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Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis.

Publication ,  Journal Article
Trivedi, PJ; Muir, AJ; Levy, C; Bowlus, CL; Manns, MP; Lu, X; Crans, G; Chung, C; Subramanian, GM; Myers, RP; Goodman, Z; Chalasani, N ...
Published in: Clin Gastroenterol Hepatol
June 2021

BACKGROUND & AIMS: Serum alkaline phosphatase (ALP) and the enhanced liver fibrosis (ELF) score are used as endpoints in trials of patients with primary sclerosing cholangitis (PSC). We aimed to quantify inter- and intra-individual variation in levels of ALP and the ELF score over time, and evaluated their association with fibrosis progression. METHODS: We analyzed data from 234 patients with large-duct PSC enrolled in a 2-year, phase 2b placebo-controlled trial of simtuzumab. Participants were assessed by laboratory tests every 4 weeks, and liver biopsies collected at time of screening, week 48, and week 96. RESULTS: Serum levels of ALP and ELF scores did not differ significantly between simtuzumab and placebo groups, so the data were pooled. Median per-patient variations in ALP between clinic visits were approximately 12% over 12 weeks, 20% over 48 weeks, and 20% over 96 weeks. Reductions, unrelated to study intervention, of more than 40% in ALP were observed in 10.9% of patients with baseline activity greater than 2-fold the upper limit of normal (ULN) and 12.5% of patients with more than 3-fold the ULN at 1 year. At 2 years, reductions of more than 40% in ALP were observed in 15.8% of patients with baseline activity greater than 2-fold the ULN and 17.9% of patients with more than 3-fold the ULN. Among the 209 patients with Ishak fibrosis stage 0-4 at baseline, serum ALP activity did not associate with development of cirrhosis or with a 2-point increase in fibrosis stage at 2 years. In contrast, the median per-patient variation in ELF scores between clinic visits was approximately 3% over 12 weeks, 4% over 48 weeks, and 4% over 96 weeks. Elevated ELF scores at baseline and at weeks 12, 24 and 48, each associated with development of cirrhosis at 2 years (odds ratio >2.75; P < .01 for all timepoints). ELF scores at baseline and weeks 12, 24 and 48, also associated with a 2-point increase in fibrosis stage at 2 years (odds ratios all greater than 2; P < .01 for all timepoints). CONCLUSIONS: In an analysis of data from patients with large-duct PSC enrolled in a prospective trial, we found large interindividual and intraindividual variations in serum ALP activity. Serum ALP activity did not associate with disease progression over a 2-year period. Variations in ELF score were smaller, and scores determined at multiple timepoints associated with fibrosis progression and development of cirrhosis.

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Published In

Clin Gastroenterol Hepatol

DOI

EISSN

1542-7714

Publication Date

June 2021

Volume

19

Issue

6

Start / End Page

1248 / 1257

Location

United States

Related Subject Headings

  • Prospective Studies
  • Prognosis
  • Humans
  • Gastroenterology & Hepatology
  • Cholangitis, Sclerosing
  • Biomarkers
  • Alkaline Phosphatase
  • 3202 Clinical sciences
  • 1103 Clinical Sciences
 

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Trivedi, P. J., Muir, A. J., Levy, C., Bowlus, C. L., Manns, M. P., Lu, X., … Hirschfield, G. M. (2021). Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol, 19(6), 1248–1257. https://doi.org/10.1016/j.cgh.2020.07.032
Trivedi, Palak J., Andrew J. Muir, Cynthia Levy, Christopher L. Bowlus, Michael P. Manns, Xiaomin Lu, Gerald Crans, et al. “Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis.Clin Gastroenterol Hepatol 19, no. 6 (June 2021): 1248–57. https://doi.org/10.1016/j.cgh.2020.07.032.
Trivedi PJ, Muir AJ, Levy C, Bowlus CL, Manns MP, Lu X, et al. Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol. 2021 Jun;19(6):1248–57.
Trivedi, Palak J., et al. “Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis.Clin Gastroenterol Hepatol, vol. 19, no. 6, June 2021, pp. 1248–57. Pubmed, doi:10.1016/j.cgh.2020.07.032.
Trivedi PJ, Muir AJ, Levy C, Bowlus CL, Manns MP, Lu X, Crans G, Chung C, Subramanian GM, Myers RP, Goodman Z, Chalasani N, Vierling JM, Guha IN, Hirschfield GM. Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol. 2021 Jun;19(6):1248–1257.
Journal cover image

Published In

Clin Gastroenterol Hepatol

DOI

EISSN

1542-7714

Publication Date

June 2021

Volume

19

Issue

6

Start / End Page

1248 / 1257

Location

United States

Related Subject Headings

  • Prospective Studies
  • Prognosis
  • Humans
  • Gastroenterology & Hepatology
  • Cholangitis, Sclerosing
  • Biomarkers
  • Alkaline Phosphatase
  • 3202 Clinical sciences
  • 1103 Clinical Sciences