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Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: A systematic review

Open AccessPublished:January 16, 2012DOI:https://doi.org/10.1016/j.jhep.2011.10.025

      Summary

      Objective

      Studies on the epidemiology of primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) show variable outcome. We aimed at systematically reviewing the incidence and prevalence rates, as well as geographical distribution and temporal trends of PSC and PBC.

      Data sources

      A systematic search of literature was performed in Medline and EMBASE (search last conducted January 10th, 2011).

      Study selection

      Population-based epidemiological studies reporting incidence and/or prevalence rates for PSC or PBC in a defined geographical area of at least 100,000 adult inhabitants were considered relevant.

      Data extraction

      Study area, study period, number of patients, number of inhabitants, incidence per 100,000 inhabitants per year, prevalence per 100,000 inhabitants, method of case-finding, method of case-ascertainment, male/female ratio and in case of PSC, occurrence of inflammatory bowel diseases (IBD) were extracted from retrieved articles.

      Results

      The literature search yielded 2286 abstracts of which 31 articles fulfilled all inclusion criteria. Studies varied in size from 10 to 770 patients in catchment areas from 100,312 to 19,230,000 inhabitants. The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 inhabitants/year and 0–16.2 per 100,000 inhabitants, respectively. PBC incidence rates range from 0.33 to 5.8 per 100,000 inhabitants/year and prevalence rates range from 1.91 to 40.2 per 100,000 inhabitants; prevalence rates are increasing in time.

      Conclusions

      Incidence and prevalence rates of both PSC and PBC vary widely and seem to be increasing. True population-based studies are scarce and therefore large population-based studies combining meticulous case-finding and case-ascertainment strategies are necessary.

      Abbreviations:

      PSC (primary sclerosing cholangitis), PBC (primary biliary cirrhosis), IBD (inflammatory bowel disease), UDCA (ursodeoxycolic acid), MOOSE (Meta-analysis Of Observational Studies in Epidemiology), ICD (International Classification of Diseases), ERCP (endoscopic retrograde cholangiopancreatography), MRCP (magnetic resonance cholangiopancreatography), AMA (antimitochondrial antibodies)

      Keywords

      Introduction

      Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are enigmatic cholestatic liver diseases ultimately resulting in cirrhosis and liver failure. Both diseases are considered complex genetic diseases, but the etiopathogenesis is still unknown [
      • Karlsen T.H.
      • Schrumpf E.
      • Boberg K.M.
      Primary sclerosing cholangitis.
      ,
      • Nguyen D.L.
      • Juran B.D.
      • Lazaridis K.N.
      Primary biliary cirrhosis.
      ]. PSC is more common in men than in women (2:1) and can occur at any age with a peak incidence around 40. PSC is strongly associated with inflammatory bowel diseases (IBD), most often ulcerative colitis, and patients have an increased risk for developing colorectal and hepatobiliary malignancies [
      • Claessen M.M.
      • Vleggaar F.P.
      • Tytgat K.M.
      • Siersema P.D.
      • van Buuren H.R.
      High lifetime risk of cancer in primary sclerosing cholangitis.
      ,
      • Bergquist A.
      • Ekbom A.
      • Olsson R.
      • Kornfeldt D.
      • Loof L.
      • Danielsson A.
      • et al.
      Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.
      ]. The course of PSC is highly variable with reported median survival rates until liver transplantation or death from 12 to 18 years [
      • Ponsioen C.Y.
      • Vrouenraets S.M.
      • Prawirodirdjo W.
      • Rajaram R.
      • Rauws E.A.
      • Mulder C.J.
      • et al.
      Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population.
      ]. PBC on the other hand predominantly affects middle aged or elderly women (1:9). Common symptoms associated with PSC and PBC are pruritus, fatigue and upper abdominal discomfort. However, more than 50% of patients are asymptomatic at time of diagnosis [
      • Prince M.I.
      • Chetwynd A.
      • Craig W.L.
      • Metcalf J.V.
      • James O.F.
      Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort.
      ,
      • 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.
      ]. Multifocal strictures and dilatations of the intra- and/or extra-hepatic bile ducts seen on cholangiography are hallmarks of PSC, although these can also be found in secondary sclerosing cholangitis due to cholelithiasis, biliary surgery, IgG4-associated cholangitis or various other causes [
      • Abdalian R.
      • Heathcote E.J.
      Sclerosing cholangitis: a focus on secondary causes.
      ]. Antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex are a sensitive serological hallmark of PBC [
      • Nishio A.
      • Keeffe E.B.
      • Gershwin M.E.
      Immunopathogenesis of primary biliary cirrhosis.
      ]. Ursodeoxycholic acid (UDCA) improves serum liver tests, histologic features and survival of PBC patients [
      • Beuers U.
      • Boyer J.L.
      • Paumgartner G.
      Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications.
      ,
      • Corpechot C.
      • Carrat F.
      • Bahr A.
      • Chretien Y.
      • Poupon R.E.
      • Poupon R.
      The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis.
      ,
      • Kuiper E.M.
      • Hansen B.E.
      • de Vries R.A.
      • den Ouden-Muller J.W.
      • van Ditzhuijsen T.J.
      • Haagsma E.B.
      • et al.
      Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid.
      ]. In PSC, the beneficial role of UDCA in disease progression and survival is still unproven [
      • Lindor K.D.
      Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group.
      ,
      • Lindor K.D.
      • Kowdley K.V.
      • Luketic V.A.
      • Harrison M.E.
      • McCashland T.
      • Befeler A.S.
      • et al.
      High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.
      ]. Several studies have investigated the epidemiology of both diseases, using different case-finding and case-ascertainment strategies. The reported incidence and prevalence figures show quite some variation, depending on the applied search strategy, the population under study, and the scrutiny of case-finding and ascertainment. We aimed at systematically reviewing the literature on incidence and prevalence rates and temporal trends for PSC and PBC.

      Methods

       Literature search

      A systematic search of the medical literature was performed using the checklist proposed by the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group with assistance of a clinical librarian, in peer-reviewed medical databases Medline and EMBASE (search last conducted January 10th, 2011) [
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • Olkin I.
      • Williamson G.D.
      • Rennie D.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      ]. The following strategy was used to search Medline: (((“Cholangitis, Sclerosing”[Mesh]) OR (primary sclerosing cholangitis∗[tiab]) OR (“liver cirrhosis, biliary”[Mesh]) OR (primary biliary cirrhosis∗[tiab])) AND ((“epidemiology”[subheading]) OR (epidemiol∗[tiab]) OR (“Incidence”[Mesh]) OR (incidenc∗[tiab]) OR (prevalen∗[tiab]) OR (“prevalence”[Mesh]))).
      The following strategy was used to search EMBASE: (((exp primary sclerosing cholangitis) OR (primary sclerosing cholangitis.ti,ab.) OR (exp primary biliary cirrhosis) OR (primary biliary cirrhosis.ti,ab.)) AND ((exp EPIDEMIOLOGY/) OR (epidemiol∗.ti,ab.) OR (exp INCIDENCE/) OR (incidenc∗.ti,ab.) OR (prevalen∗ti,ab.) OR (exp PREVALENCE/))).

       Selection criteria

      Two authors (KB and CYP) independently screened title and abstract of identified articles. Population-based epidemiological studies depicting incidence and/or prevalence rates for PSC or PBC in a defined geographical area of at least 100,000 adult inhabitants were considered relevant. Full articles of potentially relevant studies were retrieved for further analysis. Disagreement was resolved by discussion. Review articles were excluded from both search strategies. There were no language restrictions.

       Data extraction

      The following data were extracted and analyzed per study: study area, study period, number of patients, number of inhabitants, incidence per 100,000 inhabitants per year, prevalence per 100,000 inhabitants, method of case-finding, method of case-ascertainment, male/female ratio and in case of PSC, occurrence of inflammatory bowel diseases. When the full text of an article was missing, the corresponding author was asked to provide complementary data.

       Quality assessment

      Appraisal of study quality was based on (1) definition of studied population, (2) case-finding method and (3) case-ascertainment criteria. The study quality was considered ‘good’ when a case-finding method combined several hospital databases in a defined catchment area and when a well-directed case-ascertainment was performed using established diagnostic criteria. Quality was considered ‘moderate’ when the case-finding strategy was insufficient with a reasonable chance to miss cases or case-ascertainment was not performed by an expert panel using established diagnostic criteria. The quality of a study was considered ‘poor’ when case-finding or case-ascertainment had not been performed.

      Results

      The search yielded 2286 abstracts of which 30 articles in English and one in Norwegian were eligible for inclusion. Two thousand two hundred and twenty three articles were excluded based on title and abstract. For the remaining 63 articles, reasons for exclusion are depicted in Fig. 1.

       Study characteristics

      Of included articles, 19 reported incidence or prevalence rates in Europe [
      • Hamlyn A.N.
      • Macklon A.F.
      • James O.
      Primary biliary cirrhosis: geographical clustering and symptomatic onset seasonality.
      ,
      • Triger D.R.
      Primary biliary cirrhosis: an epidemiological study.
      ,
      • Danielsson A.
      • Boqvist L.
      • Uddenfeldt P.
      Epidemiology of primary biliary cirrhosis in a defined rural population in the northern part of Sweden.
      ,
      • Eriksson S.
      • Lindgren S.
      The prevalence and clinical spectrum of primary biliary cirrhosis in a defined population.
      ,
      • Lofgren J.
      • Jarnerot G.
      • Danielsson D.
      • Hemdal I.
      Incidence and prevalence of primary biliary cirrhosis in a defined population in Sweden.
      ,
      • Almdal T.P.
      • Sorensen T.I.
      Incidence of parenchymal liver diseases in Denmark, 1981 to 1985: analysis of hospitalization registry data. The Danish Association for the Study of the Liver.
      ,
      • Myszor M.
      • James O.F.
      The epidemiology of primary biliary cirrhosis in north-east England: an increasingly common disease?.
      ,
      • Remmel T.
      • Remmel H.
      • Uibo R.
      • Salupere V.
      Primary biliary cirrhosis in Estonia. With special reference to incidence, prevalence, clinical features, and outcome.
      ,
      • Berdal J.E.
      • Ebbesen J.
      • Rydning A.
      Incidence and prevalence of autoimmune liver diseases.
      ,
      • James O.F.
      • Bhopal R.
      • Howel D.
      • Gray J.
      • Burt A.D.
      • Metcalf J.V.
      Primary biliary cirrhosis once rare, now common in the United Kingdom?.
      ,
      • Metcalf J.V.
      • Bhopal R.S.
      • Gray J.
      • Howel D.
      • James O.F.
      Incidence and prevalence of primary biliary cirrhosis in the city of Newcastle upon Tyne, England.
      ,
      • Boberg K.M.
      • 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.
      ,
      • Rautiainen H.
      • Salomaa V.
      • Niemela S.
      • Karvonen A.L.
      • Nurmi H.
      • Isoniemi H.
      • et al.
      Prevalence and incidence of primary biliary cirrhosis are increasing in Finland.
      ,
      • Eaton W.W.
      • Rose N.R.
      • Kalaydjian A.
      • Pedersen M.G.
      • Mortensen P.B.
      Epidemiology of autoimmune diseases in Denmark.
      ,
      • Pla X.
      • Vergara M.
      • Gil M.
      • Dalmau B.
      • Cistero B.
      • Bella R.M.
      • et al.
      Incidence, prevalence and clinical course of primary biliary cirrhosis in a Spanish community.
      ,
      • Escorsell A.
      • Pares A.
      • Rodes J.
      • Solis-Herruzo J.A.
      • Miras M.
      • de la Morena E.
      Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver.
      ,
      • Card T.R.
      • Solaymani-Dodaran M.
      • West J.
      Incidence and mortality of primary sclerosing cholangitis in the UK: a population-based cohort study.
      ,
      • Kingham J.G.
      • Kochar N.
      • Gravenor M.B.
      Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom.
      ,
      • Lindkvist B.
      • Benito d V.
      • Gullberg B.
      • Bjornsson E.
      Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden.
      ], seven in North-America [
      • Byron D.
      • Minuk G.Y.
      Clinical hepatology: profile of an urban, hospital-based practice.
      ,
      • Kim W.R.
      • Lindor K.D.
      • Locke III, G.R.
      • Therneau T.M.
      • Homburger H.A.
      • Batts K.P.
      • et al.
      Epidemiology and natural history of primary biliary cirrhosis in a US community.
      ,
      • Hurlburt K.J.
      • McMahon B.J.
      • Deubner H.
      • Hsu-Trawinski B.
      • Williams J.L.
      • Kowdley K.V.
      Prevalence of autoimmune liver disease in Alaska Natives.
      ,
      • Myers R.P.
      • Shaheen A.A.
      • Fong A.
      • Burak K.W.
      • Wan A.
      • Swain M.G.
      • et al.
      Epidemiology and natural history of primary biliary cirrhosis in a Canadian health region: a population-based study.
      ,
      • Bambha K.
      • Kim W.R.
      • Talwalkar J.
      • Torgerson H.
      • Benson J.T.
      • Therneau T.M.
      • et al.
      Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community.
      ,
      • Kaplan G.G.
      • Laupland K.B.
      • Butzner D.
      • Urbanski S.J.
      • Lee S.S.
      The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis.
      ,
      • Witt-Sullivan H.
      • Heathcote J.
      • Cauch K.
      • Blendis L.
      • Ghent C.
      • Katz A.
      • et al.
      The demography of primary biliary cirrhosis in Ontario, Canada.
      ], three in Asia [
      • Delgado J.
      • Sperber A.D.
      • Novack V.
      • Delgado B.
      • Edelman L.
      • Gaspar N.
      • et al.
      The epidemiology of primary biliary cirrhosis in southern Israel.
      ,
      • Chong V.H.
      • Telisinghe P.U.
      • Jalihal A.
      Primary biliary cirrhosis in Brunei Darussalam.
      ,
      • Ang T.L.
      • Fock K.M.
      • Ng T.M.
      • Teo E.K.
      • Chua T.S.
      • Tan J.Y.
      Clinical profile of primary sclerosing cholangitis in Singapore.
      ], and two in Australia [
      • Watson R.G.
      • Angus P.W.
      • Dewar M.
      • Goss B.
      • Sewell R.B.
      • Smallwood R.A.
      Low prevalence of primary biliary cirrhosis in Victoria, Australia. Melbourne Liver Group.
      ,
      • Sood S.
      • Gow P.J.
      • Christie J.M.
      • Angus P.W.
      Epidemiology of primary biliary cirrhosis in Victoria, Australia: high prevalence in migrant populations.
      ]. Studies varied in size from 10 to 770 patients in catchment areas from 100,312 to 19,230,000 inhabitants.
      Various sources had been used for case-finding purposes. In 17 studies, a search was performed in a medical record database using the International Classification of Diseases (ICD) or a similar diagnosis coding system. Other sources were laboratory databases, pathology databases, personal registry of physicians, radiological databases, hospital billing system and death certificates. Of the 31 included studies, 13 (41.9%) used one source for case-finding, three studies (9.7%) used two sources, seven studies (22.6%) used three sources, five studies (16.1%) used four sources, two studies (6.5%) used five sources and one study (3.2%) combined six sources for case-finding. An overview is given in Table 1, Table 2. A quality assessment of case-finding and case-ascertainment methods is presented in Table 3. Studies of good quality are highlighted in Table 1, Table 2 and incidence and prevalence rates are shown in Fig. 2, Fig. 3.
      Table 1Incidence and prevalence of primary sclerosing cholangitis.
      Studies fulfilling all quality criteria regarding (1) definition of studied population, (2) case-finding method, and (3) case-ascertainment criteria are highlighted in blue.
      aCase-ascertainment criteria: I, clinical features; II, serum AP↑ ⩾6 months; III, ERCP or MRCP; IV, liver biopsy; V, no signs of secondary sclerosing cholangitis; VI, inflammatory bowel disease.
      §Per 100,000 inhabitants.
      ICD, International Classification of Diseases; IBD, inflammatory bowel disease; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography; n.a., not available; ?, unknown.
      Table 2Incidence and prevalence of primary biliary cirrhosis.
      Studies fulfilling all quality criteria regarding (1) definition of studied population, (2) case-finding method, and (3) case-ascertainment criteria are highlighted in blue.
      bCase-ascertainment criteria: I, AMA; IIa, serum AP↑ ⩾6 months; IIb, cholestatic liver parameters; III, liver biopsy; IV, IgM↑.
      §Per 100,000 inhabitants.
      AMA, antimitochondrial antibodies; ICD, International Classification of Diseases; n.a., not available; ?, unknown.
      Table 3Quality assessment of all included studies.
      +, good; ±, moderate; -, absent or poor; ?, unknown.
      Studies are ranged according to quality assessment score and year of publication with last published highest.
      Scoring studies on top.
      Figure thumbnail gr2
      Fig. 2Incidence of primary sclerosing cholangitis and primary biliary cirrhosis (considering high quality studies only).
      Figure thumbnail gr3
      Fig. 3Prevalence of primary sclerosing cholangitis and primary biliary cirrhosis (considering high quality studies only). No PSC patients during a 17-year study period.

       PSC

      Eleven studies on the epidemiology of PSC from 1984 till 2005 were identified of which four fulfilled quality criteria for both case-ascertainment and case-finding. Three were performed in North America between 1976 and 2005, reporting incidence rates ranging from 0 to 0.92 per 100,000 inhabitants per year [
      • Hurlburt K.J.
      • McMahon B.J.
      • Deubner H.
      • Hsu-Trawinski B.
      • Williams J.L.
      • Kowdley K.V.
      Prevalence of autoimmune liver disease in Alaska Natives.
      ,
      • Bambha K.
      • Kim W.R.
      • Talwalkar J.
      • Torgerson H.
      • Benson J.T.
      • Therneau T.M.
      • et al.
      Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community.
      ,
      • Kaplan G.G.
      • Laupland K.B.
      • Butzner D.
      • Urbanski S.J.
      • Lee S.S.
      The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis.
      ]. In Alaska, no PSC patients were identified between 1984 and 2000 [
      • Hurlburt K.J.
      • McMahon B.J.
      • Deubner H.
      • Hsu-Trawinski B.
      • Williams J.L.
      • Kowdley K.V.
      Prevalence of autoimmune liver disease in Alaska Natives.
      ]. In Canada, 49 PSC patients were diagnosed in a 5-year period in a population of 1,112,521 corresponding to an incidence rate of 0.92 per 100,000 inhabitants per year [
      • Kaplan G.G.
      • Laupland K.B.
      • Butzner D.
      • Urbanski S.J.
      • Lee S.S.
      The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis.
      ]. One prospective population-based study from Norway included 17 newly diagnosed PSC patients in a 10-year period, between 1986 and 1995, resulting in an incidence rate of 1.31 per 100,000, still the highest incidence rate for PSC found worldwide [
      • Boberg K.M.
      • 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.
      ].
      Eight studies reported the proportion of concomitant IBD in PSC patients ranging from 20% in Singapore up to 76% in Sweden [
      • Boberg K.M.
      • 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.
      ,
      • Escorsell A.
      • Pares A.
      • Rodes J.
      • Solis-Herruzo J.A.
      • Miras M.
      • de la Morena E.
      Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver.
      ,
      • Card T.R.
      • Solaymani-Dodaran M.
      • West J.
      Incidence and mortality of primary sclerosing cholangitis in the UK: a population-based cohort study.
      ,
      • Kingham J.G.
      • Kochar N.
      • Gravenor M.B.
      Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom.
      ,
      • Lindkvist B.
      • Benito d V.
      • Gullberg B.
      • Bjornsson E.
      Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden.
      ,
      • Bambha K.
      • Kim W.R.
      • Talwalkar J.
      • Torgerson H.
      • Benson J.T.
      • Therneau T.M.
      • et al.
      Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community.
      ,
      • Kaplan G.G.
      • Laupland K.B.
      • Butzner D.
      • Urbanski S.J.
      • Lee S.S.
      The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis.
      ,
      • Ang T.L.
      • Fock K.M.
      • Ng T.M.
      • Teo E.K.
      • Chua T.S.
      • Tan J.Y.
      Clinical profile of primary sclerosing cholangitis in Singapore.
      ]. When combining studies that met all quality criteria, the average proportion of IBD in PSC patients was 70% (67–73%) [
      • Boberg K.M.
      • 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.
      ,
      • Bambha K.
      • Kim W.R.
      • Talwalkar J.
      • Torgerson H.
      • Benson J.T.
      • Therneau T.M.
      • et al.
      Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community.
      ,
      • Kaplan G.G.
      • Laupland K.B.
      • Butzner D.
      • Urbanski S.J.
      • Lee S.S.
      The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis.
      ]. Temporal trends in PSC incidence were reported in four studies, all of which demonstrated increasing incidence rates in time [
      • Escorsell A.
      • Pares A.
      • Rodes J.
      • Solis-Herruzo J.A.
      • Miras M.
      • de la Morena E.
      Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver.
      ,
      • Lindkvist B.
      • Benito d V.
      • Gullberg B.
      • Bjornsson E.
      Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden.
      ,
      • Kaplan G.G.
      • Laupland K.B.
      • Butzner D.
      • Urbanski S.J.
      • Lee S.S.
      The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis.
      ,
      • Card T.R.
      • Solaymani-Dodaran M.
      • West J.
      Incidence and mortality of primary sclerosing cholangitis in the UK: a population-based cohort study.
      ].

       PBC

      Twenty-four studies describing incidence and/or prevalence rates between 1972 and 2007 for PBC were identified. When considering studies of good quality only, the lowest and highest incidence rates for PBC were both found in Newcastle Upon Tyne, United Kingdom, 0.9 per 100,000 inhabitants per year in 1977 and 5.8 per 100,000 inhabitants per year in 1994, respectively [
      • Hamlyn A.N.
      • Macklon A.F.
      • James O.
      Primary biliary cirrhosis: geographical clustering and symptomatic onset seasonality.
      ,
      • Metcalf J.V.
      • Bhopal R.S.
      • Gray J.
      • Howel D.
      • James O.F.
      Incidence and prevalence of primary biliary cirrhosis in the city of Newcastle upon Tyne, England.
      ]. The highest prevalence rate for PBC of 40.2 per 100,000 age- and sex-matched inhabitants was found in 1995 in Olmsted County, Minnesota, USA [
      • Kim W.R.
      • Lindor K.D.
      • Locke III, G.R.
      • Therneau T.M.
      • Homburger H.A.
      • Batts K.P.
      • et al.
      Epidemiology and natural history of primary biliary cirrhosis in a US community.
      ]. When combining studies, the mean proportion of female patients was 92% (76–100%). All eight studies depicting yearly prevalence rates for several consecutive years reported increased prevalence rates in time (Fig. 4) [
      • Eriksson S.
      • Lindgren S.
      The prevalence and clinical spectrum of primary biliary cirrhosis in a defined population.
      ,
      • Myszor M.
      • James O.F.
      The epidemiology of primary biliary cirrhosis in north-east England: an increasingly common disease?.
      ,
      • Remmel T.
      • Remmel H.
      • Uibo R.
      • Salupere V.
      Primary biliary cirrhosis in Estonia. With special reference to incidence, prevalence, clinical features, and outcome.
      ,
      • James O.F.
      • Bhopal R.
      • Howel D.
      • Gray J.
      • Burt A.D.
      • Metcalf J.V.
      Primary biliary cirrhosis once rare, now common in the United Kingdom?.
      ,
      • Metcalf J.V.
      • Bhopal R.S.
      • Gray J.
      • Howel D.
      • James O.F.
      Incidence and prevalence of primary biliary cirrhosis in the city of Newcastle upon Tyne, England.
      ,
      • Boberg K.M.
      • 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.
      ,
      • Pla X.
      • Vergara M.
      • Gil M.
      • Dalmau B.
      • Cistero B.
      • Bella R.M.
      • et al.
      Incidence, prevalence and clinical course of primary biliary cirrhosis in a Spanish community.
      ,
      • Myers R.P.
      • Shaheen A.A.
      • Fong A.
      • Burak K.W.
      • Wan A.
      • Swain M.G.
      • et al.
      Epidemiology and natural history of primary biliary cirrhosis in a Canadian health region: a population-based study.
      ].
      Figure thumbnail fx4

      Discussion

      This systematic review yielded a wide range in incidence and prevalence rates as well as study quality for PSC and PBC in Europe, North America, Asia and Australia. The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 inhabitants/year and 0–16.2 per 100,000 inhabitants, respectively. In case of PBC, incidence rates range from 0.33 to 5.8 per 100,000 inhabitants/year and prevalence rates range from 1.91 to 40.2 per 100,000 inhabitants. Several causes may underlie the differences found. Improvement of diagnostic tools, increasing disease awareness, and digitalized patient registration likely contributed to the rising incidence and prevalence rates. In 1970, gastroenterologists were able for the first time to successfully cannulate the papilla of Vater and selectively intubate the ducts using a duodenoscope with omnidirectional angulation, the first ERCP [
      • Oi I.
      Fiberduodenoscopy and endoscopic pancreatocholangiography.
      ]. A disadvantage of ERCP is the risk of pancreatitis, bleeding or perforation. More than 20 years after the introduction of ERCP, MRCP was introduced making it possible to visualize the intra- and extra-hepatic ducts without the risks associated with ERCP [
      • Wallner B.K.
      • Schumacher K.A.
      • Weidenmaier W.
      • Friedrich J.M.
      Dilated biliary tract: evaluation with MR cholangiography with a T2-weighted contrast-enhanced fast sequence.
      ]. The introduction of MRCP lowered the threshold for diagnostic imaging and may have resulted in a higher frequency of cholangiographies diagnosing PSC. In 1965, antimitochondrial antibodies were identified as the most important serological marker for PBC [
      • Walker J.G.
      • Doniach D.
      • Roitt I.M.
      • Sherlock S.
      Serological tests in diagnosis of primary biliary cirrhosis.
      ]. At that time there was no effective treatment available, but that changed in 1982 when the first trials were initiated administering UDCA at a dose of 13–15 mg/kg daily, with good results [
      • Poupon R.
      • Chretien Y.
      • Poupon R.E.
      • Ballet F.
      • Calmus Y.
      • Darnis F.
      Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis?.
      ]. Improvement of diagnostic tools and disposition of therapeutic modalities likely play a role in increasing prevalence over time, but may also contribute to global differences since these tools and therapies are not equally distributed around the world.
      The introduction of computers in healthcare has been a big leap forward in clinical epidemiological research. Case-finding became easier and more accurate after the introduction of digitalized laboratory and pathology databases. Although some studies in the seventies and eighties seemed well performed, the increase in incidence and prevalence rates, especially for PBC, is in all probability partly attributable to a more exhaustive case-finding strategy using computer databases. The method stated by Metcalf and James already published in 1997 is an excellent example of a meticulous case-finding strategy and has set a standard for subsequent studies [
      • Metcalf J.
      • James O.
      The geoepidemiology of primary biliary cirrhosis.
      ]. These guidelines include: stringent case inclusion criteria; definition of date of disease onset; well-defined study period, area and population; multiple case finding methods and rigorous tracing of all possible cases [
      • Metcalf J.
      • James O.
      The geoepidemiology of primary biliary cirrhosis.
      ]. Temporal trends may partly be explained by these technological developments and case-finding strategies, yet increasing incidence and prevalence rates in time are even observed within studies. Other factors like the ones discussed below, may play a role in increasing incidence and prevalence rates and geographical differences.

       PSC

      Although true population-based studies are lacking for PSC, two factors seem to play a significant role in the global distribution of the disease: a variable frequency of IBD around the world and differences in HLA-susceptibility among ethnic groups causing population differences. A recent review combining 47 studies concerning the epidemiology of Crohn’s disease showed a wide variety in incidence and prevalence rates with the highest numbers found in Northern Europe, New Zealand and North America, and lowest numbers in South America, Africa and Asia [
      • Economou M.
      • Pappas G.
      New global map of Crohn’s disease: genetic, environmental, and socioeconomic correlations.
      ]. Recently, a large PSC cohort listed for liver transplantation in the United States was clinically and genetically investigated. The authors were able to demonstrate that the risk of being listed for liver transplantation is significantly associated with ancestral origin and that phenotype differences in PSC exist across ethnicities [
      • Bowlus C.L.
      • Li C.S.
      • Karlsen T.H.
      • Lie B.A.
      • Selmi C.
      Primary sclerosing cholangitis in genetically diverse populations listed for liver transplantation: unique clinical and human leukocyte antigen associations.
      ].
      Based on these reports, the genetic background seems to play a significant role in the etiology and global distribution of the disease. Unfortunately, no population-based epidemiological studies were performed in Africa or Asia. One study from Singapore falls short in proper case-finding method, hence it is difficult to draw conclusions [
      • Ang T.L.
      • Fock K.M.
      • Ng T.M.
      • Teo E.K.
      • Chua T.S.
      • Tan J.Y.
      Clinical profile of primary sclerosing cholangitis in Singapore.
      ]. Three out of four of the highest scoring studies were performed in North America. An outlier among these well-conducted studies in North America is a study published in 2002 [
      • Hurlburt K.J.
      • McMahon B.J.
      • Deubner H.
      • Hsu-Trawinski B.
      • Williams J.L.
      • Kowdley K.V.
      Prevalence of autoimmune liver disease in Alaska Natives.
      ]. Clinical records of all cases of autoimmune liver disease at the Alaska Native Medical Center from 1983 till June 2000 were reviewed. Only one referral center in a population of 100,312 provides a solid foundation for an epidemiological study, even though the authors estimate that 10–20% of Alaska natives seek medical care outside the health care delivery system. Strikingly, no PSC patients were found in a 17-year period. A possible explanation may be the low incidence of inflammatory bowel disease in this population consisting of Eskimo’s, Aleuts and Indians.
      With a catchment area of 19,230,000 inhabitants, the study of Escorsell et al. in Spain between 1984 and 1988 is the largest ever conducted [
      • Escorsell A.
      • Pares A.
      • Rodes J.
      • Solis-Herruzo J.A.
      • Miras M.
      • de la Morena E.
      Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver.
      ]. Unfortunately, the case-finding and case-ascertainment method based on a questionnaire sent to gastroenterologists and hepatologists is insufficient for population-based epidemiology.
      Recently, a systematic review and meta-analysis of the incidence of PSC has been published. Six population-based studies form North America and Europe resulted in a combined incidence rate of 1.0 (0.82–1.17) per 100,000 inhabitants [
      • Molodecky N.A.
      • Kareemi H.
      • Parab R.
      • Barkema H.W.
      • Quan H.
      • Myers R.P.
      • et al.
      Incidence of primary sclerosing cholangitis: a systematic review and meta-analysis.
      ]. Incidence rates did not differ when stratified for continent. However, the study from the Alaska Native Medical Center was not included in this analysis.

       PBC

      Between 1972 and 2007, 23 articles have been published describing incidence and prevalence of PBC. Since the introduction of the guidelines for proper epidemiological studies by Metcalf and James in 1997, the quality of studies improved [
      • Metcalf J.
      • James O.
      The geoepidemiology of primary biliary cirrhosis.
      ]. The highest incidence and prevalence rates to date have been found in Olmsted County, USA, and Newcastle upon Tyne, UK, pointing towards possible geographic or genetic risk factors. However, until 2005 no studies were performed outside the Western world. In 2005, the first study from the Middle East was published, identifying 47 women in Southern Israel resulting in an overall prevalence rate of 5.5 per 100,000 inhabitants, a 7-fold lower prevalence rate compared to the UK and USA [
      • Delgado J.
      • Sperber A.D.
      • Novack V.
      • Delgado B.
      • Edelman L.
      • Gaspar N.
      • et al.
      The epidemiology of primary biliary cirrhosis in southern Israel.
      ]. Five years later, an even lower prevalence rate was found in Brunei Darussalam, Southeast Asia [
      • Chong V.H.
      • Telisinghe P.U.
      • Jalihal A.
      Primary biliary cirrhosis in Brunei Darussalam.
      ]. Ten patients were identified in a catchment area of 390,000 inhabitants. Strikingly, the prevalence rate in the Chinese population was almost twice as high as in the Malay population (4.1 per 100,000 and 2.3 per 100,000, respectively), though the small number of patients is a limitation of the study. Notable differences in sex ratio were found. At present, it remains unclear whether there is a true variation in sex ratio among populations of different geographical areas with different ethnic backgrounds or if this is a consequence of varying study quality.The current hypothesis regarding etiology is that PBC is a complex genetic autoimmune disease, meaning that a combination of genetic susceptibility and environmental factors triggers disease. Besides infectious and life-style factors, several environmental triggers for PBC have been suggested in the last thirty years and these may partly account for differences in geographical distribution. Triger published a study in 1980 revealing a cluster of PBC patients in Sheffield, UK [
      • Triger D.R.
      Primary biliary cirrhosis: an epidemiological study.
      ]. Almost all patients in this cluster received water from a single water source. However, chemical analysis of the water did not unravel a potential trigger. Twenty years later, another study from the UK showed strong variations in geographical distribution of patients in Northeast England, but this distribution could not be explained by geographical or demographic features [
      • Prince M.I.
      • Chetwynd A.
      • Diggle P.
      • Jarner M.
      • Metcalf J.V.
      • James O.F.
      The geographical distribution of primary biliary cirrhosis in a well-defined cohort.
      ]. In New York, a significant association between a cluster of PBC patients and superfund toxic waste sites contaminated with volatile aromatic hydrocarbons and trichloroethylene was identified, supporting the hypothesis that environmental toxins play a role in development of PBC [
      • Ala A.
      • Stanca C.M.
      • Bu-Ghanim M.
      • Ahmado I.
      • Branch A.D.
      • Schiano T.D.
      • et al.
      Increased prevalence of primary biliary cirrhosis near Superfund toxic waste sites.
      ]. In conclusion, incidence and prevalence rates of both PSC and PBC vary widely and seem to be increasing. True population-based epidemiological studies are scarce, especially in PSC, so it is unclear whether these are true variations or due to methodological differences. Proper worldwide epidemiological data may help identifying etiologic factors for these complex diseases. Hence, large population-based studies combining meticulous case-finding and case-ascertainment strategies as stated by Metcalf and James are necessary and may provide clues as to possible genetic background and environmental risk factors for these chronic cholestatic diseases.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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      Linked Article

      • Biliary atresia: Does ethnicity matter?
        Journal of HepatologyVol. 57Issue 3
        • Preview
          We wish to call the readership’s attention to the recent study by Boonstra et al. [1] on the systematic review that showed that the incidence and the prevalence of primary sclerosing cholangitis and primary biliary cirrhosis vary widely based on the geographical distribution. Further, it was previously observed that the severity and the incidence of primary sclerosing cholangitis were influenced by ethnicity [2,3]. We expanded here the scope of this methodology to another biliary disease, i.e. biliary atresia (BA), which is a destructive cholangiopathy of neonates that leads to biliary cirrhosis.
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      • Reply to “Biliary atresia: Does ethnicity matter?”
        Journal of HepatologyVol. 57Issue 3
        • Preview
          We welcome the comment of Girard et al. [1] to our systematic review on the epidemiology of primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) [2]. The authors underscore the need for proper assessment of ethnicity in epidemiological studies of rare diseases such as biliary atresia, PSC, and PBC. The apparent familial risk, albeit with a low absolute risk, together with the reported genetic risk loci, point in the direction of a complex genetic predisposition belying both PSC and PBC.
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