Autoimmune Pancreatitis

Autoimmune Pancreatitis

Review Article

INTRODUCTION

Autoimmune pancreatitis (AIP) represents a uniquesubset of chronic inflammatory pancreatic disease withdistinct clinical, morphologic, and histopathologic featuresthat typically responds dramatically to steroid treatment [1-3]. Named in 1995 by Yoshida and colleagues [4-5], theclinical characteristics of the disease had been described asearly as 1961. It took several decades for it to be accepted asa distinctive entity; in fact, as recently as 2003, the AmericanPancreatic Association still debated its existence [6]. In thelast 5 years, however, AIP has generated significant interestfrom clinicians and researchers. Although still a rare disease,it is increasingly being recognized and its existence is nolonger in doubt.

HISTORICAL MILESTONES

Sarles and colleagues [5] in 1961 were the first todescribe an autoimmune phenomenon in relation to“sclerosis of the pancreas”. Although treatment withimmune-modulating therapy was not suggested at that time,this spurred interest in this entity over the next severaldecades. Several terms were then used to subsequentlydescribe the disease, including “chronic sclerosingpancreatitis,” “lymphoplasmacytic sclerosing pancreatitis,”“nonalcoholic duct-destructive pancreatitis,” “sclerosingpancreatitis,” “sclerosing pancreaticocholangitis,” and“autoimmune chronic pancreatitis” [7-9]. In 1991,Kawaguchi and colleagues [10] described a variant ofcholangitis extensively involving the pancreas. Thisdescription was quickly followed by several other reportsdescribing other organ involvement in patients who had AIP[7,11].

269 Apollo Medicine, Vol. 7, No. 4, December 2010

AUTOIMMUNE PANCREATITIS

Abid SattarConsultant Gastroenterologist, Department of Gastroenterology, Apollo BGS Hospital, Kuvempu Nagar,

Mysore 570 023, India. e-mail: [email protected]

Autoimmune pancreatitis is the pancreatic manifestation of a systemic disorder that affects various organs,including the bile duct, retroperitoneum, kidney, and parotid and lacrimal glands. It represents a recentlydescribed subset of chronic pancreatitis that is immune mediated and has unique histologic, morphologic, andclinical characteristics. A hallmark of the disease is its rapid response to corticosteroid treatment. Although stilla rare disease, autoimmune pancreatitis is increasingly becoming recognized clinically, leading to evolution inthe understanding of its prognosis, clinical characteristics, and treatment.

Key words: Auto immune Pancreatitis (AIP), Serum IgG4, CT Scan, MRI, Steroids.

Ito and colleagues [12] subsequently described the firstthree cases of AIP that were successfully treated withcorticosteroids. In a seminal study published in 2001,Hamano, et al.[9] reported that elevated serum IgG4 levelswere associated with sclerosing pancreatitis and thattreatment with corticosteroid therapy successfullydecreased these levels. The first diagnostic criteria wereproposed by the Japanese Pancreas Society in 2001 andsubsequently modified in 2006 [13-14]. Chari, et al. [1] in2006 proposed new diagnostic criteria, which includedhistologic, imaging, and serologic characteristics and otherorgan involvement and response to corticosteroids.

DEFINITION

AIP has been defined as “the pancreatic manifestationof a systemic fibroinflammatory disease which affects notonly the pancreas but also various other organs includingbile duct, salivary glands, the retroperitoneum and lymphnodes. Organs affected by AIP have a lymphoplasmacyticinfiltrate rich in IgG4 positive cells and the inflammatoryprocess responds to steroid therapy” [1]. The systemicdisease of which AIP is a manifestation has been calledIgG4-related systemic disease (ISD) in recognition that allorgans afflicted show a dense lymphoplasmacytic infiltraterich in IgG4-positive cells [15-16].

EPIDEMIOLOGY

Almost all data describing the epidemiology of AIPcome from Japan. In 2002, Nishimori and colleagues [17]randomly surveyed Japanese hospitals on how manypatients they had who had pancreatitis in 2002 who fulfilledthe diagnostic criteria for AIP as proposed by the Japan

Apollo Medicine, Vol. 7, No. 4, December 2010 270

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Pancreas Society. Based on this survey, the prevalence ofpatients who had AIP in Japan was estimated to be 0.82 per100,000. AIP was predominantly seen in men past middleage (older than 45 years). Other Japanese series havedescribed the prevalence of disease between 5% and 6% ofall patients who have chronic pancreatitis [18-19].

The prevalence of AIP in the United States is unknown,because no extensive population-based studies have beenperformed. Because AIP often mimics pancreatic cancer inits initial presentation, the best estimates of prevalence ofAIP are in patients undergoing resection for presumedpancreatic cancer because of obstructive jaundice or apancreatic mass. In three recent studies, 43 of 1808 (2.4%)pancreatic resections were reported to havelymphoplasmacytic sclerosing pancreatitis (LPSP) onhistologic examination of the resected specimen.. Anotherretrospective evaluation of 245 pathology specimens at theMayo Clinic from patients who underwent resection forbenign pancreatic disease revealed that 27 (11%)represented AIP with a “tumefactive” presentation.

Males are nearly twice as likely as females to developAIP and the average age of onset is in the fifth decade [17].In fact, 85% of patients are older than 50 years of age [19].

PATHOGENESIS

Currently, the pathogenesis of AIP is unknown,although it almost certainly reflects an immune-mediatedprocess. Genetic susceptibility to AIP has been linked toboth the HLA-DRB1"0405-DQB1"0401 in the class II andthe ABCF1 proximal to C3-2-11 telomeric of HLA-E in theclass I regions [20]. In addition, a recent report described thegenetic association of Fc receptor-like 3 polymorphismswith AIP in Japanese patients [21].

The trigger for AIP remains elusive. It is hypothesizedthat HLA-DR antigens on the pancreatic ductal and acinarcells may serve as antigens recognized by CD4+ producinginterferon-c and CD8+ T lymphocytes, leading tosubsequent inflammation. Polymorphisms of the cytotoxicT lymphocyte-associated antigen 4, a key negative regulatorof the T-cell immune response, have been demonstrated inpatients who have AIP [22]. An etiologic role for antigenicHelicobacter pylori infection by way of molecular mimicryhas also been proposed. Like many immune-mediateddiseases, AIP has been linked to many other autoimmuneconditions, such as Sjögren syndrome, retroperitonealfibrosis, and primary sclerosing cholangitis (PSC) [23-25].The work by Kamisawa and colleagues, however [26], hasshown that these associated conditions are in factmanifestations of a new clinicopathological entity, IgG4-related systemic disease (ISD) that is characterized by tissueinfiltration with abundant IgG4-positive plasma cells. For

example, unlike Sjögren syndrome, Reidel thyroiditis andIgG4-associated nephritis [27]. Whether AIP is trulyassociated with any other distinct autoimmune disorderneeds confirmation in case-control studies.

Clinical features

Most patients who have AIP are male and older than 50years[17,19,20]. The male/female predominance isapproximately 2:1 [21]. Female patients are more prevalentin the subset of AIP associated with parotid glandinvolvement, however http://www.mdconsult.com/das/article/body/225139942-12/jorg=journal&source=MI&sp=20688639 &sid=1077935416/N/644914/1.html?issn=0889-8553- r08000150035. Although the age of onsetis typically in the sixth decade, AIP has been described inpatients in their 30s [19].

The clinical presentation of AIP may include pancreaticor extrapancreatic manifestations:

Pancreatic manifestationsObstructive jaundiceDiabetesSteatorrheaUpper abdominal discomfort or painWeight lossAcute pancreatitis (rare)

Extrapancreatic manifestationsBiliary stricturesSclerosing cholangitisSialoadenitisRetroperitoneal fibrosisHilar or abdominal lymphadenopathyChronic thyroiditis, Interstitial nephritis

The most common presentation, seen in over two thirdsof patients with an acute presentation, is obstructivejaundice associated with a biliary stricture and a focal massor diffuse enlargement of the pancreas [28]. The majordifferential diagnosis in this situation is pancreatic or biliarycancer, often leading to surgical resection. Other pancreaticmani-festations include the presence of a pancreatic mass,diffuse or focal enlargement of the pancreas in the absenceof obstructive jaundice, and new onset or worsening ofexisting diabetes or steatorrhea . In contrast to other forms ofchronic pancreatitis, abdominal pain and attacks of acutepancreatitis are uncommon manifestations of AIP. Mostpatients with AIP have no or mild abdominal pain ordiscomfort that is controlled by nonnarcotic analgesics.Pancreatic enzyme elevations maybe seen in some patients.The pancreatic manifestations of AIP thus can mimicpancreatic cancer, acute pancreatitis, painless chronicpancreatitis, or unexplained pancreatic functionalinsufficiency.

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not seen in AIP; however, long-standing or recurrent AIPcan be associated with stone formation.

Classically, the predominant histologic feature of AIPhas been dense infiltration of the periductal space withplasma cells and T lymphocytes. Associated with thisinfiltrate is acinar destruction, obliterative phlebitisinvolving the major and minor veins, and storiform or“whirling” fibrosis of the pancreatic parenchyma, whichcan extend to contiguous peripancreatic soft tissue. Thisconstellation of histopathologic findings defines LPSP

AIP has been associated with involvement of severalother organs. These extrapancreatic manifestations of AIPcan be seen in up to 49% of patients and include biliarystrictures, sclerosing cholangitis, sialadenitis, retro-peritoneal fibrosis, hilar or abdominal lymphadenopathy,chronic thyroiditis, interstitial nephritis, and inflammatory-bowel disease. The extrapancreatic manifestations mayoccur concurrently with pancreatic disease, may be presentbefore the recognition of pancreatic disease, or can occurweeks to months after their initial presentation [27,29].

Table 1 summarizes the common, atypical, and rareclinical features encountered in AIP.

HISTOPATHOLOGY

On gross examination, the pancreas in AIP is often notedto be indurated and firm, the fibroinflammatory processwithin the pancreas can mimic pancreatic ductaladenocarcinoma because it is commonly localized in thehead of the pancreas ( Fig. 1) [6]. The involved area is firmand gray to white; the normal lobular architecture is lost andthe fibrosis can sometimes be seen infiltrating theperipancreatic soft tissue. When AIP involves the head ofthe pancreas, involvement of the main pancreatic ductresults in proximal stenosis or obstruction and distaldilatation; the common bile duct is also usually involved (ingreater than 90% of the cases) and appears thickened andstenotic with proximal dilatation. Unlike other forms ofchronic pancreatitis, such as alcoholic pancreatitis andhereditary pancreatitis, calcifications, duct dilatation withinthe fibrotic areas, fat necrosis, and pseudocysts are typically

Table 1. Clinical features of autoimmune pancreatitis

Feature Typical (>50%) Less common (10-50%) Rare (<10%)

Presenting Obstructive jaundice Abdominal pain, weight loss, Clinical acute pancreatitis,complaint diabetes, steatorrhea asymptomaticHistology LPSP IDCP Extensive fibrosis, minimal

inflammationPancreatic Diffusely enlarged gland Parenchymal atrophy, intraductal Pseudocystimaging with delayed and rim calcification

enhancement, irregularnarrowed pancreatic duct

Serology Elevated serum IgG4 Normal serum IgG4 levelslevels

Other organ Bile duct, kidneys, Retroperitoneum, salivary Mesenteritis, inflammatoryinvolvement lymphadenopathy gland bowel disease Response to Complete Incomplete Refractory to steroidssteroids

Abbreviation: IDCP, idiopathic duct-centric chronic pancreatitis.Data from Lara LP, Chari ST. Autoimmune pancreatitis. Curr Gastroenterol Rep 2005;7:101–6.

Fig. 1. Gross appearance of AIP. A cross section through thepancreas is shown. Dense, white fibrotic tissue hasreplaced the normal pancreatic parenchyma. There isenhancement of the process around the common bileduct (*). There are foci of fat necrosis present in thisexample (yellow flecks).


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(Fig. 2) [10,30]. A less common histopathologic varianttermed idiopathic duct-centric chronic pancreatitis ischaracterized by a neutrophilic infiltrate with occasionalmicroabscesses and rare obliterative phlebitis [9,31].Nearly a third of patients who have AIP develop pancreaticcalcification and atrophy and the appearance can resembleusual chronic calcific pancreatitis.

Pathologic features of autoimmune pancreatitis

Characteristic findingsFirm, tumor-like mass within the head of the pancreasLymphoplasmacytic inflammation with associatedfibrosis (periductal or lobular)Obliterative venulitis

Increased numbers of IgG4-positive plasma cells (>10/high-powered field)

Less commonly seenDiffuse fibrosisNeutrophilic infiltrate within the lobules and ducts withoccasional microabscessbular fibrosis without significant inflammation

Not typically seenDuctal dilatationCalcifications or stonesFat necrosisPseudocyst formation

http://www.mdconsult.com/das/article/body/225139942-12 / jo rg= jou rna l&source=MI&sp=20688639&

Fig.2 Histopathologic features of AIP. (A) Low magnification showing a fibroinflammatory process diffusely involving anddestroying the pancreatic parenchyma (hematoxylin-eosin, original magnification _40). (B) Periductal inflammation andfibrosis extends into the adjacent parenchyma; the ductal epithelium is relatively spared (hematoxylin-eosin, originalmagnification _100). (C) On higher magnification, destruction of the normal acini by plasma cells (arrows), lymphocytes,and fibroblasts can be seen; the acinar cells contain pink cytoplasmic granules (hematoxylin-eosin, original magnification_400). (D) Obliterative venulitis is a characteristic finding in AIP. Here, the vein lumen (*) is nearly obliterated by theinflammatory process; an uninvolved artery is present in the lower right corner (hematoxylin-eosin, original.

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Because elevated IgG4 serum levels are typicallyidentified in patients with AIP, the presence of IgG4 plasmacells, detected by immunohistochemistry, is anothercharacteristic histopathologic finding of AIP and can beused as a diagnostic tool in AIP and related sclerosingdiseases. A dense infiltration of IgG4-positive plasma cellsin the pancreas is characteristic of AIP (Fig. 3). In theJapanese literature, ‘‘dense’’ is defined as greater than 30IgG4-positive cells per high-power field (hpf). A recentpublication by the Mayo Clinic divides the IgG4-positiveinfiltrate into mild (<10/hpf), moderate (11–30/hpf), andmarked (>30/hpf). They found that patients with AIP oftenhad moderate or marked infiltration by IgG4-positiveplasma cells in their pancreatic tissue. This was particularlytrue in classic LPSP, in which 16 (94%) of 17 cases showedelevated numbers of IgG4-positive cells, compared with 5(42%) of 12 cases of IDCP, highlighting yet anotherdifference between these two histologic variants of AIP.Both sets of researchers rarely found IgG4 staining inpatients with chronic alcoholic pancreatitis and pancreaticductal adenocarcinoma. Based on these studies of IgG4staining in AIP, another diagnostic feature of AIP is thepresence of a lymphoplasmacytic infiltrate with greaterthan10 IgG4-positive cells/hpf in the pancreas.

Imaging features

Although several distinguishing imaging features ofAIP have been proposed in the literature, the lack offamiliarity of this entity by radiologists and referringclinical services often results in an errant diagnosis ofpancreatic carcinoma.

The characteristic appearance of AIP observed byvarious imaging modalities is that of a diffusely enlargedpancreas, forming a sausage-shaped gland with featurelessborders (Fig.4) [1,32]. Other classic features that may bepresent include delayed and prolonged contrastenhancement, a rimlike capsule surrounding the gland ondelayed enhancement sequences (the hypoattenuationhalo), a nondilated, ectatic pancreatic duct, and the absenceof peripancreatic fat hypoenhancement, calcifications,stones, and pseudocysts are typically not seen.

On CT, in addition to appearing diffusely enlarged(Fig.4- A), the pancreas has delayed and prolonged contrastenhancement and can have a capsulelike low-density rimsurrounding the pancreas. In a large study by Sahani andcolleagues, uniform pancreatic enlargement andisoenhancement were common features in most patientswith diffuse AIP; peripancreatic infiltration, when present,was minimal. Absence of normal pancreatic clefts and asubtle rim of hypoattenuation were thought to be caused byinflammatory exudates (Fig. 2A). More focal AIP, typicallywithin the head and uncinate process, was difficult todistinguish from pancreatic carcinoma.

MRI characteristically reveals enlargement of thepancreas with decreased signal intensity on T1-weightedMR images, increased signal intensity on T2-weighted MRimages, and, occasionally, a hypointense capsule-like rim(Fig 4 B) [30]. Magnetic resonance cholangiopancreato-graphy (MRCP) is often helpful in characterizing thepancreatic and bile ducts, although the narrowed segment ofthe pancreatic duct is not well visualized. Narrowing of theanterior superior pancreaticoduodenal artery, posteriorsuperior pancreaticoduodenal artery, and transpancreaticartery on angiographic evaluation has also been described inAIP patients [33].

Increasingly, endoscopic ultrasound has been used toevaluate patients for AIP [34,35]. Not only can theparenchyma and biliary and pancreatic ducts be visualized,EUS also provides an opportunity to obtain Trucut biopsysamples. Intraductal ultrasound can also be used to evaluateindeterminate biliary strictures. Levy and colleagues [36]have reported on the diagnostic usefulness of Trucut biopsyin three patients who had suspected pancreaticadenocarcinoma with planned surgical resection followingindeterminate fine-needle aspiration. In two of the patients,AIP was diagnosed using Trucut biopsy; in the other chronicpancreatitis was diagnosed. In all patients, unnecessarysurgery was avoided.

On endoscopic retrograde cholangiopancreatography(ERCP), the pancreatic duct has an irregular contour andcan be either segmentally or diffusely narrowed [28]. If the

Fig. 3 Numerous IgG4-positive plasma cells are present inthis case of AIP (IgG4 immunostain).


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proximal duct is strictured, there is often dilation of thedistal pancreatic duct or proximal common bile duct. UnlikeERCP, MRCP may not be able to detect the irregularnarrowing of the main pancreatic duct, but the MRCPfindings of skipped, nonvisualized main pancreatic ductlesions, in conjunction with other imaging studies, areuseful in supporting a diagnosis of AIP .Cholangiographyhas been shown to be an accurate method to differentiateAIP from primary sclerosing cholongitis (PSC). Nakazawaand colleagues [37] reported that bandlike stricture, beadedor pruned-tree appearance, and diverticulum-like formationwere significantly more frequent in patients who had PSC.In contrast, segmental stricture, long stricture withprestenotic dilatation, and stricture of the distal commonbile duct were significantly more common in sclerosingcholangitis with AIP. Increased uptake with whole-body(18)F-fluorodeoxyglucose positron emission tomographyis seen in the pancreas and extrapancreatic lesions ofpatients who have AIP [38-40].

FEATURES OF AUTOIMMUNE PANCREATITIS BYVARIOUS IMAGING MODALITIESGeneral findings

Diffusely or focally enlarged pancreasWith structuring of the main pancreatic duct, can seedilatation of the upstream pancreatic or common bileductsTypically absent: calcifications, pancreatic duct stones,and pseudocysts

CTDiffuse pancreatic enlargement, uniform enhancement,minimal pancreatic infiltrationThe focally enlarged pancreas can mimic pancreaticcancerCapsule-like low-density rim surrounding the pancreas

MRIGlobal pancreatic enlargement decreased T1 signal,increased T2 signal, peripancreatic decreased signalintensity

Fig. 4. Images from a 42-year-old woman with mild abdominal pain and history of undifferentiated connective tissue disease.(A) Contrast-enhanced CT shows global pancreatic enlargement.The pancreas enhances uniformly. (B) Fat saturationT1-weighted image shows diffuse pancreatic enlargement (asterisk). (C) Contrast-enhanced CT performed after steroidtreatmentshows a decrease in size of the pancreas (compare measure bar with Fig. 1A).

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ERCPSegmental or diffuse irregular narrowing of the mainpancreatic duct

MRCPSkipped, nonvisualized main pancreatic duct lesions ±upstream dilatationSegmental or diffuse irregular narrowing of the mainpancreatic duct may not be seen

EUSDuring routine evaluation of a pancreatic mass, EUS canprovide targeted fineneedleaspirates or core biopsies toaid in the distinction between carcinoma

SEROLOGY

Increased numbers of circulating immunoglobulins,specifically immunoglobulin subclass 4, are a hallmark ofthe disease [9,16]. In a landmark study, Hamano andcolleagues [9] reported that serum IgG4 levels were highly(95%) sensitive and highly (97%) specific for AIP. In arecent study of 510 patients from the United States [16]including 45 who had AIP, 135 who had pancreatic cancer,62 who had no pancreatic disease, and 268 who had otherpancreatic diseases, the sensitivity, specificity, and positivepredictive values for elevated serum IgG4 (>140 mg/dL) fordiagnosis of AIP were 76%, 93%, and 36%, respectively.When using a cutoff of twice the upper limit of normal forserum IgG4 (>280 mg/dL), the corresponding values were53%, 99%, and 75%, respectively [16]. In this study, 5-10%of non-AIP patient groups, including 10% of patients whohad ductal adenocarcinoma, had elevated IgG4 levels [16].In addition, serum IgG4 levels, even in the presence ofclassic histologic findings of AIP, can be normal (Table 2)[32,40].

Elevated titers of many autoantibodies have beendescribed in AIP. Autoantibodies against carbonicanhydrase II and IV and lactoferrin are detected in most

patients who have AIP [41,42]. Involvement of antinuclearand anti–smooth muscle antibodies has also been described[41]. Autoantibodies to the pancreatic secretory trypsininhibitor have been shown to be elevated in nearly 50% ofAIP patients compared with controls [43]. None of theseautoantibodies have prediction characteristics that equalthat of IgG4. Levels of total IgG and gamma globulins arealso increased in AIP. In our experience, however, it isunusual to have elevated serum levels of IgG or gammaglobulins without elevation of serum IgG4 levels. Althougha combination of serum IgG4 levels and autoantibody titersof antinuclear antibodies and rheumatoid factor modestlyincreases sensitivity, it also significantly reduces specificity.The authors do not routinely use autoantibody titers todiagnose AIP.

OTHER ORGAN INVOLVEMENT

Other organs are often involved in AIP; theirinvolvement may be diagnosed before, simultaneous with,or after the diagnosis of AIP. Biliary tract is involved in 60%to 100% of all patients presenting with AIP [1,44], and hasrecently been termed IAC http://www.mdconsult.com/das/article/body/225139942-12/jorg=journal&source=MI&sp=20688639&sid=1077935416/N/644914/1.html?issn=0889-8553 - r08000150042. IAC affects bothintra- and extrahepatic bile ducts, with the distal commonbile duct being the most common site of involvement [48].Biliary imaging may not necessarily reveal involvement,even when present microscopically [30]. Histologically, alymphoplasmacytic infiltrate surrounds the bile ducts in apattern similar to that seen in the pancreas and IgG4-positive staining is often present [24], http://www.mdconsult.com/das/article/body/225139942-12/jorg=journal&source=MI&sp=20688639&sid=1077935416/N/644914/1.html?issn=0889-8553 - r08000150095.

AIP coexisting with PSC has been described, although

Table 2. IgG4 level in patients who have different diseases of the pancreas

AIP Normal Pancreatic Benign pancreatic Chronicpancreas cancer tumor pancreatitis

Numbera* 45 62 135 64 79Mean IgG4 ± SM 550 ± 99 49 ± 6 68 ± 9 47 ± 5 46 ± 5Range 16–2890 3–263 3–1140 3–195 3–231Proportion elevated 76% 4.8% 9.6% 4.7% 6.3%

>140 mg/dL

* Based on 510 patients referred to the Mayo Clinic for evaluation of pancreatic disease from January 2005 through June 2006.Data fromGhazale A, Chari ST, Smyrk TC, et al. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it frompancreatic cancer. Am J Gastroenterol 2007;102(8):1646-1653.


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this is likely not primary sclerosing cholangitis but IgG4-associated cholangitis. It has also been shown that in a smallproportion of patients who have aggressive PSC, serumIgG4 levels are elevated suggesting a possible role forcorticosteroid therapy. One should be cautious indiagnosing IAC simply based on elevated serum IgG4levels, however, because false-positive elevations mayoccur in true PSC. IAC differs from PSC in that there isgenerally less intrahepatic involvement, the strictures canbe transient under observation, the strictures are usuallysegmental, and patients are typically pANCA negative [46].Inflammatory bowel disease, which is present in 70% ofPSC, is less common (6%) in IAC. Analogous to theresponse seen in the inflammatory component of pancreaticinvolvement, inflammation of the biliary tree typicallyresponds to corticosteroid treatment, although the specificresponse of each duct segment is still being evaluated [47].

In addition to the biliary system, multiple other organsmay be involved in ISD. Hamano and colleagues reviewedthe frequency, distribution, clinical characteristics, andpathology of five extrapancreatic lesions in 64 patients whohad AIP and found the most frequent extrapancreatic lesionwas hilar lymphadenopathy (80.4%), followed byextrapancreatic bile duct lesions (73.9%), lacrimal andsalivary gland lesions (39.1%), hypothyroidism (22.2%),and retroperitoneal fibrosis (12.5%). No patients had all fivetypes of lesions. Patients who had hilar lymphadenopathy orlacrimal and salivary gland lesions were found to havesignificantly higher IgG4 levels than those who did not.Both intrinsic (tubulointestinal fibrosis) and extrinsic(hydro-nephrosis secondary to retroperitoneal fibrosis)renal disease have been associated with AIP, as hasinflammatory pneumonitis and inflammatory pseudotumorof the liver [27,44,48].

Diagnostic criteria

In 1995 Yoshida and colleagues [14] reported a list of 12features suggestive of AIP, but stopped short of providingclinical criteria for its diagnosis. The first diagnostic criteriawere proposed by the Japan Pancreas Society in 2002 andlater modified in 2006. These guidelines were developed todistinguish between AIP and pancreatic adenocarcinoma.To make the diagnosis of AIP based on the Japaneseguidelines, it is mandatory that findings on radiography beconsistent with AIP. These findings include the presence ofdiffuse or segmental narrowing of the main pancreatic ductwith irregular wall diagnosed by endoscopic retrogradepancreatogram and diffuse or localized enlargement of thepancreas on abdominal ultrasonography, CT, or MRI. Inaddition, one of serologic (high serum c-globulin, IgG, orIgG4, or the presence of autoantibodies, such as antinuclearantibodies and rheumatoid factor) or histologic (marked

interlobular fibrosis and prominent infiltration oflymphocytes and plasma cells in the periductal area,occasionally with lymphoid follicles in the pancreas)criteria are required to satisfy Japanese criteria for diagnosisof AIP. The Japanese criteria do not take into account thatAIP has unique histologic features, characteristic findingson IgG4 immunostaining of the organs involved, otherorgan involvement, or response to steroids.

In 2006, Chari and colleagues [1] published an alternateset of guidelines based on the Mayo Clinic experience withAIP. These criteria, known by the mnemonic HISORt,recognize characteristic features of AIP on pancreatichistology and imaging, serology, other organ involvement,and response to corticosteroid therapy. Based on theHISORt criteria patients can be diagnosed as AIP if they fallinto one of three groups: (a) diagnostic pancreatic histologyor presence of 10 or more IgG4-positive cells per high-power field (HPF) on immunostain of lymphoplasmacyticinfiltrate with storiform fibrosis; (b) typical pancreaticimaging with elevated serum IgG4 ≥140 mg/dL, or (c)unexplained pancreatic disease with negative workup forother pancreatic diseases, especially malignancy, withelevated serum IgG4 levels ≥140 mg/dL or other organinvolvement confirmed by presence of abundant IgG4-positive cells, and resolution/marked improvement inpancreatic or extrapancreatic manifestations with steroidtherapy (Table 3). By including additional features, thesecriteria identify a wider spectrum of clinical presentations ofAIP.

ASAIAN CONSENSUS CRITERIA

Histology

Lymohoplasmacytic infiltration with fibrosis andabundant IgG4

–positive cell infiltration.

Imaging: Both of the followingDiffuse, segmental or focal enlargement of the gland, withor without a mass or hypoattenuated rimDiffuse, segmental, or focal pancreatic duct narrowing,with or with out stenosis of the bile duct

Serology: one of the followingHigh levels of total IgG or IgG4Detection of autoantibodies ( ANA, RF)

Response to glucocorticoid therapy: included as optionalcriteria, but only in patients with both imaging criteria abovewith a negative workup for pancreatobiliary cancer

Treatment

The cornerstone of treatment of AIP is the use of

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Table 3. Mayo Clinic HISORt criteria for the diagnosis of autoimmune pancreatitis

Diagnostic criteriaHistology

At least one of the following:• Periductal lymphoplasmacytic infiltrate with obliterative phlebitis and storiform fibrosis• Lymphoplasmacytic infiltrate with storiform fibrosis with abundant (≥10 IgG4 cells/HPF)

Imaging• Typical: diffusely enlarged gland with delayed rim enhancement, diffusely irregular, attenuated main

pancreatic duct• Other: focal pancreatic mass/enlargement, focal pancreatic ductal stricture, pancreatic atrophy,

calcification, pancreatitisSerology

• Elevated serum IgG4 level (normal 8–140 mg/dL)Other organ involvement

• Hilar/intrahepatic biliary strictures, persistent distal biliary stricture, parotid/lacrimal gland involvement,mediastinal lymphadenopathy, retroperitoneal fibrosis

Response to steroid therapy• Resolution/marked improvement of pancreatic/extrapancreatic manifestation with corticosteroid therapy

Diagnostic groups*

Group A: diagnostic pancreatic histologyPresence of one or more of the following criteria:• Specimen demonstrating the full spectrum of LPSP• ≥10 IgG4 cells/HPF on immunostain of pancreatic lymphoplasmacytic infiltrate

Group B: typical imaging + serologyPresence of all of the following criteria:

• CT or MRI scan showing diffusely enlarged pancreas with delayed and rim enhancement• Pancreatogram showing diffusely irregular pancreatic duct• Elevated serum IgG4 levels

Group C: response to corticosteroidsPresence of all of the following criteria:

• Unexplained pancreatic disease after negative workup for other causes• Elevated serum IgG4 or other organ involvement confirmed by presence of abundant IgG4-positive cells• Resolution/marked improvement in pancreatic or extrapancreatic manifestations with corticosteroid

therapy*Patients meeting criteria for one or more of the groups have AIP.Data from Chari ST, Smyrk TC, Levy MJ, et al. [1].

corticosteroids with multiple authors reporting dramaticresponse rates with prolonged therapy [1,9,48]. A word ofcaution, however, is that it is imperative to thoroughly ruleout other possible causes of pancreatic disease, mostnotably pancreatic malignancy, before initiatingcorticosteroid therapy.

Although spontaneous remissions do occur in AIP, theuse of corticosteroids seems to hasten recovery and may

prevent recurrences. There are several reasons, therefore, toinitiate treatment of AIP with corticosteroids. For one, if thediagnosis remains in doubt and malignancy has beenexcluded, response to corticosteroids can be a reasonablemethod of diagnosing AIP. The clinical suspicion for AIPshould be high before initiation of therapy, however, andpatients should be followed closely for any symptoms (e.g.,profound weight loss, anorexia, night sweats) moreconsistent with malignancy than AIP. Treatment can also be


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a means of reducing clinical symptoms from acutepancreatic (pancreatic endocrine insufficiency, rarely acutepancreatitis) or extrapancreatic (jaundice from biliarystrictures, sialadenitis) manifestations of disease http://www.mdconsult.com/das/article/body/225139942-12/jorg=journal&source=MI&sp=20688639&sid=1077935416/N/644914/1.html?issn=0889-8553 - r08000150062,[48,49]. In addition, there can sometimes be structuralimprovement, for example in the pancreatic duct, withcorticosteroid therapy The degree of structural responsedepends on the extent of fibrosis versus inflammation;patients who have more inflammatory injury typically havea greater structural response and extensive fibrosis may notallow complete remission to occur [48].

The exact corticosteroid treatment protocol for patientswho have AIP is not standardized; however, mostpractitioners initiate therapy with between 30 and 40 mg ofprednisone daily. These doses are usually effective to induceremission; it is unclear if starting at lower doses would beequally effective. Resolution of symptoms is generallyrapidly achieved within 2 to 3 weeks of corticosteroidinitiation. It usually takes several weeks to months forevidence of serologic (normalization of IgG4) or radiologicremission. Occasionally, because of fibrotic involvement oftissue, radiologic remission is not seen, especially inproximal biliary strictures resembling cholangiocarcinoma,intrahepatic strictures resembling PSC, and retroperitonealfibrosis. Progression toward normalization of serum IgG4levels can be used to guide treatment in these instances.Because histologic specimens are often difficult to obtain,we generally do not use histology as a marker for remission.

At the Mayo Clinic, we treat patients diagnosed withAIP with a prolonged steroid taper. Patients are started on40 mg/d of prednisone for 4 weeks. After 4 weeks, theirclinical response is gauged and repeat cross-sectionalimaging and serologic evaluation are performed to check forresponse. If clinical, serologic, or radiographic response isdocumented, the prednisone dose is tapered 5 mg/wk untilgone. In patients in whom a biliary stent has been placed,this usually can be removed at 6 to 8 weeks followinginitiation of therapy. IgG4 levels are also followed and inpatients who have AIP, a decrease in IgG4 (although notnecessarily normalization) should occur within 4 weeks oftreatment initiation.http://www.mdconsult.com/das/article/b o d y / 2 2 5 1 3 9 9 4 2 - 1 2 / j o r g = j o u r n a l & s o u r c e =MI&sp=20688639&sid=1077935416/N/644914/If08000150005.fig - top

Recently, in patients who present with jaundicebecause of biliary stricturing disease who do not wish toundergo initial endoscopic retrogradecholongiopancreatography with stent placement, we have

occasionally treated with a large initial bolus ofintravenous corticosteroids. Although our experience islimited and at this time anecdotal, jaundice does seem torespond rapidly to this treatment, thus obviating the needfor biliary stent placement. Further prospective studies areneeded to determine if large initial doses of corticosteroidsare an effective alternative to initial biliary stent placementin newly diagnosed AIP.

Between 30% and 40% of patients have clinical orradiographic relapse following treatment with prolongedcorticosteroids requiring retreatment with a secondprolonged course [1,25,48,49]. These relapses generallyoccur in the short term; data on long-term relapse arelacking. Relapse may be symptomatic, radiologic,serologic, or histologic. The presence of symptoms(recurrent abdominal pain, weight loss, and so forth) is oftena clue to relapse within the pancreas; only in the presence ofsymptoms is cross-sectional imaging repeated. Serologicrelapse alone can be seen in patients who do not haveclinical symptoms or radiologic changes; whether or not thisrepresents a subclinical disease relapse is unclear at thistime. It is also unclear if certain types of organ involvementare more prone to relapse than others. For example, Ghazaleand colleagues [25] found that in patients who had IACtreated with 11 weeks of corticosteroids, proximal biliaryinvolve-ment (proximal extrahepatic and intrahepaticbiliary strictures) relapsed with a rate of 65% compared witha 25% relapse rate in those who had intrapancreaticstricturing of the distal common bile duct.

In a certain subset of patients who have relapse after asecond prolonged course of steroids, either chronicprednisone therapy or use of another agent, such asazathioprine or 6-mercaptopurine, may be necessary. InJapan, it is often standard of care to continue patients on achronic low dose (2.5–10 mg/d) of prednisone indefinitely[48,49]. Although there are only case reports evaluating theefficacy of long-term treatment of AIP with immuno-modulating therapy, we have had favorable, althoughlimited, experience with these medications [50]. As moreexperience is gained about the long-term pathogenesis ofAIP, recommendations on the use of chronic suppressivetherapy needs to be developed. In addition, because there issuch a high frequency of short-term relapse, whethermaintenance therapy should be used in all patients, and whattype of maintenance therapy should be used, remains to beestablished.

It is unclear at this time whether corticosteroid therapyalters the long-term natural history of disease, prevents thedevelopment of future pancreatic or extrapancreaticinvolvement and organ dysfunction, or is adequate as a long-term suppressive strategy.

Review Article


Misdiagnosis

Increasingly, we are evaluating patients in whom AIPhas been inaccurately diagnosed. The misdiagnosis occursin the setting of patients who have other unrelatedconditions, such as pancreatic adenocarcinoma, beingtreated inappropriately with corticosteroids. We have alsoseen several patients who had functional abdominal paincomplaints treated with prolonged courses of high-dosecorticosteroids without evidence of AIP. Conversely,multiple patients have undergone therapies, such aspancreatic head resections or partial hepatectomy, withoutconsideration of an autoimmune cause.

It is therefore important that AIP be considered in thedifferential diagnosis of patients who have chronicpancreatitis or biliary strictures. It is imperative, however,that a thorough evaluation be performed for other causes ofdisease, with histopathologic analysis if possible, before theinitiation of corticosteroid therapy. Once corticosteroidtherapy has been initiated, patients should be followedclosely for signs of worsening or refractory diseasesymptoms; it is highly unusual for AIP not to quicklyrespond to appropriate corticosteroid therapy. In addition,clinicians must be cognizant that AIP is a rare disease, and inpatients who do not meet the Japanese Pancreas Society orMayo HISORt guidelines, corticosteroid therapy is likelynot advisable.

Prognosis

There are limited data about the long-term outcome ofpatients who have AIP. Hirano and colleagues published themost comprehensive report on prognosis when theyevaluated 42 patients who had AIP, 19 of whom receivedcorticosteroid treatment at the time of diagnosis. In the 23patients who did not have corticosteroid treatment initially,16 developed unfavorable events, including obstructivejaundice attributable to distal bile duct stenosis in 4,growing pseudocyst in 1, and sclerogenic changes ofextrapancreatic bile duct in 9, over an average observationperiod of 25 months. After an average observation period of23 months in the initial treatment group, 6 patientsdeveloped unfavorable events consisting of interstitialpneumonia in 3 and recurrence of obstructive jaundice in 3.Their conclusions were that early introduction ofcorticosteroids is important to prevent subsequent diseasecomplications.

Most patients treated with corticosteroids develop “burnout” of disease, rendering the pancreas usually somewhatatrophic following treatment [9]. The degree of residualpancreatic exocrine or endocrine insufficiency is likelyrelated to the degree of gland fibrosis at the time oftreatment [48].

At this time, given the relatively recent description andactive investigation of AIP, there are no data regarding thelong-term mortality rate of patients who have this disease. Inaddition, it has not been investigated whether lifeexpectancy is altered by the course of this disease.

Future directions

There are several lines of investigation that need to beaddressed in regard to AIP. Continued work to determine thecause of this disease and its relationship with IgG4 isimperative. Specifically, the antigenic trigger of CD4 andCD8 T-cell activation needs to be identified. Clinically,investigation should focus on the natural history of AIP withspecific attention to the wide-ranging effects of IgG4-related systemic disease. It is not currently known whetherdifferent manifestations of IgG4-related disease haveunique or alternate prognoses. The role of corticosteroids,specifically their role in changing the natural history ofdisease, needs to be investigated. In asymptomatic patients,it will be important to determine if treatment helps toprevent future organ dysfunction. Furthermore, the role ofchronic suppressive therapy, either with corticosteroids oranother immune-modulating drug, in preventing relapseand affecting long-term prognosis is yet to be determined.

SUMMARY

AIP is a unique subtype of recently identified chronicpancreatitis that is immune mediated and represents onemanifestation of a systemic IgG4-related disease process.Although a rare condition, it is important to recognizebecause it responds often dramatically to immune system–modulating treatment. Diagnosing AIP can sometimes bechallenging, however, and it is imperative that clinicians becautious when considering this diagnosis in patientssuspected of having a pancreatic malignancy. As clinicalexperience with AIP increases, refinement of diagnosticcriteria and development of standardized therapeuticprotocols should allow further optimization of care for ourpatients.

REFERENCES

1. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis ofautoimmune pancreatitis: the Mayo Clinic experience. ClinGastroenterol Hepatol 2006; 4 (8): 1010-1016. [Abstract ].

2. Kamisawa T. IgG4-positive plasma cells specificallyinfiltrate various organs in autoimmune pancreatitis.Pancreas 2004; 29 (2): 167-168 [Citation].

3. Kamisawa T, Egawa N, Nakajima H. Autoimmunepancreatitis is a systemic autoimmune disease. Am JGastroenterol 2003; 98 (12): 2811-2812 [Citation].

4. Yoshida K, Toki F, Takeuchi T, et al. Chronic pancreatitiscaused by an autoimmune abnormality. Proposal of the


Review Article

concept of autoimmune pancreatitis. Dig Dis Sci 1995; 40(7): 1561-1568. [Abstract].

5. Sarles H, Sarles JC, Muratore R, et al. Chronicinflammatory sclerosis of the pancreas–an autonomouspancreatic disease?. Am J Dig Dis 1961; 6. 688-698.

6. Pearson RK, Longnecker DS, Chari ST, et al.Controversies in clinical pancreatology: autoimmunepancreatitis: does it exist?. Pancreas 2003; 27 (1): 1-13.[Citation].

7. Sood S, Fossard DP, Shorrock K. Chronic sclerosingpancreatitis in Sjogren’s syndrome: a case report.Pancreas 1995; 10 (4): 419-421 [Citation].

8. Weber SM, Cubukcu-Dimopulo O, Palesty JA, et al.Lymphoplasmacytic sclerosing pancreatitis: inflammatorymimic of pancreatic carcinoma. J GastrointestSurg 2003; 7 (1): 129-137 [Abstract].

9. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4concentrations in patients with sclerosing pancreatitis. NEngl J Med 2001; 344 (10): 732-738 [Abstract].

10. Kawaguchi K, Koike M, Tsuruta K, et al.Lymphoplasmacytic sclerosing pancreatitis withcholangitis: a variant of primary sclerosing cholangitisextensively involving pancreas. Hum Pathol 1991; 22 (4):387-395 [Abstract ].

11. Ichimura T, Kondo S, Ambo Y, et al. Primary sclerosingcholangitis associated with autoimmune pancreatitis.Hepatogastroenterology 2002; 49 (47): 1221-1224[Abstract].

12. Ito T, Nakano I, Koyanagi S, et al. Autoimmunepancreatitis as a new clinical entity. Three cases ofautoimmune pancreatitis with effective steroid therapy. DigDis Sci 1997; 42 (7): 1458-1468 [Abstract].

13. Kim KP, Kim MH, Kim JC, et al. Diagnostic criteria forautoimmune chronic pancreatitis revisited. World JGastroenterol 2006; 12 (16): 2487-2496 [Abstract].

14. Choi EK, Kim MH, Kim JC, et al. The Japanese diagnosticcriteria for autoimmune chronic pancreatitis: is itcompletely satisfactory?. Pancreas 2006; 33(1): 13-19.[Abstract].

15. Kamisawa T: IgG4-related sclerosing disease. InternMed 2006; 45(3): 125-126 [Citation].

16. Ghazale A, Chari ST, Smyrk TC, et al. Value of serum IgG4in the diagnosis of autoimmune pancreatitis and indistinguishing it from pancreatic cancer. Am JGastroenterol 2007; 102 (8): 1646-1653. [Abstract].

17. Nishimori I, Tamakoshi A, Otsuki M. Prevalence ofautoimmune pancreatitis in Japan from a nationwidesurvey in 2002. J Gastroenterol 2007; 42 (Suppl 18): 6-8[Abstract].

18. Kim KP, Kim MH, Lee SS, et al. Autoimmune pancreatitis:it may be a worldwide entity. Gastroenterology 2004; 126(4): 1214. [Citation].

19. Kamisawa T, Wakabayashi T, Sawabu N. Autoimmunepancreatitis in young patients. J Clin Gastro-enterol 2006;

40 (9): 847-850.

20. Ota M, Katsuyama Y, Hamano H, et al. Two critical genes(HLA-DRB1 and ABCF1) in the HLA region are associatedwith the susceptibility to autoimmune pancreatitis.Immunogenetics 2007; 59 (1): 45-52 [Abstract].

21. Umemura T, Ota M, Hamano H, et al. Genetic associationof Fc receptor-like 3 polymorphisms with autoimmunepancreatitis in Japanese patients. Gut 2006; 55 (9):1367-1368 [Citation].

22. Kountouras J, Zavos C, Gavalas E, et al. Challenge in thepathogenesis of autoimmune pancreatitis: potential role ofhelicobacter pylori infection via molecular mimicry.Gastroenterology 2007; 133 (1): 368-369 [Citation].

23. Kitagawa S, Zen Y, Harada K, et al. Abundant IgG4-positive plasma cell infiltration characterizes chronicsclerosing sialadenitis (Kuttner’s tumor). Am J SurgPathol 2005; 29 (6): 783-791 [Abstract ].

24. Bjornsson E, Chari ST, Smyrk TC, et al. ImmunoglobulinG4 associated cholangitis: description of an emergingclinical entity based on review of the literature.Hepatology 2007; 45 (6): 1547-1554. [Citation].

25. Ghazale A, Chari ST, Zhang L, et al. IgG4-associatedcholangitis: clinical profile and response to therapy.Gastroenterol 2008; 134: 706-715.

26. Kamisawa T, Funata N, Hayashi Y, et al. A newclinicopathological entity of IgG4-related autoimmunedisease. J Gastroenterol 2003; 38 (10): 982-984 [Abstract] .

27. Saeki T, Nishi S, Ito T, et al. Renal lesions in IgG4-relatedsystemic disease. Intern Med 2007; 46(17): 1365-1371[Abstract].

28. Finkelberg DL, Sahani D, Deshpande V, et al.Autoimmune pancreatitis. N Engl J Med 2006; 355(25):2670-2676. [Citation].

29. Kamisawa T, Egawa N, Nakajima H, et al.Extrapancreatic lesions in autoimmune pancreatitis. JClin Gastroenterol 2005; 39 (10): 904-907 [Abstract].

30. Kamisawa T, Chen PY, Tu Y, et al. MRCP and MRI findingsin 9 patients with autoimmune pancreatitis. World JGastroenterol 2006; 12 (18): 2919-2922 [Abstract].

31. Chari ST, Echelmeyer S. Can histopathology be the “GoldStandard” for diagnosing autoimmune pancreatitis?. Gastroenterology 2005; 129 (6): 2118-2120 [Citation].

32. Chari ST. Diagnosis of autoimmune pancreatitis using itsfive cardinal features: introducing the Mayo Clinic’sHISORt criteria. J Gastroenterol 2007; 42 (Suppl 18): 39-41 [Abstract].

33. Kamisawa T. Angiographic findings in patients withautoimmune pancreatitis. Radiology 2005; 236 (1): 371.[Citation].

34. Farrell JJ, Garber J, Sahani D, et al. EUS findings inpatients with autoimmune pancreatitis. GastrointestEndosc 2004; 60 (6): 927-936.

Review Article


35. Salla C, Chatzipantelis P, Konstantinou P, et al. EUS-FNA contribution in the identification of autoimmunepancreatitis: a case report. JOP 2007; 8 (5): 598-604. [Abstract].

36. Levy MJ, Reddy RP, Wiersema MJ, et al. EUS-guidedTrucut biopsy in establishing autoimmune pancreatitis asthe cause of obstructive jaundice. GastrointestEndosc 2005; 61 (3): 467-472.

37. Nakazawa T, Ohara H, Sano H, et al. Cholangiographycan discriminate sclerosing cholangitis with autoimmunepancreatitis from primary sclerosing cholangitis.Gastrointest Endosc 2004; 60 (6): 937-944.

38. Nakajo M, Jinnouchi S, Fukukura Y, et al. The efficacy ofwhole-body FDG-PET or PET/CT for autoimmunepancreatitis and associated extrapancreatic autoimmunelesions. Eur J Nucl Med Mol Imaging 2007; 34: 2088-2095 [Abstract ].

39. Hirano K, Kawabe T, Yamamoto N, et al. Serum IgG4concentrations in pancreatic and biliary diseases. ClinChim Acta 2006; 367 (1–2): 181-184. [Abstract].

40. Choi EK, Kim MH, Lee TY, et al. The sensitivity andspecificity of serum immunoglobulin G andimmunoglobulin G4 levels in the diagnosis ofautoimmune chronic pancreatitis: Korean experience.Pancreas 2007; 35 (2): 156-161. [Abstract ].

41. Okazaki K, Uchida K, Ohana M, et al. Autoimmune-related pancreatitis is associated with autoantibodiesand a Th1/Th2-type cellular immune response. Gastroenterology 2000; 118 (3): 573-581 [Abstract].

42. Kawa S, Hamano H. Clinical features of autoimmunepancreatitis. J Gastroenterol 2007; 42 (Suppl 18): 9-14.

[Abstract].

43. Asada M, Nishio A, Uchida K, et al. Identification of a novelautoantibody against pancreatic secretory trypsin inhibitorin patients with autoimmune pancreatitis. Pancreas 2006;33 (1): 20-26 [Abstract].

44. Hamano H, Kawa S, Ochi Y, et al. Hydronephrosisassociated with retroperitoneal fibrosis and sclerosingpancreatitis. Lancet 2002; 359 (9315): 1403-1404[Abstract].

45. Nishino T, Toki F, Oyama H, et al. Biliary tract involvementin autoimmune pancreatitis. Pancreas 2005; 30 (1): 76-82[ Abstract ].

46. Ohara H, Nakazawa T, Ando T, et al. Systemicextrapancreatic lesions associated with autoimmunepancreatitis. J Gastroenterol 2007; 42 (Suppl 18): 15-21[Abstract].

47. Horiuchi A, Kawa S, Hamano H, et al. Sclerosingpancreato-cholangitis responsive to corticosteroidtherapy: report of 2 case reports and review. GastrointestEndosc 2001; 53 (4): 518-522.

48. Kamisawa T, Yoshiike M, Egawa N, et al. Treating patientswith autoimmune pancreatitis: results from a long-termfollow-up study. Pancreatology 2005; 5 (2-3): 234-238[ Abstract ].

49. Kamisawa T, Okamoto A. Prognosis of autoimmunepancreatitis. J Gastroenterol 2007; 42 (Suppl 18): 59-62[ Abstract].

50. van Buuren H R, Vleggaar FP, Willemien Erkelens G, et al.Autoimmune pancreatocholangitis: a series of tenpatients. Scand J Gastroenterol 2006; Suppl 243: 70-78[Abstract].

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Health & Medicine

Autoimmune Pancreatitis