C RT

Im angR

AM MASMA EARSSA . FA

*Div ent oMa

Basotioflaa cIgtreIAtraMeagIAoldobmune pancreatitis (92%), increased serum IgG4 lev-els (74%), and abundant IgG4-positive cells in bileduiarbihetatfo(nwamodrwiintrobilFiaftadste

mouncreeaespno

Eordsisstuofhigaftabnot only of AIP but also the other organs involved in AIP.Based on this observation they proposed the term IgG4-related systemic disease (ISD) to describe this condition.6

CLIN

ICALLIV

ER,

PANCREA

S,AND

BILIA

RYTRACT

GASTROENTEROLOGY 2008;134:706715ct biopsy specimens (88%). At presentation, bil-y strictures were confined to the intrapancreaticle duct in 51%; the proximal extrahepatic/intra-patic ducts were involved in 49%. Initial presen-ion was treated with steroids (n 30; medianllow-up period, 29.5 months), surgical resection 18; median follow-up period, 58 months), ors conservative (n 5; median follow-up period, 35nths). Relapses occurred in 53% after steroid with-awal; 44% relapsed after surgery and were treatedth steroids. The presence of proximal extrahepatic/rahepatic strictures was predictive of relapse. Ste-id therapy normalized liver enzyme levels in 61%;iary stents could be removed in 17 of 18 patients.fteen patients treated with steroids for relapseer steroid withdrawal responded; 7 patients on

Other groups have since confirmed these observations.7,8

ISD can be defined as a syndrome characterized byincreased levels of serum IgG4 and multifocal IgG4-richlymphoplasmacytic infiltrate associated with intense scle-rosis. Although the fibrosis associated with ISD maydamage and even destroy the affected organ, the inflam-matory process typically responds to steroid therapy.9

Although in many series of ISD the pancreas is reportedto be the most commonly affected organ, there also arereports of predominant salivary gland involvement.10 It isbecoming increasingly clear that the disease can involve

Abbreviations used in this paper: AIP, autoimmune pancreatitis;hpf, high-power eld; IAC, IgG4-associated cholangitis; ISD, IgG4-related systemic disease; PSC, primary sclerosing cholangitis.LINICALLIVER, PANCRACT

munoglobulin G4Associated Cholesponse to Therapy

AAR GHAZALE,* SURESH T. CHARI,* LIZHI ZHANG, THORK D. TOPAZIAN,* JONATHAN E. CLAIN,* RANDALL K. PNTHI SWAROOP VEGE,* KEITH LINDOR,* and MICHAEL B

ision of Gastroenterology and Hepatology, Department of Pathology, Departmyo Clinic College of Medicine, Rochester, Minnesota

See Topazian M et al on page 364 in CGH.

ckground & Aims: Immunoglobulin (Ig)G4-as-ciated cholangitis (IAC) is the biliary manifesta-n of a steroid-responsive multisystem fibroin-mmatory disorder in which affected organs haveharacteristic lymphoplasmacytic infiltrate rich inG4-positive cells. We describe clinical features,atment response, and predictors of relapse inC and compare relapse rates in IAC with in-pancreatic vs proximal bile duct strictures.thods: We reviewed clinical, serologic, and im-ing characteristics and treatment response in 53C patients. Results: IAC patients generally wereer (mean age, 62 y) men (85%), presenting withstructive jaundice (77%) associated with autoim-ditional immunomodulatory drugs remain inroid-free remission (median follow-up period, 6EAS, AND BILIARY

itis: Clinical Profile and

C. SMYRK, NAOKI TAKAHASHI, MICHAEL J. LEVY,*ON,* BRET T. PETERSEN,*

RNELL

f Radiology, and Division of Gastroenterologic and General Surgery,

nths). Conclusions: IAC should be suspected inexplained biliary strictures associated with in-ased serum IgG4 and unexplained pancreatic dis-se. Relapses are common after steroid withdrawal,ecially with proximal strictures. The role of immu-modulatory drugs for relapses needs further study.

arly descriptions of autoimmune pancreatitis (AIP)included its association with other autoimmune dis-

ers such as Sjgrens syndrome, retroperitoneal fibro-, and primary sclerosing cholangitis.13 In a landmarkdy Hamano et al4 reported that increased serum levelsthe immunoglobulin (Ig)G4 subclass of IgG werehly sensitive and highly specific for AIP. Shortly there-er, Kamisawa5 reported that tissue infiltration withundant IgG4-positive cells was a characteristic feature 2008 by the AGA Institute0016-5085/08/$34.00

doi:10.1053/j.gastro.2007.12.009

muret

nenouatatinintrefcasbilprimaturHourde

trauncoresdudiftur

ofidehofollogtosteanintwiitsWeOngutre

inswi(S.anpacera pcenSeapwe

dubilthedisaschparel

pafrolymdufib

hupohig(NJaphpofAI

mo(Ncre

38Ne19lev

HInekid

tie(regrotrethe

CLINICALLIVER,

PANCREA

S,AND

BILIARYTRACT

March 2008 IGG4ASSOCIATED CHOLANGITIS 707ltiple organs including the biliary tree, salivary glands,roperitoneum, lymph nodes, and kidneys.5,7,8,11

The concept of a systemic IgG4 disease is relativelyw. Previous reports have given distinct names to whatw are recognized as manifestations of ISD in individ-l organs. For example, AIP is the pancreatic manifes-ion of ISD. The biliary tree also commonly is involvedISD, especially in those with AIP. In a recent review, weroduced the term IgG4-associated cholangitis (IAC) toer to the biliary manifestations of ISD.12 Several smalle series have described the association of AIP andiary strictures.1322 Unlike biliary strictures seen inmary sclerosing cholangitis (PSC), and similar to thenifestations of ISD in other organs, the biliary stric-es in ISD typically respond to steroid therapy.16,23

wever, the response to treatment of IAC and its nat-al history after treatment has not yet been studied inpth.The strictures in IAC can occur distally, in the in-pancreatic portion of the bile, or more proximally. It isclear whether distal strictures are a result of externalmpression from pancreatic enlargement or in fact rep-ent disease involvement of the intrapancreatic bilect wall. Whether distal strictures present and respondferently to treatment compared with proximal stric-es is unknown.

Since 1999, we have maintained a prospective databasepatients investigated for AIP. From this database, wentified 53 patients with IAC. Based on this large co-rt of patients with IAC, the aims of this study were aslows: (1) to describe the clinical, imaging, and sero-ic characteristics of IAC; (2) to describe the responsetherapy and the natural history after surgical and

roid therapy; and (3) to compare the characteristicsd treatment response of IAC patients with isolatedrapancreatic biliary strictures compared with those

th proximal biliary strictures. The diagnosis of ISD andmanifestations in individual organs can be difficult.recently suggested criteria for the diagnosis of AIP.9

the basis of our experience with IAC, we proposeidelines for suspecting and diagnosing IAC and discussatment response and natural history in these patients.

Materials and MethodsThe protocol was approved by the Mayo Clinic

titutional review board. From a database of patientsth AIP, prospectively maintained by one of the authorsT.C.), we identified 49 patients with biliary stricturesd proven AIP; 14 of these patients had undergone ancreaticoduodenectomy for suspected pancreatic can-

owing to presentation with obstructive jaundice andancreatic head mass. AIP was diagnosed by the re-tly published HISORt criteria (Histology, Imaging,rology, Other organ involvement, Response to ther-y).9 In addition to the 49 patients with confirmed AIP,

identified 4 more patients who had undergone bile

nostespct resection for suspected cholangiocarcinoma whosee duct histology was characteristic for IAC (see later);se 4 patients did not have evidence of pancreaticease (AIP) clinically or on imaging. Demographic datawell as clinical, laboratory, imaging, and histologic

aracteristics were assessed for all patients. In thosetients treated with steroids, treatment response andapse rates were evaluated.

HistologyAll histologic specimens were reviewed by a single

thologist (T.C.S.). IAC was diagnosed histologicallym a resection specimen or core biopsy if there was aphoplasmacytic infiltrate within and around bile

cts with associated obliterative phlebitis and storiformrosis leading to sclerosis of the bile duct.13,16,20

Tissue IgG4 ImmunostainingTissue immunostaining using monoclonal anti-

man IgG4 antibody was performed as previously re-rted.9 The number of IgG4-positive plasma cells perh-power field (hpf) was counted in each specimen

ikon E 600, field diameter 0.625 mm; Nikon, Tokyo,an). Moderate (1130 cells/hpf) to severe (30 cells/f) infiltration with IgG4-positive cells5 in the presencecharacteristic histology was considered diagnostic of

P.

ImagingAvailable cholangiograms and computerized to-

graphy scans were reviewed by a single radiologist.T.). Strictures were characterized as distal (intrapan-atic), proximal extrahepatic, and intrahepatic.

SerologyIgG4 levels in serum (mg/dL) were measured in

patients using automated nephelometry24 (Behringphelometer II; Dade Behring, Inc, Newark, DE). CA-9 levels were measured in 40 patients. Liver enzymeels at presentation and after therapy were noted.

Other Organ InvolvementThe presence of AIP was identified by use of

SORt criteria.9 The presence or history of retroperito-al fibrosis, sialoadenitis, mediastinal adenopathy, andney involvement was noted.

Initial Therapy, Response, and RelapseBased on initial therapy at presentation the pa-

nts were classified into 3 groups: surgical treatmentsections performed for suspicion of malignancy in thisup), steroid therapy, and no treatment. In patients

ated with steroids or other immunomodulatory drugsindications, dosage, and duration of therapy wereted. The most common protocol followed for initialroid treatment and for monitoring therapeutic re-onse is described (Table 1). Response to treatment was

de2strmowecrelogWewhoftomab

paAfingrev(wde

Insevatesquabthetogrostawa

14oftatlostespain

Ta roto

eatm

InitP a tot

ImaF

ngiopmove

LabI

, alaF

week

week

aTh lapsefor nosisfea gh s

CLIN

ICALLIV

ER,

PANCREA

S,AND

BILIA

RYTRACT

708 GHAZALE ET AL GASTROENTEROLOGY Vol. 134, No. 3fined as a decrease in liver enzyme levels to less thanthe upper limit of normal and/or improvement in

ictures leading to sustained (3 months) stent re-val. Relapses after the initial response to treatment

re classified as follows: (1) biochemical relapse: in-ase in liver enzyme levels (2 fold increase); (2) sero-ic relapse: increase in serum IgG4 level (at least 2-fold).also analyzed recurrence of symptoms with patients

o relapsed. However, because of the nonspecific naturemany disease-related symptoms, recurrence of symp-

s alone was not considered indicative of relapse in thesence of biochemical or serologic relapse.

Follow-up InformationWith institutional review board approval, study

tients were contacted to obtain follow-up information.ter patient consent, all recent clinical notes and imag-

studies from outside institutions were sent to us andiewed. Recent clinical and imaging follow-up data

ithin 6 months of the study or within 6 months ofath) were available for 92% of study patients.

Statistical AnalysisData were analyzed using JMP version 6.0.0 (SAS

titute Inc, Cary, NC). Differences between groups wereluated by using the chi-square test or the Fisher exactt for qualitative variables, and the Student t test forantitative variables. Nonparametric quantitative vari-les (eg, median follow-up times) were compared using

MannWhitney test. KaplanMeier curves were usedassess differences in relapse-free survival rates between

ble 1. Most Commonly Used IAC Treatment and Monitoring P

IAC initial steroid tr

ial steroid regimenrednisone 40 mg/day orally for 4 weeks then taper by 5 mg/wk forgingollow-up evaluationIf biliary stent placed on presentation: endoscopic retrograde chola

improvement in strictures noted (no tight strictures), stents reIf no biliary stent placed, then no follow-up imaging performed

oratory evaluationnitial

Serum bilirubin, alkaline phosphatase, aspartate aminotransferaseollow-up evaluationBiliary stent in place: earlier-described laboratory tests repeated 4

then every 812 weeks thereafterNo biliary stent: earlier-described laboratory tests repeated 68

then laboratory tests repeated every 812 weeks thereafter

is is the initial treatment protocol only. For details on treatment of recancer (eg, cholangiocarcinoma) has been unrevealing and the diagtures. A steroid trial should not be used as a substitute for a thorouups over time. Values are represented as the mean ndard error of the mean and a P value of less than .05s considered significant.

metha16ResultsDemographics and Presenting ClinicalFeatures

The mean patient age was 62 2 years (range, 85 y) and 83% were older than age 50. The majoritypatients were men (85%). Clinical features on presen-ion included obstructive jaundice in 41 (77%), weights in 27 (51%), steatorrhea in 8 (15%), new-onset diabe-mellitus in 4 (8%), and abdominal pain in 14 of the 53

tients (26%). Abdominal pain did not require narcoticsany patient.

Histology and IgG4 Immunostaining

Four patients had resection (surgical) specimenst revealed a lymphoplasmacytic infiltrate in andund the bile duct with surrounding storiform fibrosis

d obliterative phlebitis, a pattern that is characteristicIAC. IgG4 immunostaining revealed more than 104-positive cells per high-power field in all 4 patients.

ese 4 patients had IAC with no obvious evidence ofP clinically or radiographically. Of the remaining 49tients who had AIP, pancreatic resection specimensre available in 14 patients and core biopsy specimens15 patients. These specimens showed lymphoplasma-ic sclerosing pancreatitis with abundant IgG4-positivels on immunostaining, a pattern characteristic for AIP.doscopic biopsy specimens of biliary epithelium wereilable in 16 patients. Although all specimens had

equate epithelial tissue present, a histologic diagnosisIAC could not be made on any of these biopsy speci-

col

ent protocola

al of 11 weeks of treatment

ancreatography repeated 68 weeks after initiating treatment; ifd

nine aminotransferase, IgG4, CA 19-9 at baseline

s after stent removal (see earlier for stent removal protocol),

s after initiating steroid treatment; if a response is documented,

s, see Figure 3. This protocol assumes that a rigorous evaluationof IAC is highly likely based on clinical, laboratory, and imaging

earch for the etiology of biliary strictures.thaaroanforIgGThAIpaweincytcelEnavaadofns. However, IgG4 immunostaining revealed moren 10 IgG4-positive cells per high-power field in 14 of(88%) patients.

ennachblioffinbilprefintur(36Se

putopalaratrfusAllhaimpapacrein13padistie

IgGlis

invha(nsal

gicweoudidresanpativ

gicIgGturinigrothesucalturdeheThuncreon20grotiotrepapabilofwa

Ta Pati

nge)

Ser 90)

CA 05)

Bili .1)Alk 556)

AlaAsp

CLINICALLIVER,

PANCREA

S,AND

BILIARYTRACT

March 2008 IGG4ASSOCIATED CHOLANGITIS 709ImagingCholangiograms were available in all patients: 44

doscopic retrograde cholangiograms, 5 magnetic reso-nce cholangiograms, and 4 percutaneous transhepaticolangiograms. Intrapancreatic biliary strictures, resem-ng those seen in pancreatic cancer, were present in 3753 patients (70%), and were present as an isolatedding in 27 of 53 patients (51%). Proximal extrahepaticiary strictures, mimicking cholangiocarcinoma, weresent in 18 of 53 patients (34%), yet were an isolatedding in only 5 of 53 patients (9%). Intrahepatic stric-es, similar to PSC, were found in 19 of 53 patients%), and were found alone in 4 of 53 patients (8%).

venteen patients (32%) had multifocal strictures.In patients with AIP (n 49), pancreas protocol com-terized tomography scans were available in 48 patientsevaluate the pancreas. Twenty-four patients had focalncreatic enlargement, 17 had diffuse pancreatic en-gement, 2 had changes of acute pancreatitis, 3 had anophic pancreas, 1 had a normal-size gland with dif-ely decreased enhancement, and 1 had a normal gland.4 histologically proven IAC patients (postresection)

d a normal pancreas on computerized tomographyaging. Pancreatograms were available in 31 of 49 AIPtients and showed a diffusely irregular duct in 14tients, a focal stricture in 13 patients (12 in the pan-atic head, 1 in the body), and a normal pancreatogram4 patients. In the patients with focal strictures (n ), moderate distal ductal dilation occurred only in 1tient, mild dilation occurred in 3 patients, and thetal duct was normal or small in the remaining pa-nts.

SerologyLaboratory results including liver enzyme, serum

4, and carbohydrate antigen 19-9 (CA 19-9) levels areted in Table 2.

Other Organ InvolvementThe pancreas was the most common other organ

olved in our group of IAC patients with 49 of 53 (92%)ving AIP. Other organs included kidney involvement 14), retroperitoneum (retroperitoneal fibrosis, n 5),ivary gland (sialoadenitis, n 3), lymph nodes (medi-

ble 2. Pretreatment Laboratory and Serologic Data in 53 IAC

Laboratory tests Mean SEM (ra

um IgG4 level, mg/dL 516 98 (624

19-9 level, IU/mL 91 30 (110

rubin level, mg/dL 7.5 1 (0.319aline phosphatase level, U/L 512 64 (771nine aminotransferase level, U/L 190 64 (182445)artate aminotransferase level, U/L 98 17 (16745)inal and axillary, n 2), and lung (pulmonary infil-tes, n 2). Histology revealing lymphoplasmacytic in-ration with IgG4-positive cells in the involved organ wasilable on 1 patient with kidney involvement (tubuloin-stitial nephritis), 1 with sialoadenitis, 2 with lymphade-pathy, and 1 patient with pulmonary disease. Inflamma-y bowel disease was present in 3 patients (6%).

TreatmentEighteen patients were treated initially with sur-

al resection (all for suspected malignancy), 30 patientsre treated with steroids, and 5 patients had spontane-s resolution of strictures on initial presentation and

not receive treatment. In the group with spontaneousolution (n 5), 1 patient died from unrelated causesd limited follow-up time was available on 1 othertient, leading us to exclude this group from compara-e analysis with the other 2 groups.Baseline characteristics did not differ between the sur-al and steroid-treated groups with regard to age, sex,4 levels, liver enzyme levels at presentation, or stric-

e location. The median follow-up evaluation from thetial clinical presentation was longer in the surgicalup (58 vs 29.5 months; P .01), which is explained byfact that our earlier patients primarily were treated

rgically because of suspected malignancy. In the surgi-group, 4 patients presented with isolated biliary stric-es without pancreatic disease and these patients un-

rwent segmental hepatectomy, bile duct resection, andpaticojejunostomy for presumed cholangiocarcinoma.e remaining 14 patients had pancreatic disease andderwent pancreaticoduodenectomy for presumed pan-atic cancer. Because of increasing recognition of AIP,ly 2 of 29 AIP cases diagnosed at our institution since03 have undergone surgical resection. In the surgicalup, all patients responded to surgery, with normaliza-

n of liver tests postoperatively. Thirty patients wereated initially with steroids, all with prednisone. Of 30tients, 29 (97%) showed a response to steroids. Onetient was a nonresponder and has required prolongediary stent placement. In the steroid group, resolutionstrictures and/or normalization of liver enzyme levelss achieved in 18 of 30 patients (60%) (Figure 1), and

ents

Normal range Distribution

8140 140 mg/dL: 74%280 mg/dL: 50%

037 37 IU/mL: 48%100 IU/mL: 18%

0.11.0 5 mg/dL: 65%45115 115 U/L: 84%asttrafiltavaternotor500 U/L: 34%929 100 U/L: 62%

1231 100 U/L: 32%

imen

su(FipaRewipathaofnispreIgGimsexwhtwimtrealoTh

strtioothstrhamorel1 imowecothemgmgsumerem(malo

Fig(ngrobetgrolap(Pwidonlpat[wiAZnol

CLIN

ICALLIV

ER,

PANCREA

S,AND

BILIA

RYTRACT

710 GHAZALE ET AL GASTROENTEROLOGY Vol. 134, No. 3provement in strictures and/or improvement in liverzyme levels was achieved in 11 of 30 patients (37%).Relapse rates after treatment did not differ in thergical vs the steroid-treated groups (44% vs 54%; P .1)gure 2). Biochemical relapse occurred in all relapsetients except 3, who had isolated serologic relapse.currence of disease-related symptoms was associatedth biochemical and/or serologic relapse in 8 of 18tients (44%). In the steroid group, relapse occurred lessn 6 months after discontinuation of prednisone in 1217 patients (71%). Two patients relapsed during pred-one taper before discontinuation of the drug. Factorsdicting relapse in the steroid group were increased4 levels and the presence of proximal strictures (prox-

al extrahepatic or intrahepatic, or both). Patient age,, symptoms (obstructive jaundice), and proportiono normalized IgG4 after treatment did not differ be-een relapsers and nonrelapsers. The presence of prox-al strictures was predictive of relapse regardless ofatment group when compared with distal stricturesne (relapse rates of 64% vs 32%; P .02) (Figure 3).e 2 groups (distal strictures alone vs any proximal

ure 2. Flowchart of study patients 53) according to treatmentups. *Relapse rates did not differween the surgery and steroidups (P .1, NS). The time to re-se was longer in the surgery group .03); however, the range wase. Serologic relapse occurred iny 1 patient in this group (overall, 3

ients had only serologic relapsethout a biochemical relapse]).A, azathioprine; MM, mycophe-ate mofetil.ictures) were similar with respect to age, sex, propor-n with obstructive jaundice, serum IgG4 levels, ander organ involvement; however, all patients with distal

ictures alone had AIP, and all 4 patients who did notve AIP were in the proximal stricture group. Immuno-dulatory drugs eventually were used (after at least one

apse) in a total of 7 patients, 6 in the steroid group andn the surgical group (4 azathioprine, 2 mycophenolatefetil, and 1 cytoxan). Two of these patients initially

re started on low doses (azathioprine 50 mg/day, my-phenolate 500 mg twice daily) and experienced fur-r relapse. Doses were increased to azathioprine 22.5/kg and mycophenolate mofetil was increased to 750twice daily with no further relapses. All 7 patients

bsequently were maintained in remission on thesedications with no further relapses, and 6 patientsained on the medications at the time of the study

edian follow-up period on immunomodulatory drugsne, 6 months; range, 219 months).

Of 53 patients, 4 progressed to develop portal hyper-sion and cirrhosis. Three of these patients were treat-nt-naive at the time of diagnosis of cirrhosis and 1

Figure 1. IgG4-associated scleros-ing cholangitis with intrahepatic stric-tures mimicking PSC (A) before treat-ment, and (B) after 12 weeks ofsteroid therapy.tenme

paonwatieImtrehethepacofietielivacupn(nrestencanimcomapowaim

ofcaswiifede

Sum

mar

yof

Larg

est

Publ

ishe

dS

erie

sof

Bili

ary

Invo

lvem

ent

inPa

tient

sW

ithAI

P

dyN

umbe

rof

patie

nts

Dia

gnos

ticcr

iteria

for

AIP

Dia

gnos

ticbi

liary

hist

olog

y?

Mea

nag

e, yM

ale

(%)

Obs

truc

tive

jaun

dice

%In

crea

sed

seru

mIg

G4

leve

lsTr

eatm

ent

resp

onse

IBD

(%)

Loca

tion

ofst

rictu

res

13

20

04

14

His

tolo

gyYe

s67

79%

NA

NA

No

trea

tmen

t(s

urgi

cal

spec

imen

s)

0C

omm

onB

D:

71%

Extr

ahep

atic

BD

:50%

Intr

ahep

atic

BD

:43%

etal

,14

apan

)2

6JP

Scr

iteria

NA

62

62%

NA

NA

NA

0Ex

trah

epat

icB

D(in

clud

ing

CB

D):

100%

Intr

ahep

atic

BD

:9/2

6;

35%

etal

,15

apan

)2

8JP

Scr

iteria

NA

NA

64%

41%

NA

Ste

roid

s:100

%re

spon

se0

Extr

ahep

atic

BD

:23/2

8;

82%

Intr

ahep

atic

BD

:23/2

8;

82%

al,1

6

apan

)1

6JP

Scr

iteria

,hi

stol

ogy

in7

patie

nts

Yes,

4pa

tient

s63

75%

50%

NA

Ste

roid

s:100

%re

spon

seN

AIn

trap

ancr

eatic

CB

D:

13/1

6;

81%

Extr

ahep

atic

BD

:5/1

6;

31%

Intr

ahep

atic

BD

:2/1

6;

13%

net

06

(The

nds)

10

JPS

crite

ria,

hist

olog

yin

3pa

tient

s

NA

52

100%

80%

NA

Ste

roid

s(5

patie

nts)

:100%

resp

onse

0B

oth

intr

ahep

atic

and

extr

ahep

atic

BD

stric

ture

spr

esen

tin

allp

atie

nts

etal

,18

apan

)2

3JP

Scr

iteria

,hi

stol

ogy

in1

0pa

tient

s

NA

68

81%

87%

82%

(dat

afr

omsc

atte

rplo

t)N

AN

AIn

trap

ancr

eatic

bile

duct

:20/2

3;

87%

Extr

ahep

atic

bile

duct

:1/2

3;

4%

Intr

ahep

atic

bile

duct

s:2/2

3;

9%

uct;

JPS

,Ja

pane

sePa

ncre

asS

ocie

ty;

NA,

info

rmat

ion

not

avai

labl

efr

omar

ticle

.

Figdisture27)

CLINICALLIVER,

PANCREA

S,AND

BILIARYTRACT

March 2008tient was a treatment nonresponder. The time fromset of initial symptoms to the diagnosis of cirrhosiss 62, 36, and 9 months in the 3 treatment-naive pa-nts and 26 months in the treatment nonresponder.portantly, the 2 patients with rapid progression in theatment-naive group (36 and 9 months) had segmentalpatectomies with Roux-en-Y hepaticojejunostomy for

suspicion of malignancy. With the exception of 1tient who had a history of moderate alcohol intake, no-existing etiologies of chronic liver disease were identi-d in these 4 patients. Death occurred in 7 of 53 pa-nts. Cause of death was complications of end-stageer disease (n 1), metastatic pancreatic cancer (n 1),

te stroke (n 1), congestive heart failure (n 1),eumonia and sepsis (n 1), and unknown cause 2). The patient with pancreatic cancer had an initialection for presumed cancer and histology was consis-t with AIP. Five years later he developed pancreaticcer in the remaining gland. The initial resection spec-

en was reviewed again by our pathologist (T.C.S.),nfirming the initial diagnosis of AIP and the absence oflignancy and a discussion of this case has been re-rted elsewhere.25 Sepsis in one patient described earliers not associated temporally with the use of steroids ormunomodulatory medications.

DiscussionAIP now is viewed as the pancreatic manifestation

a systemic disease referred to as ISD.6 Several smalle series have described biliary strictures in association

ure 3. KaplanMeier curve of relapse-free survival in patients withtal (intrapancreatic) strictures only vs patients with any proximal stric-s (proximal extrahepatic, intrahepatic, or both). , Distal only (n ; - - -, any proximal (n 26). *P .02.th AIP1322 (Table 3) that characterize the biliary man-station of ISD. We have proposed the term IAC toscribe this entity.12 Similar to AIP, IAC patients have a Ta

ble3.IGG4ASSOCIATED CHOLANGITIS 711Stu

Zen

etal

,(J

apan

)

Nak

azaw

a20

04

(JTa

kika

wa

20

04

(JN

ishi

noet

20

05

(J

Van

Buu

real

,17

20

Net

herla

Kam

isaw

a20

06

(J

BD

,bi

led

strsixdictierh

histhelimthacelofinflIgGforhisutianingthedefroimpotabrecme

turmeduhaclibilpatan

IAtiv74anlevpo36hativinIgGheusoflik60

diadis

supreidedisabthiorgretinflpa

stefrastematwinAnorththstukastupeanincco

IAmgtapbilpahoonmoinregreslaplapsuanstrmodisthatredewestufac

CLIN

ICALLIV

ER,

PANCREA

S,AND

BILIA

RYTRACT

712 GHAZALE ET AL GASTROENTEROLOGY Vol. 134, No. 3iking male preponderance and typically present in theth and seventh decades of life with obstructive jaun-e, weight loss, and mild abdominal discomfort. Pa-nts with pancreatic disease may present with steator-ea and new-onset diabetes mellitus.On resection specimens IAC shows a characteristictology and positive IgG4 immunostaining.13 Although

superficial nature of endoscopic biopsy specimensits the ability to see characteristic histology, we showt positive IgG4 immunostaining (10 IgG4-positive

ls/hpf) of bile duct biopsy specimens is present in 88%patients. Thus, a bile duct biopsy specimen showingamed mucosa, negative for malignant cells, with many4-positive plasma cells provides histologic supporta diagnosis of IAC. The specificity of IgG4 immuno-

tochemistry for IAC has not yet been studied and itslity will rest on its ability to distinguish IAC from PSCd cholangiocarcinoma. The use of IgG4 immunostain-

on biliary cytology specimens is problematic becausedensity of IgG4-positive cells in the tissue cannot be

termined from these specimens. In addition, we knowm IgG4 immunostaining of pancreatic resection spec-ens that mild tissue IgG4 immunostaining (10 IgG4-sitive cells/hpf) can occur in other diseases, most no-ly pancreatic cancer.26 In light of this, we do notommend IgG4 immunostaining on cytology speci-ns.

Unlike AIP, in which typical pancreatic imaging fea-es such as diffuse sausage-shaped pancreatic enlarge-nt and diffuse irregular narrowing of the pancreaticct have been described, biliary strictures in IAC do notve any highly specific diagnostic features. However,nical clues to the diagnosis of IAC include proximale duct or intrahepatic strictures in a patient withncreatic mass, multifocal biliary strictures, and spon-eously resolving or fleeting biliary strictures.

Although a serum IgG4 increase is characteristic ofC, it may not be diagnostic of the disease. The sensi-ity of serum IgG4 for IAC in the present study was%, comparable with that seen in AIP.26 The specificityd positive predictive value of increased serum IgG4els for IAC is not known. We recently reported that thesitive predictive value of serum IgG4 for AIP was only%.26 We also recently showed that 9% of PSC patientsve increased IgG4 levels.27 Because this was a retrospec-e study it is unclear what proportion of PSC patientsthis study actually may have had IAC. Nevertheless, an

4 increase does occur in the absence of ISD, andnce increased serum IgG4 levels alone should not beed to diagnose IAC. Serum CA 19-9 levels also can beuse because levels greater than 100 IU/mL are less

ely in IAC compared with cholangiocarcinoma (18% vs% 80%28,29).

Other organ involvement is an important clue to thegnosis of IAC. The presence of unexplained pancreaticease in patients with biliary strictures should raise the

ofsterelspicion for IAC. Although pancreatic disease wassent in the majority of our study patients, we recentlyntified IAC patients who have no obvious pancreaticease by clinical or imaging criteria. Therefore, thesence should not dissuade clinicians from considerings diagnosis. Attention also should be given to otherans that can be involved such as the salivary glands,

roperitoneum, lymph nodes, or kidneys. Interestingly,ammatory bowel disease (IBD), present in 70% of PSC

tients, occurred only in 6% of our IAC patients.Unlike PSC, biliary strictures in IAC respond toroids. Only one patient in our study remained re-ctory to steroids and has required prolonged biliarynting. Complete resolution of strictures and/or nor-lization of liver tests were seen in approximately

o thirds of patients, whereas improvement was seenthe remaining one third. In contrast, in a study bygulo et al,30 only 4 of 21 PSC patients treated with

al budesonide (9 mg/day for 12 months) decreasedeir alkaline phosphatase levels to less than 2 timese upper limit of normal (19% vs 97% in IAC in ourdy), and none of the patients normalized their al-

line phosphatase levels (0% vs 60% in IAC in ourdy). In a subsequent study,27 serum IgG4 levels were

rformed on stored serum from these PSC patientsd 2 of 4 patients who responded to budesonide hadreased serum IgG4 levels, and thus potentially

uld have had undiagnosed IAC.There are no data on what the duration of treatment ofC should be. Our typical protocol is to treat with 40/day of prednisone for 4 weeks followed by a 5-mg/wker for a total of 11 weeks on treatment. Pretreatment

iary stenting was performed on the majority of ourtients and leads to quicker resolution of symptoms;wever, we also have documented resolution of jaundicesteroid treatment without stent placement. Stent re-val was possible 6 8 weeks after treatment initiationall but one patient in our study. On this steroidimen we observed that despite an excellent initialponse to steroids in IAC, there was a high rate of re-se (54%) on steroid withdrawal. Interestingly, the re-se rates were similar in those treated with steroids or

rgical resection for their initial presentation. Furtheralyses of the relapses showed that those with proximalictures (proximal extrahepatic or intrahepatic) werere likely to relapse compared with those with isolatedtal strictures (65% vs 23%, P .02). Thus, it is evidentt distal strictures have a different clinical course after

atment than patients with proximal disease. Althoughmographics and clinical presentation of these groupsre similar, all patients with distal strictures in ourdy had AIP, and it remains unclear whether this is int a compressive phenomenon. The lower relapse rate

patients with distal strictures suggests that our currentroid regimen is sufficient in most patients to preventapse and maintain disease remission over the long

terratnethesmInproimvensuAzhaimsmareazamgven

anenrecsitincralknoplatdiatreprocan

resoldlikisoinpaHoofwi

ingstelis

Ta

His g chlls/hposis)

Ima ing incture

Ser G4Oth f AIP

argemduct

iple p

gemeRes leve

aBi defin1 ty ofbIgG /hpf.cTh nce odDi e rimstrieSefCofibr

CLINICALLIVER,

PANCREA

S,AND

BILIARYTRACT

March 2008 IGG4ASSOCIATED CHOLANGITIS 713m. On the other hand, the significantly higher relapsee in proximal disease indicates that these patients mayed maintenance therapy over the long term. In Japan,

practice has been to leave patients indefinitely on aall dose of prednisone (10 mg/day) to prevent relapses.view of the potential adverse effects of such an ap-ach, especially in the elderly, we have elected to use

munomodulatory drugs such as azathioprine to pre-t relapse and to maintain remission, and have been

ccessful in a small number of relapsers in this study.athioprine, mycophenolate mofetil, and cytoxan allve been effective in our patients. Low doses of thesemunomodulatory drugs did not prevent relapse in aall patient subset and thus it appears that higher dosesneeded. Based on this initial experience, we now usethioprine 22.5 mg/kg or mycophenolate mofetil 750twice daily. This practice appears promising in pre-

ting relapse, yet needs further study.We categorized relapses in our study into biochemicald serologic. Biochemical relapse with increased liverzyme levels was considered a surrogate for diseaseurrence and was treated in our series. The most sen-ive and early marker for a biochemical relapse was anrease in serum alkaline phosphatase levels. The natu-

history of untreated biochemical relapses is notown. In our study, a subset of patients (n 4) devel-ed portal hypertension and cirrhosis presumably re-ed to IAC, 3 of whom were untreated at the time ofgnosis of cirrhosis and one was a nonresponder toatment. Thus, it appears that untreated IAC cangress to end-stage liver disease and this progressionbe rapid; however, it is not yet clear whether treat-

ble 4. Diagnostic Criteria for IAC: HISORt Criteria for IAC

Feature

tology of bile duct Lymphoplasmacytic sclerosinwith 10 IgG4-positive cephlebitis and storiform fibr

ging of bile duct One or more strictures involvFleeting/migrating biliary stri

ology Increased levels of serum Iger organ involvementb,c Pancreas: classic features o

focal pancreatic mass/enlmasses, focal pancreatic

Retroperitoneal fibrosisRenal lesions: single or mult

diffuse patchy)e

Salivary/lacrimal gland enlarponse to steroid therapy Normalization of liver enzyme

le duct biopsy specimens often do not provide sufficient tissue for a0 IgG4-positive cells/hpf is suggestive of IAC; however, the specifici4 immunostaining of involved organs show 10 IgG4-positive cells

e presence of IBD suggests PSC rather than IAC; however, the abseffusely enlarged pancreas with delayed enhancement and capsule-lik

ctures or long stricture without upstream dilatation.e Takahashi et al35 for more detail.mplete resolution of stricture may not be seen in all patients, especially thotic strictures.nt will prevent progression of disease or whether re-se worsens prognosis. None of our study patientsgressed to cirrhosis after successful treatment andintenance of remission. These data have prompted ustreat IAC patients aggressively with steroids (and im-nomodulatory drugs for relapse) with the goal ofieving and maintaining clinical remission. Another

portant clinical dilemma is the significance of isolatedologic relapse (n 3 in our study) and whether treat-nt is indicated in these patients. Prolonged observa-n (12 months) in 2 patients has shown no evidencebiochemical or symptomatic relapse. This is an areat needs further study.

The diagnosis of IAC requires a high index of suspiciond should be entertained in all patients with unex-ined biliary strictures. The differential diagnosis, de-

nding on the location and characteristics of the biliaryicture, include PSC, cholangiocarcinoma, and pancre-c cancer. Intrahepatic strictures in IAC can closelyemble PSC. Compared with PSC, IAC presents at aner age (mean age, 62 vs 40 y in PSC) and is much more

ely to present with jaundice, even when presenting aslated intrahepatic disease (75% in our study vs 5%30%PSC3133). IBD, typically seen in 70% 80% of PSC

tients,32,34 is uncommon in IAC (6% in our study).wever, absence of IBD is not useful for the diagnosisIAC in an individual patient because 30% of patients

th PSC do not have associated IBD.The characteristic features of IAC on histology, imag-, serology, other organ involvement, and response toroid therapy, which parallel the HISORt criteria pub-hed for AIP, are listed in Table 4. The diagnosis of IAC

Characteristics

olangitis on resection specimens (lymphoplasmacytic infiltratef within and around bile ducts with associated obliterativea

trahepatic, proximal extrahepatic, or intrapancreatic bile ductss

on imaging or histology;d suggestive pancreatic imaging findings:ent without pancreatic duct dilatation, multiple pancreatic

stricture without upstream dilatation, pancreatic atrophy

arenchymal low-attenuation lesions (round, wedge-shaped, or

ntls or resolution of stricturef

itive diagnosis. In such specimens, IgG4 immunostaining showingthis finding is not known.

f IBD does not help diagnose IAC in an individual patient.. Diffusely irregular, attenuated main pancreatic duct or multiplemelappromatomuachimsermetiooftha

anplapestratiose early in the course of treatment (6 wk) or with predominantly

cana pinpaofstrturmegrooftrimathecri

ouinha(TtheanguhethesustiIApatre

fladia

noorsuunthemo

CLIN

ICALLIV

ER,

PANCREA

S,AND

BILIA

RYTRACT

714 GHAZALE ET AL GASTROENTEROLOGY Vol. 134, No. 3be made definitively if there is typical histology fromrevious pancreaticobiliary resection (as was available18 patients in our study) or from core biopsy of thencreas (15 patients)9 (group A, Figure 4). The presenceIAC also can be diagnosed in patients with biliary

icture(s) having typical radiologic and serologic fea-es of AIP (group B, Figure 4); 6 patients in our studyt these criteria. In patients not meeting criteria forup A or B in whom there is a high index of suspicionIAC (see Figure 4, group C for indications for steroidal) and after every effort has been made to excludelignancy, a response of the biliary stricture to steroidrapy confirms the diagnosis (14 patients met these

teria in our study).Recognition of IAC requires familiarity with the vari-s presentations of the disease and can be challengingsome patients. We have found it extremely helpful tove at least one radiologist (N.T.) and pathologist.C.S.) at our institution with the expertise to recognize

imaging and histologic features, respectively, of IACd AIP. Our ability to obtain endoscopic ultrasoundided core biopsy specimens of the pancreas36 also haslped to confirm the diagnosis of AIP before steroidrapy in many patients. We, however, recognize that

ch expertise to obtain pancreatic core biopsy specimensll is limited to very few centers in the country. UntilC and AIP are recognized more widely, referral of sometients to centers with expertise in recognizing andating IAC may be necessary.

In conclusion, IgG4-associated cholangitis is a fibroin-mmatory disease that should be in the differentialgnosis of all unexplained biliary strictures. The diag-

8.sis can be made histologically on resection specimensafter a steroid trial in a patient with a high clinical

spicion for IAC or with documented ISD who hasdergone a rigorous search for malignancy. Although

initial steroid response is excellent, relapses are com-n after early withdrawal of steroids. Initial experience

ggests that immunomodulatory drugs can maintaing-term remission in IAC.

ReferencesMontefusco PP, Geiss AC, Bronzo RL, et al. Sclerosing cholangi-tis, chronic pancreatitis, and Sjogrens syndrome: a syndromecomplex. Am J Surg 1984;147:822826.Kawaguchi K, Koike M, Tsuruta K, et al. Lymphoplasmacyticsclerosing pancreatitis with cholangitis: a variant of primary scle-rosing cholangitis extensively involving pancreas. Hum Pathol1991;22:387395.Uchida K, Okazaki K, Asada M, et al. Case of chronic pancreatitisinvolving an autoimmune mechanism that extended to retroperi-toneal fibrosis. Pancreas 2003;26:9294.Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concen-trations in patients with sclerosing pancreatitis. N Engl J Med2001;344:732738.Kamisawa T. IgG4-positive plasma cells specifically infiltrate var-ious organs in autoimmune pancreatitis. Pancreas 2004;29:167168.Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathologicalentity of IgG4-related autoimmune disease. J Gastroenterol2003;38:982984.Deshpande V, Chicano S, Finkelberg D, et al. Autoimmune pan-creatitis: a systemic immune complex mediated disease. Am J

Figure 4. Algorithm for the diagnosisand management of suspected IAC.sulon

1.

2.

3.

4.

5.

6.

7.Surg Pathol 2006;30:15371545.Zhang L, Notohara K, Levy MJ, et al. IgG4-positive plasma cellinfiltration in the diagnosis of autoimmune pancreatitis. ModPathol 2007;20:2328.

9. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmunepancreatitis: the Mayo Clinic experience. Clin GastroenterolHepatol 2006;4:10101016.

10. Zamboni G, Luttges J, Capelli P, et al. Histopathological featuresof diagnostic and clinical relevance in autoimmune pancreatitis:a study on 53 resection specimens and 9 biopsy specimens.Virchows Arch 2004;445:552563.

11. Takahashi N, Kawashima A, Fletcher JG, et al. Renal involvementin patients with autoimmune pancreatitis: CT and MR imagingfindings. Radiology 2007;242:791801.

12. Bjrnsson E, Chari ST, Smyrk TC, et al. IgG4 associated cholan-gitis: description of an emerging clinical entity based on review ofthe literature. Hepatology 2007;45:15471554.

13. Zen Y, Harada K, Sasaki M, et al. IgG4-related sclerosing cholan-gitis with and without hepatic inflammatory pseudotumor, and

14

15

16

17

18

19

20

21

22

23. Kojima E, Kimura K, Noda Y, et al. Autoimmune pancreatitis andmultiple bile duct strictures treated effectively with steroid.J Gastroenterol 2003;38:603607.

24. Vlug A, Nieuwenhuys EJ, van Eijk RV, et al. Nephelometric mea-surements of human IgG subclasses and their reference ranges.Ann Biol Clin (Paris) 1994;52:561567.

25. Ghazale A, Chari S. Is autoimmune pancreatitis a risk factor forpancreatic cancer? Pancreas 2007;35:376.

26. Ghazale A, Chari S, Smyrk TC, et al. Value of serum IgG4 in thediagnosis of autoimmune pancreatitis and in distinguishing itfrom pancreatic cancer. Am J Gastroenterol 2007;102:16461653.

27. Mendes FD, Jorgensen R, Keach J, et al. Elevated serum IgG4concentration in patients with primary sclerosing cholangitis.Am J Gastroenterol 2006;101:20702075.

28

29

30

31

32

33

34

35

36

RA

Strsur

CLINICALLIVER,

PANCREA

S,AND

BILIARYTRACT

March 2008 IGG4ASSOCIATED CHOLANGITIS 715sclerosing pancreatitis-associated sclerosing cholangitis: dothey belong to a spectrum of sclerosing pancreatitis? Am J SurgPathol 2004;28:11931203.

. Nakazawa T, Ohara H, Sano H, et al. Cholangiography can dis-criminate sclerosing cholangitis with autoimmune pancreatitisfrom primary sclerosing cholangitis. Gastrointest Endosc 2004;60:937944.

. Takikawa H, Takamori Y, Tanaka A, et al. Analysis of 388 casesof primary sclerosing cholangitis in Japan; presence of a sub-group without pancreatic involvement in older patients. HepatolRes 2004;29:153159.

. Nishino T, Toki F, Oyama H, et al. Biliary tract involvement inautoimmune pancreatitis. Pancreas 2005;30:7682.

. van Buuren HR, Vleggaar FP, Willemien Erkelens G, et al. Auto-immune pancreatocholangitis: a series of ten patients. Scand JGastroenterol Suppl 2006;243:7078.

. Kamisawa T, Nakajima H, Egawa N, et al. IgG4-related sclerosingdisease incorporating sclerosing pancreatitis, cholangitis, sialad-enitis and retroperitoneal fibrosis with lymphadenopathy. Pancre-atology 2006;6:132137.

. Hirano K, Shiratori Y, Komatsu Y, et al. Involvement of the biliarysystem in autoimmune pancreatitis: a follow-up study. Clin Gas-troenterol Hepatol 2003;1:453464.

. Uehara T, Hamano H, Kawa S, et al. Distinct clinicopath-ological entity autoimmune pancreatitis-associated sclerosingcholangitis. Pathol Int 2005;55:405411.

. Sekhon JS, Chung RT, Epstein M, et al. Steroid-responsive (au-toimmune?) sclerosing cholangitis. Dig Dis Sci 2005;50:18391843.

. Nakazawa T, Ohara H, Yamada T, et al. Atypical primary scleros-ing cholangitis cases associated with unusual pancreatitis.Hepatogastroenterology 2001;48:625630.. Tangkijvanich P, Thong-Ngam D, Theamboonlers A, et al. Diag-nostic role of serum interleukin 6 and CA 19-9 in patientswith cholangiocarcinoma. Hepatogastroenterology 2004;51:1519.

. Qin XL, Wang ZR, Shi JS, Lu M, Wang L, He QR. Utility of serumCA19-9 in diagnosis of cholangiocarcinoma: in comparison withCEA. World J Gastroenterol 2004;10:427432.

. Angulo P, Batts KP, Jorgensen RA, et al. Oral budesonide in thetreatment of primary sclerosing cholangitis. Am J Gastroenterol2000;95:23332337.

. Broome U, Olsson R, Loof L, et al. Natural history and prognosticfactors in 305 Swedish patients with primary sclerosing cholan-gitis. Gut 1996;38:610615.

. Bambha K, Kim WR, Talwalkar J, et al. Incidence, clinicalspectrum, and outcomes of primary sclerosing cholangitis in aUnited States community. Gastroenterology 2003;125:13641369.

. Nakazawa T, Ohara H, Sano H, et al. Clinical differences betweenprimary sclerosing cholangitis and sclerosing cholangitis withautoimmune pancreatitis. Pancreas 2005;30:2025.

. Talwalkar JA, Lindor KD. Primary sclerosing cholangitis. InflammBowel Dis 2005;11:6272.

. Takahashi N, Kawashima A, Fletcher JG, et al. Renal involvementin patients with autoimmune pancreatitis: CT and MR imagingfindings. Radiology 2007;242:791801.

. Levy MJ, Reddy RP, Wiersema MJ, et al. EUS-guided trucut biopsyin establishing autoimmune pancreatitis as a cause of obstruc-tive jaundice. Gastrointest Endosc 2005;61:467472.

eceived June 4, 2007. Accepted November 26, 2007.ddress requests for reprints to: Suresh T. Chari, MD, 200 Firsteet SW, Mayo Clinic, Rochester, Minnesota 55905. e-mail: chari.esh@mayo.edu; fax: (507) 284 5486.

Immunoglobulin G4Associated Cholangitis: Clinical Profile and Response to TherapyMaterials and MethodsHistologyTissue IgG4 ImmunostainingImagingSerologyOther Organ InvolvementInitial Therapy, Response, and RelapseFollow-up InformationStatistical Analysis

ResultsDemographics and Presenting Clinical FeaturesHistology and IgG4 ImmunostainingImagingSerologyOther Organ InvolvementTreatment

DiscussionReferences