Fluctuating biomarkers in primary sclerosing cholangitis: A longitudinal comparison of alkaline phosphatase, liver stiffness, and ELF

Guri Fossdal; Anders B Mjelle; Kristine Wiencke; Ida Bjørk; Odd Helge Gilja; Trine Folseraas; Tom Hemming Karlsen; William Rosenberg; Lasse M Giil; Mette Vesterhus

doi:10.1016/j.jhepr.2021.100328

Fluctuating biomarkers in primary sclerosing cholangitis: A longitudinal comparison of alkaline phosphatase, liver stiffness, and ELF

JHEP Rep. 2021 Jul 2;3(5):100328. doi: 10.1016/j.jhepr.2021.100328. eCollection 2021 Oct.

Authors

Guri Fossdal^{1

2

3}, Anders B Mjelle⁴, Kristine Wiencke^{1

5

6}, Ida Bjørk⁷, Odd Helge Gilja^{4

8}, Trine Folseraas^{1

5

6}, Tom Hemming Karlsen^{1

5

6

9}, William Rosenberg¹⁰, Lasse M Giil³, Mette Vesterhus^{1

2

3}

Affiliations

¹ Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
² Department of Clinical Science, University of Bergen, Bergen, Norway.
³ Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.
⁴ Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁵ Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
⁶ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁷ Department of Radiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁸ National Centre for Ultrasound in Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen, Norway.
⁹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁰ UCL Institute for Liver and Digestive Health, University College London & Royal Free London NHS Foundation Trust, London, UK.

Abstract

Background & aims: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin.

Methods: We included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin.

Results: At baseline, the median (range) ELF test was 9.3 (7.5-12.9) and median LSM 1.26 m/s (0.66-3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p = 0.005, vs. 0.12 point/year, 95% CI [0.03, 0.21], p = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86).

Conclusions: ELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC.

Lay summary: Primary sclerosing cholangitis (PSC) is characterised by substantial disease variability between patients and fluctuating liver biochemistries. Hence, new biomarkers are needed to identify individuals with an increased risk of developing end-stage liver disease. We explore the change over time of 2 putative prognostic biomarkers in PSC, the serum Enhanced Liver Fibrosis (ELF®) test and LSMs by ultrasound, demonstrating differences that may reflect differing abilities to discriminate risk.

Keywords: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Alkaline phosphatase; Biomarker; CRP, C-reactive protein; ELF, enhanced liver fibrosis; Elastography; Enhanced liver fibrosis test; FIB-4, Fibrosis-4 Index for Liver Fibrosis; GGT, gamma-glutamyl transferase; HA, hyaluronic acid; ICC, intraclass correlation; INR, international normalised ratio; IgG4, immunoglobulin G4; LSM, liver stiffness measurement; Liver stiffness; PIIINP, propeptide of type III procollagen; PSC, primary sclerosing cholangitis; Primary sclerosing cholangitis; ROI, region of interest; Risk stratification; TE, transient elastography; TIMP-1, tissue inhibitor of metalloproteinases-1; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; pSWE, point shear wave elastography.