An update on primary sclerosing cholangitis epidemiology, outcomes and quantification of alkaline phosphatase variability in a population-based cohort

  • Zeinab Bakhshi
  • Moira B. Hilscher
  • Gregory J. Gores
  • William S. Harmsen
  • Jason K. Viehman
  • Nicholas F. LaRusso
  • Andrea A. Gossard
  • Konstantinos N. Lazaridis
  • Keith D. Lindor
  • John E. EatonEmail author
Original Article—Alimentary Tract



Contemporary primary sclerosing cholangitis (PSC) population-based cohorts describing the epidemiology, natural history, and long-term fluctuations in serum alkaline phosphatase (SAP) and their prognostic relevance are lacking. Therefore, we investigated the incidence and natural history of PSC and quantified SAP fluctuations among those with PSC in Olmsted County, Minnesota over the last 41 years.


The Rochester Epidemiology Project was used to identify 56 subjects diagnosed with PSC between 1976 and 2017 in Olmsted County. The primary endpoint (n = 19) included liver transplantation, hepatic decompensation, and cholangiocarcinoma.


The age- and sex-adjusted incidence of PSC (per 100,000 person years) nearly doubled from 2001 to 2017 compared to 1976–2000 (1.47; 95% CI 0.99–1.96 versus 0.79; 95% CI 0.42–1.16, p = 0.02). This increase paralleled a rise in patients with markers of a milder phenotype at the time of diagnosis: normal SAP (26.32% versus 0%, p < 0.01) and lower Mayo PSC risk score [0.36 (− 0.57 to 1.55) versus − 0.50 (− 1.25 to 0.35), p = 0.03]. Intra-individual SAP fluctuates with a median coefficient of variation of 36.20%. SAP normalization and dropping below 1.5 × upper limit of normal (ULN) occurs at a rate of 5% and 10% per year, respectively. SAP less than 1.5 × ULN was associated with a lower risk of PSC-related complications (hazard ratio 0.11; 95% CI 0.03–0.42).


The patients with PSC are increasingly being diagnosed with a milder phenotype. While a lower SAP is associated with improved outcomes, the high intra-individual variation of SAP levels calls into question the practice of using a single SAP value as a surrogate endpoint in clinical trials.


Primary sclerosing cholangitis Cirrhosis Liver function tests Epidemiology Cholangiocarcinoma 



Primary sclerosing cholangitis


Inflammatory bowel disease


Serum alkaline phosphatase


Upper limit of normal


Rochester epidemiologic project




Hepatic decompensation


Model for end-stage liver disease


PSC risk estimate tool


Magnetic resonance cholangiopancreatography


Confidence interval


Interquartile range


Liver transplant


Hazard ratio




Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

535_2020_1663_MOESM1_ESM.pdf (320 kb)
Survival of those with PSC versus expected survival among age and gender adjusted Olmsted County residents. (PDF 319 kb)
535_2020_1663_MOESM2_ESM.docx (13 kb)
Supplementary file2 (DOCX 12 kb)


  1. 1.
    Eaton JE, Talwalkar JA, Lazaridis KN, et al. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology. 2013;145:521–36.CrossRefGoogle Scholar
  2. 2.
    Ponsioen CY. Diagnosis, differential diagnosis, and epidemiology of primary sclerosing cholangitis. Dig Dis. 2015;33(Suppl 2):134–9.CrossRefGoogle Scholar
  3. 3.
    Williamson KD, Chapman RW. Primary sclerosing cholangitis: a clinical update. Br Med Bull. 2015;114:53–64.CrossRefGoogle Scholar
  4. 4.
    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;48:939–44.CrossRefGoogle Scholar
  5. 5.
    Eaton JE, McCauley BM, Atkinson EJ, et al. Variations in primary sclerosing cholangitis across the age spectrum. J Gastroenterol Hepatol. 2017;32:1763–8.CrossRefGoogle Scholar
  6. 6.
    Weismuller TJ, Trivedi PJ, Bergquist A, et al. Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology. 2017;152:1975.CrossRefGoogle Scholar
  7. 7.
    Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56:1181–8.CrossRefGoogle Scholar
  8. 8.
    Liu K, Wang RX, Kariyawasam V, et al. Epidemiology and outcomes of primary sclerosing cholangitis with and without inflammatory bowel disease in an Australian cohort. Liver Int. 2017;37:442–8.CrossRefGoogle Scholar
  9. 9.
    Ponsioen CY, Vrouenraets SM, Prawirodirdjo W, et al. Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population. Gut. 2002;51:562–6.CrossRefGoogle Scholar
  10. 10.
    Boonstra K, Weersma RK, van Erpecum KJ, et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology. 2013;58:2045–55.CrossRefGoogle Scholar
  11. 11.
    Stanich PP, Bjornsson E, Gossard AA, et al. Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. Dig Liver Dis. 2011;43:309–13.CrossRefGoogle Scholar
  12. 12.
    Al Mamari S, Djordjevic J, Halliday JS, et al. Improvement of serum alkaline phosphatase to %3c 1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol. 2013;58:329–34.CrossRefGoogle Scholar
  13. 13.
    Lindstrom L, Hultcrantz R, Boberg KM, et al. Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2013;11:841–6.CrossRefGoogle Scholar
  14. 14.
    Rupp C, Rossler A, Halibasic E, et al. Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis. Aliment Pharmacol Ther. 2014;40:1292–301.CrossRefGoogle Scholar
  15. 15.
    de Vries EM, Wang J, Leeflang MM, et al. Alkaline phosphatase at diagnosis of primary sclerosing cholangitis and 1 year later: evaluation of prognostic value. Liver Int. 2016;36:1867–75.CrossRefGoogle Scholar
  16. 16.
    Ponsioen CY, Chapman RW, Chazouilleres O, et al. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process. Hepatology. 2016;63:1357–67.CrossRefGoogle Scholar
  17. 17.
    Goode EC, Clark AB, Mells GF, et al. Factors associated with outcomes of patients with primary sclerosing cholangitis and development and validation of a risk scoring system. Hepatology. 2019;69:2120–35.CrossRefGoogle Scholar
  18. 18.
    Hilscher M, Enders FB, Carey EJ, et al. Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis. Ann Hepatol. 2016;15:246–53.PubMedGoogle Scholar
  19. 19.
    Thygesen LC, Ersboll AK. When the entire population is the sample: strengths and limitations in register-based epidemiology. Eur J Epidemiol. 2014;29:551–8.CrossRefGoogle Scholar
  20. 20.
    Toy E, Balasubramanian S, Selmi C, et al. The prevalence, incidence and natural history of primary sclerosing cholangitis in an ethnically diverse population. BMC Gastroenterol. 2011;11:83.CrossRefGoogle Scholar
  21. 21.
    Bambha K, Kim WR, Talwalkar J, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology. 2003;125:1364–9.CrossRefGoogle Scholar
  22. 22.
    Melton LJ III. History of the Rochester epidemiology project. Mayo Clin Proc. 1996;3:266–74.CrossRefGoogle Scholar
  23. 23.
    Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51:660–78.CrossRefGoogle Scholar
  24. 24.
    Karlsen TH, Folseraas T, Thorburn D, et al. Primary sclerosing cholangitis—a comprehensive review. J Hepatol. 2017;67:1298–323.CrossRefGoogle Scholar
  25. 25.
    Rizvi S, Eaton JE, Gores GJ. Primary sclerosing cholangitis as a premalignant biliary tract disease: surveillance and management. Clin Gastroenterol Hepatol. 2015;13:2152–65.CrossRefGoogle Scholar
  26. 26.
    Kim WR, Therneau TM, Wiesner RH, et al. A revised natural history model for primary sclerosing cholangitis. Mayo Clin Proc. 2000;7:688–94.CrossRefGoogle Scholar
  27. 27.
    Eaton JE, Vesterhus M, McCauley BM, et al. Primary sclerosing cholangitis risk estimate tool (PREsTo) predicts outcomes of the disease: a derivation and validation study using machine learning. Hepatology. 2018. Scholar
  28. 28.
    Ederer F, Axtell LM, Cutler SJ. The relative survival rate: a statistical methodology. Natl Cancer Inst Monogr. 1961;6:101–21.PubMedGoogle Scholar
  29. 29.
    Shivashankar R, Tremaine WJ, Harmsen WS, et al. Incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota from 1970 through 2010. Clin Gastroenterol Hepatol. 2017;15:857–63.CrossRefGoogle Scholar
  30. 30.
    Lindkvist B, de Valle MB, Gullberg B, et al. Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden. Hepatology. 2010;52:571–7.CrossRefGoogle Scholar
  31. 31.
    Kuo A, Gomel R, Safer R, Lindor KD, Everson GT, Bowlus CL. Characteristics and outcomes reported by patients with primary sclerosing cholangitis through an online registry. Clin Gastroenterol Hepatol. 2019;17(7):1372–8.CrossRefGoogle Scholar
  32. 32.
    Takakura WR, Tabibian JH, Bowlus CL. The evolution of natural history of primary sclerosing cholangitis. Curr Opin Gastroenterol. 2017;33:71–7.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Tischendorf JJ, Hecker H, Kruger M, et al. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol. 2007;102:107–14.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2020

Authors and Affiliations

  • Zeinab Bakhshi
    • 1
  • Moira B. Hilscher
    • 1
  • Gregory J. Gores
    • 1
  • William S. Harmsen
    • 2
  • Jason K. Viehman
    • 2
  • Nicholas F. LaRusso
    • 1
  • Andrea A. Gossard
    • 1
  • Konstantinos N. Lazaridis
    • 1
  • Keith D. Lindor
    • 3
  • John E. Eaton
    • 1
    Email author
  1. 1.Division of Gastroenterology and HepatologyMayo Clinic College of MedicineRochesterUSA
  2. 2.Division of Biomedical Statistics and InformaticsMayo ClinicRochesterUSA
  3. 3.Department of Gastroenterology and HepatologyArizona State University College of Health SolutionsPhoenixUSA

Personalised recommendations