Gut 1992; 33: 1376-1380

Sclerosing cholangitis and biliary tract calculi-primary or secondary?

C S Pokorny, GW McCaughan, N D Gallagher,W S Selby

AbstractThe clinical features of 61 patients withsclerosing cholangitis were reviewed. Thisgroup included 23 patients with biliary tractcalculi, commonly considered as excluding thediagnosis of primary scierosing cholangitis.The aim of this study was to compare these23 patients (group A) with 38 patients withsclerosing cholangitis free of calculi (group B).Both groups had the following features incommon: (i) age at presentation, (ii) incidenceof inflammatory bowel disease, (iii) extent ofradiological disease, (iv) prevalence of HLA-B8 and DR3 haplotype, (v) incidence ofcholangiocarcinoma, and (vi) progression tohepatic transplantation (mean follow up 49.9months). All patients in group A were sympto-matic at diagnosis compared with 23 of the 38patients (61%) in group B. Recurrent ascend-ing cholangitis occurred in 12 patients in groupA (52%) and two patients (5%) in group B. Thesimilarity between the two groups was main-tained when the nine patients in group A whodeveloped calculi after sclerosing cholangitiswas diagnosed were excluded. It is concludedthat choledocholithiasis is part ofthe spectrumof primary sclerosing cholangitis and that it isnot necessary to invoke choledocholithiasis asthe initial lesion of the bile ducts in suchpatients.(Gut 1992; 33: 1376-1380)

A W MorrowGastroenterology andLiver Centre, RoyalPrince Alfred Hospital,Camperdown, NSW,AustraliaC S PokornyGW McCaughanN D GallagherW S SelbyCorrespondence to:Dr C S Pokorny, A W MorrowGastroenterology and LiverCentre, Royal Prince AlfredHospital, Camnperdown, NSW2050, Australia.Accepted for publication11 March 1992

Primary sclerosing cholangitis is a chronicinflammatory disorder which results in fibrosisand obliteration of the intrahepatic and/or extra-hepatic bile ducts leading to the typical radio-logical appearance of stricturing and beading ofthe biliary tree. The aetiology is unknown,although immunological factors have beenimplicated.' Between 50% and 75% of cases are

associated with inflammatory bowel disease,mostly ulcerative colitis. Ultimately biliarycirrhosis results and the median survival hasbeen estimated to be 12 years.2 The diagnosis ofprimary sclerosing cholangitis is based on typicalclinical, histological, and radiological features.By conventional criteria, it is excluded by (a) thepresence of biliary tract calculi, (b) a historyof previous biliary tract surgery, and (c) thepresence of a cholangiocarcinoma.36 Despitethese criteria, patients with biliary tract calculihave been included in several studies of primarysclerosing cholangitis.7 We have also encount-ered a number of patients with the radiologicalfeatures of sclerosing cholangitis but in whomthere were also biliary tract calculi. The aim ofthe present study was to review a group ofpatients in whom sclerosing cholangitis was

present. Twenty three of these patients had, or

subsequently developed, intrahepatic and/orextrahepatic bile duct calculi. The features ofthese patients were compared with those ofpatients without calculi. The results indicate thatboth groups ofpatients can be considered to haveprimary sclerosing cholangitis.

Methods

PATIENTSSixty one patients diagnosed as having sclerosingcholangitis were seen between 1984 and 1991 atthe Gastroenterology and Liver Centre of theRoyal Prince Alfred Hospital, Sydney. Thediagnosis was made in 57 patients by endoscopicretrograde cholangiopancreatography and inthree by percutaneous transhepatic cholangio-graphy. In one patient, the diagnosis of scleros-ing cholangitis became apparent only afterexamination of the native liver after hepatictransplantation. All radiological examinationswere reviewed by at least two gastroenterologistsand two radiologists. The date of diagnosis wasdefined as the point when radiological evidenceof intrahepatic and/or extrahepatic ductstrictures were first demonstrated.The patients were divided into two groups

based on whether or not biliary tract calculi werepresent, either at diagnosis or at any stage duringthe course of their illness. Their clinical featureswere compared, as was the extent of disease, theclinical course, and prognosis. The mean periodof follow up was 49-9 months (range 1-192months).HLA class I and class II alleles were serologic-

ally typed at the Tissue Typing Laboratory,NSW Division, Australian Red Cross SocietyBlood Transfusion Service using the standardNational Institutes ofHealth test for class I and amodified National Institutes of Health test usingimmunomagnetic beads for class II. ` Anti-neutrophil cytoplasmic antibody was measuredin 31 patients by indirect immunofluorescence.The substrate used was an alcohol fixed neutro-phil rich preparation with patient sera screenedat a dilution of 1:20."

Comparisons between the two groups weremade using Fisher's exact test.

ResultsIn 23 patients (group A) biliary tract calculi werepresent either at the time of diagnosis (14patients) (Fig 1) or subsequently developed sometime after the diagnosis of sclerosing cholangitishad been made (nine patients). The calculi inthese latter nine patients were found at intervalsvarying from 18 to 156 months (mean 58.7months) after sclerosing cholangitis had been

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Sclerosing cholangitis and biliary tract calculi - primary or secondary?

diagnosed (Fig 2). In each case, the calculi werefound on repeat endoscopic retrograde cholan-giopancreatography, performed because ofrecurrent ascending cholangitis (six patients) orprogressive liver failure (three patients). Five ofthese nine patients had undergone cholecystec-tomy from three months to 30 years previously,making passage of a stone from the gall bladderan unlikely cause of the biliary tract calculi.Thirty eight patients (group B) did not havebiliary calculi either on diagnosis or during thecourse of their illness. Biochemical analysis ofcalculi was not performed.The clinical features of the two groups as well

as the subgroups in group A - that is, those whohad calculi at the time sclerosing cholangitis wasdiagnosed and those who developed calculi aftersclerosing cholangitis was diagnosed, are shownin Table I. Because of the similarities betweenthe two subgroups in group A, they are hereafterreferred to as one group. There were proportion-ally more women in the group with calculi thanin the group without (16 of 23 in group A, 17 of38 in group B; p=004). The mean age atdiagnosis was similar in both groups. No differ-ence was found in the frequency of associatedinflammatory bowel disease: in group A, 12patients of the 23 (52%) had ulcerative colitis,while in group B, 21 patients (55%) had ulcera-tive colitis and two (5%) had Crohn's disease.HLA typing was performed in 13 patients ingroup A and 14 in group B. HLA-B8 was presentin six of 13 patients in group A (46%) and six of14 (43%) in group B, while HLA-DR3 was foundin six patients tested in group A (46%) and five ingroup B (36%). Antineutrophil cytoplasmic anti-body was measured in 31 patients (12 in group A

and 19 in group B). Of patients in group A, six(50%) had detectable antibody with a perinuclearpattern on immunofluorescent staining com-pared with three of 19 (16%) in group B. Allpatients in group A were symptomatic at initialpresentation (11 patients had right upperquadrant pain, eight had cholangitis, two hadpruritus, and two had symptoms related tohepatic decompensation). This was the casewhether or not calculi were present at the time.In contrast, only 23 of the 38 patients in group B(61%) had clinical manifestations of their disease(cholangitis in eight patients, right upper quad-rant pain in six patients, pruritus in threepatients, and evidence of hepatic decompensa-tion in six patients; p=0 0002). The remainderwere asymptomatic and were being investigatedfor abnormal liver function tests.The radiological extent of bile duct disease was

similar in the two groups (Table II). Of thepatients in group A, the biliary calculi werepresent in the intrahepatic ducts in six patients,in both intrahepatic and extrahepatic ducts in afurther six and in the extrahepatic ducts alone in11 patients. In only three patients were singlestones found. The remaining 20 had multiplebiliary calculi of varying size. Thirteen patientsin group A (57%) and seven in group B (18%) hadassociated cholecystolithiasis, diagnosed eitherbefore or at the time of diagnosis of sclerosingcholangitis (p=0002). This excess was largelyaccounted for by women (10/13 in group A v twoof seven in group B).Twelve patients (52%) in group A had recur-

rent episodes of ascending cholangitis duringfollow up compared with two patients in group B(5%). This difference was highly significant (p=000005).

Nineteen patients in group A underwentvarious therapeutic manoeuvres in an attempt toclear the biliary tree of calculi. Endoscopicsphincterotomy was performed in 16 patientswith successful removal of all calculi in seven. Ina further five, percutaneous removal of residualintrahepatic stones was possible. Five of these 12patients had endoscopic insertion of a biliarystent. A further five underwent percutaneousstent insertion in order to achieve biliary decom-pression. Despite these measures, biliary tractcalculi recurred in all 12 patients after removal.Nine patients in group A (39%) and eight

patients in group B (21%) underwent hepatictransplantation because of progressive disease(p=0 07; NS). Uncontrollable intrahepaticsepsis, the result of recurrent calculi, compli-cated the course of three patients in group A, andwas the indication for hepatic transplantation.Cholangiocarcinoma occurred in three patientsin group A (13%) and five patients in group B(13%).

Six deaths occurred in group A (26%) and 10in group B (26%) during the follow up period.Three patients in group A died after livertransplantation (one week to 19 months posttransplant), two died from postoperative compli-cations after cholecystectomy and one frommassive hepatic necrosis of unknown cause. Ingroup B, four patients died as a result of compli-cations after hepatic transplantation (one week to18 months post transplantation), four others

Figure 1: Endoscopicretrogradecholangiopancreatographyperformed on a patient withulcerative colitis whopresented with right upperquadrant pain, fever, andjaundice. Beading andstricturing ofthe intrahepaticand extrahepatic bile ductsare evident with numerouscalculi being present in theintrahepatic ducts(arrowed).

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Pokorny, McCaughan, Gallagher, Selby

F'gure 2 A Iido's .opi' retrogradte ilI/oIalaoi(p0realau)rrlphSlxh1Zripllbtadingr and.strictldrnzofi t* i/I u,rahlupalic and intraliepaibtic ile duts. B,: repeat endoscopwi retrograde

chov/an?lg-wpanl rfleatoraphv perfoirmed thlrec vcarS later in ithet same putientll afier recurrent

episodes ofi holan ito U/tiple calculi are preseit iZ th/i common hil/c duct and ga/I h/adderwith a long.si rttuiL at 1lwlower end ofit/ commnon hil8 duct.

_~~~~~0 '

died of progressive hepatic failure while awaitingtransplantation and two died from hepatictumours. On histological review, it was felt thatthese two tumours were more consistent withhepatocellular carcinoma than cholangiocar-cinoma. These two patients have not beenincluded in the analysis of cholangiocarcinomasin the two groups.

DiscussionThe findings of this study show that a number ofpatients with sclerosing cholangitis also havebiliary tract calculi. The similarity of the clinicalfeatures, the frequency of associated inflamma-tory bowel disease, age at diagnosis, and radio-logical extent of disease all indicate that thesepatients can be considered to have primarysclerosing cholangitis rather than sclerosingcholangitis secondary to calculi damaging thebiliary tree and resulting in stricture formation.The clinical and radiological features are similarto those reported in other studies of primarysclerosing cholangitis.3 1213 In addition, the pre-valence of HLA-B8 and DR3 was similar in thetwo groups although not as high as reported inprevious studies of primary sclerosing cholan-gitis.'4'5 The prevalence of HLA-B8, however,was similar to that found in an earlier study ofprimary sclerosing cholangitis in an Australianpopulation.'6 Antineutrophil cytoplasmic anti-body, with a perinuclear pattern on immuno-fluorescent staining has been reported to have asensitivity of 65% and specificity of 100% inprimary sclerosing cholangitis.'7 In the presentstudy, such antibody was detectable in six of 12patients (50%) examined in group A and three of19 in group B (16%). Finally, nine patients withtypical primary sclerosing cholangitis subse-quently developed biliary tract stones after amean interval of 58.7 months from diagnosis.The pathogenesis of the calculi found in

patients with primary sclerosing cholangitis maydepend on several factors. Increased bile litho-genicity is suggested by the significantly higherfrequency of cholecystolithiasis in the patientswith bile duct stones (57%), which contrasts withthe reported prevalence of 10-20% in developedcountries.'8-20 This would also account for thesignificantly greater proportion of women ingroup A, as the incidence of gall stones is higherin women than men and in this study the excessof patients with gall bladder calculi was made upby women. Biliary stasis would further predis-pose to the development of stones in the presenceof lithogenic bile. The same is true of recurrentascending cholangitis.2' It could be argued thatin the patients with cholecystolithiasis the calculihad passed from the gall bladder into the bileducts. Cholecystectomy had been performed forsuspected biliary colic three months to 30 yearspreviously, however, in five of nine patients whowent on to develop biliary tract calculi, discount-ing this theory. Further evidence against this isthe finding that the occurrence of choledocho-lithiasis was much higher in patients in group Awho underwent cholecystectomy (16/23: 70%)than is generally seen in association with chole-cystolithiasis.22 Finally, the presence of multipleintrahepatic calculi is not typical of the pattern of

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Sclerosing cholangitis and biliary tract calculi - primary or secondary? 1379

TABLE I Clinicalfeatures of61 patients with sclerosing cholangitis

Group A

Subgroup I Subgroup 2 Total Group B(n= 14) (n=9) (n=23) (n=38)

Sex:Male 6 (43%) 1(11%) 7 (30%) 21 (55%)Female 8 (57%) 8 (89%) 16 (70%)* 17 (45%)

Mean age at diagnosis (yr) 48 3 46-4 47-4 43-3(range) (36-78) (33-60) (33-78) (18-74)

Assoc inflammatory bowel disease:Ulcerative colitis 8 (57%) 4(44%) 12 (52%) 21 (55%)Crohns 0 0 0 2 (5%)

Clinical presentation:Asymptomatic 0 0 ot 15Cholangitis 6 2 8 8Pain 6 5 11 6Pruritus 1 1 2 3Hepatic decompensation 1 1 2 6

*p=0-04tp=0-0002

Group A: Patients with sclerosing cholangitis and biliary tract calculi. Subgroup 1: Patients who hadbiliary tract calculi at the time of diagnosis of sclerosing cholangitis. Subgroup 2: Patients whodeveloped calculi after the diagnosis of sclerosing cholangitis was made.Group B: Patients with sclerosing cholangitis who did not have biliary tract calculi either at diagnosisor during the course of their illness.

biliary calculi seen after cholecystectomy forcholecystolithiasis in patients without primarysclerosing cholangitis.23 24

Patients with primary sclerosing cholangitiscomplicated by biliary tract calculi were morelikely to be symptomatic at presentation thanthose without calculi. They were also more proneto recurrent ascending cholangitis, although theradiological extent of their disease is similar. Itwould seem reasonable to assume that measuresaimed at treating calculi in these patients mayreduce the frequency of infection. Attempts atremoving the stones and improving biliarydrainage, however, led to a reduction in thenumber of episodes of cholangitis in only four of16 patients. Moreover, calculi returned in all 12patients in whom they were removed. Thispresumably reflects the fact that biliary stasisremains with a nidus of infection already presenteven after stones are removed. The recurrence ofcalculi after removal and the lack of substantialreduction in frequency of cholangitis indicatesthat there may be little to be gained in many ofthese patients by multiple manipulations of thebiliary tree to achieve clearance. These pro-cedures carry the risk of introducing furtherinfection into the biliary tree. Although meanfollow up was only 49-9 months, there was noevidence to suggest that removal of stonesresulted in any improvement in prognosis. Infact, there was a trend towards a greater likeli-

hood of requiring hepatic transplantation,although this did not reach statistical signific-ance. Mortality was not different between thetwo groups.

In the long term, the use of ursodeoxycholicacid has been reported to be of benefit in primarysclerosing cholangitis,25 26 but the mechanism bywhich ursodeoxycholic acid exerts a beneficialeffect is unknown. The effect of this agent maybe a result of its ability to reduce the lithogenicityof bile and it may therefore be of particularbenefit in patients with complicating biliarycalculi.

In conclusion, the results of this study indicatethat biliary tract calculi may complicate thecourse of otherwise typical primary sclerosingcholangitis and therefore their presence shouldnot necessarily exclude the diagnosis of primarysclerosing cholangitis. Recurrent ascendingcholangitis is significantly more common in thisgroup of patients and calculi should be suspectedwhen this complication or hepatic decompensa-tion develops in a patient with known primarysclerosing cholangitis. Measures to removebiliary tract calculi can be considered, althoughfrom the present study benefit from such pro-cedures only occurred in four of 16 patients andstones recurred in 12 of 12.

The authors express their thanks to Mrs Jan Austin for typing themanuscript. This paper was presented in part, in abstract form tothe Combined Quadrennial Scientific Meeting of the New ZealandSociety of Gastroenterology and the Gastroenterological Society ofAustralia in September, 1991.

1 Chapman RW. Role of immune factors in the pathogenesis ofprimary sclerosing cholangitis. Semin Liver Dis 1991; 11:1-4.

2 Farrant JM, Hayllar KM, Wilkinson ML, Karani J, PortmannBC, Westaby D, et al. Natural history and prognosticvariables in primary sclerosing cholangitis. Gastroenterology1991; 100: 1710-7.

3 Helzberg JH, Petersen JM, Boyer JL. Improved survival withprimary sclerosing cholangitis. A review of clinico-pathologic features and comparison of symptomatic andasymptomatic patients. Gastroenterology 1987; 92: 1869-75.

4 Wiesner RH, La Russo NF, Ludwig J, Dickson ER. Compari-son of clinicopathological features of primary sclerosingcholangitis and primary biliary cirrhosis. Gastroenterology1985; 88: 108-14.

5 La Russo NF, Wiesner RH, Ludwig J, MacCarty RL.Primary sclerosing cholangitis. N Engl J Med 1984; 310:899-903.

6 PoraykoMK,WiesnerRH, LaRussoNF, LudwigJ,MacCartyRL, Steiner BL, et al. Patients with asymptomatic primarysclerosing cholangitis frequently have progressive disease.Gastroenterology 1990; 98: 1594-602.

7 Johnson GK, Geenen JE, Venu RP, Schmalz MJ, Hogan WJ.Endoscopic treatment of biliary tract strictures in sclerosingcholangitis: a larger series and recommendations for treat-ment. Gastrointest Endosc 1991; 37: 38-43.

8 Martin FM, Rossi RL, Nugent FW, Scholz FJ, Jenkins RL,Lewis WD, et al. Surgical aspects of sclerosing cholangitis:results in 178 patients. Ann Surg 1990; 212: 551-4.

9 Hamilton I, Soutar JS, Bouchier IAD, Cuschieri A. Short-term biliary dilatation and stenting in primary sclerosingcholangitis. J Clin Gastroenterol 1987; 9: 70-5.

10 Vartdal F, Gaudernack G, Funderud S, Bratlie A, Lea T,Ugelstad J, et al. HLA Class I and II typing using cellspositively selected from blood by immunomagnetic isolation- a fast and reliable technique. Tissue Antigens 1986; 28:301-12.

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12 Wiesner RH, La Russo NF. Clinicopathologic features of thesyndrome of primary sclerosing cholangitis. Gastroenterology1980; 79: 20-6.

13 Chapman RWG, Arborgh BAM, Rhodes JM, SummerfieldJA, Dick R, Scheuer PJ, et al. Primary sclerosingcholangitis: a review of its clinical features, cholangio-graphy, and hepatic histology. Gut 1980; 21: 870-7.

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TABLE II Radiological involvement and biliary tract calculi

Group A (n=23)

Subgroup I Subgroup 2 Total Group B(n= 14) (n=9) (n=23) (n=38)

Radiological involvementIHD only 6 (43%) 3 (33%) 9 (39%) 15 (40%)EHD only 0 0 0 2 (5%)IHD and EHD 8 (57%) 6 (67%) 14 (61%) 21 (55%)

Biliary tract calculiCholecystolithiasis 9 (64%) 4 (44%) 13 (57%) 7 (18%)IHD only 3 (21%) 3 (33%) 6EHD only 6 (43%) 5 (56%) 11IHD and EHD 4 (29%) 2 (22%) 6

Calculi (n)Single 2 (14%) 1(11%) 3Multiple 12 (86%) 8 (89%) 20

IHD: intrahepatic ducts; EHD: extrahepatic ducts.

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16 Jeffrey GP, Reed WD, Laurence BH, Shilkin KB. Primarysclerosing cholangitis: clinical and immunopathologicalreview of 21 cases. J Gastroenterol Hepatol 1990; 5: 135-40.

17 Duerr RH, Targan SR, Landers CJ, La Russo NF, LindsayKL, Wiesner RH, et al. Neutrophil cytoplasmic antibodies:a link between primary sclerosing cholangitis and ulcerativecolitis. Gastroenterology 1991; 100: 1385-91.

18 Friedman GD, Kannel WB, Dawber TR. The epidemiology ofgallstone disease observations in the Framingham study.J Chronic Dis 1966; 19: 273-92.

19 Barker DJP, Gardner MJ, Power C, Hutt MSR. Prevalence ofgallstone at necropsy in nine British towns: a collaborativestudy. BMJ 1979; 4: 1389-92.

20 Bainton D, Davies GR, Evans KT, Gravelle IH. Gallbladderdisease: prevalence in a South Wales industrial town. N EnglJ7Med 1976; 294: 1147-9.

21 Cetta FM. Bile infection documented as the initial event in thepathogenesis of brown pigment biliary stones. Hepatology1986; 6:482-9.

22 Edholm P, Jonsson G. Bile duct stones related to age and ductwidth. Acta Chir Scand 1962; 124: 75-9.

23 Girard RM, Legros G. Retained and recurrent bile duct stones- surgical or non surgical removed? Ann Surg 1981; 193:150-4.

24 Allen B, Shapiro HA, Way LW. Management of recurrent andresidual common duct stones. Am J Surg 1981; 142: 41-7.

25 Chazouilleres 0, Poupon R, Capron JP, Metman EH,Dhumeax D, Amouretti M, et al. Ursodeoxycholic acid forprimary sclerosing cholangitis. i Hepatol 1990; 11: 120-3.

26 Senior JR, O'Brien CB, Wiesner RH. Ursodial therapy ofprimary sclerosing cholangitis reduces the reportedmortality risk. Gastroenterology 1990; 98: A630.

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