Assessment of biochemical response in primary biliary cholangitis (PBC)

  • Studies have shown that biochemical response to ursodeoxycholic acid (UDCA) as early as 6 months can predict long-term prognosis1
  • Adequate response to UDCA may be defined as serum bilirubin less than 1 mg/dL, aspartate aminotransferase (AST) less than 2 times the upper limit of normal, and alkaline phosphatase (ALP) less than 3 times the upper limit of normal at the end of the first year of therapy2

Among the various response criteria, ALP and bilirubin are almost always included to define inadequate response.

Criteria of “biochemical response to UDCA” in PBC

Criteria name End of study responder criteria Definition of adverse outcome
Barcelona3 Decrease of serum ALP by >40% or ALP normalization (after 1 year) Death or liver transplant
Paris I4 ALP ≤3 x ULN, AST ≤2 x ULN, and serum bilirubin ≤1 mg/dL (after 1 year) Death or liver transplant
Paris II5 ALP and AST ≤1.5 x ULN and normal bilirubin level (after 1 year) Death or liver transplant
Rotterdam6 Normalization of abnormal serum bilirubin and/or albumin (after 1 year) Death or liver transplant
Toronto I7 ALP <1.67x ULN (after 2 years) Progression by ≥1
HS Progression by ≥2 HS
Toronto II7 ALP <1.67 x ULN (after 2 years)
Mayo II8 ALP ≤ 1.67 x ULN and total bilirubin ≤1 mg/dL
Abbreviations: AST, aspartate aminotransferase; HS, histological stage; ULN, upper limit of normal.
These criteria appear beneficial in predicting long-term outcomes in patients with PBC and allow identification of inadequate responders who may benefit from further trials.

In a study of 192 patients with PBC treated with UDCA for a mean of 6.8 years3:

  • Patients with treatment failure (death or transplant) were significantly older
  • Patients had poorer baseline liver biochemistries, higher Mayo risk scores, and more advanced histologic stage than those without treatment failure
  • 61% responded to treatment, based on the Barcelona criteria
  • No changes in ALP were seen in the remaining inadequate responders

Inadequate responders to UDCA

While UDCA lowers ALP in many patients with PBC, a considerable number of patients continue to have an inadequate response to treatment.5,6
  • Definitions of “inadequate response” vary across response criteria5,6
  • Biochemical response to UDCA is an essential predictor of long-term outcomes (death or liver transplant), even in patients lacking poor prognostic factors at baseline (advanced histologic stage or hyperbilirubinemia)4
  • Men and young women (<45 years of age) are more likely to have an inadequate response and are at risk for disease progression9
AASLD guidelines suggest frequent monitoring of liver biomarkers such as ALP and bilirubin10
  • Monitor ALP and bilirubin levels every 3 to 6 months10

References:  1. Zhang L-N, Shi T-Y, Shi X-H, et al. Early biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis: results of a 14-year cohort study. Hepatology. 2013;58(1):264-272. doi:10.1002/hep.26322.  2. Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52(5):745-758. doi:10.1016/j.jhep.2009.11.027.  3. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130(3):715-720. doi:10.1053/j.gastro.2005.12.029.  4. Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871-877. doi:10.1002/hep.22428.  5. Corpechot C, Chazouilléres O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol. 2011;55(6):1361-1367. doi:10.1016/j.jhep.2011.02.031.  6. 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.  7. Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 2010;105(10):2186-2194. doi:10.1038/ajg.2010.216.  8. Momah N, Silveira MG, Jorgensen R, Sinakos E, Lindor KD. Optimizing biochemical markers as endpoints for clinical trials in primary biliary cirrhosis. Liver Int. 2012;32(5):790-795. doi:10.1111/j.1478-3231.2011.02678.x.  9. Carbone M, Mells G, Pells G, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology. 2013;144(3):560-569. doi:10.1053/j.gastro.2012.12.005.  10. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ. Primary biliary cirrhosis. Hepatology. 2009;50(1):291-308. doi:10.1002/hep.22906. (AASLD guidelines)