Background & Aims
Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient
care and the development of therapy. We aimed to identify novel protein biomarkers
of disease severity and prognosis in primary sclerosing cholangitis (PSC).
Methods
Using a bead-based array targeting 63 proteins, we profiled a derivation panel of
Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls)
and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified
proteins were measured in serum from two Norwegian PSC cohorts (n = 167 [1992–2006] and n = 138 [2008–2012]), inflammatory bowel disease (n = 96) and healthy controls (n = 100).
Results
In the bile derivation panel, the levels of 14 proteins were different between PSC
patients and controls (p <0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile
derivation panel were significantly (p <0.05) different between PSC patients with mild compared to severe cholangiographic
changes (modified Amsterdam criteria); this was replicated for 18 proteins in the
validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex,
S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with
both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients
according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent
discrimination for transplant-free survival both in the serum derivation and validation
cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable
analyses in both serum panels independently of age and disease duration, indicating
an independent influence on PSC progression. However, the Enhanced Liver Fibrosis
(ELF®) test and Mayo risk score proved to be stronger predictors of transplant-free
survival.
Conclusions
Based on assaying of biliary proteins, we have identified novel biliary and serum
biomarkers as indicators of severity and prognosis in PSC.
Lay summary
Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient
care and the development of therapy. We have identified inflammatory proteins including
calprotectin and IL-8 as important indicators of disease severity and prognosis in
bile and serum from patients with primary sclerosing cholangitis.
Graphical abstract
Graphical Abstract
Keywords
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References
- Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055
- Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.Gut. 1996; 38: 610-615
- Review article: controversies in the management of primary biliary cirrhosis and primary sclerosing cholangitis.Aliment Pharmacol Ther. 2014; 39: 282-301
- Primary sclerosing cholangitis.Lancet. 2013; 382: 1587-1599
- Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management.Gastroenterology. 2013; 145: 521-536
- Surrogate endpoints for clinical trials in primary sclerosing cholangitis; review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367
- Enhanced liver fibrosis score predicts transplant-free survival in primary sclerosing cholangitis.Hepatology. 2015; 62: 188-197
- Diagnosis and management of primary sclerosing cholangitis.Hepatology. 2010; 51: 660-678
- EASL Clinical Practice Guidelines: Management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267
- Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population.Gut. 2002; 51: 562-566
- Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study).Scand J Gastroenterol. 2009; 44: 431-440
- A revised natural history model for primary sclerosing cholangitis.Mayo Clin Proc. 2000; 75: 688-694
- Multiplexed immuno-precipitation with 1725 commercially available antibodies to cellular proteins.Proteomics. 2011; 11: 4578-4582
- Antibody array analysis of labelled proteomes: how should we control specificity?.N Biotechnol. 2012; 29: 578-585
- An automated analysis of highly complex flow cytometry-based proteomic data.Cytometry A. 2012; 81: 120-129
- The lasso method for variable selection in the Cox model.Stat Med. 1997; 16: 385-395
- Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults.Am J Physiol Gastrointest Liver Physiol. 2011; 300: G303-G315
- Interleukin-8 is activated in patients with chronic liver diseases and associated with hepatic macrophage accumulation in human liver fibrosis.PLoS One. 2011; 6e21381
- Serum levels of interleukins 8 and 10, interferon gamma, granulocyte-macrophage colony stimulating factor and soluble CD23 in patients with primary sclerosing cholangitis.Autoimmunity. 1997; 26: 223-229
- Interleukin-8: A critical chemokine in biliary atresia.J Gastroenterol Hepatol. 2015; 30: 970-976
- Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis.Hepatology. 2014; 59: 2263-2275
- Calprotectin in bile: a disease severity marker in patients with primary sclerosing cholangitis.J Clin Gastroenterol. 2014; 48: 866-869
- Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis.Hepatology. 2011; 53: 875-884
- Evaluation of biliary calprotectin as a biomarker in primary sclerosing cholangitis.Medicine. 2016; 95e3510
- Monitoring disease activity by stool analyses: from occult blood to molecular markers of intestinal inflammation and damage.Gut. 2009; 58: 859-868
- Elevated interleukin-8 in bile of patients with primary sclerosing cholangitis.Liver Int. 2016; 36: 1370-1377
Article info
Publication history
Published online: February 01, 2017
Accepted:
January 20,
2017
Received in revised form:
January 3,
2017
Received:
May 11,
2016
Identification
Copyright
© 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
