Natural History of Primary Biliary Cholangitis (PBC)

The risk of liver failure and death increases as PBC progresses1,a

Natural History

Disease characteristics by stage1-5
  • Positive antimitochondrial antibodies (AMAs)
  • Normal serum biomarkers
  • Bile duct loss of function and destruction may begin
  • Increasing cholestasis
  • Liver biomarkers, such as alkaline phosphatase (ALP) and gamma-glutyamyl transpeptidase, start to increase
  • Liver fibrosis may begin and may be detected
  • Potential appearance of symptoms such as
    • Pruritus
    • Fatigue
    • Abdominal pain
    • Jaundice
  • Continuing progression of fibrosis
  • Cirrhosis and complications such as
    • Hepatic decompensation
    • Hepatocellular carcinoma
    • Portal hypertensionb
      • Variceal bleeding
      • Ascites
Natural History

Disease characteristics by stage1-5

Stage One

Silent preclinical

  • Positive antimitochondrial antibodies (AMA)
  • Normal serum biomarkers
  • Bile duct loss of function and destruction may begin

Stage Two

Asymptomatic

  • Increasing cholestasis
  • Liver biomarkers, such as alkaline phosphatase (ALP) and gamma-glutyamyl transpeptidase, start to increase
  • Liver fibrosis may begin and may be detected

Stage Three

Symptomatic

  • Potential appearance of symptoms such as
    • Pruritus
    • Fatigue
    • Abdominal pain
    • Jaundice
  • Continuing progression of fibrosis

Stage Four

Silent preterminal

  • Cirrhosis and complications such as
    • Hepatic decompensation
    • Hepatocellular carcinoma
    • Portal hypertensionb
      • Variceal bleeding
      • Ascites

aChart is a representation of possible PBC disease progression. Progression can very widely across patients.

bIn PBC, unlike in other liver diseases, portal hypertension can occur in noncirrhotic patients.5

Adapted from Selmi et al, Lancet, 2011.


Overview of PBC

  • PBC is a liver disease that primarily results from autoimmune destruction of the bile ducts that transport bile acids (BAs) out of the liver, resulting in cholestasis1
  • As PBC progresses, persistent toxic buildup of BAs causes progressive liver damage6,7
  • If left untreated, or if a patient does not respond adequately to treatment, chronic inflammation and fibrosis can advance to cirrhosis and liver failure1
  • Disease progression in PBC is usually relatively slow, but can vary significantly2
  • Without intervention:
    • A significant number of patients progress to liver failure, transplant, or death within 5 to 10 years8,9
    • Some patients with PBC may experience rapid disease progression and advance through histological stages as rapidly as every 2 years10
  • Since 1988 PBC has been the second leading cause of liver transplant in women in the United States, behind hepatitis C11
  • Typical initial presentation occurs between 30 and 65 years of age12
  • An estimated 90% of patients are women12
  • Fatigue and pruritus are the most common symptoms in patients with PBC, and their impact on daily life can be significant9,13,14
  • In a Canadian study of patients with PBC, the standardized mortality ratio was 2.87 (95% CI, 1.38-4.63)15,16

Survival of treated patients with early-, moderately advanced–, and advanced-stage PBC17

Natural History

Adapted from Kuiper et al, Gastroenterology, 2009.
The Dutch multicenter PBC study was a prospective cohort study to determine transplant-free survival of patients with PBC treated with UDCA. One hundred and ninety-one patients with early-stage PBC, 87 patients with moderately advanced–stage PBC, and 33 patients with advanced-stage PBC were compared with the general Dutch population. Survival of treated patients with early-stage PBC was comparable to survival of the control population. Survival of treated patients with moderately advanced–stage PBC was significantly worse than that of the general Dutch population.


Early treatment may reduce the risk of poor outcomes17

When treatment is delayed until PBC has progressed, survival is significantly worse than that seen in the general population.17

  • Survival for patients with early-stage PBC was comparable to survival for the control population (P=.254)17
  • Survival for patients with (moderately) advanced-stage PBC was significantly worse than for the control population (P<.001)17

References:  1. Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52(5):745-758. doi:10.1016/j.jhep.2009.11.027.  2. Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis. Lancet. 2011;377(9777):1600-1609. doi:10.1016/S0140-6736(10)61965-4.  3. Silveira MG, Brunt EM, Heathcote J, Gores GJ, Lindor KD, Mayo MJ. American Association for the Study of Liver Diseases endpoints conference: design and endpoints for clinical trials in primary biliary cirrhosis. Hepatology. 2010;52(1):349-359. doi:10.1002/hep.23637.  4. European Association for the Study of the Liver. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237-267. doi:10.1016/j.jhep.2009.04.009.  5. Crosignani A, Battezzati PM, Invernizzi P, Selmi C, Prina E, Possa M. Clinical features and management of primary biliary cirrhosis. World J Gastroenterol. 2008;14(21):3313-3327. doi:10.3748/wjg.14.3313.  6. Scheuer PJ. Ludwig Symposium on biliary disorders—part II. Pathologic features and evolution of primary biliary cirrhosis and primary sclerosing cholangitis. Mayo Clin Proc. 1998;73(2):179-183. doi:10.1016/s0025-6196(11)63652-5.  7. Poupon R, Chrétien Y, Poupon RE, Ballet F, Calmus Y, Darnis F. Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet. 1987;1(8537):834-836. doi:10.1016/S0140-6736(87)91610-2.  8. Al-Harthy N, Kumagi N. Natural history and management of primary biliary cirrhosis. Hepat Med. 2012;4:61-71. doi:10.2147/HMER.S25998.   9. Prince M, Chetwynd A, Newman W, Metcalf JV, James OFW. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology. 2002;123(4):1044-1051. doi:10.1053/gast.2002.36027.  10. Locke GR III, Therneau TM, Ludwig J, Dickson ER, Lindor KD. Time course of histological progression in primary biliary cirrhosis. Hepatology. 1996;23(1):52-56. doi:10.1053/jhep.1996.v23.pm0008550048.  11. Organ Procurement and Transplantation Network. US Health Resources and Services Administration website. http://optn.transplant.hrsa.gov/converge/latestData/rptData.asp. Updated May 22, 2015. Accessed August 20, 2015.  12. Primary biliary cirrhosis (PBC). American Liver Foundation website. http://www.liverfoundation.org/abouttheliver/info/pbc. Updated May 7, 2015. Accessed August 20, 2015.  13. Bergasa NV. The pruritus of cholestasis. J Hepatol. 2005;43(6):1078-1088. doi:10.1016/j.jhep.2005.09.004.  14. Rishe E, Azarm A, Bergasa NV. Itch in primary biliary cirrhosis: a patients’ perspective. Acta Derm Venereol. 2008;88(1):34-37. doi:10.2340/00015555-0350..  15. Blachier M, Leleu H, Peck-Radosavljevic M, Valla D-C, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58(3):593-608. doi:10.1016/j.jhep.2012.12.005.  16. Springer J, Cauch-Dudek K, O’Rourke K, Wanless IR, Heathcote EJ. Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis. Am J Gastroenterol. 1999;94(1):47-53. doi:10.1111/j.1572-0241.1999.00770.x.  17. Kuiper EMM, Hansen BE, De Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136(4):1281-1287. doi:10.1053/j.gastro.2009.01.003.