclear antibody; AST, aspartate aminotransferase; IAIHG, International Autoimmune

Hepatitis Group; LKM-1 type 1, liver-kidney microsomal antibody; pANCA, antineutrophiliccytoplasmatic antibody; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SLA,

soluble liver antigen; SMA, smooth muscle antibody.a The ALP/AST (or ALP/AST) ratio relates to the degree of elevation above upper normal limits

(unl) of these enzymes, (ie, IU/l ALP/unl ALP)/(IU/l AST/unl AST).b Titers determined by indirect immunofluorescence on rodent tissues or, for ANA, on Hep-2

cells. Lower titers (especially of LKM-1) are significant in children and should be scored at least + 1.c Score for markers of hepatitis A, B, and C viruses (ie, positive/negative for IgM anti-HAV,

HbsAG, IgM, anti-HBc, anti-HCV, and HCV-RNA). If a viral etiology is suspected despite

seronegativity for these markers, tests for other potentially hepatotropic viruses such as CMV and

EBV may be relevant.d

History of recent or current use of known or suspected hepatotoxic drugs.e Biliary changes refers to bile duct changes typical of PBC or PSC (ie, granulomatous

cholangitis, or severe concentric periductal fibrosis, with ductopenia, established in an adequate

biopsy specimen) and/or a substantial periportal ductular reaction (so-called marginal bile duct

proliferation with a cholangiolitis) with copper/copper-associated protein accumulation.f Any other prominent feature or combination of feature suggestive of different etiology.g Score for history of any other autoimmune disorder(s) in patient or first-degree relatives.h The additional points for other defined autoantibodies and HLA DR3 or DR4 (if results for these

parameters are available) should be allocated only in patients who are seronegative for ANA, SMA,

and LKM-1.i Other defined autoantibodies are those for which there are published data relating to

methodology of detection and relevance to AIH. These include pANCA, anti-LCI, anti-SLA, anti-ASGRP, anti-LP, and anti-sulfatide (see text).

j HLA DR3 and DR4 are mainly of relevance to North European Caucasoid and Japanese

populations. One point may be allocated for other HLA Class II antigens for which there is published

evidence of their association with AIH in other populations.k Assessment of response to therapy may be made at any time. Points should be added to those

accrued for features at initial presentation.l Response and relapse.



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involved in the inflammatory process and show degenerative changes (in about

one third of the cases). These changes are not due to genuine cholangitis but to a

reaction that is characterized by the inflammatory process spilling over into thebile ducts. The essential difference between PBC and the rare case of AIH bile

duct lesions is the basement membrane involvement in PBC (disruptures).

In conclusion, in AIH, necroinflammatory lesions are most prominent around

the portal tracts, leading to interface hepatitis that may obtain high-grade activity

and result in peripheral collapse of the parenchyma (Fig. 1). Surviving hepato-

cytes in that area often show a rosette formation or microacinar transformation.

Fibrosis in AIH follows the course of portal enlargement and septal formation as

in other forms of chronic hepatitis.

The diagnosis of PBC

For a definitive diagnosis of PBC, the following criteria must be met [2225]:

Elevated cholestatic liver tests A high titer (more than 1:40) of AMA Compatible or diagnostic histologic findings

On examination of these criteria, it becomes evident that none of them

except a fully developed histomorphologic lesionwould be specific or sensitive

enough to support the diagnosis. However, studies have shown that although

AMA titers are not specific for autoimmune diseases (drug-induced disorders,

collagen diseases, syphilis, or heart diseases), four of the nine described AMAs

(anti-M2, anti-M4, anti-M8, and anti-M9) are particularly characteristic for PBC

[2629]. Unfortunately, they are often not detectable by routine immunofluo-

Fig. 1. Autoimmune hepatitis with severe activity in the form of interface hepatitis (hemotoxylin and

eosin, original magnification 180).



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rescence methods. The most specific AMA is the anti-M2 antibody against the E2

subunit of the pyruvate dehydrogenase complex (PDC-E2) located on the

mitochondrial membrane and detectable by ELISA against PDH-E2 [8,30].

Histopathology of PBC

There are two main patterns of damage in PBC [31]. Bile ducts, preferentially

small interlobular segments, are affected by lymphocytic infiltration accompan-

ied by degenerative changes in biliary epithelium. Bile duct epithelia show

swelling, sometimes cytoplasmatic vacuolation, and fragmentation of the bile

duct basement membrane. The second lesion consists of granuloma formation

around injured bile ducts (Fig. 2). Granulomas are composed of histocytes and

epitheloid cells, and occasionally giant cells surrounded by a lymphocytic rim.

With progression of the disease, bile ducts are destroyed, whereas proliferation of

ductules and ductular transformation occurs at the periphery of the portal area

(stage of ductular proliferation) [32]. In the late stages of the disease, bile ducts

may disappear; this is associated with increasing fibrosis and cirrhosis at the final

stage of the disease.

There are four stages of PBC, or, more accurately, chronic, nonsuppurative,

destructive cholangitis [32], as follows:

First stage: florid duct lesion Second stage: ductular proliferation Third stage: scarring Fourth stage: cirrhosis

Fig. 2. Primary biliary cirrhosis stage of ductular lesion: medium-sized bile duct is undergoing

destruction in the center of a granuloma with giant cells (hematoxylin-eosin, original magnification

160).



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The presence of lymphocytic piecemeal necrosis has been interpreted as an

indicator for progression [31]. Mild, spotty parenchyma inflammation is com-

monly seen in PBC and may include occasional epitheloid granulomas. In a smallpercentage of cases, considerable interface hepatitis and intralobular necrosis may

occur, thus obscuring the histologic diagnosis of PBC. The diagnosis of PBC may

be elusive in liver needle biopsies. In a study of 258 patients, Wiesner et al [25]

found the formation of granulomas in only 32% of patients. However, granulo-

mas may be seen in other diseases, such as in Hodgkins lymphoma and

sarcoidosis, and in drug reactions.

AIH/PBC overlap syndrome

The overlap syndrome of AIH and PBC has long been recognized, and the

classification of such cases that show key biochemical, clinical, and histopatho-

logic features of PBC and AIH continues to be discussed in the literature. The

frequency of these cases has been reported at between 7% [3] and 20% [10].

There is general consensus that the definition of overlap syndrome between AIH

and PBC should apply only to those patients with a disease that fulfills the criteria

of AIH, according to the scoring system, and PBC (Table 3).

Histopathology of AIH/PBC overlap syndrome

The histology shows a moderate to severe hepatitis in the lobules [33]. The

lesions range from spotty necrosis with inflammation distributed over the lobules

to severe, confluent necrosis, preferentially localized in the periportal area or

bridging hepatic necrosis, connecting portal tracts to central veins. All cases show

considerable portal inflammation and bile duct lesions or ductopenia in later stages

(Fig. 3). Bile ducts are affected by lymphocytic infiltrates, basement membrane

Table 3

Main features of the overlap syndromes (AIH/PBC and AIH/PSC)

AIH/PBC overlap syndrome AIH/PSC overlap syndrome

Mean age 50 60 y 30 40 y

Gender Female Male

Autoantibody ANA, SMA, LKM, SLA, AMA ANA, pANCA

HLA typing B8, DR3, DR4 DR4

Biochemical/serologic

parameter

ALT, g globuline, IgM IgM, AST, AP, IgG,

Histopathology Interface hepatitis, lobular

inflammation, zone 3 necrosis,

medium-sized bile duct,

nonsuppurative destructive

granulomatous cholangitis

Interface hepatitis,

lobular inflammation,

zone 3 necrosis,

all bile ducts,

fibro-obliterative cholangitis

Abbreviations: AIH, autoimmune hepatitis; ALT, alanine aminotransferase; AMA, antimitochondrial

antibody; ANA, antinuclear antibody; AP, alkaline phosphatase; AST, aspartate aminotransferase;



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disrupture, and epitheloid granulomas surrounding bile ducts. In liver biopsies

from these patients, bile duct lesions were observed in 60% to 80% of patients.In most cases of AIH/PBC overlap syndrome, clinical symptoms, biochemical

parameters, and histopathology of both entities occur simultaneously [3,34 37].

Only in a few patients is there a consecutive manifestation, with PBC being the

first disease, followed by AIH. This has also been described in two patients who

underwent liver transplantation after end-stage PBC, and who subsequently

developed de novo AIH in the transplanted liver [15].

The diagnosis of AIH/PBC overlap syndrome should be made only when the

disease fulfills the criteria for both diseases in all points.

The following four theories have emerged [4]:

1. The overlap syndrome is in the middle of a spectrum with AIH at one end and

PBC at the other, and there is continuous transition between the appearances.

2. Patients with overlap syndrome might be simultaneously suffering from two

distinct conditions.

3. There is no true overlap. The diagnostic boundaries of one disease include

features of one or more of the other conditions and reflect the imprecision in

definition of the individual diseases.

4. The overlap syndrome of PBC and AIH is one form of PBC that developsan additional hepatic disease in genetically susceptible individuals, and

PBC is the leading and course-determining disease with an additional

hepatitis [37].

Discussions about the pathogenesis and causative relationships between these

disease entities are ongoing [35,38]. The conclusions from these studies,

Fig. 3. Liver from a patient with AIH/PBC overlap syndrome: in addition to dense portal inflammatory

infiltrates and bile duct destruction, there is considerable necroinflammatory activity in the lobules

(hemotoxylin and eosin, original magnification 80).



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however, are important for the treatment of these patients. In two reports, patients

with PBC/AIH overlap received combined treatment with UDCA and additional

immunosuppresion with steroids alone and with or without azathioprine. In bothstudies, transaminase levels normalized and alkaline phosphatase were reduced

by this treatment.

The diagnosis of PSC

Unlike PBC and AIH, PSC affects predominantly men and is associated with

inflammatory bowel disease in about 70% of cases. The diagnosis is based on

biochemical findings of cholestasis, serology with antineutrophilic cytoplasmatic

antibody, or pANCA, titer (which can also be positive in AIH), and typical

cholangiographic changes. However, imaging cannot distinguish primary from

secondary sclerosing cholangitis. Therefore, in many cases, the diagnosis of PSC

is difficult to establish [25,3941].

Histopathology of PSC

In liver biopsy specimens, the distinct lesions of PSC may be missed because

this lesion is largely restricted to medium-sized bile duct segments that may not

be represented in needle biopsy samples. The characteristic bile duct lesion in

PSC is a fibrous, obliterative cholangitis. Bile ducts are surrounded by a zone ofedema and loose concentric periductal fibrosis. Mild infiltrates, primarily

lymphocytes and some histocytes, are usually present (Fig. 4). The bile duct

epithelia usually show degenerative changes with nuclear pyknosis, cell shrink-

age, and some isolated lymphocytes between the epithelia. In contrast to PBC, the

Fig. 4. Liver biopsy from a patient with primary sclerosing cholangitis: bile ducts are surrounded by

dense fibrous cuff with only mild inflammatory activity in the portal tract (hematoxylin-eosin, original

magnification 220).



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bile duct basement membrane is not disrupted but may show a hyaline

thickening, shown by PAS stain. With disease progression, periductular fibrosis

becomes more obvious and bile ducts in the centers of the concentric fibrosisoften atrophy and gradually disappear. In the end stage, the bile duct is replaced

by a fibro-obliterative scar, resulting in the loss of bile ducts and ductopenia.

Portal inflamation is commonly seen in PSC and is frequently accompanied by

varying degrees of interface hepatitis. In PSC, the necroinflammatory lesions

rarely extend into the parenchyma.

AIH/PSC overlap syndrome in adults

AIH/PSC overlap syndrome in adults seems to be less frequent than PBC/

AIH overlap, between 1.4% and 8% in patients with PSC [35,42 44]. Thediagnosis should be made only when the patients meet the strict criteria of

cholangiographic lesions, cholestatic parameters, and an IAIHG score corre-

sponding to definite AIH.

Histopathology of AIH/PSC overlap syndrome

Liver histology shows portal and periportal lymphocytic infiltration with

disruption of the limiting plate, piecemeal necrosis, and lymphocytic infiltrates

in the lobule. Bile ducts are also infiltrated by lymphocytes and show periductular

fibrosis to a varying degree with thickening of the basement membrane. In the

lobule, spotty necrosis of hepatocytes and bridging hepatic necrosis between

portal tracts and central veins may be detected [45,46] (Fig. 5).

The pathogenesis of PSC/AIH overlap syndrome is more obscure than that of

PBC/AIH overlap. Both patient groups share common genetic backgrounds with

Fig. 5. Liver biopsy from a patient with autoimmune hepatitis/primary sclerosing cholangitis overlap

syndrome: there is fibrous enlargement of portal tracts with periductular fibrosis and moderate

necroinflammatory activity in the lobule (hematoxylin-eosin, original magnification 160).



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HLA B8DR3; the immune mechanisms leading to the bile duct lesion and loss in

PSC are still being debated. In PSC, the bile duct epithelia do not seem to present as

target cells of an immune attack [25], and other nonimmune factors, such as bac-terial or viral infection or enteral toxins, are discussed as causative mechanisms.

AIH/sclerosing cholangitis (SC) overlap syndrome in children

In children, SC and the overlap with AIH seems to be different from that in

adults. Gregorio et al [47] have tried to define a disease entity called auto-

immune sclerosing cholangitis. In childhood, autoimmune SC is the most

frequent cause of SC. Gregorio et al and Roberts [48] have concluded that

autoimmmune SC and AIH are likely to belong to the same disease process. This

observation differs in adults, where PSC seems to be the consequence of different

pathologic lesions, and the overlap of PSC and AIH is a rare event.

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