Gut 1996; 38: 610-615

Natural history and prognostic factors in 305Swedish patients with primary sclerosingcholangitis

U Broome, R Olsson, L Loof, G Bodemar, R Hultcrantz, A Danielsson, H Prytz,H Sandberg-Gertzen, S Wallerstedt, G Lindberg

Department ofMedicine, HuddingeHospital, Stockholm,SwedenU BroomeG Lindberg

Department ofMedicine, KarolinskaHospital, Stockholm,SwedenR Hultcrantz

Department ofMedicine, SahlgrenskaHospital, G6teborg,SwedenR Olsson

Department ofMedicine, AcademicHospital, Uppsala,SwedenL L66f

University Hospital,Linkoping, SwedenG Bodemar

University Hospital,UmeA, SwedenA Danielsson

University Hospital,Lund, SwedenH Prytz

Regional Hospital,Orebro, SwedenH Sandberg-Gertzen

Osta Hospital,G6teborg, SwedenS Wallerstedt

Correspondence to:Dr U Broome, Departmentof Gastroenterology andHepatology, K63, HuddingeUniversity Hospital, 141 86Huddinge, Sweden.

Accepted for publication9 October 1995

AbstractBackground/Aims-The course ofprimary sclerosing cholangitis (PSC) ishighly variable and unpredictable. Thisstudy describes the natural history andoutcome of PSC. These data were used toconstruct a prognostic model for patientswith PSC.Methods-A total of 305 Swedish patientswith PSC were studied. The medianfollow up time was 63 (1-194) months andall patients could be traced for follow up.Some 79 patients died or had a liver trans-plant. The prognostic significance ofclinical, biochemical, and histologicalfindings at the time of diagnosis wereevaluated using multivariate analysis.Results-The estimated median survivalfrom time of diagnosis to death or livertransplantation was 12 years. Cholangio-carcinoma was found in 24 (8%) of thepatients and 134 (44%) ofthe patients wereasymptomatic at the time of diagnosis.The estimated survival rate was signifi-cantly higher in the asymptomatic group(p<0.001). However, 29 (22%) of theasymptomatic patients became sympto-matic during the study period. It wasfound that age, serum bilirubin concen-tration, and histological stage at the timeof diagnosis were independent predictorsof a bad prognosis. These variables wereused to construct a prognostic model.Conclusions-This prognostic modeldeveloped from a large homogeneouspopulation of PSC patients should be ofvalue for the timing oftransplantation andpatient counselling in PSC.(Gut 1996; 38: 610-615)

Keywords: ulcerative colitis, prognostic models, livertransplantation, cholangiocarcinoma.

Primary sclerosing cholangitis (PSC) is achronic biliary destructive disease of unknownaetiology. The natural history is highly vari-able, some patients being asymptomatic foryears, others rapidly progressing to prematuredeath resulting from liver failure or cholangio-carcinoma.' 2 There is no effective treatment.With optimal timing for liver transplantation,however, excellent results have beenachieved.3-6 It is therefore of importance todevelop prognostic models that can be usedto classify patients for therapeutic trials, fortiming of liver transplantation, as well as in the

counselling of patients. The results of studiesfrom large referral centres are conflictingbecause of differences in sample size, referralpatterns, definition of start and end point ofthe disease but may also be because of ethnicdifferences.7-'0PSC is a heterogeneous disease and there-

fore it is important to describe the natural his-tory and factors of prognostic importance in ahomogeneous population.The aim of this retrospective study was

threefold: (a) to describe the natural historyand outcome for 305 PSC patients of Swedishdescent; (b) to evaluate the prognostic signifi-cance of clinical, biochemical, and histologicalfindings at the time of diagnosis using multi-variate analysis; and (c) to construct a prog-nostic model.

Methods

PatientsThree hundred and five patients of Swedishdescent with PSC were included in the study.The patients were treated by doctors who aremembers of the Swedish Internal MedicineLiver Club (SILK) at nine hospitals through-out Sweden. The hospitals all serve both asprimary and referral hospitals. Liver transplan-tation in Sweden is only performed atHuddinge and Sahlgrenska hospitals, bothcentres participating in the study. All patientsthat have been personally treated by therespective investigators were included in thestudy. The data were collected and verifiedusing a questionnaire agreed upon in allcentres by the investigators.

DiagnosisThe diagnosis of PSC was based on typicalcholangiographic findings in all patients incombination with clinical, histological, andlaboratory data." 12 The cholangiographictechniques used were either endoscopic retro-grade (n= 266), percutaneous transhepatic(n=9) or operative (n=30). The confluence ofthe bile ducts at the hilum was used to distin-guish between the extra and intrahepaticbiliary system.

Clinical, histological, and biochemical variablesSymptoms and signs including jaundice, rightupper quadrant pain, pruritus, fever, ascites,and variceal haemorrhage were recorded at the

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time of diagnosis and at follow up. Patientswere classified according to the presence ofsymptoms at diagnosis as asymptomatic orsymptomatic. Histological staging was basedon previously established criteria.13 For theregression analysis, all biopsy specimens wererestaged according to the Mayo Clinic modelusing value 1 for stage I and II, 2 for stage III,and 4 for stage IV.8 The diagnosis of cholan-giocarcinoma was based on histological exami-nation.

Biochemical analyses including total bili-rubin, albumin, alkaline phosphatase, aspar-tate and alanine aminotransferases wereperformed using standardised techniques atthe local hospital. Evidence for inflammatorybowel disease (IBD) was investigated by sig-moidoscopy, colonoscopy or barium enema inall patients. A diagnosis of ulcerative colitis(UC) and Crohn's disease (CD) was based onaccepted criteria.'4 15

Statistical methodsThe starting point of the disease was defined asthe time of typical findings at cholangiography.The time of onset of persistently abnormalliver function tests was also recorded. Endpoint was either death from liver disease orliver transplantation. The patients werestudied until the end of 1992. The x2 test orStudent's t test for continuous variables wereused to compare differences between sympto-matic and asymptomatic patients, referred andnon-referred patients, and patients with andwithout cholangiocarcinoma. Kaplan-Meieranalysis was used to calculate actuarial sur-vival. The prognostic significance of differentvariables present at the time of diagnosis wasanalysed using the Cox proportional hazardmodel. A prognostic model was constructedwith factors found to be of independent prog-nostic value.

Results

General characteristicsAmong the 305 patients, 195 were males(64%) and 110 females; 146 (48%) patientscame from the primary catchment area of eachhospital, whereas 159 patients had beenreferred from hospitals in other areas of thecountry. The median age at the time of diag-nosis was 39 (range 5-80) years. The mediandelay from the first presentation ofbiochemicalsigns or symptoms compatible with PSC untilthe time of diagnosis was 52 (range 0-451)months. Most, 203 (67%), of the patients hadboth intra and extrahepatic PSC, whereas 83

TABLE I Symptoms presented at time ofPSC diagnosis

Number (%)

Symptomatic patients 171 (56)Abdominal pain 112 (37)Jaundice 91 (30)Pruritus 90 (30)Fever 52 (17)Ascites 10 (4)Variceal haemorrhage 10 (4)

(27%) had intrahepatic involvement only, and19 (6%) had only extrahepatic PSC. In 249(81%) patients, PSC was associated with IBD:220 (72%) had UC, 20 (7%) had CD, andnine (2%) had unspecific colitis. Among thepatients with CD, 12 had involvement of thecolon only and in eight patients the disease wasfound in both the small bowel and the colon.Seventy four patients (30%) with IBD had pre-viously undergone proctocolectomy. Patientswithout IBD were significantly older at thetime of PSC diagnosis than the patients withIBD (44.8 v 38.5 years, p<0002). Sex,number of patients with intra/extrahepatic dis-tribution of disease, observation time, time todiagnosis, and development of cholangiocarci-noma did not differ between patients with andwithout an associated IBD.

SymptomsAt the time of diagnosis, 171 (56%) patientshad one or more of the symptoms listed inTable 1. The most common symptom waspain localised to the right upper quadrant,described by 112 (37%) patients. During amedian observation period of 69 months, 29(22%) of the asymptomatic became sympto-matic.

Laboratory and histologicalfindings at time ofdiagnosisThe bilirubin concentration was normal in 179(59%) patients at the time of diagnosis and themean figure for the whole group was 39,umolll. Alkaline phosphatase activity wasnormal in 26 (8.5%) patients and the averagefor the group was 18 ,ukat/l (Table II). Liverbiopsy was carried out in 254 patients at thetime of diagnosis and stage I or II was presentin 118 (46%), stage III in 73 (28%), and livercirrhosis (stage IV) in 67 (26%).

Asymptomatic and symptomatic patientsTable II shows data from patients with andwithout symptoms at the time of diagnosis.Significantly more women than men werefound in the symptomatic group and patientswith symptoms were older than asymptomaticones at the time of diagnosis. The prevalenceof an associated IBD differed significantlybetween the two groups and almost all asymp-tomatic patients had an IBD, probablyreflecting the fact that most IBD patients inSweden are regularly screened with liver func-tion tests. Furthermore, PSC has activelybeen looked for in UC.16 There was no differ-ence between the groups in time from firstpresentation of abnormal liver function testsuntil the diagnosis of PSC was establishedwith a cholangiogram. The observation timefor the asymptomatic group was slightlylonger than for the symptomatic group.Symptomatic patients had significantly higherserum values of bilirubin, aspartate amino-transferase and alkaline phosphatase, andlower values of albumin than those withoutsymptoms.

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Broome, Olsson, L66f, Bodemar, Hultcrantz, Danielsson, Prytz, Sandberg-Gertzen, Wallerstedt, Lindberg

TABLE II Clinical and biochemicalfeatures in 305 PSC patients who were asymptomatic and symptomatic respectively atthe time of diagnosis

Patients Patients p Valuesymptomatic asymptomatic (comparisonat time of at time of symptomatic and

All patients diagnosis diagnosis asymptomatic(n=305) (n= 171) (n= 134) patients)

Age at diagnosis (y) (mean (SD)) 39 (14) 41 (13-3) 37 (14-6) p<0 05Male (%) 195 (64) 98 (57) 97 (72) p<0001IBD (%) 249 (81) 126 (74) 123 (92) p<0 001Extra hepatic involvement of the biliary tree (/) 222 (72) 138 (80) 84 (63) p<0-001Follow up (months) (SD) 63 (47) 59 (48) 69 (46) p<0 05Death or transplantation (O/o) 79 (26) 62 (36) 17 (13) p<0-001Cirrhosis (%) 67 (22) 50 (29) 17 (13) p<001Bilirubin (<21 ,umolll) (mean (SEM)) 39 (3 55) 57 (5.86) 16 (1-12) p<0 001Alkaline phosphatase (<4.2 ,ukat/l) (mean (SEM)) 13 (0.78) 20-7 (1.19) 14 (0.8) p<0 001Aspartate aminotransferase (<0-80 gjkat/l) (mean (SEM)) 2-1 (0.15) 2-5 (0.24) 1-7 (0-15) p<0-01Albumin (35-46 g/l) (mean (SEM)) 38 (0.47) 37 (0.60) 40 (0.72) p<0 01

Referred and non-referred patients at the time ofPSC diagnosisClinical and epidemiological data concerningage, sex, follow up time, presence of IBD, andsymptoms did not differ between referred andnon-referred patients.

PSC and cholangiocarcinomaThere was no significant difference between thepatients who developed cholangiocarcinomaand those who did not with respect to sex, age atpresentation, extra or intrahepatic involvementofthe biliary disease, or associated IBD. Nine of24 patients who developed cholangiocarcinomadid so within one year after the PSC diagnosis.As the presenting features of these nine patientscould have been caused by the cholangiocarci-noma, these patients were excluded from thecomparisons regarding symptoms and bio-chemical tests. The only symptom that occurredsignificantly more often at time of diagnosis inthe cholangiocarcinoma group than in thetumour free group was abdominal pain (59% v35%) (p<001). Serum bilirubin at diagnosiswas higher in the patients who later developedcholangiocarcinoma (82-9 v 35.1 gmol/l)(p<0 005).

Follow upAt follow up in 1992, information was avail-able for all 305 patients. The median follow up

0 24 48 72 96 120 144 168 192 216Time (months)

Figure 1: Kaplan-Meier estimated survival curves ofsymptomatic and asymptomatic PSCpatients (p<0001).

time to death, transplantation, or closing of thestudy was 63 (1-211) months. At follow up,226 (74%) patients were alive and had not hada transplant 66 (range 1-211) months afterdiagnosis, 45 (14%) had died after 51 (range1-154) months, and 34 (11%) had had livertransplantation 62 (range 1-137) months afterdiagnosis. Twenty nine (64%) of all deathswere caused by liver failure. Furthermore, fourpatients died in massive variceal haemorrhage.Cholangiocarcinoma was the main cause ofdeath in 12 patients; when the patients whohad had a transplant were included cholangio-carcinoma was diagnosed in 24 (8%) patients,32.5 (1-154) months after the diagnosis ofPSC. There were no differences in time fromthe first findings consistent with PSC until thediagnosis was confirmed with a cholangiogrambetween patients developing and not develop-ing cholangiocarcinoma. Thus, among the 79patients who died or underwent liver trans-plantation, cholangiocarcinoma was diagnosedin 24 (30%). In the whole group of patientswith a follow up >five years 16% developedcholangiocarcinoma. Only 69% of all patientswho died had a necropsy, but all liversremoved at liver transplantation were, how-ever, carefully examined for cholangiocarci-noma. Among the 65 patients who died andhad a necropsy or had a liver transplant 19(29%) had cholangiocarcinoma.

Survival analysisThe estimated median survival time for thewhole PSC group was 144 months. Kaplan-Meier survival curves showed a significantlybetter median survival for the asymptomaticpatients than for those who were symptomaticat the time of diagnosis (112 months)(p<0.001) (Fig 1).

Univariate and multivariate analysisThe prognostic value of 19 variables presentat the time of diagnosis were studied usingunivariate analysis (Table III). Variablesfound to be of prognostic significance by uni-variate analysis were entered into a multivari-ate analysis. Symptoms were also tested incombination with each other. Using backwardelimination as well as forward selection, fourvariables available at diagnosis of PSC werefound to be of independent prognostic value:

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TABLE III Prognostic significance of variables at time ofPSC diagnosis entered intounivariate Cox regression procedure

Patients Relative Confidence pVariable (n) risk (eP) intervals Value

DemographicAge 305 1-03 1-01 to 1-04 <0-001Sex 305 1-19 0 75 to 1.80 NS

ClinicalAssociated IBD 305 0-98 0.54 to 1-66 NSExtrahepatic PSC 304 3-38 1-62 to 7.03 <0 001Abdominal pain 303 1-65 106 to 258 <0 05Fever 302 1-51 0-88 to 2 57 <0 05Jaundice 304 4.09 2-55 to 6-54 <0-001Pruritus 301 2-26 1-42 to 3-60 <0-001Ascites 302 6-38 2-88 to 14-3 <0-001Variceal bleeding 303 6-23 2-96 to 13-10 <0-001

BiochemicalBilirubin (log2 value) 297 1-64 1-42 to 1-89 <0-001Aspartate aminotransferase 292 1-09 1-03 to 1-15 <0-01AST (log2value) 292 1-43 1-20 to 1-69 <0-001Alanine aminotransferase 291 1-03 1-00 to 1-03 <0 05ALT (log2 value) 291 1-11 0.93 to 1-31 NSAlkaline phosphatase 299 1-02 1-01 to 1-03 <0-01ALP (log2 value) 299 1-43 1-17 to 1-76 <0-001Albumin 217 0.94 0-96 to 1-04 <0-001

Histological stage* 257 1-44 1-05 to 1-54 <0-001

*For stages 1 and 2, use 1; for stage 3, use 2; for stage 4, use 4.

TABLE IV Prognostic modelfor Swedish patients withPSC without a history or variceal haemorrhage

Regression Standard Confidence pVariable coefficient error intervals Value

Histology* 0-24 0-096 1-05 to 1-54 <0-01Age 0.03 0-010 1-01 to 1-04 <0 05Log2bilirubin 0 49 0-080 1-42to 1-89 <0-001

*For stages 1 and 2 use 1; for stage 3 use 2; for stage 4 use 4.

age, histological stage, serum bilirubin con-

centration, and a history of variceal haemor-rhage. As a history of variceal haemorrhage(occurring in only 4% of all patients) in itselfstrongly indicated poor survival (median 28months), patients who had bled were

excluded from the construction sample for theprognostic index (Table IV).

Prognostic indexA prognostic index (PI) was constructed fromthe three variables identified with multivariateanalysis using the regression coefficients pre-sented in Table IV, resulting in the equation:PI=0 24Xhistology stage+0.03Xage+0.49Xlog2 bilirubin. Histology stage I+II=1, stageIII=2, and IV=4. Age is age in years and log2

bilirubin is logarithm 2 of serum bilirubin con-

centration (,umol/l).The PI for a hypothetical example of a 30

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Prognostic indexFigure 2: A graph of estimated median survival plotted against prognostic index.

year old man with stage 1 on liver biopsy andserum bilirubin concentration of 22 gumol/l iscalculated:PI=0.24X 1 +003X30+0.49Xlog2=3.33.

In Fig 2, a graph of estimated median sur-vival is plotted against the prognostic index.

DiscussionThis study describes the natural history of 305PSC patients from Sweden, a country withapproximately eight million inhabitants. Incomparison 174 PSC patients from the UnitedStates and 126 from England, countries withconsiderably greater numbers of people havebeen presented.8 9 The prevalence of PSC inSwedish patients with UC has previously beendescribed.'6 If the prevalence of UC is around150/100 000 inhabitants and approximately50/o of all UC patients have PSC, this studycomprising 305 PSC patients representsapproximately 40-50°/O of all PSC patients inSweden.Our material differs from that of the

American and English studies in its high per-centage of patients from the primary catch-ment area, probably giving a morerepresentative reflection of the natural historyof PSC.The general characteristics of the patients in

this study resemble those found in Norway,England, and the United States with a malepredominance, a mean onset of disease around40 years of age with a very large span (5-80years) with respect to the age at diagnosis, anda close association with IBD.8 9 17 It can beargued that the inclusion of unspecified colitis(nine patients, 2%) into the IBD group isunjustified, but during the observation timesome of the patients with unspecified colitiswere reclassified as suffering from UC or CD.Thus, the prevalence of IBD is 8 1% in thisstudy whereas results of studies from theUnited States show (71%),8 England (71%),9and Norway (100%).17 The Norwegian studyis the only one in which all patients underwentcolonoscopy and patients with unspecifiedcolitis were included.Twenty seven per cent of the patients in this

study had intrahepatic PSC only. This is inagreement with a study from Yale,7 but in con-trast with studies from both the Mayo Clinic8and King's College Hospital9 showing a con-siderably lower percentage of patients withintrahepatic PSC only. Although real differ-ences may exist between the various PSC pop-ulations, there may also be differences inanatomical definition of the extra and intra-hepatic ductal system.The important differences between the PSC

populations in the various studies seem, how-ever, not to be found in the general character-istics of the patients but rather in the severity ofthe disease. In four studies describing thenatural history ofPSC the number of asympto-matic patients ranged from 1 5-25%,7-10whereas a figure of 44% was noted in ourstudy. Differences concerning definition ofsymptoms do exist between the previousstudies. Fatigue was defined as a symptom in

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614 Broome, Olsson, Loof, Bodemar, Hultcrantz, Danielsson, Piytz, Sandberg-Gertzen, Wallerstedt, Lindberg

some studies7 9 but not in this one because ofproblems in defining this subjective symptomretrospectively. In the study by Farrant et al,9fatigue was the most common symptom,reported by 65% of the patients.

This study comprises the largest number ofasymptomatic PSC patients described; thismay in part be explained by the high rate ofpatients with PSC restricted to the intrahepaticbiliary tree, as 60% of these patients wereasymptomatic. Significant differences betweenasymptomatic and symptomatic patients werefound in survival, biochemical, and histologicalparameters, but also with respect to age at pre-sentation and sex. Survival rate for the asymp-tomatic groups was 700/0 at 16 years afterdiagnosis (Fig 1). This benign course for theasymptomatic group is in agreement with thestudy by Heltzberg.7 However, 22% of allasymptomatic patients developed symptomsduring a median observation time of 69months, and approximately 13% of the asymp-tomatic patients died or had liver transplants.This emphasises the progressive nature of PSCeven in the asymptomatic group.

Despite the pronounced differences in sur-vival between symptomatic and asymptomaticpatients, the only symptom that was found tobe of independent prognostic significanceusing multivariate analysis was varicealhaemorrhage, which occurred in only 4%/o of allpatients.

Differences in both definition of start andend point of the disease may influence actuar-ial survival time in different studies. In thestudy from King's College Hospital, reportingan estimated median survival time of 12 years,the start point of disease was defined as theonset of abnormal liver function test or signscompatible with PSC.9 In our study an averageof 52.5 months elapsed from onset of abnor-mal liver biochemistry until the diagnosis wasconfirmed with a cholangiogram. The mediansurvival time would probably therefore belonger if we had used King's definition of startpoint. As 81% of our patients had an associ-ated IBD and activity of the colitis, and astreatment with drugs for the bowel disease andparenteral nutrition can cause abnormal liverfunction tests, we defined the start point ofdisease as the time of cholangiographic diag-nosis.18 The Mayo Clinic study reporting anestimated median survival time of 11.9 years,defined start point as date of referral to theClinic.8 10 As 59% of all patients were jaun-diced at time of referral to the Mayo Cliniccompared with 30°/0 in this study, the diseaseprocess was probably more advanced at inclu-sion in the Mayo study.End points in the various prognostic studies

comprise both date for liver related deaths andliver transplantation or include only liverrelated deaths. The addition of liver transplan-tation as an end point in this study was chosenbecause over 30%/ of Swedish PSC patientssubmitted for liver transplantation died whilewaiting for a liver transplant.19The reliability of a description of the natural

history of a disease depends upon the size of apatient cohort in relation to the size of the

background population. The importance ofsample size may well be illustrated in the multi-centre study presented by Dickson et al.'0 Theprognostic significance of different variableswas calculated for 426 PSC patients. For mostof these patients, prognostic factors had beencalculated in smaller separate studies. Thefactors found to be of prognostic importance inthe large multicentre study differed from thoseidentified in the smaller studies. The multi-centre study showed that serum bilirubin con-centration, histological stage at liver biopsy,age and, the presence of splenomegaly wereindependent predictors ofhigh risk of dying. Inour study with a large number of patients, bili-rubin concentration, histological stage, and agewere all factors found to be of prognostic sig-nificance.The presence of splenomegaly was not eval-

uated in this study. The most accurate way todetermine enlargement of the spleen is withisotopic scan, computed tomography or ultra-sound. Although, one of these investigationshad usually been done in our patients, theinvestigation had usually not been done at thesame time as the time of diagnosis or the size ofthe spleen had not been described.No investigated factors in this study could

identify those PSC patients who would laterdevelop cholangiocarcinoma. The detectionrate of cholangiocarcinoma in 8% of thepatients is comparable with that of otherstudies. It is probably an underestimation,however, as 3 1O% of all patients who died didnot have a necropsy. Furthermore, cholangio-carcinoma is often difficult to diagnose inliving patients with PSC.8 9 1820 Perhaps theintroduction oftime dependent variables into adynamic prognostic model could be of value inthe identification of PSC patients at risk formalignant transformation of the bile ducts.2'We conclude that although genetic differ-

ences exist concerning HLA class II antigenassociation between Swedish, American, andEnglish patients,22-26 the natural history andfactors of prognostic importance seem more tobe related to selection bias and sample sizethan to real differences between PSC patientsfrom different countries.The authors acknowledge the financial support by G D SearleLtd.

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3 Marsh J Jr, Iwatsuki S, Makowka L, Esquivel CO, GordonRD, Todo S, et al. Orthotopic liver transplantation forprimary sclerosing cholangitis. Ann Surg 1988; 207:212-5.

4 Krom RAF, Wiesner RH, Rettke SR, Ludwig J, SouthornPA, Hermans PE, et al. The first 100 liver transplantationsat the Mayo Clinic. Proc Mayo Clin 1989; 64: 89-94.

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6 Wiesner RH, Porayko MK, Dickson ER, Gores GJ, LaRusso NF, Hay JE, et al. Selection and timing of livertransplantation in primary biliary cirrhosis and primarysclerosing cholangitis. Hepatology 1992; 16: 1290-9.

7 Heltzberg JH, Petersen JM, Boyer JL. Improved survivalwith primary sclerosing cholangitis. A review of clinico-pathologic features and comparison of symptomatic andasymptomatic patients. Gastroenterology 1987; 92:1869-75.

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