Prevalence of Primary Sclerosing Cholangitis in Patients With Ulcerative Colitis

GASTROENTEROLOGY 1991;100:1319-1323

LIVER, PANCREAS, AND BILIARY TRACT

Prevalence of Primary Sclerosing Cholangitis in Patients With Ulcerative Colitis ROLF OLSSON, AKE DANIELS SON, GUNNAR JARNEROT, EVA LINDSTROM, LARS LOOF, PETER ROLNY, BENGT-OLOF RYDEN, CURT TYSK, and SVEN WALLERSTEDT Medical Clinics at Sahlgrenska Sjukhuset and Ostra Sjukhuset, Goteborg; Regionsjukhuset, Umea; Regionsjukhuset, Orebro; Akademiska Sjukhuset, Uppsala; Regionsjukhuset, Linkoping; and the Surgical Clinic, Regionsjukhuset, Linkoping, Sweden

All patients ~ 16 years old with a diagnosis of ulcerative colitis were identified in five well-defined catchment areas, representing 12.7% ofthe Swedish population. Exactly 1500 patients were retrieved, giving a point prevalence of 170/105 inhabitants. It was possible to obtain liver function test results < 2 years old in 94% of the patients and to obtain endoscopic retrograde cholangiographic results in 65 of the 72 patients with abnormal serum alkaline phosphatase values. Primary sclerosing cholangitis was diagnosed in 55 of the patients (3.7%). The prevalence of the disease was 5.5% in patients with substantial colitis and 0.5% in patients with distal colitis. There was a marked male predominance in cholangitis patients compared with colitis patients without cholangitis. Ninety-five percent of the patients with cholangitis had substantial colitis, which was more than the 62% of patients without cholangitis who had colitis. Female patients with cholangitis were older than male patients at the time of diagnosis of both cholangitis and colitis, which contrasted to the equal age at diagnosis of colitis in male and female patients without cholangitis.

S

ince the introduction of modern techniques for cholangiography, primary sclerosing cholangitis (PSC), previously considered a rare disease, has become a common explanation for abnormalities in liver laboratory test results in patients with ulcerative colitis (UC). Different studies have reported prevalences of PSC in UC of between 1% and 5.6% (1-4). However, these studies comprised only those patients with UC who were registered at specialized clinics during a certain period. This may have created a referral bias toward patients with more severe or complicated disease (e.g., with liver abnormalities).

Therefore, these studies may not reflect the true prevalence of PSC in UC. We report a study describing the point prevalence of PSC in all patients with UC living in five welldefined catchment areas in Sweden, based on a cholangiographic study of all patients with abnormally high serum alkaline phosphatase (ALP) levels. Patients and Methods This was an epidemiological study performed by members ofthe Swedish Internal Medicine Liver Club. The study population lived within strictly defined catchment areas of the hospitals in Dmea, Dppsala, Linkoping, Orebro, and Goteborg. To identify all patients who had not undergone surgery as well as colectomized patients with a definite diagnosis of DC residing within these areas, the last 20-25 years' registers regarding inpatients and outpatients were scrutinized as well as stoma nurses' registers and endoscopy registers. Furthermore, inquiries were sent to the primary health care and private practitioners within each area about patients with definite or possible DC treated there. The diagnosis of DC was based on the clinical history with more than 3 weeks' symptoms, negative fecal cultures, and a sigmoidoscopy report compatible with DC. Furthermore, rectal biopsies had to show changes diagnostic of or compatible with DC. Patients who did not fulfill these criteria were excluded. The extent of disease was based on barium enema and/or colonoscopy. Only definite radiological and/or macroscopic evidence of active or inactive colitis was used in this

Abbreviations used in this paper: ALP, alkaline phosphatase; ERC, endoscopic retrograde cholangiography; LIT, liver function test; PSC, primary sclerosing cholangitis. © 1991 by the American Gastroenterological Association 0016-5085/91/$3.00

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OLSSON ET AL.

respect. The greatest extension observed with any of the two methods was used for this evaluation. Because of the diagnostic difficulties regarding whether proctitis was ulcerative proctitis or not, patients with proctitis were excluded. Proctitis was defined as inflammation in the rectum not reaching beyond 15 cm from the anus and having a definite demarcation between abnormal and normal mucosa. The remaining patients were defined as having distal UC if the inflammation did not reach beyond the splenic flexure or substantial colitis if the inflammation passed the splenic flexure. All patients without already established PSC were asked to undergo the liver function tests (LFT) between January 1, 1987, and December 31,1988. Patients with elevated serum ALP values of> 5 ILkatlL that did not occur during an acute attack ofUC or postoperatively had LFTs repeated 2 months later. If the ALP value was still abnormal, patients were offered the chance to have an endoscopic retrograde cholangiography (ERG) performed. The cholangiograms were interpreted separately and blindly at the end of the study by two independent examiners (E.L. and P.R.). To avoid bias, the radiological material also contained ERCs from other patients not included in the study. Concordant judgment was considered necessary for acceptance of the diagnosis. The duration of colitis was calculated as number of years from the time of diagnosis until proctocolectomy in patients who had undergone surgery and until December 1988 in all other patients. For each patient, a classification was made concerning (a) appearance of first LFT abnormality: increase of ALP level only, aspartate aminotransferase (AST) level only, alanine aminotransferase (AL T) level only, or combined ALP and AST levels and/or ALT levels with or without increase of bilirubin level; (b) extent of the bile duct involvement on ERC: intrahepatic, extrahepatic, or total; and (c) general clinical judgment of the course of the PSC in patients with a follow-up of at least 1 year, taking into

account appearance of symptoms and course of the LFTs: progressive or nonprogressive. Differences between means were tested with Student's t test (two-tailed), differences in frequencies with the X2 test, and correlations with multiple regression analysis. The study was approved by the Committees for Medical Ethics in Umea, Uppsala, Link6ping, brebro, and G6teborg.

Results

Ulcerative Colitis On December 31, 1988, the five study areas had a total population of 1,076,569 inhabitants. Of these, 878,317 were aged ~ 16 years (81.6%). On the same date the total Swedish population was 8,458,B88, with 80.8% ~ 16 years of age so that the study covered 12.7% of the Swedish population. Table 1 gives details in this respect regarding the five study areas. Within these areas, exactly 1500 patients with UC, excluding those with proctitis, were residing, which gives a point prevalence of 171 per 105 inhabitants [95% confidence interval (CI), 145-197]. As shown in Table 1, the prevalence varied considerably from 148 to 244 per 105 inhabitants, with Orebro outside the confidence interval. The extent of disease also varied between the areas; the frequency of distal UC was considerably higher in the Orebro region (53.8%) than in the other four regions (26.9%-40.3%). However, the prevalence of substantial colitis was fairly similar within all five areas, varying between 102 and 121 per 10 5 inhabitants; for all regions combined, the prevalence was 108 per 10 5 inhabitants (95% CI, 83-123). Differences

Table 1. Prevalence and Clinical Features of Ulcerative Colitis in the Different Areas of the Study Giiteborg Population Population aged ~ 16 yr No. of patients with UC Prevalence of UC per 100,000 aged ~ 16 yr Prevalence of substantial colitis per 100,000 aged ~ 16 yr Male-female ratio Age at diagnosis (yr)" Follow-up (yr)" Extent (% afpatients) Substantial Distal Clinical course (% of patients) Continuous Remittent Single attack Rate of colectomy in patients with single attack Colectomy (% of all UC patients) NOTE. Colectomy aMean ± SD.

=

subtotal

Uppsala

Orebro

Linkiiping

Umea

382,344 324,455 486

260,214 205,282 303

165,776 134,104 327

146,163 118,039 224

122,072 96,437 160

150

148

244

190

166

103 0.99 31 ± 15 15 ± 11

102 1.15 31 ± 15 17 ± 11

114 1.38 31 ± 15 12 ± 9

121 1.13 32 ± 16 10 ± 8

+ total colectomy.

113 1.3 35 ± 15 13 ± 7

68.5 31.5

69.3 30.7

46.2 53.8

59.7 40.3

73.2 26.9

8.6 81.1 10.3

7.5 84.4 8.1

3.4 83.5 13.1

7.2 79.2 13.6

10.0 83.1 6.9

17.6 37.9

12.5 30.4

39.5 30.3

26.7 28.1

18.2 26.9

May 1991

PRIMARY SCLEROSING CHOLANGITIS IN UC

were also found regarding the clinical course. For instance, the percentage of single-attack patients varied between 6.9% and 13.6%. The mean age at diagnosis of UC of about 32 years was fairly constant in all areas, as was a follow-up period of about 13 years. Liver Disease

Of the 1500 patients with UC, 91 (6.1%) had to be excluded because of missing data. Of the remaining 1409 patients, 139 (10%) showed increased liver enzyme levels in serum: ALP only in 15 patients, AST or AL T only in 67 patients, and combined ALP and AST/ALT in 57 patients. Endoscopic retrograde cholangiography was performed in 65 of the 72 patients with increased ALP (7 patients refused the investigation) and showed the characteristic features of PSC in 53 patients. The diagnosis had been established before the screening in 32 patients and was made during the screening period in 21 patients. Endoscopic retrograde cholangiography had previously shown PSC in two additional patients with normal ALP levels, in whom the investigation was performed on other indications. Thus, the overall prevalence of PSC was 55 per 1500 patients with UC (3.7%; 95% CI, 2.7%4.7%; range, 2.5%-5.6% in different areas). There was full concordance between the two radiological examiners in every case as to whether PSC was present or not. With few exceptions, the PSC patients had substantial colitis (Table 2), giving a prevalence of 5.7% (95% CI, 4.2%-7.2%; range, 3.4%-8.1% in different areas) in this extension of the disease, with a significantly higher male-to-female ratio than in UC patients withoutPSC. The age at diagnosis of PSC varied within wide limits (Table 3), but female patients with PSC were significantly older than male patients at the time of diagnosis of both PSC (50 vs. 35 years; P = 0.0003)

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(Figure 1) and UC (34 vs. 25 years; P = 0.035). In contrast, when the patients with PSC were excluded from the total population, there was no difference between female and male patients in age at the time of diagnosis ofUC (32 ± 15 vs. 33 ± 16 years). Most patients with PSC had involvement of both intrahepatic and extrahepatic bile ducts (no patient had only extrahepatic PSC) were asymptomatic and had a nonprogressive course (Table 3). However, patients with only intrahepatic bile duct involvement had fever more often than patients with both intrahepatic and extrahepatic PSC (50% vs. 9%). The course was not related to sex, age at diagnosis of PSC, extent or follow-up of PSC, or pattern of first LFT abnormality. There was a significant correlation between age at diagnosis of PSC and age at diagnosis of UC (y = 0.594x + 23.602; r = 0.4; P = 0.0001) but not with course or extent of colitis, pattern of first LFT abnormality, or course of PSC. Discussion

The prevalence of UC within four of the five areas was fairly similar. The Orebro region differed from the other four with a prevalence of UC of 244 per 10 5 inhabitants aged ~ 16 years. It is also evident that the percentage of distal UC was considerably higher in Orebro. The differences could possibly be explained by the exclusion of some cases of distal UC, erronously diagnosed as proctitis in low-prevalence areas. Proctitis was defined as inflammation not extending 15 em from the anus. The extent of disease in this study was usually obtained retrospectively, and it is likely that the extent was not always noted exactly in the original report. For instance, a patient with a clear-cut demarcation between inflamed and normal mucosa at 20 em could have been labeled in a sigmoidoscopy report as having proctitis and not proctosigmoiditis. Such a case would be excluded

Table 2. Comparison of Ulcerative Colitis Patients With and Without Primary Sclerosing Cholangitis No. of patients Male-female ratio Age at diagnosis of UC (yr)" History of UC (yr)" Follow-up (yr)" Course of colitis [n (%)] Continuous Remittent Single attack Extension of colitis [n (%)] Distal Substantial Colectomy [n (%)] "Mean ± SD.

UC with PSC

UC without PSC

55 2.06 28 ± 16 14 ± 13 17 ± 14

1445 1.13 32 ± 15 12 ± 9 14 ± 9

7 (13%) 40 (73%) 8 (14%)

101 (7%) 1180 (82%) 164 (11%)

3 (5%) 52 (95%) 13 (24%)

552 (38%) 893 (62%) 468 (32%)

P

0.039 NS NS NS

NS

0.0001 NS

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OLSSON ET AL.

GASTROENTEROLOGY Vol. 100, No.5

Table 3. Clinical Features in Patients With Primary Sclerosing Cholangitis and Comparison of Patients With Total or Only Intrahepatic Involvement of the Biliary Tree All patients No. of patients Male-female ratio Features ofUC Age at diagnosis (yr)" Duration of UC at PSC diagnosis (yr)" Proctocolectomy (% of

patients)

Course [n (%)] Continuous Remittent Single attack Extension of colitis [n (%)] Distal Substantial Features ofPSC Age at diagnosis (yr l" Time from first LFT abnormality to diagnosis (yr)" Follow-up after diagnosis (yr)" First LFT abnormality [n (%)] ALP ALP + ASAT/ALAT ALP + ASAT/ALAT + bilirubin ASAT/ALAT Symptoms [n (%)] Asymptomatic Fever Pain Pruritus Course [n (%)]b Progressive Nonprogressive

Intrahepatic and extrahepatic PSC

Intrahepatic PSC only

47 2.1

8 1.7

NS

28 (4-70)

29 ± 16

21 ± 19

NS

12 (-6-51)

12 ± 13

12 ± 9

NS

55 2.1

p

20

17

38

NS

7 (13%) 40 (73%) 8 (14%)

6 33 8

1 7

a

NS

3 (5%) 52 (95%)

2 45

a

NS

8

40 (16-74) 3.1 (-5-17) 5.7 (0-24) 13 (24%) 35 (64%)

41 ± 15

34 ± 18

NS

2.8 ± 4.0 5.3±4.1

3.8 ± 5 8.1 ± 7.7

NS NS

11 31

2 4

2 3

1 1

(65%) (15%) (31%) (7%)

33 4 13 3

4 4

10 (20%) 39 (80%)

9 38

3 5

3 (5%) 4 (7%) 36 8 17 4

3

1

NS 0.0026 NS NS NS

"Mean with range (all patients) or SD. bOnly in patients with a follow-up of at least 1 year.

from the analyses. If this is the explanation of the differences between regions, the prevalence of substantial DC should be similar unless definite geographic differences exist within Sweden. In fact, the prevalence of substantial DC was very similar, varying only between 102 and 121 per 105 inhabitants in different areas. The possibility that the differences in total prevalence could be explained by the difficulty to define proctitis could be substantiated further by comparing the prevalence of colitis plus proctitis in the different areas. However, the number of excluded proctitis patients had been recorded only in Drebro (57 patients) and Dppsala (220 patients). If these figures are added to the DC population, the two areas had point prevalences of 286 per 105 inhabitants (95% CI, 253-319) and 255 per 105 inhabitants (95% CI, 224-286), respectively. On the basis of this, we believe that the epidemiological data given are reliable, especially regarding substantial DC, although the frequency of distal DC has sometimes been under-

estimated. The prevalence of DC in this study is higher than usually reported, which may partly be explained by exclusion of patients aged < 16 years. On December 31,1988,18.4% of the population in the study areas was 0-15 years old. Assuming that no case of DC existed at all in this age group, the prevalence in the total population of the five study areas would be 139 per 10 5 inhabitants (95% CI, 116-162) and, including proctitis patients (DrebroDppsala regions only), 213 per 10 5 inhabitants (95% CI, 184-242), which is still high. The figure from the combined five areas approaches those reported from Iceland (122 per 105 ) (5), Faroe Islands (157 per 10 5 ) (6), and Copenhagen (117 per 105 ) (7). The prevalence in the Drebro-Dppsala regions, 213 per 105 , including proctitis patients, is very similar to that in a study from Olmsted county, Minnesota (225 per 105 ), which for decades has had well-established epidemiological traditions (8). The prevalence of PSC observed in the present

May 1991

%

PRIMARY SCLEROSING CHOLANGITIS IN UC

time of diagnosis of PSC than that recorded in the DC patients without PSC when the study was closed. Furthermore, they did not have a continuous course of the colitis any more often and had, if anything, a lower rate of colectomy, which might be considered an indicator of the severity of the disease. Further arguments against such a causal relationship are the well-known facts that PSC may appear many years before DC (as in one of our patients; Table 3) as well as several years after colectomy and that its course is not influenced by colectomy (13).

50 40 30 20 10

A %

0 10

20

30

40

50

60

70

80

90

years

References

40

30

20

10

B

o

1323

10

20

30

40

50

60

70

80

90

years

Figure 1. Age at diagnosis ofUe (A) and pse (B) in male (_) and female (f2l) patients with pse.

study is likely to be an underestimate of the true prevalence, considering the drop-out of 6.1 % of the DC patients due to missing data and 9.7% of the patients with increased ALP levels who refused ERC, as well as the reported existence of PSC patients with normal ALP levels (9-12). This latter observation was confirmed in the present study because two PSC patients had persistently normal ALP levels and several of the other PSC cases had normal ALP levels during prolonged periods. It is evident from the present data that risk factors for PSC in DC are male gender and substantial colitis and that the diagnosis is made at an older age in women. On the other hand, there was no evidence that the course of the colitis or the age at diagnosis of DC constituted any risk factors or that the risk of having PSC increased with increased duration of DC. The significantly higher prevalence of substantial colitis in PSC patients than in DC patients without PSC and the strong correlation between the ages at diagnosis of DC and PSC suggest a causal relationship between the inflammatory process in the colon and the bile duct disease. On the other hand, such a hypothesis is contradicted by our observation that PSC patients did not have a longer history of DC at the

1. Lupinetti M, Mehigan D, Cameron JL. Hepatobiliary complications of ulcerative colitis. Am J Surg 1980;139:113-117. 2. Schrumpf E, Fausa 0, Kolmannskog F, Elgjo K, Ritland S, Gjone E. Sclerosing cholangitis in ulcerative colitis. A follow-up study. Scand J GastroenteroI1982;17:33-39. 3. Shepherd HA, Selby WS, Chapman RWG, Nolan D, Barbatis C, McGee JO'D, Jewell DP. Ulcerative colitis and persistent liver dysfunction. QJ Med 1983;52:503-513. 4. Rasmussen HH, Fallingborg J. Mortensen PB, Freund L, Rasmussen SN. Primary sclerosing cholangitis in patients with ulcerative colitis during a 12-year period (abstr). Scand J GastroenteroI1989;24(SuppI159j:57. 5. Bjornsson S, Thorgeirsson T. Ulcerative colitis in Iceland 1950-1979. Nord Med 1983;98:298-301. 6. Berner J. Kiaer T. Ulcerative colitis and Crohn's disease on the Faroe Islands 1964-1983. A retrospective epidemiological survey. Scand J GastroenteroI1986;21:188-192. 7. Binder V, Both H, Hansen PK, Hendriksen C, Kreiner S, Torp-Petersen K. Incidence and prevalence of ulcerative colitis and Crohn's disease in the county of Copenhagen 1962-1978. Gastroenterology 1982;83:563-568. 8. Stonnington CM, Phillips SF, Melton LJ, Zinsmeister AR. Chronic ulcerative colitis: incidence and prevalence in a community. Gut 1987;28:402-409. 9. Balasubramaniam K, Wiesner RH, LaRusso NF. Primary sclerosing cholangitis with normal serum alkaline phosphatase activity. Gastroenterology 1988;95:1395-1398. 10. Cooper IF, Brand EJ. Symptomatic sclerosing cholangitis in patients with a normal alkaline phosphatase: two case reports and a review of the literature. Am J Gastroenterol 1988;83 :308311. 11. Keeffe EB. Diagnosis of primary sclerosing cholangitis in a blood donor with elevated serum alanine aminotransferase. Gastroenterology 1989;96:1358-1359. 12. Clements D, Rhodes JM, Elias E. Severe bile duct lesions without biochemical evidence of cholestasis in a case of sclerosing cholangitis. J HepatoI1986;3:72-74. 13. Stockbrugger R, Olsson R, Jaup B, Jensen J. Forty-six patients with primary sclerosing cholangitis: radiological bile duct changes in relationship to clinical course and concomitant inflammatory bowel disease. Hepatogastroenterology 1988;35: 289-294. Received May 3,1990. Accepted September 28,1990. Address requests for reprints to: Rolf Olsson, M.D., Medical Clinic, Sahlgrenska Sjukhuset, S-413 45 G6teborg, Sweden. The authors acknowledge the financial support of G. D. Searle Ltd.