SEMINARS IN LIVER DISEASE-VOL.

1 1, NO. 1, 1991

Relationship of Inflammatory Bowel Disease and Primary Sclerosing Cholangitis OLAV FAUSA, M.D., ERIK SCHRUMPF, M.D., and KJELL ELGJO, M.D.

EPIDEMIOLOGY The frequency of the associated occurrence of IBD and PSC varies considerably between different studies,

From the Departments of Internal Medicine A and Pathology, Rikshospitalet, Oslo, Norway Reprint requests: Dr. Fausa, Medical Department A, Rikshospitalet, 0027 Oslo I, Norway

TABLE 1. Frequency of Primary Sclerosing Cholangitis in Patients with Ulcerative Colitis UC with PSC

Reference

UC fn)

No.

%

Schrumpf et all4 Shepherd et all' Tobias et allh

336 68 1 250

14 17 8

4* 2.4 3t

*Later follow-up: 25 (7.5%). "FSC was diagnosed in 1.3% of patients with Crohn's disease

partly due to differences in diagnostic methods applied and probably also to differences in the selection of patients. A prevalence of PSC of 2.4 to 7.5% has been found in patients who presented primarily with UC and also had persistently abnormal liver tests (Table 1). The Oxford study'' showing PSC in 2.4% was performed among patients who attended the outpatient clinic, whereas the Oslo studyi4showed that 4% of hospitalized patients with UC had concomitant PSC. Later follow-up of this selected group of 336 patients with UC has disclosed PSC in 7.5% of the patients.' Our experience and that from England" and South AfricaI6 demonstrate that PSC is the most common form of chronic liver disease in patients with IBD. The true frequency of PSC in UC may, however, be unknown, since several patients may be asymptomatic without laboratory abnormalities9,I7 and no investigation of unselected patients with IBD has been performed. Most studies of PSC have dealt with patients who have been found coincidentally to have IBD (Table 2), and it is usually reported that 70 to 75% of patients with PSC also have IBD. The Norwegian9," and also the Swedish experiences" have been different from that in England and the United States in that practically all patients with PSC had, or subsequently developed, IBD. In a more recent study from the Mayo Clinic,I8 including 57 consecutive patients with PSC, IBD was seen in 9 1% of the patients, thus approximating the Scandinavian data and supporting the idea that all patients with PSC have or will develop IBD. Those who disagree with this assumption may argue that the patients of the Norwegian study were recruited from patients with known IBD. This is, however, not completely true, since our hospital

Copyright 0 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

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The association between primary sclerosing cholangitis (PSC) and chronic ulcerative colitis (UC) has been recognized for several years, and a frequency of 25 to 30% of inflammatory bowel disease (IBD) in PSC was reported in the pioneer studies by Warren et al' and Thorpe et al.2 The development and widespread utilization of endoscopic retrograde cholangiopancreatography (ERCP) have permitted a complete visualization of the extra- and intrahepatic bile ducts without much discomfort to the patients and have enabled physicians to diagnose PSC more easily and far more frequently than in the past.' Considerable uncertainty still exists, however, regarding the frequency, nature, and natural history of concomitant IBD and PSC. Studies from the last decade have reported a 54 to 100% prevalence of IBD in PSC4-" and a 2.4 to 4% prevalence of PSC in UC.14-'hMost of these studies have primarily dealt with the hepatobiliary disease, and the intestinal involvement has not been systematically evaluated. Our experience is that IBD is seen in practically all patients with PSC, and furthermore that systematic evaluation of patients with IBD has shown PSC to be the most common form of associated chronic liver disease.',14.15 It is unknown if the IBD that occurs in association with PSC is an entity different from IBD without PSC; by contrast, some controversial data are available concerning the clinical features and natural history of PSC in individuals with and without IBD.'.I2 The purpose of this presentation is to discuss these matters on the basis of what is known about epidemiology, etiology, pathogenesis, clinical features, and the clinical course. Since diagnostic criteria have not been well defined in relation to the IBD in these patients, this has a major impact on the validity of the conclusions drawn in studies dealing with IBD and PSC.

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TABLE 2.

1 1, NUMBER 1, 1991

Frequency of Inflammatory Bowel Disease in Patients with Primary Sclerosing Cholangitis PSC Wirh

Reference

No.

UC* O/o

No.

CD* %

No.

Unclussijied O/o

No.

O/o

Chapman et alJ Wiesner and LaRussoi (1970-1977) Sivak et aIb Lebovics et a17 Helzberg et alx Aadland et al' (1975-1985) Stockbriigger et allu (1975-1984) Wiesner et all1 (1970- 1984) Rabinovitz et al" ( 1985-1987) Fausa et all7 (1975-1987) *UC: ulcerative colitis; CD: Crohn's disease.

serves as a referral center for both gut and liver diseases. It must, however, be admitted that bowel symptoms have been more pronounced than the symptoms of liver disease in our patients with IBD and PSC.' Against the view that only around 70 to 75% of PSC patients have or will develop IBD, one may argue that in the majority of studies cited in Table 2 the bowel was inadequately examined in most, leading to an underestimation of the prevalence of IBD. The discrepancy between these studies could also be explained by the possibility that PSC without IBD is less frequently seen in Europe than in the States. Most patients who develop PSC are under the age of 40 years and the ratio of males to females is approximately 2:l.' Rabinovitz et all2 have, however, found a slightly higher age in patients without IBD than in those with combined IBD and PSC, and also a significantly lower male to female ratio in patients without IBD (0.77:l) than in those with concomitant PSC and IBD (2.9: 1). These data could support the idea that there are two subsets of PSC-ne associated with IBD and one unassociated.

ETIOLOGY AND PATHOGENESIS The causes of UC and Crohn's disease (CD) are still unknown. There is currently much interest in the search for infective agents, but attempts to identify specific microorganisms as causative agents for IBD have generally been unrewarding. The association with IBD raises the possibility that PSC is secondary to the bowel disease, particularly that gut toxins may be important etiologically. Experimental colitis in rats is associated with a picture in the liver resembling PSC." However, the hypothesis is not supported by the observation that proctocolectomy has no beneficial effect on the hepatobiliary lesion,20although the mechanism is not excluded by this finding. That PSC may be seen in patients without evidence of IBD, as well as after proctocolectomy in colitis,4,5,10,14 also speaks against PSC being secondary to the

bowel disease, provided diagnostic work-up has been adequate. Finally, it has been excluded that PSC is secondary to sulfasalazine, which is taken by most patients with colitis, since a substantial number of patients had not taken this drug before the diagnosis of PSC.""' Several findings are compatible with an important role of genetic or immunologic factors in the pathogenesis of PSC (for review see the chapter by Chapman in this issue of Seminars).There is also abundant evidence for the immune systems to play a role in the pathogenesis of IBD.21Only a limited number of articles have, however, questioned whether different immune mechanisms are involved when PSC and IBD occur separately or in combination. McFarlane et a122found inhibition of leukocytes in response to biliary antigen from eight patients with PSC alone or combined with IBD, but not in 11 controls with isolated UC. Minuk et a123have shown reduced clearance of immune complex-like material from the systemic circulation in five patients with UC and PSC, whereas the clearance was normal in 25 healthy controls and 19 patients with isolated UC. Chapman et a124found a significantly higher frequency of serum anticolon antibodies and portal tract antibodies in combined PSC and UC when compared with patients with UC or Crohn's colitis alone. Also, our own findings of a higher prevalence of several types of autoantibodies in PSC and IBD than in IBD alone25 and a significantly higher rate of HLA-B8 and HLA-DR3 in PSC and UC than in UC alone26are compatible with the view that different immune mechanisms are involved when IBD occurs alone or together with PSC. The most recent contribution in this field is the demonstration of the specific HLA haplotype DRw52a to be present in 100% of patients with PSC, irrespective of the presence or absence of IBD.27 In conclusion, evidence has been found of a difference in involvement of immune mechanisms in patients with IBD alone and in those with combined IBD and PSC. No such difference has been found between patients with PSC alone and PSC associated with IBD.

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IBD PSC (n)

DIAGNOSIS Diagnostic Criteria and Extent of Primary Sclerosing Cholangitis The diagnosis of PSC has in all studies been established by findings at cholangiography, usually by endoscopy (ERCP). The radiologic criteria include mural irregularities, diffuse multifocal strictures and beading of extrahepatic or intrahepatic bile PSC must be distinguished from secondary sclerosing cholangitis.' Extrahepatic involvement has been demonstrated in 88 to 100% in some whereas other studies have reported abnormalities limited to the intrahepatic bile ducts in 21 and 35%.X.'0Since similar intrahepatic abnormalities may be seen in other chronic liver diseases as well,2yone should be reluctant to include patients with intrahepatic involvement only. In most patients with extrahepatic involvement there is a concomitant involvement of the intrahepatic A division of PSC patients into two groups, those with small duct PSC and those with cholangiographically identifiable "large duct PSC," has been proposed3" (see review by Ludwig in this issue of Seminars). Both conditions may be components of a disease spectrum, the PSC syndrome.31So far, however, the diagnosis of PSC has been reserved for those with cholangiographically identifiable disease.

Diagnostic Criteria for Inflammatory Bowel Disease The diagnosis of IBD and distinction between UC and CD has mainly been based on review of clinical, radiologic, endoscopic and histopathologic evidence. Infective colitis and other forms of colitis due to known causes have to be excluded. Colonoscopy with multiple biopsies is superior to radiology, and an important procedure in the evaluation of patients when IBD is susp e ~ t e d . ~Quiescent :.~~ IBD may be found in patients with PSC without any clinical or radiologic evidence of bowel disease and full colonoscopy with biopsies is necessary for the diagnosis and classification of IBD in patients with PSC.y.ls Although endoscopy is useful for evaluating the terminal ileum, radiologic examination must be performed to diagnose CD of the small intestine.'." The discrepancy in the frequency and type of IBD associated with PSC that has been reported may partly be explained by differences in the diagnostic procedures of patients suspected of having PSC. Endoscopy with biopsies had been performed in all patients in only one study" in addition to our In some series all oatients with PSC have had their bowel examined with colonoscopy or combined proctoscopy and barium In several studies many patients had no bowel examination or complete data have not been g i ~ e n . ' ~ ' ~ ~ ~ " ' In the Oslo study, the IBD was diagnosed and classified on radiologic (for small bowel disease), endoscopic, and histologic riter ria.^:,^' The endoscopic features of inflammation were mucosal granularity, abnormal vascular pattern, mucosal vulnerability, and mu-

SCHRUMPF, ELGJO

33

cosal damage. Colitis was diagnosed with two or more endoscopic criteria fulfilled and chronic inflammation verified histologically. Endoscopic feature of UC was diffuse mucosal involvement in continuity from distal to proximal colon. The endoscopic criteria for CD were discrete aphthoid ulcerations with asymmetric involvement, deep or longitudinal ulcers surrounded by uninvolved mucosa, or segmental distribution of inflammation. Endoscopic and histologic features suggestive of both UC and CD were classified as indeterminate colitis. When verified by histologic examination, inactive colitis with mucosal atrophy was diagnosed at endoscopic findings of pale mucosa with tortuous and interrupted vessels and minimal or no sign of inflammation. The overall severity of the bowel disease may be estimated according to a combination of clinical and laboratory parametres.".j4

CLINICAL FEATURES Primary Sclerosing Cholangitis With and Without Inflammatory Bowel Disease The disorder often begins insidiously, making it difficult to determine the onset of the disease accurately. The clinical presentation of PSC is variable. Gradual onset of progressive fatigue and pruritus followed by jaundice represents the most frequent symptom complex that leads to the diagnosis of PSC." It should, however, be emphasized that many patients with PSC are asymptomatiC.4.5.7.Y.10.14.1SIn the Oslo study, most patients had no clinical symptoms of hepatobiliary disease at the diagnosis of PSC.I4 In patients with PSC and concomitant IBD, the bowel symptoms may be dominant, but are usually Serum biochemical analysis usually indicates cholestasis. In asymptomatic patients PSC will be suspected when laboratory data give evidence of cholestasis, and LaRusso et als' claimed that a cholestatic biochemical profile is present in all patients with PSC. Follow-up studies have revealed that this is not always the case."I7 In the Oslo study, one in four patients had alkaline phosphatase values within the normal range and the mean bilirubin level was still within the normal range at the follow-up examination 6.3 years after the diagnosis. In the studies of Chapman et a14 and Wiesner and LaRusso' the mean levels of bilirubin were between two and six times the upper normal limit at diagnosis. The symptoms of PSC and the biochemical evidence of cholestasis obviously depend on selection of patients. Only few studies have dealt with the question whether clinical and laboratory data are related to the presence of concomitant IBD. Wiesner et all' found that patients with concomitant IBD had a worse prognosis, whereas Helzberg et alx found no such difference. Rabinovitz et all2 found either jaundice, pruritus, or fatigue at presentation in 72% of patients without concomitant IBD; these symptoms were seen in only 41% of patients with combined IBD and PSC. They state, however, that the difference in presentation between the two groups may reflect different stages of the same disease spec-

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INFLAMMATORY BOWEL DISEASE AND PSC-FAUSA,

trum, rather than an intrinsic difference between the two groups. As previously stated, the frequency of cholangiographic changes restricted to the extrahepatic or intrahepatic duct systems seems to vary (see before). In a study of liver biopsy and autopsy specimens from 43 patients, Ludwig et alj6 found essentially the same hepatobiliary abnormalities both when PSC was or was not associated with IBD. The same conclusion was reached by MacCarty et a12#in their detailed study of 86 patients with PSC, of whom 57 had concomitant IBD. Rabinovitz et all2 found, on the other hand, combined intrahepatic and extrahepatic bile duct involvement to be more frequently present in PSC associated with IBD compared with PSC without IBD. Involvement of the extrahepatic bile ducts alone was more frequently seen in patients without IBD.I2

Inflammatory Bowel Disease With and Without Primary Sclerosing Cholangitis The symptoms at presentation of an IBD associated with PSC are not different from IBD without PSC and are usually Nevertheless, the symptoms of bowel disease have in our experience tended to be more pronounced than the symptoms of the hepatobiliary disease.9 In the majority of patients, the IBD had been known for several years at the time of diagnosis of PSC,4.5.h.',."'.14or PSC and IBD will be diagnosed at the same time.4.10.14 Moreover, PSC has been diagnosed in a significant number of patients who subsequently develand in some patients PSC may be dioped UC,4.5.y.10.14 agnosed many years after proctocolectomy.4~5~~0~~4 It cannot, however, be excluded that asymptomatic PSC was present at colectomy in these patients.' Finally, the occurrence of asymptomatic colitis," respectively ~ S C , ~ . S . ~ . ~ .hIasO to . I be ~ .considered I S . ~ ~ when discussing all aspects of interrelationship between the two. It has been claimed that PSC usually develops in

1 1 , NUMBER I , 1991

patients who have had colitis for more than a d e ~ a d e . ~ , ' ~ Apparently, PSC may occur in any time sequence of the IBD,4.5.9.10.14 S'igns of liver disease early in the course of the IBD in patients later diagnosed as having PSC14.37 suggest that the hepatobiliary involvement is initiated at an earlier stage of IBD than generally recognized. Neither the age at onset or at diagnosis of IBD, nor the duration or activity of the bowel disease, is related to the stage of the hepatobiliary d i s e a ~ e . ~ . ~UC . ' ~is. ~ ~ . ~ ~ the most common type of IBD diagnosed in association with PSC. Previously, CD was rarely reported, 35 but some recent ~ e r i e s ~ ~ h~ave ~ ' reported ~ ' ~ ~ ' a~ 5~ to' ~13% prevalence of CD (Table 3). CD isolated to the small bowel is not associated with PSC.9.12Recurrent granulomatous ileitis was, however, diagnosed by follow-up ileoscopy, even in asymptomatic patients several years after proctocolectomy for IBD primarily diagnosed as UC.' Our data indicate a 13% or higher prevalence of CD in PSC-associated IBD, and that extensive colonic involvement seems to be mandatory if PSC is to be found in CD. We have suggested that PSC occurs as frequently in extensive Crohn's colitis as in extensive UC.' In a population of patients with UC or CD, extensive colonic involvement is observed in two thirds and one fourth of patients, re~pectively.~' Nevertheless, IBD associated with PSC regularly occurs as a universal Colitis4.~.~.fi.~3 (Table 3). In CD an extensive, segmental distribution of the inflammation of colonic mucosa may be found.' Left-sided or distal UC has been diagnosed in only a few patients with PSC (Table 3). Moreover, unequivocal extensive colitis may be found in asymptomatic patients,"I3 at endoscopy and with histologic examination with mild inflammation or in a chronic inactive stage. Normal barium enema occurs in a high proportion (20%) of patients with PSC and IBD.4 Therefore proctosigmoidoscopy and barium enema are insufficient procedures in the diagnosis and classification of IBD. For several years we have searched for PSC when IBD patients have signs of hepatobiliary disease, and il-

TABLE 3. Type and Extent of Colitis in Patients with Primary Sclerosing Cholangitis

Rejerence

IRD" (17)

Chapman et al' Shepherd et al" Wiesner and LaRusso'

21 UC 17 UC 24 UC 3 CD 36 UC 2 CD 5 UNCL 39 UC 8 CD 37 UC 6 CD 2 UNCL 47 UC 8 CD 4 UNCL

Stockbriigger et al"' Rabinovitz et all' Aadland et alq Fausa et all1

E.rtri~.si~,c Colitis 01)

IS 10 23 3 33 I 2 35 8 37 6 I 47 8 2

*UC: ulcerative colitis: CD: Crohn's disease; UNCL: unclassified

Lqft-Sidrd Colitis (11)

6

2

Distal Colitis (/IJ

2 I I

Unknown or Other ( n )

4

I 1

3 4

I 2

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SCHRUMPF, ELGJO

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INFLAMMATORY BOWEL DISEASE AND PSC-FAUSA,

FIG. 1. Endoscopical large bowel biopsy from a patient without bowel symptoms at the diagnosis of PSC. Endoscopy gave evidence of inactive colitis with pale mucosa and patchy edema. Microscopically (A), the biopsies from the proximal part of the colon revealed a moderately atrophic mucosa with patchy infiltration by lymphocytes and plasma cells. The crypts were short, dilated, and the epithelium displayed areas of hyperplasia with hyperchromatic nuclei and loss of goblet cells. A normal biopsy (B) is included for comparison (Hematoxylin, erythrosin, and saffron. Original magnification, x 100.)

eocolonoscopy is routinely performed in patients with PSC. Our data indicate that all, or almost all, patients with PSC have concomitant IBD or will develop IBD in the future. In a series of 60 patients with PSC diagnosed during a 13-year period, IBD was found in 59 patients with a mean follow-up of 12 years (range, 1 to 33).13 Endoscopy (and histologic findings) demonstrated the presence of an IBD in seven asymptomatic patients (Fig.

I). One has remained without symptoms of the IBD for 18 years after the diagnosis of IBD was made (Fig. 2). The diagnostic criteria may not be fulfilled in all patients, neither for UC nor CD, and at the time of diagnosis the IBD then has to be classified as indeterminate colitis from the macroscopic and microscopic lesions at ileocolonoscopy and from the histologic finding~.','~

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FIG. 2. The microphotographs are from a patient who had been without any clinical symptoms of inflammatory bowel disease for a period of 18 years after the diagnosis of colitis. The two biopsies were taken at 6 and 13 years after the diagnosis of IBD was made. The first of the two endoscopical examinations revealed definite pathologic changes with an abnormal vascular pattern and granular mucosa. Histologically (A), biopsies of the colon mucosa at this time showed a moderate infiltration by lymphocytes, plasma cells, and polymorphonuclear leukocytes. Some of the crypts were branched at the base, and most crypts had a reduced number of goblet cells. Destruction of crypt epithelium or crypt abscesses were not seen. The second endoscopical examination 7 years later showed minimal vascular changes and edema. The biopsies (B), however, revealed a severe atrophy of the colon mucosa with loss of crypts and decreased mucosal height. (Hematoxylin, erythrosin, and saffron. Original magnification, x 100.)

CLINICAL COURSE Inflammatory Bowel Disease With and Without Primary Sclerosing Cholangitis In the majority of patients, the colitis is mild with prolonged remission at the time of diagnosis of PSC.4.'.14 Whether the clinical course of IBD associated with PSC is different from that seen in patients with isolated IBD has never been examined. According to our experience, a sustained clinical remission is observed during the long-term follow-up of most patients with IBD associated with PSC.'," At follow-up colonoscopy, a macroscopically and microscopically mild or inactive disease was found in more than 75% of patients (Fig. 3). The colectomy rate among our patients of 26%' fits well with the colectomy rate of 14 to 23% of other report^.^,"-'^ In all series reported, therapy for IBD was given according to accepted indications for drug treatment or surgery. Although not reported by other authors, Wiesner et observed the development of varices around ileostomy stoma in 10 of 19 patients with PSC operated on, with abdominal ileostomy. To avoid this life-threatening complication, ileoanal anastomosis should be considered. Although not proven, this procedure may have less risk of bleeding problems than conventional ileostomy." The incidence of colonic carcinoma is increased in UC, patients with long-standing extensive colitis being at high risk.40 Consequently, single patients with combined UC and PSC have been reported to develop colonic cancer.',' Our experience among 47 patients with UC associated with PSC has been that colonic carcinoma occurred in five and dysplasia was diagnosed in 16 pa-

SCHRUMPF, ELGJO

37

tients altogether.13 It is unknown whether patients with combined UC and PSC have a higher risk of developing colonic cancer than comparable patients with UC alone. Since the risk of cancer development is hardly less, annual colonoscopic screening for dysplasia and early cancer should be done in patients with extensive colitis of 10 or more years' duration."

Primary Sclerosing Cholangitis With and Without Inflammatory Bowel Disease The data on prospective long-term follow-up examinations of PSC patients with and without IBD are scarce. In the Oslo study9 45 patients with both PSC and IBD were followed for a mean of more than 8 years after the demonstration of hepatobiliary disease (2.2 years since diagnosis of PSC). Clinical, biochemical, choleangiographic, and liver bioptic findings indicated a nonprogressive course in most patients. The 50% survival since the demonstration of hepatobiliary disease was calculated to be 17 years in patients with PSC and 50 years in a comparable group among the general population. The Mayo Clinic study,ll comprising 174 patients, evaluated the relationship of clinical, biochemical, radiologic, and hepatic histologic features with survival. A multivariate statistical survival model developed by the group identified age, serum bilirubin level, hemoglobin concentration, histologic stage on liver biopsy, and presence of IBD as independent predictors of high risk of dying. Median survival time from the time of diagnosis of PSC was 1 1.9 years. Helzberg et alx have followed 53 patients and found that 75% of the patients were alive 9 years after the diagnosis of PSC. The presence of IBD did not affect

FIG. 3. Endoscopical biopsy 10 years after the diagnoses of active ulcerative colitis and PSC. No clinical symptoms for the last 8 years. Endoscopy showed only minimal inflammatory changes. Histologically, colon, especially the proximal part, showed heavy infiltration by lymphocytes, plasma cells, and polymorphonuclear leukocytes. The crypts were dilated, branched, and with loss of goblet cells. (Hematoxylin, erythrosin, and saffron. Original magnification, x 100.)

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INFLAMMATORY BOWEL DISEASE AND PSC-FAUSA,

the outcome. In a series from Mount Sinai Hospital,' in which 38 patients were followed for 75 + 59 months, a poor outcome defined as death, variceal hemorrhage, hepatic encephalopathy, or hepatic transplantation was seen in 45%. The differences in prognosis among these studies may reflect a variable rate of disease progression but are more likely due to differences in the patient populations. Noteworthy is the lower age at demonstration of hepatobiliary disease seen in our studyy when compared with that in the Mayo study. There is still considerable disagreement whether PSC is a ominous disease or not.4' Anyway, most authors seem to agree that median survival from diagnosis of PSC is at least 10 years, which is far better than indicated in the pioneer study of Warren et al.' Whether the presence of concomitant IBD influences the prognosis of patients with PSC is also controversial. Helzberg et alRfound no such influence, whereas Wiesner et all' did. When looking at the clinical details a direct association between death and the presence of IBD obviously seldom occurs. An increased prevalence of bile duct carcinoma (BDC) in patients with UC has been known for a long time4244Converse et suggested that BDC in patients with UC was different from BDC seen in patients without UC. In 1980 reports on BDC complicating PSC ap~ e a r e d . ~Later, . ~ . ~ it has become clear that a strong association between BDC and PSC e ~ i s t s , ' . " . ' ~with . ~ ~a ~ ~ prevalence of up to 13% in 60 patients consecutively diagnosed in our d e ~ a r t m e n t BDC . ~ ~ has become a major cause of death in these patients. ",".48 The current view is that BDC in PSC is usually seen in patients with concomitant IBD.".45 This finding may indicate that PSC patients with and without IBD represent two different subgroups of patients. Two recent reports have, however, opposed this view in finding similar prevalence of BDC in both groups of p a t ~ e n t s . ' ~ . ~ ' The final question to be addressed is whether proctocolectomy has any effect on the clinical course of PSC. Some single patient experiences have suggested a favorable effect,'.4ybut most recent reports on PSC have concluded that no such effect exist^.^^^^^"^^ This conclusion has also been supported by the finding of PSC years after c~lectomy.~." The most significant contribution has been reported by Cangemi et al.20They followed 45 patients with both PSC and UC, of whom 20 had undergone proctocolectomy. No effect of surgery was seen on clinical, biochemical, histologic, and radiologic parameters. The conclusion that proctocolectomy for chronic UC has no beneficial effect on the PSC in patients with both diseases is in line with the view that no relationship appears to exist between the activity, duration, or extent of colonic involvement in UC and the natural history of the hepatobiliary d i s e a ~ e . ~ ~ ~ ~ ' ~ ~ ' ~ ~ ~ ~

SUMMARY There is a strong association between PSC and IBD. PSC is the most common hepatobiliary lesion seen in association with IBD. Whether there are two subsets of PSC, one associated with IBD and one unassociated, is

1 1, NUMBER 1, 1991

controversial. A lower male to female ratio in patients without IBDI2 supports this view. The demonstration of the haplotype DRw52a in 100% of patients with PSC, irrespective of the absence of IBD,27speaks against this view. Patients with isolated PSC tend to present with jaundice, pruritus, and fatigue more frequently than those with combined PSC and IBD.I2 There may also be a difference in bile duct involvement between patients with and without IBD combined with PSC.I2 Apart from usually being a total colitis, either Crohn's colitis or UC, the IBD associated with PSC cannot be distinguished from IBD without PSC with respect to symptoms and clinical course. Patients with combined IBD and PSC may have somewhat worse prognosis than those with isolated PSC. ' I The majority of patients developing BDC have concomitant IBD," suggesting that patients without IBD represent a different subgroup of PSC and run a different clinical course. Most studies have, however, found no differences in epidemiology, pathogenetic factors, clinical findings related to the hepatobiliary disease and prognosis between those who present with PSC alone and those who present with combined PSC and IBD. A major problem when discussing the relationship between IBD and PSC is that the bowel is inadequately examined in many of the studies relating to this question. When diagnostic criteria concerning both the hepatobiliary lesion and the bowel lesion have been agreed on, the final question may be answered: whether there are two subsets of PSC, one associated with IBD and one unassociated, or simply one subset that is usually associated with IBD.

REFERENCES Warren KW, Athanassiades S , Monge JI: Primary sclerosing cholangitis. A study of forty-two cases. Am J Surg 1 1 1:2338, 1966. Thorpe MEC, Scheuer PJ, Sherlock S: Primary sclerosing cholangitis, the biliary tree, and ulcerative colitis. Gut 8:435448, 1967. Schrumpf E, Fausa 0 , Elgjo K, Kolmannskog F: Hepatobiliary complications of inflammatory bowel disease. Semin Liver Dis 8:201-209, 1988. Chapman RWG, Marborgh BAM, Rhodes JM, et al: Primary sclerosing cholangitis: A review of its clinical features, cholangiography, and hepatic histology. Gut 21:870-877, 1980. Wiesner RH, LaRusso NF: Clinicopathologic features of the syndrome of primary sclerosing cholangitis. Gastroenterology 79:200-206, 1980. Sivak MJ, Farmer RG, Lalli AF: Sclerosing cholangitis: Its increasing frequency of recognition and association with inflammatory bowel disease. J Clin Gastroenterol 3:261-266, 1981. Lebovics E, Palmer M, Woo J , Schaffner F: Outcome of primary sclerosing cholangitis. Arch Intern Med 147:729-731, 1987. Helzberg JH, Petersen JM, Boyer JL: Improved survival with primary sclerosing cholangitis: A review of clinicopathologic features and comparison of symptomatic and asymptomatic patients. Gastroenterology 92: 1869-1 875, 1987. Aadland E, Schrumpf E, Fausa 0 , et al: Primary sclerosing cholangitis: A long-term follow-up study. Scand J Gastroenterol 22:655-664, 1987.

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INFLAMMATORY BOWEL DISEASE AND PSC-FAUSA,

Relationship of inflammatory bowel disease and primary sclerosing cholangitis.

There is a strong association between PSC and IBD. PSC is the most common hepatobiliary lesion seen in association with IBD. Whether there are two sub...
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