Primary sclerosing cholangitis (PSC) is a chronic. Incidence and Prevalence of Primary Sclerosing Cholangitis in a Defined Adult Population in Sweden

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1 Incidence and revalence of rimary Sclerosing Cholangitis in a Defined Adult opulation in Sweden Björn Lindkvist, 1 Maria Benito de Valle, 1 Bo Gullberg, 2 and Einar Björnsson 1 opulation-based studies on the epidemiology of primary sclerosing cholangitis (SC) are sparse. The aim of the present study was to investigate prevalence and temporal trends in the incidence of SC in an adult population in Västra Götaland, a region in southern Sweden with a defined population of about 1.5 million. atients with SC aged 18 years or above were identified through a computerized search for diagnostic codes. A total number of 199 incident cases fulfilling Mayo criteria for SC were identified through retrospective validation of clinical records. Temporal trends in the incidence of SC were investigated by oisson regression and expressed as average annual percent change (AAC) with a 95% confidence interval (CI). The point prevalence of SC on December 31, 2005, was 16.2/100,000 in the total adult population (men, 23.7/100,000; women, 8.9/ 100,000). The annual incidence was 1.22/100,000 in the total adult population (men, 1.78/100,000; women, 0.69/100,000). The overall incidence rate of SC increased significantly over the investigation period (AAC 3.06, 95% CI ). Stratified analysis revealed significantly increasing trends for inflammatory bowel disease (IBD) associated SC (AAC 7.01, 95% CI ) and large duct SC (AAC 6.32, 95% CI ) in women and for SC without IBD (AAC 9.69, 95% CI ) and small duct SC (AAC 17.88, 95% CI ) in men. Conclusion: This is the first study to report a significantly increasing trend in the incidence of SC. The prevalence of SC at the end of the study period is the highest reported to date. This implies that the medical burden of SC may be higher than estimated previously. (HEATOLOGY 2010;52: ) rimary sclerosing cholangitis (SC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the biliary tree. Biliary cirrhosis and liver failure are common complications during long-term follow-up. 1-3 Studies on the natural history of SC have reported a median liver transplant free survival between 12 and 18 years. 4-7 SC usually presents in early adulthood and is more common in men than in women. 4,8 Inflammatory bowel Abbreviations: AAC, average annual percentage change; CI, confidence interval; ERC, endoscopic retrograde cholangiopancreatography; IBD, inflammatory bowel disease; MRC, magnetic resonance cholangiopancreatography, SC, primary sclerosing cholangitis. From the 1 Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and 2 Institution of Clinical Sciences, Lund University, Lund, Sweden. Received September 23, 2009; accepted March 13, Address reprint requests to: Björn Lindkvist, Med ol II, Department of Medicine, Sahlgrenska University Hospital, SE Göteborg, Sweden. bjorn.lindkvist@vgregion.se; fax: (46) Copyright VC 2010 by the American Association for the Study of Liver Diseases. ublished online in Wiley InterScience ( DOI /hep otential conflict of interest: Nothing to report. disease (IBD) is present in approximately 70% of cases in most studies. 4,6,8,9 The epidemiology of SC has mainly been investigated in case series from referral centers. This introduces a risk for selection bias and does not allow estimates of prevalence and incidence rates. Current knowledge on incidence and prevalence of SC is derived from small population-based studies reporting incidence rates of and prevalence rates of per 100,000 person-years. One recent study from the United Kingdom investigated the incidence and prevalence of SC in the General ractice Research Database, reporting a considerably lower incidence and prevalence compared with previous studies. 14 The need for larger population-based studies has been emphasized by several investigators. 11,12 Västra Götaland is a regional health care unit in Sweden wherein one university hospital and seven regional hospitals together serve a defined population of about 1.5 million. Exact age- and sex-stratified population statistics are available. All liver transplantations in the region are performed at the university hospital, and no patients with SC are referred to hospitals 571

2 572 LINDKVIST ET AL. HEATOLOGY, August 2010 outside the region. This allows complete retrieval of cases with SC and calculation of age- and sex-standardized incidence rates. The aim of the present study was to perform a population-based study on the incidence and prevalence of SC in a sufficiently large population over a period long enough to allow analysis of temporal trends in the incidence of SC. The adult population of Västra Götaland from 1992 to 2005 was therefore considered an appropriate study population. atients and Methods Study opulation. Västra Götaland is a regional health care unit in southwestern Sweden for which detailed annual age- and sex-stratified population statistics are available. The mean number of inhabitants in the region was 1,492,000 during the period Gothenburg is the largest city in the region and had a mean population of 788,000 during the study period. There is one university hospital situated in Gothenburg (Sahlgrenska University Hospital), and seven regional hospitals are spread throughout the region. Referral of patients from regional hospitals or from hospitals outside the region to the university hospital occurs in selected cases for clinical second opinion, advanced diagnostic or therapeutic procedures, and/or liver transplantation. No patients are referred out of the region. Case Ascertainment. atients with SC during the study period were identified from inpatient and outpatient registers at all departments of internal medicine and surgery at all hospitals in the region using a computerized search for relevant codes according to the International Classification of Diseases, ninth and tenth revision (codes 576 and K830, respectively). The computerized search was extended to the end of 2006 (1 year beyond the end of the study period) so as to include patients with an uncertain diagnosis at the end of the study period. Only subjects aged 18 years were considered; no diagnostic searches were performed in pediatric clinics. Clinical, pathological, and radiological records were reviewed in all cases and were validated according to a standard protocol. Information collected in the protocol included sex, date of birth, date of diagnosis, date of death, date of loss of follow-up, and diagnostic workup, including all cholangiographic examinations, liver biopsies, and results of relevant blood tests. The diagnosis of large duct SC was defined using Mayo criteria: (1) laboratory findings consistent with cholestasis including elevated serum alkaline phosphatase; (2) characteristic radiological findings proven by endoscopic, percutaneous, or perioperative cholangiography or magnetic resonance cholangiopancreaticography (MRC); and (3) no evidence for secondary sclerosing cholangitis. 11 Cases were defined as small duct SC when no evidence for biliary tract disease was detected on cholangiography but histopathology from liver biopsy showed features of SC and criterion 1 and 3 were present. Clinical data at diagnosis, laboratory findings, extension of biliary involvement (intrahepatic, extrahepatic, intrahepatic and extrahepatic, or small duct disease), and date of first biochemical sign or symptom of SC were extracted from clinical records. The confluence of the bile ducts at the hilum was used to distinguish between the extra and intrahepatic bile duct system. In three cases, the diagnosis was established on symptoms, laboratory findings, and liver biopsy alone without any cholangiographic imaging performed; these cases were classified as unknown extension. Cases of SC were classified as related or not related to IBD and large or small duct SC. Overlapping autoimmune hepatitis was not considered a criterion for exclusion. Two different investigators, working in close contact, reviewed all cases. Cases with a doubtful diagnosis were discussed between all investigators in order to obtain a uniform case ascertainment. Annual age-stratified data on the population of Västra Götaland was obtained from Statistics Sweden ( The national registration at Statistics Sweden was used to establish residency in all cases in order to identify patients who resided outside Västra Götaland at the time of diagnosis or moved outside the region during the study period and to obtain dates of death. Statistical Methods. oint prevalence of SC was calculated from the number of SC patients aged 18 years residing in Västra Götaland as of December 31, atients who were diagnosed outside Västra Götaland and moved into the region before this date were included in the analysis. atients who had died, undergone liver transplantation, or moved outside the region before this date were excluded from prevalence estimates. Incident cases of SC were defined as patients 18 years of age who fulfilled the criteria for SC and resided in Västra Götaland at the time of diagnosis. atients who were diagnosed outside Västra Götaland or resided outside the region at the time of diagnosis were excluded from incidence estimates. Age at diagnosis was categorized into nine groups: years, years, years, years, years, years, years, years, and >95 years. Changes in age and sex composition of the

3 HEATOLOGY, Vol. 52, No. 2, 2010 LINDKVIST ET AL. 573 Table 1. Incident Cases of SC in an Adult opulation of Västra Götaland, Sweden, Factor Category Sub Category All (N 5 199) Men (n 5 142) Women (n 5 57) Age in years, median (range) 38.5 ( ) 38.7 ( ) 37.6 ( ) Inflammatory bowel disease (IBD) Yes Any IBD 152 (76.4%) 117 (82.4%) 35 (61.4%) Ulcerative colitis 129 (64.8%) 104 (73.2%) 25 (43.9%) Crohn disease 17 (8.5%) 9 (6.3%) 8 (14.0%) Indeterminate colitis 5 (2.5%) 3 (2.1%) 2 (3.5 %) Microscopic colitis 1 (0.5%) 1 (0.7%) 0 (0%) No 47 (23.6%) 25 (17.6%) 22 (38.6%) Extension of biliary involvement Only intrahepatic 61 (30.7%) 47 (33.1%) 14 (24.6%) Extrahepatic and/or intrahepatic 115 (57.8%) 81 (57.0%) 34 (59.6%) Small duct disease 20 (10.1%) 12 (8.5%) 8 (14.0%) Unknown 3 (1.5%) 2 (1.4%) 1 (1.8%) Symptoms at diagnosis Yes Any symptom 93 (46.7%) 62 (43.7%) 31 (54.4%) Jaundice 48 (24.1%) 32 (22.5%) 16 (28.1%) Cholangitis 19 (9.5%) 13 (9.2%) 6 (10.5%) Itching 20 (10.1%) 14 (9.9%) 6 (10.5%) Abdominal pain 50 (25.1%) 34 (23.9%) 16 (28.1%) Other 66 (33.2%) 48 (33.8%) 18 (31.6%) No 106 (53.3%) 80 (56.3%) 26 (45.6%) background population was adjusted for by using the annual age- and sex-specific population of Västra Götaland as a denominator in all incidence rate calculations. Crude incidence was calculated as the average annual incidence for the period oisson regression was used to simultaneously analyze temporal, age-associated, and sex-associated effects on the overall incidence rate of SC and specific incidence rates of large duct SC and SC with or without IBD. Exact oisson regression was used to analyze time trends in the incidence of small duct SC due to the small number of cases in this category. Both ageadjusted and age-stratified trends were investigated. Average annual percentage change (AAC) with a 95% confidence interval (CI) was obtained by multiplying incidence rate ratios related to year of diagnosis obtained in the adjusted oisson model by 100. The effect of age on the incidence of SC was investigated using age categories as a continuous variable. For all statistical analyses, a value of less than 0.05 was considered statistically significant. SSS version 15.0 software was used to calculate baseline characteristics. All regression analyses were performed using STATA 10 with robust standard error estimates. Results atient Characteristics. Between 1992 and 2005, a total of 199 incident cases of SC were detected in Västra Götaland; 142 (71.4%) were men and 57 (28.6%) were women. Diagnostic delay as estimated by time from first biological sign or clinical symptom of SC until the establishment of the diagnosis could be assessed in 67% (134/199) of cases. The median diagnostic delay was 16 months; this time was unchanged when comparing the first and second half of the study period (16.1 versus 16.3 months, respectively). There was a change in the use of diagnostic tools during the study. Among patients diagnosed during the first half of the study period, 84% underwent endoscopic retrograde cholangiopancreatography (ERC) and 46% underwent MRC, whereas among patients diagnosed during the second half of the study period, 45% underwent ERC and 77% underwent MRC. The demographic and clinical characteristics of these patients are presented in Table 1. Crude Incidence and revalence. The mean crude annual incidence of SC was 1.22 per 100,000 in the total population aged 18 years in Västra Götaland during the period Among men and women, the incidence was 1.78 and 0.69, respectively, in the corresponding population. The point prevalence of SC in the same population was 16.2 (23.7 among men and 8.9 among women) per 100,000 as of December 31, Time Trends in Overall Incidence of SC. Trends in age-adjusted SC incidence expressed as AAC are presented in Table 2. The overall incidence of SC increased significantly in the total adult population with an AAC of 3.06 (95% CI ) which equals an increase of 35.1 percent (95% CI ) over a 10-year period. Sex-stratified analysis showed tendencies toward increasing trends in men (AAC 2.30, 95% CI 1.35 to 6.08) and particularly in women (AAC 4.98, 95% CI 0.46 to 10.72), but none of these tendencies were statistically significant.

4 574 LINDKVIST ET AL. HEATOLOGY, August 2010 Table 2. AAC With 95% CI in the Incidence of SC in Relation to Extension of Biliary Involvement and resence or Absence of IBD All Men Women AAC (95% CI) AAC (95% CI) AAC (95% CI) All SC 3.06 ( ) ( 1.35 to 6.08) ( 0.46 to 10.72) Extension Large duct 2.13 ( 1.05 to 5.41) ( 2.95 to 4.34) ( ) Small duct 8.31 ( 3.17 to 21.76) ( ) ( to 15.67) IBD No 5.91 ( 0.64 to 12.89) ( ) ( 7.68 to 12.54) Yes 2.22 ( 1.25 to 5.82) ( 3.19 to 5.07) ( ) Time Trends in Incidence of Large and Small Duct SC. The time trends in age-adjusted incidence of large and small duct SC are presented in Table 2. There was a significant increase in the incidence of large duct SC among women (AAC 6.32, 95% CI ) but not among men (Table 2). The incidence of small duct SC increased significantly among men (AAC 17.88, 95% CI ) but not among women (Table 2). Time Trends in Incidence of IBD-Associated SC. Diverging trends were observed for the incidence of SC related to IBD when comparing men and women (Table 2). In women, there was a significant increase in the incidence of IBD-associated SC (AAC 7.01, 95% CI ), but no significant trends in the incidence of SC without concurrent IBD (Table 2). In men, the incidence of SC without IBD increased significantly (AAC 9.69, 95% CI ), but there was no statistically significant trend for IBD-associated SC (Table 2). Effects of Age on Incidence of SC. The agerelated effects on the incidence of SC are given in Table 3. Age had a strong and statistically significant influence on the incidence of IBD-associated SC and large duct SC, with a decreasing incidence with increasing age. There was no significant effect of age on the incidence of small duct SC and SC without IBD. These findings were consistent in both sexes. Discussion We investigated the prevalence and incidence of SC in a defined adult population in a regional health care unit in Sweden. The overall incidence rate of SC increased significantly over the investigated period. Stratified analysis revealed significantly increasing trends for IBD-associated SC and large duct SC among women and for SC without IBD and small duct SC among men. The prevalence of SC at the end of the study period (16.2/100,000) is the highest reported to date. To our knowledge, this is the largest population-based study of the incidence and prevalence of SC. The study s strengths are the population-based methodology, the size of the cohort, and the standardized validation of all cases. This is the first population-based study showing a statistically significant increase in the incidence of SC. Trends in the overall incidence of SC have been investigated previously in two studes from the United States 11 and the United Kingdom. 14 Both of these studies reported a tendency toward increasing incidence that did not reach statistical significance, Table 3. Incidence Rate Ratios for SC Related to Age Stratifying for Extension of Biliary Involvement and resence or Absence of IBD Men and Women Men Women IRR (95% CI) IRR (95% CI) IRR (95% CI) All SC 0.81 ( ) < ( ) < ( ) Extension Large duct 0.82 ( ) < ( ) < ( ) Small duct 0.76 ( ) ( ) ( ) IBD No 1.01 ( ) ( ) ( ) Yes 0.75 ( ) < ( ) < ( ) <0.001 The incidence rate ratio (IRR) represents the change in incidence for every 10-year increase in age, using the incidence for 18- to 25-year-olds as a reference.

5 HEATOLOGY, Vol. 52, No. 2, 2010 LINDKVIST ET AL. 575 possibly due to a lack of power owing to the relatively small cohorts. We also found significant trends in different subtypes of SC with an increase of small duct SC and SC not associated with IBD in men and large duct SC and IBD-associated SC in women. Although these trends were statistically significant, the possibility of a type I error (i.e., that these trends appeared by chance) has to be considered, as should the relatively small number of cases in each subgroup. Studies on the total incidence of IBD in Sweden during the investigation period are lacking. One study, which investigated the incidence of Crohn s disease in Stockholm, reported increasing incidence from 1991 to 1996 and thereafter a decrease in incidence from 1996 to A study from Olmsted County, Minnesota, reported increasing incidence of IBD until the early 1970s, after which the incidence rates for both Crohn disease and ulcerative colitis stabilized. 16 In our study, there was a significant increase in the incidence of IBD-associated SC but not in SC without IBD in men, and the opposite situation was observed in women, with a significantly increasing incidence of SC without IBD but not with IBD. The reasons for these diverging trends are unclear. We found a crude incidence of 1.22 and a prevalence of 16.2 per 100,000 in the present study. This finding indicates a disease duration of about 13 years, which is in accordance with the literature. 4-7 The incidence and prevalence of SC have been investigated previously in four small population-based studies (each including cases) from Norway, 10 the United States, 11 Wales, 12 and Canada. 13 Incidence rates of and prevalence rates of per 100,000 person-years have been reported in these studies. Limited data exist on the incidence of SC in Asia; one publication from Singapore indicates a significantly lower incidence than in western countries. 17 In a recent study from the United Kingdom, the incidence and prevalence of SC was studied in the General ractice Research Database. 14 Even though that study was not based on a general population, it is less likely to encounter the problems of studies performed at referral centers with biased selection of cases and difficulties in determinating the population at risk when calculating incidence ratios. It was also considerably larger than previous population-based studies, including 149 incident cases with SC. Markedly lower prevalence (3.85/100,000) and incidence (0.41/ 100,000) was reported in this study. Because these figures represent the incidence and prevalence in the General ractice Research Database and hence not the general population, they are not directly comparable with our results. Even lower incidence and prevalence rates have been reported from Spain (0.07/100,000 and 0.08/100,000, respectively), 18 the authors speculate that this may be explained by the low prevalence of IBD in Spain. A detection bias through underreporting may also have influenced these results, because the study relied on active reporting of cases by the treating physician through a questionnaire. The male/female ratio in our series (71% male patients) is similar to what has been reported in population-based studies from Norway (71%) and the United States (68%) but is slightly higher than what has been observed in the United Kingdom (62%-64%) and Canada (55%) The diagnosis of SC was associated with IBD in 76% of all cases in our study, a finding that is similar to estimates from the all other population-based studies except for Card et al. 14 from the United Kingdom, who reported a significantly lower prevalence of IBD in their population (48%); however, the investigators in that study did not have access to patient files, so some IBD diagnoses may have been missed. The median age at presentation in the present study was 38.5 years, which is also highly similar to all of the aforementioned studies, with the exception of the United Kindgdom studies, in which the mean and median age at presentation was around 15 years higher. 12,14 When comparing data on age at presentation between these studies, it is essential to bear in mind that we excluded pediatric cases from our series, whereas Kaplan et al. 13 included them. The remaining population-based studies do not state whether a search for SC patients was conducted at pediatric clinic registries. 10,11,14 Not surprisingly, the association between age and the overall incidence of SC was statistically significant. However, stratified analysis revealed that this association was only present in IBD-associated SC; the incidence of SC without IBD was not associated with age. This aspect of SC has not been studied, and further investigation into the clinical characteristics and natural course of SC with and without concurrent IBD is warranted. Certain possible methodological limitations of the study have to be taken into consideration. As in most retrospective studies, a detection bias could produce false temporal trends. The International Classification of Diseases (ninth and tenth revision) codes are not exclusive for SC but comprise all forms of cholangitis, and careful validation of the SC diagnosis is therefore mandatory. In the present study, we used the Mayo criteria for the validation of the SC diagnosis. 11 Follow-up data in case records were scrutinized

6 576 LINDKVIST ET AL. HEATOLOGY, August 2010 for other potential etiologies of cholangitis, and cases were excluded if there was a suspicion of secondary cholangitis. Applying these strict criteria for the diagnosis, we believe that the risk for overestimation of prevalence and incidence rates due to a detection bias is very low. We have only been able to search diagnostic registers from departments of surgery and internal medicine for diagnostic codes for SC. Consequently, cases that never have been seen by a surgeon or an internist/gastroenterologist have not been identified. However, patients with SC in Sweden are routinely managed by gastroenterologists and in some cases surgeons, whereas general practitioners do not provide care for these patients. Some cases may have been missed, because the early stages of SC may be without any symptoms. However, because diagnostic registers were searched until the end of 2006, we believe that most patients with an uncertain diagnosis at the end of the study period would have presented a more clear clinical picture during the following year given the natural course of the disease. New diagnostic tools or increased availability of established methods can introduce another form of detection bias. The use of MRC has increased during the study period and has partly replaced ERC as the standard diagnostic tool (presumably because of the risk of ERC-related complications). A possible detection bias related to this shift from ERC to MRC has to be considered even though the result of such a bias is difficult to predict. The sensitivity of MRC for SC changes in the biliary tree is probably inferior to that of ERC, 19 which can be predicted to result in a false decrease in the incidence of SC. However, this false trend could be compensated by a bias in the opposite direction if the total number of investigated patients and/or investigations per patient increased due to the less invasive nature of MRC. Considering the progressive nature of SC, one would expect that sooner or later the diagnosis will be made regardless of the imaging method used. Any significant detection bias would therefore manifest itself as a change in the diagnostic delay (i.e., the time from the first biochemical sign or symptom of the disease until the time when the diagnosis is established). In our study, the diagnostic delay was constant over the entire study period. This implies that although a detection bias related to the shift from MRC to ERC cannot be excluded completely, it is unlikely that it is important enough to have had any significant impact on the observed trends. The increasing use of MRC may also have led to a classification bias, because the sensitivity for subtle changes in the large bile ducts may be different from previous diagnostic methods, leading to an illusory change in the ratio between the incidence of large and small duct SC. We did not observe any trends in the incidence of small and large duct SC that would raise such a suspicion. On the contrary, trends in small duct SC were opposite in men and women and a detection bias in this aspect therefore seems unlikely since the same diagnostic work up was used in both sexes. In conclusion, we investigated the incidence and prevalence of SC in a defined population in southwestern Sweden. We confirm the clinical characteristics of SC reported in smaller population-based studies. In addition, we provide new and reliable estimates of the prevalence and incidence of SC, and our study is the first to report a significantly increasing incidence of SC. This finding may be due to improved ascertainment of the diagnosis; however, it may also reflect a true increase of SC, suggesting that the medical burden of this disease may be higher than previously estimated. References 1. Bjornsson E, Chapman RW. Sclerosing cholangitis. Curr Opin Gastroenterol 2003;19: LaRusso NF, Shneider BL, Black D, Gores GJ, James S, Doo E, et al. rimary sclerosing cholangitis: summary of a workshop. HEATOLOGY 2006;44: Weismuller TJ, Wedemeyer J, Kubicka S, Strassburg C, Manns M. The challenges in primary sclerosing cholangitis aetiopathogenesis, autoimmunity, management and malignancy. J Hepatol 2008;48(Suppl. 1):S38-S Broome U, Olsson R, Loof L, Bodemar G, Hultcrantz R, Danielsson A, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996;38: Farrant JM, Hayllar KM, Wilkinson ML, Karani J, ortmann BC, Westaby D, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology 1991;100: onsioen CY, Vrouenraets SM, rawirodirdjo W, Rajaram R, Rauws EA, Mulder CJ, et al. Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population. Gut 2002;51: Wiesner RH, LaRusso NF. Clinicopathologic features of the syndrome of primary sclerosing cholangitis. Gastroenterology 1980;79: Tischendorf JJ, Hecker H, Kruger M, Manns M, Meier N. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol 2007;102: Wiesner RH, Grambsch M, Dickson ER, Ludwig J, MacCarty RL, Hunter EB, et al. rimary sclerosing cholangitis: natural history, prognostic factors and survival analysis. HEATOLOGY 1989;10: Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol 1998;33: Bambha K, Kim WR, Talwalkar J, Torgerson H, Benson JT, Therneau TM, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology 2003;125:

7 HEATOLOGY, Vol. 52, No. 2, 2010 LINDKVIST ET AL Kingham JG, Kochar N, Gravenor MB. Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom. Gastroenterology 2004;126: Kaplan GG, Laupland KB, Butzner D, Urbanski SJ, Lee SS. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol 2007;102: Card TR, Solaymani-Dodaran M, West J. Incidence and mortality of primary sclerosing cholangitis in the UK: a population-based cohort study. J Hepatol 2008;48: Lapidus A. Crohn s disease in Stockholm County during : an epidemiological update. World J Gastroenterol 2006;12: Loftus CG, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Tremaine WJ, Melton LJ 3rd, et al. Update on the incidence and prevalence of Crohn s disease and ulcerative colitis in Olmsted County, Minnesota, Inflamm Bowel Dis 2007;13: Ang TL, Fock KM, Ng TM, Teo EK, Chua TS, Tan JY. Clinical profile of primary sclerosing cholangitis in Singapore. J Gastroenterol Hepatol 2002;17: Escorsell A, ares A, Rodes J, Solis-Herruzo JA, Miras M, de la Morena E. Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver. J Hepatol 1994;21: Weber C, Kuhlencordt R, Grotelueschen R, Wedegaertner U, Ang TL, Adam G, et al. Magnetic resonance cholangiopancreatography in the diagnosis of primary sclerosing cholangitis. Endoscopy 2008;40: