Autoimmune Hepatitis and PSC Connection

Autoimmune Hepatitis and PSCConnection

Diego Vergani, MD, PhD*,Giorgina Mieli-Vergani, MD, PhD

Institute of Liver Studies, King’s College London School of Medicine at King’s College

Hospital, Denmark Hill, London SE5 9RS, UK

This article describes the connection between autoimmune hepatitis(AIH) and primary sclerosing cholangitis (PSC). It is useful to start fromthe classical definition of the two disorders.

AIH is an inflammatory liver disease, affecting mainly females, character-ized by elevated transaminase levels; a histologic picture of interface hepa-titis; elevated IgG; and positive autoantibodies (antinuclear [ANA] oranti-smooth muscle [SMA] antibodies in AIH type 1, anti–liver kidney mi-crosomal antibody type 1 [anti–LKM-1] in AIH type 2). Immune reactionsagainst host liver antigens are believed to be the major pathogenic mecha-nism. AIH responds to immunosuppressive treatment in most cases.

PSC is a chronic cholestatic disorder of unknown etiology and pathogen-esis, affecting more males than females, characterized by liver inflammationand progressive obliterative fibrosis of the intrahepatic or extrahepatic bileducts. ANA and SMA, autoantibodies characteristic of type 1 AIH, are fre-quently present in PSC. Antineutrophil cytoplasmic antibodies (ANCA) arefrequent in PSC, particularly when associated with inflammatory bowel dis-ease (IBD), but may also be positive in AIH type 1. PSC does not usuallyrespond to immunosuppressive treatment and it progresses slowly and oftenasymptomatically to biliary cirrhosis, liver failure, or cholangiocarcinoma.The two conditions have chronicity, liver inflammation, and a positiveautoimmune serology in common, although they differ in terms of genderdistribution and bile duct damage.

The first full description of AIH was given by the Swedish physician Wal-denstrom [1] who described in 1950 a ‘‘hepatitis sui generis,’’ characterizedby female preponderance, hyper-IgG, and response to corticosteroids. In

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188 VERGANI & MIELI-VERGANI

1955, Joske and King [2] reported the finding of lupus erythematosus cells inthe blood of two patients with active chronic hepatitis and hypergammaglo-bulinemia active chronic hepatitis. In a landmark article, Mackay and col-leagues [3] described five additional hypergammaglobulinemic chronichepatitis patients recruited in the same unit. Because of the presence of lupuserythematosus cells, they provisionally designated this liver disorder as ‘‘lu-poid hepatitis.’’ Ten years later, when it was apparent that ‘‘lupoid hepati-tis’’ was a different entity from systemic lupus erythematosus, a condition inwhich liver disease is rare, and that lupus erythematosus cells reflect thepresence of ANA, Mackay and colleagues [4] suggested the alternativename of ‘‘autoimmune hepatitis.’’ This term, however, was finally acceptedonly in the 1990s, after several different labels had been given to this condi-tion over the years. In addition to seropositivity for ANAs, reports from theearly 1960s showed that anti-SMAs could also act as markers of what isknown today as AIH type 1 [5,6]. Thirty years after the first descriptionof ‘‘lupoid hepatitis,’’ AIH type 2, characterized by the presence in the se-rum of anti-LKM-1, was described [7].

Sclerosing cholangitis (SC) was first described in 1924 by a Parisian sur-geon, Delbet [8], who reported a patient with ‘‘irregular fibrosis and stenosisof the biliary tree.’’ In 1927, Miller [9] referred to a similar condition as ‘‘be-nign stricture of common bile duct.’’ Until the 1960s, SC remained largelyundiagnosed, with only a few cases reported in the literature. In 1964 [10],the condition was called for the first time ‘‘primary sclerosing cholangitis’’to distinguish it from SC secondary to lesions of the bile ducts or systemicdisease like primary or secondary immunodeficiency. Until the advent of en-doscopic retrograde cholangiopancreatography (ERCP) and percutaneoustranshepatic cholangiography, recognition was rare, being made at laparot-omy in patients with persistent jaundice. With the availability of cholangi-ography the disease is now recognized in anicteric patients and itsreported prevalence in both adults and children is increasing. The associa-tion of SC with ulcerative colitis was first clearly established in 1966 [11].

From the 1990s, there have been several mostly anecdotal reports de-scribing patients with features of both conditions, AIH and SC. This com-bined pathology has been referred to as ‘‘AIH-PSC overlap syndrome.’’

Clinical features

Autoimmune hepatitis

The diagnosis of AIH is based on the presence of positive autoantibodies,elevated transaminase and IgG levels, and interface hepatitis on liver biopsy(Fig. 1) [12,13]. The latter is required to confirm the diagnosis and to eval-uate the severity of liver damage. Other hepatic disorders that may sharesome of these features, including viral hepatitides, Wilson’s disease, anddrug-induced liver disease, need to be considered in the differential diagno-sis. Females outnumber male patients 3:1. A family history of autoimmune

Fig. 1. Portal and periportal lymphocyte and plasma cell infiltrate, extending to and disrupting

the parenchymal limiting plate (interface hepatitis). Swollen hepatocytes, pyknotic necroses,

and acinar inflammation are present (hematoxylin-eosin, original magnification �40). (Courtesyof A. Quaglia, MD, London, UK.)

189AUTOIMMUNE HEPATITIS AND PSC CONNECTION

diseases is found in some 40% of the patients. Associated autoimmune dis-orders are present at diagnosis or develop during follow-up in at least onefifth of the patients and include thyroiditis, IBD, insulin-dependent diabetes,vitiligo, nephrotic syndrome, hypoparathyroidism, and Addison’s disease,the latter two being observed in particular in anti–LKM-1–positive patientsor in patients with autoimmune polyendocrinopathy-candidiasis-ectodermaldystrophy, a monogenic disorder with a variable phenotype that includesAIH in about 20% of the cases [14,15].

Typically, AIH responds to immunosuppressive treatment, which shouldbe instituted as soon as diagnosis is made. The distinction in type 1 andtype 2 AIH is particularly relevant in pediatrics, because anti–LKM-1–posi-tive disease is quite rare, but not absent, in adults. The mode of presentationof AIH is variable, including an acute onset (especially in young patients); aninsidious onset with nonspecific symptoms of malaise; or complications ofportal hypertension. Some patients, however, are completely asymptomaticand are diagnosed after incidental discovery of abnormal liver function tests.

The criteria for the diagnosis of AIH have been defined and revised by theInternational Autoimmune Hepatitis Group (IAIHG) [12,13]. This diagnos-tic system includes positive and negative scores. Differences between a definiteand probable diagnosis of AIH relate mainly to the degree of serum gammaglobulin or IgG elevation, levels of ANA, SMA, or anti–LKM-1. Exposuresto alcohol, medications, or infections that can cause liver injury and chole-static laboratory and histologic changes carry a negative score. Responseto steroids weights strongly toward the diagnosis of AIH and has been incor-porated into the scoring system. At times autoantibodies are present at lowtiter or even absent, particularly in children, the titer rising or becoming de-tectable during follow-up. Seronegative individuals classified at presentationas having cryptogenic chronic hepatitis may later be firmly diagnosed when


conventional markers appear or when other autoantibodies that can be asso-ciated with AIH, but not generally tested, such as antiasialoglycoprotein re-ceptor, anti–liver-specific cytosol antigen type 1, anti–soluble liver antigen/liver pancreas, and ANCA, become detectable [16].

Primary sclerosing cholangitis

SC occurs in all age groups, with some features being unique to children.In adult PSC, most patients are men. They are often initially asymptomatic,and identified on the basis of abnormal liver function tests, in particularelevated levels of alkaline phosphatase or g-glutamyltransferase. These pa-tients may also have increased levels of IgG and IgM and positive autoan-tibodies (ANA, SMA, ANCA). Some patients may present with entirelynormal alkaline phosphatase [17]. Further investigations are usually promp-ted by the persistence of laboratory abnormalities. Cholangiography showsthe characteristic changes of SC (ie, multifocal strictures and dilatations,usually involving both the intrahepatic and extrahepatic bile ducts)(Fig. 2). In early stages, ulcerations of the common bile duct similar to thoseseen in the colon in early ulcerative colitis may be seen. Some patients, usu-ally with associated IBD, have chronic cholestasis and hepatic histologycompatible with SC but normal findings on cholangiography. This condi-tion, called ‘‘small duct SC’’ [18], may represent an early stage of classicPSC and is associated with a significantly better long-term prognosis.Some patients progress to fully blown SC. Patients with PSC may have

Fig. 2. Cholangiogram of a patient with primary sclerosing cholangitis showing widespread bile

duct strictures and dilatations. (Courtesy of M. Sellars, MD, London, UK.)


advanced radiologic and histologic disease without overt symptoms. In-crease in serum bilirubin with a decrease in serum albumin heralds impend-ing liver failure. The most common symptoms of decompensation arejaundice, fatigue, itching, and weight loss. Fever and acute cholangitis areuncommon, being present in 10% to 15% of cases [19]. In addition to chol-angiocarcinoma, PSC is a risk factor for the development of colorectal ad-enocarcinoma independently from the presence of IBD.

In pediatrics, SC is characterized by florid autoimmune features, includ-ing elevated titers of autoantibodies, in particular ANA and SMA anti-bodies; elevated IgG; and interface hepatitis (Fig. 3) [20]. Because thesefeatures are shared in common with AIH, in the absence of cholangio-graphic studies, many of these children are diagnosed and treated as AIH,although the diagnosis of SC may become apparent during follow-up.This condition is increasingly referred to as ‘‘autoimmune SC’’ (ASC). Cur-rent IAIHG criteria do not allow distinction between AIH and ASC.

Autoantibodies


Autoantibody detection not only assists in the diagnosis but also allowsdifferentiation of AIH in type 1 and type 2. ANA and SMA that characterizetype 1 AIH and anti–LKM-1 that defines type 2 AIH are practically mutuallyexclusive. The basic technique for the routine testing of autoantibodies rele-vant toAIH is indirect immunofluorescence on a freshly prepared rodent sub-strate that should include kidney, liver, and stomach to allow the detection ofANA, SMA, anti–LKM-1, and anti–liver-specific cytosol antigen type 1 [21].According to IAIHG criteria, autoantibody positivity at a titer of 1/40 is sig-nificant in adults, whereas in pediatrics titers of 1/20 for ANA and SMA and

Fig. 3. Interface hepatitis in a case of juvenile sclerosing cholangitis positive for antinuclear and

anti–smooth muscle antibodies (hematoxylin-eosin, original magnification �40). (Courtesy of

A. Quaglia, MD, London, UK)


1/10 for anti–LKM-1 are clinically relevant, because autoantibody reactivityis infrequent in healthy children. HEp2 cell immunofluorescence testingshould not be used at the screening level, as frequently done, because it givespositive ANA results in a high proportion of healthy individuals [22]. Its useshould be reserved to the definition of the ANA pattern, which is mostly ho-mogeneous in AIH type 1. Likely molecular targets of ANA include nuclearchromatin and histones, akin to lupus, but there are probably several others[21]. SMA is detected on kidney, stomach, and liver, where it stains the wallsof the arteries. In the stomach it also stains the muscularis mucosa and thelamina propria. On the renal substrate, it is possible to visualize the V (ves-sels), G (glomeruli), and T (tubules) patterns [21]. Although the V pattern ispresent also in nonautoimmune inflammatory liver disease, in autoimmunediseases not affecting the liver and in viral infections, the VG and VGT pat-terns aremore specific for AIH. The VGTpattern corresponds to the so called‘‘F actin’’ ormicrofilament pattern observed using cultured fibroblasts as sub-strate. Anti–LKM-1 stains brightly the liver cell cytoplasm and the P3 portionof the renal tubules, but does not stain gastric parietal cells. It is often con-fused with anti–mitochondrial antibody, the hallmark of primary biliary cir-rhosis. The molecular target of anti–LKM-1 is cytochrome P-4502D6(CYP2D6), whereas that of anti–mitochondrial antibody is pyruvate dehy-drogenase complex. There are now commercially available ELISAs for thedetection of anti–LKM-1 and anti–mitochondrial antibody that should beused in case of doubt. Anti–liver cytosol type 1 was originally described eitherin association with anti–LKM-1, or in isolation, in both instances defininga clinical entity similar to AIH type 2 [23]. Its molecular target is formi-mino-transferase cyclodeaminase. Anti–soluble liver antigen/anti–liver-pan-creas, described separately in AIH, targets the same antigen and is the sameautoantibody. Its molecular target is UGA tRNA suppressor associatedantigenic protein [24]. Although anti–soluble liver antigen/liver pancreas isfound occasionally in patients with AIH who are negative for ANA, SMA,and anti–LKM-1, it is also frequently present in typical cases of AIH type 1and type 2, and also in ASC [25]. Anti-SLA seems to be highly specific forthe diagnosis of autoimmune liver disease. Its detection at the time of diagno-sis identifies patients with more severe disease and worse outcome [25,26].


Patients with PSC often have elevated levels of IgG and IgM and circu-lating autoantibodies, in particular ANA, SMA, and ANCA. The relevanceof these autoantibodies in the diagnosis of PSC is a matter of debate. ANAhas been described in 7% to 77%, SMA in 13% to 20%, and ANCA in upto 88% of patients [27]. In the juvenile form (ASC), 97% of patients are pos-itive for ANA or SMA [20]. Whether there is a specific immunofluorescencepattern for ANA and SMA in PSC and ASC remains to be investigated. Thevariability of the reported autoantibody prevalences is almost certainly


caused by the lack of standardization in autoantibody detection. It is advis-able to apply to PSC the same guidelines used in the diagnosis of AIH,where ANA and SMA are considered positive at a titer greater than or equalto 1:40 in adults (R1:20 in children) when tested on frozen composite sec-tions of rodent liver, kidney, and stomach [12,13].

ANCA are a fairly consistent feature of PSC, but are also detected ina high proportion of patients with other autoimmune diseases, in particularulcerative colitis [28] and type 1 AIH [29,30]. ANCA associated with PSCand AIH type 1 are distinct from cytoplasmic ANCA and classical perinu-clear ANCA, which are diagnostic seromarkers for Wegener’s granulomato-sis and microscopic polyangitis, respectively. PSC, ulcerative colitis, andAIH are associated with ‘‘atypical perinuclear ANCA,’’ which has a distinctstaining pattern on indirect immunofluorescence microscopy. Recent evi-dence indicates that the target of ‘‘atypical perinuclear ANCA’’ is locatedwithin the nuclear membrane and for this reason it has been proposed torename it peripheral anti-neutrophil nuclear antibody (pANNA) [31].

Histologic features


Histologic lesions typically present in AIH are periportal lymphocytic orlymphoplasmacytic infiltration (interface hepatitis), hepatocyte swelling, orpycnotic necrosis (see Fig. 1). Lymphocytes, plasma cells, and histiocytessurround individual dying hepatocytes at the portal-parenchymal interfaceand in the lobule. Plasma cells are usually abundant at the interface andthroughout the lobule. In AIH presenting acutely or relapsing, panlobularhepatitis is often present, associated to bridging necrosis and, in the caseof a fulminant presentation, to massive necrosis. Although sampling varia-tion may occur in needle biopsy specimens, especially in the presence of cir-rhosis, the severity of the histologic appearance is of prognostic value,although even patients with cirrhosis at presentation respond well to immu-nosuppressive treatment.


Histologically, PSC has been divided into four stages, a classificationused more as a research tool than for clinical management [32]. In stage 1there is degeneration of the bile duct epithelial cells and infiltration of thebile ducts by mononuclear cells, with occasional neutrophils. The portaltracts may be expanded because of fibrosis and edema, and may show pro-liferation of bile ducts; vacuolization of ductular epithelial cells; and concen-tric layers of connective tissue surrounding individual bile ducts (onionskinfibrosis) (Fig. 4). Stage 2 is characterized by more widespread fibrosis andinflammation, which infiltrates the periportal parenchyma with damage ofperiportal hepatocytes (interface hepatitis). A prominent feature is bile

Fig. 4. Onionskin fibrosis around a damaged bile duct. This is the characteristic lesion of scle-

rosing cholangitis, but is rarely seen in percutaneous liver biopsies (hematoxylin-eosin, original

magnification �40). (Courtesy of A. Quaglia, MD, London, UK)


ductopenia. This becomes more severe in stage 3, where bile ducts may beabsent and porto-portal bridging fibrosis prominent, with cholestasis inperiportal and paraseptal hepatocytes. Stage 4 is characterized by frank bil-iary cirrhosis. The typical onionskin fibrosis lesion (see Fig. 4) is rarely seenon a percutaneous liver biopsy, where paucity of normal bile ducts with non-specific portal tract fibrosis and inflammation are the most common find-ings. In view of the variable and largely nonspecific histologic lesions, thediagnosis of SC rests on cholangiographic imaging. In ASC, the most fre-quent juvenile form of SC, the early histologic findings include a portal tractmononuclear cell inflammatory infiltrate, comprising lymphocytes, macro-phages, and plasma cells, with interface hepatitis indistinguishable fromthat of AIH (see Fig. 3) [20].

Genetic features

Both AIH and PSC are complex trait diseases (ie, conditions not inheritedin a mendelian autosomal-dominant, autosomal-recessive, or gender-linkedfashion). The mode of inheritance of a complex trait disorder is unknownand involves one or more genes, operating alone or in concert, to increaseor reduce the risk of the trait, and interacting with environmental factors.


Susceptibility to AIH is imparted by genes within the HLA region on theshort arm of chromosome 6, especially those encoding DRB1 alleles [33,34].The function of these class II major histocompatibility complex molecules ispeptide antigen presentation to CD4 T cells, suggesting the involvement ofmajor histocompatibility complex class II antigen presentation and T-cellactivation in disease pathogenesis.


In Europe and North America, susceptibility to AIH type 1 is conferredby the possession of HLA DR3 (DRB1*0301) and DR4 (DRB1*0401). InJapan, Argentina, and Mexico, susceptibility is linked to DRB1*0405 andDRB1*0404. Susceptibility to AIH type 2 is conferred by the possessionof HLA DR7 (DRB1*0701) and DR3 (DRB1*0301), patients positive forDRB1*0701 having a more aggressive disease and severe prognosis [35].


Small, early studies identified significant associations between PSC andpossession of HLA B8 and DR3. Subsequent investigations in different Eu-ropean populations uncovered three potential susceptibility haplotypes con-taining as key alleles B*08/DRB1*03, DRB1*13, or DRB1*15 [27,36].Whether these alleles or other flanking HLA genes present in the individualhaplotypes, such as MICA or DQ, contribute most to disease susceptibilityremains to be determined [36]. A key role in conferring susceptibility and re-sistance seems to be played by specific amino acids at position DQb-87 andDQb-55, respectively [37].

Because the end result of inflammation in PSC is periductal fibrosis, thereported association between a polymorphism of MMP-3 (stromelysin) [38],a gene involved in the regulation of the production and destruction of extra-cellular matrix, and susceptibility to PSC and its progression is of interest.Susceptibility to ASC is imparted by possession of DRB1*13 [39].

Pathogenic mechanisms


An unknown but powerful stimulus must be promoting the formation ofthe massive inflammatory cell infiltrate present at diagnosis in AIH. What-ever the initial trigger, the high number of activated inflammatory cells islikely to initiate and perpetuate liver damage. An autoimmune attack can fol-low different pathways to inflict damage on hepatocytes. It is believed thatliver damage is orchestrated by CD4þ T lymphocytes recognizing a self-anti-genic peptide on hepatocytes. To trigger an autoimmune response, the pep-tide must be embraced by an HLA class II molecule and presented touncommitted (naive) CD4þ T helper (Th0) cells by professional antigen-pre-senting cells, with the costimulation of ligand-ligand (CD28 on Th0, CD80 onantigen-presenting cells) fostering interaction between the two cells. Th0 cellsbecome activated, differentiate into functional phenotypes according to thecytokines prevailing in the microenvironment and the nature of the antigen,and initiate a cascade of immune reactions determined by the cytokines theseactivated T cells produce. Th1 cells, arising in the presence of the macro-phage-produced interleukin (IL)-12, secrete mainly IL-2 and interferon-g,which activate macrophages; enhance expression of HLA class I (increasingliver cell vulnerability to a CD8þ T-cell cytotoxic attack); and induce


expression of HLA class II molecules on hepatocytes. Th2 cells, which differ-entiate from Th0 if the microenvironment is rich in IL-4, produce mainlyIL-4, IL-10, and IL-13, which favor autoantibody production by B lympho-cytes. Physiologically, Th1 and Th2 antagonize each other. Th17 cells, a re-cently described population [40,41], arise in the presence of transforminggrowth factor-b and IL-6 and seem to have an important effector role in in-flammation and autoimmunity. The process of autoantigen recognition isstrictly controlled by regulatory mechanisms, such as those exerted byCD4þCD25þ regulatory T cells, which are derived from Th0 in the presenceof transforming growth factor-b, but in the absence of IL-6. If regulatorymechanisms fail, the autoimmune attack is perpetuated.

Over the past three decades different aspects of this pathogenic scenariohave been investigated. In particular, a defect in immunoregulation affectingCD4þCD25þ regulatory T cells has been demonstrated in AIH [42–44].These cells are numerically and functionally defective in patients withAIH, particularly at diagnosis or during relapse. Advances in the study ofautoreactive T cells have occurred mostly in AIH type 2, because the knowl-edge that CYP2D6 is the main autoantigen has enabled the characterizationof both CD4 and CD8 T cells targeting this cytochrome. One study hasshown that CD4 T cells from patients with type 2 AIH positive for the pre-disposing HLA allele DRB1*0701 recognize seven regions of CYP2D6 [35],five of which have later been shown also to be recognized by CD8 T cells[45]. High numbers of interferon-g–producing CD4 T cells and CD8 T cellsare associated with biochemical evidence of liver damage, suggesting a com-bined cellular immune attack.


A number of environmental factors have been proposed in the pathogen-esis of the bile duct injury typical of SC, including chronic portal bacter-emia, toxic bile acid metabolites produced by the enteric flora, toxinsproduced directly by the enteric bacteria, chronic infections, and ischemicvascular damage [27]. The strong association between PSC and IBD hasled to the hypothesis that the initial insult in PSC is the reaction of a genet-ically susceptible host to bacterial cell wall products entering the portal cir-culation through a permeable gut wall either caused by colitis or duringepisodes of intestinal infection [46]. This may lead to activation of Kupffercells in the liver, with the consequent production of peribiliary cytokines andchemokines that attract inflammatory cells. As a result of this peribiliary in-flammatory process, concentric fibrosis around the bile ducts ensues, withconsequent ischemia and atrophy of the biliary epithelial cells. Bile ductloss then leads to progressive cholestasis, and eventually to biliary cirrhosis.PSC, however, exists also in the absence of IBD, may present several yearsbefore IBD or after colectomy, and colectomy does not alter the course ofthe disease [47,48].


An interesting hypothesis, supported by some experimental evidence,proposes a role for an enterohepatic circulation of lymphocytes, whereby in-testinal lymphocytes produced in the gut mucosa during active inflammationrecirculate as memory cells through the liver [49]. Activated intestinal lym-phocytes express a4b7, a gut-specific homing receptor that binds its corecep-tor mucosal addressin cell adhesion molecule-1, which is gut specific. Theliver endothelial cells in PSC express aberrantly mucosal addressin cell adhe-sion molecule-1, providing a docking station for lymphocytes originatingfrom the gut. It is not the microorganism or product thereof to trigger theimmune-mediated liver inflammation of PSC, but memory T cells activatedin the gut and capable of microbe-self cross-reactivity. The long life of mem-ory T cells explains why the disease may occur a long time after colectomyand why colectomy does not affect the course of PSC. This hypothesis isattractive, but does not explain why PSC can exist without IBD, althoughsubclinical intestinal inflammation may be sufficient to trigger the process.

Treatment and outcome


Immunosuppressive treatment with steroids and azathioprine is beneficialin patients with severe symptomatic disease and it should be started as soon aspossible, without waiting for 6 months as suggested in early studies. Most pa-tients, including those with cirrhosis [50], achieve remission on 30mg prednis-olone daily for 1 month, after which azathioprine can be introduced at 1 mg/kg/day and the dose of prednisolone reduced to 5 to 15mg/day tomaintain theaminotransferase activity within the normal range. If the patient develops ste-roid side effects, the dose of azathioprine can be increased to 2mg/kg/day anda complete withdrawal of steroids considered. The optimal duration of treat-ment is unknown, but it is prudent not to attempt withdrawal of immunosup-pression within 2 years of diagnosis. During withdrawal attempts the liverfunction tests should be monitored closely because relapse may be severeand even fatal. It is now clear that there are patients with a milder form ofthe disease who may be asymptomatic or paucisymptomatic and are detectedincidentally, during routine check-ups. For these patients the approach totreatment is less clear. The benefit of therapy is undefined and it may be solow that the risk of corticosteroid side effects is unjustified. This is particularlyrelevant to postmenopausal women and elderly patients, although a recent pa-per shows that aggressive treatment of the latter is associated with an excellentprognosis [36]. When the standard treatment fails, other drugs that have beentried include cyclosporin, ursodeoxycholic acid, budesonide, andmycopheno-late mofetil. Although encouraging results are described, these reports areanecdotal. Liver transplantation is the ultimate treatment for most patientswho present with fulminant hepatic failure and those who reach end-stagechronic liver disease. AIH may recur after transplant.



Several choleretic, immunosuppressive, and antifibrotic agents have beenused to treat adult PSC, but no drug has been shown to alter its natural his-tory. Ursodeoxycholic acid is a hydrophilic bile acid that stabilizes liver cellmembranes exposed to toxic concentrations of the naturally occurring che-nodeoxycholic acid. Although early studies using ursodeoxycholic acid ata dose of 13 to 15 mg/kg/day showed an improvement in laboratory tests,but not long-term beneficial changes [51], more recent evidence suggeststhat higher doses (25–30 mg/kg/day) can be of benefit [52,53]. Despite earlyreports of improvement with steroids and azathioprine in adult patients withPSC [54,55], their use is controversial.

In ASC, the juvenile form of SC that has strong autoimmune features,treatment with steroids and azathioprine akin to that used in AIH hasbeen reported to be beneficial in abating the parenchymal inflammatorylesion, but to be less effective in controlling the bile duct disease [20]. Forpatients with advanced PSC, liver transplantation is the only effective ther-apeutic option and for optimal results it should be offered when the diseaseis not too advanced. Both PSC and ASC can recur in the graft.

The connection

AIH and PSC have been considered separate nosologic entities, the formerinvolving exquisitely the liver parenchyma, the latter the bile ducts. Therehave been, however, a series of anecdotal reports documenting bile ductlesions typical of SC in patients, both adult and children, originally diagnosedas suffering from AIH. The question as to whether biliary lesions could havebeen present at outset was raised but not experimentally addressed. The obser-vation that some children originally thought to have AIH on the basis of highIgG, presence of autoantibodies, and interface hepatitis on histology presentduring follow-up colangiopathic changes diagnostic of SC [56] has promptedthe King’s group to perform a prospective study [20]. All 55 pediatric patientswith liver disease and serologic evidence of autoimmunity referred between1984 and 1997 underwent liver and rectal biopsies and ERCP at referral. Bi-opsies and ERCPs were repeated at follow-up. It was found that half of thesepatients had bile duct changes diagnostic of SC at the time of presentation. Allbut one had serology of AIH type 1 and interface hepatitis and, in the absenceof cholangiographic studies, at least a quarter would have been diagnosed asAIH type 1. This condition was referred to as ‘‘autoimmune sclerosing chol-angitis.’’ Gender distribution was different, females being 79% in AIH and55% inASC.An interesting finding of this study is that levels of alkaline phos-phatase and g-glutamyltransferase did not differ between the two groups, theonly biochemical difference being a higher ratio between alkaline phosphataseover aspartate aminotransferase in those with ASC. In both groups theparenchymal lesions responded satisfactorily to immunosuppression with


prednisolone and azathioprine, but half of the patients with ASC, also treatedwith 10 to 15 mg/kg ursodeoxycholic acid, showed progression of bile ductdisease on follow-up ERCP. One patient with AIH type 1 who had normalERCP at presentation developed florid bile duct changes 8 years later. Thequestion as to whether AIH and ASC are different diseases or different man-ifestations of the same disease remains to be answered. The similarities includethe autoimmune serology, the histologic lesions, and the parenchymal re-sponse to immunosuppression; the differences include gender distributionand HLA association, as discussed previously. Also awaiting an answer arethe questions as to whether adult PSC is a burnt-out form of juvenile ASCand whether ASC is present in the adult AIH population. The latter questionis partially answered by a cross-sectional study investigating the possible pres-ence of bile duct changes in a large cohort of adult patients with AIH type 1[57]. Using magnetic resonance cholangiography, a technique less sensitivethan ERCP, alteration of bile ducts diagnostic of SC was detected in 18%.A study where cholangiography is performed at presentation in a cohort ofadult patients with features of AIH remains to be done.

Summary

There is evidence suggesting that both AIH and PSC are immune-medi-ated diseases. It can be argued that the juvenile form of ASC, characterizedby unambiguous serologic and histologic features of autoimmunity, andresponsive to immunosuppression, represents the early stage of adult PSC.In contrast to juvenile ASC, adult PSC has an insidious onset, being oftencompletely asymptomatic, and could represent a late burnt-out stage ofthe same condition, too advanced to respond to treatment. The discrepancyin gender distribution between ASC, which is slightly more common in fe-males, and adult PSC, which has a male preponderance, could be causedby the fact that the disease is more progressive in males. A plausible alter-native is that the course of the disease, more aggressive and symptomaticin young women frequently diagnosed as having AIH, is favorably modifiedby early immunosuppressive treatment. PSC and AIH could lie within thespectrum of the same disease process. Future studies should determinehow frequently AIH evolves to PSC and what is the ultimate outcome ofjuvenile ASC treated with immunosuppression.

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Autoimmune Hepatitis and PSC Connection