Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis

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 (R)) 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. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Peer reviewe

Automated spectrophotometric bicarbonate analysis in duodenal juice compared to the back titration method

AbstractObjectivesWe have recently evaluated a short endoscopic secretin test for exocrine pancreatic function. Bicarbonate concentration in duodenal juice is an important parameter in this test. Measurement of bicarbonate by back titration as the gold standard method is time consuming, expensive and technically difficult, thus a simplified method is warranted. We aimed to evaluate an automated spectrophotometric method in samples spanning the effective range of bicarbonate concentrations in duodenal juice. We also evaluated if freezing of samples before analyses would affect its results.MethodsPatients routinely examined with short endoscopic secretin test suspected to have decreased pancreatic function of various reasons were included. Bicarbonate in duodenal juice was quantified by back titration and automatic spectrophotometry. Both fresh and thawed samples were analysed spectrophotometrically.Results177 samples from 71 patients were analysed. Correlation coefficient of all measurements was r = 0.98 (p < 0.001). Correlation coefficient of fresh versus frozen samples conducted with automatic spectrophotometry (n = 25): r = 0.96 (p < 0.001)ConclusionsThe measurement of bicarbonate in fresh and thawed samples by automatic spectrophotometrical analysis correlates excellent with the back titration gold standard. This is a major simplification of direct pancreas function testing, and allows a wider distribution of bicarbonate testing in duodenal juice. Extreme values for Bicarbonate concentration achieved by the autoanalyser method have to be interpreted with caution

Three-dimensional surface model analysis in the gastrointestinal tract

The biomechanical changes during functional loading and unloading of the human gastrointestinal (GI) tract are not fully understood. GI function is usually studied by introducing probes in the GI lumen. Computer modeling offers a promising alternative approach in this regard, with the additional ability to predict regional stresses and strains in inaccessible locations. The tension and stress distributions in the GI tract are related to distensibility (tension-strain relationship) and smooth muscle tone. More knowledge on the tension and stress on the GI tract are needed to improve diagnosis of patients with gastrointestinal disorders. A modeling framework that can be used to integrate the physiological, anatomical and medical knowledge of the GI system has recently been developed. The 3-D anatomical model was constructed from digital images using ultrasonography, computer tomography (CT) or magnetic resonance imaging (MRI). Different mathematical algorithms were developed for surface analysis based on thin-walled structure and the finite element method was applied for the mucosa-folded three layered esophageal model analysis. The tools may be useful for studying the geometry and biomechanical properties of these organs in health and disease. These studies will serve to test the structure-function hypothesis of geometrically complex organs

Visual analogue scale (VAS).

<p>Table defining the visual analogue scale for signal intensity after Worthen & Al (37).</p><p>Visual analogue scale (VAS).</p

Development of and Gathering Validity Evidence for a Theoretical Test in Contrast-Enhanced Ultrasound.

Contrast-enhanced ultrasound (CEUS) is an imaging modality applied in a broad field of medical specialties for diagnostic uses, guidance during biopsy procedures and ablation therapies and sonoporation therapy. Appropriate training and assessment of theoretical and practical competencies are recommended before practicing CEUS, but no validated assessment tools exist. This study was aimed at developing a theoretical multiple-choice question-based test for core CEUS competencies and gathering validity evidence for the test. An expert team developed the test via a Delphi process. The test was administered to medical doctors with varying CEUS experience, and the results were used to evaluate test items, internal-consistency reliability, ability to distinguish between different proficiency levels and to establish a pass/fail score. Validity evidence was gathered according to Messick's framework. The final test with 47 test items could distinguish between operators with and without CEUS experience with acceptable reliability. The pass/fail score led to considerable risk of false positives and negatives. The test may be used as an entry test before learning practical CEUS competencies but is not recommended for certification purposes because of the risk of false positives and negatives

Inclusion flow chart.

<p>The figure displays the inclusion and exclusion of cystic fibrosis patients and healthy controls. (CF: Cystic fibrosis. CFI/CFS: Cystic fibrosis insufficient/ sufficient. HC: Healthy controls).</p

Pancreas ultrasonography.

<p>The figure is displaying a normal pancreas in pancreas sufficient patient (left) and a typical hyper echoic pancreas in an insufficient patient (Right). The Visual score graded echogenicity 1 for the left pancreas and 4 for the right pancreas. The image to the right display region of interest (ROI) for Echo intensity measures (1: Liver, 2: pancreas, 3: Vessel (superior mesenteric vein)).</p