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1. Biomarkers of tissue remodelling are elevated in serum of COVID-19 patients who develop interstitial lung disease - an exploratory biomarker study

Author

Helene Wallem Breisnes, Diana Julie Leeming, Morten Asser Karsdal, Hannah Burke, Anna Freeman, Tom Wilkinson, Aishath Fazleen, and Jannie Marie Bülow Sand

Subjects
COVID-19, ILD, Extracellular matrix, Biomarker, Neutrophil activity, Collagen, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Coronavirus disease 2019 (COVID-19) is a viral pneumonia that can result in serious respiratory illness. It is associated with extensive systemic inflammation, changes to the lung extracellular matrix, and long-term lung impairment such as interstitial lung disease (ILD). In this study, the aim was to investigate whether tissue remodelling, wound healing, and neutrophil activity is altered in patients with COVID-19 and how these relate to the development of post-COVID ILD. Method Serum samples were collected from 63 patients three months after discharge as part of the Research Evaluation Alongside Clinical Treatment study in COVID-19 (REACT COVID-19), 10 of whom developed ILD, and 16 healthy controls. Samples were quantified using neo-epitope specific biomarkers reflecting tissue stiffness and formation (PC3X, PRO-C3, and PRO-C6), tissue degradation (C1M, C3M, and C6M), wound healing (PRO-FIB and X-FIB), and neutrophil activity (CPa9-HNE and ELP-3). Results Mean serum levels of PC3X (p

Published
2024
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2. Quantification of extracellular matrix remodeling for the non-invasive identification of graft fibrosis after liver transplantation

Author

Bastian Engel, Ida Falk Villesen, Mette Juul Fisker Nielsen, Morten Karsdal, Richard Taubert, Elmar Jaeckel, and Diana Julie Leeming

Subjects
Medicine, Science
Abstract

Abstract Detecting patients with early post-transplant fibrosis after liver transplantation (LT) is very important. Non-invasive tests are needed to avoid liver biopsies. We aimed to detect fibrosis in liver transplant recipients (LTR) using extracellular matrix (ECM) remodeling biomarkers. ECM biomarkers for type III (PRO-C3), IV (PRO-C4), VI (PRO-C6) and XVIII (PRO-C18L) collagen formation and type IV collagen degradation (C4M) were measured by ELISA in prospectively collected, cryopreserved plasma samples (n = 100) of LTR with paired liver biopsies from a protocol biopsy program. Fibrosis ≥ F2 was present in 29% of patients (median 44 months post-LT). APRI and FIB-4 neither identified significant fibrosis nor were correlated with histopathological fibrosis scores, while ECM biomarkers (AUCs 0.67–0.74) did. The median levels of PRO-C3 (15.7 vs. 11.6 ng/ml; p = 0.002) and C4M (22.9 vs. 11.6 ng/ml; p = 0.006) levels were elevated in T-cell-mediated rejection compared to normal graft function. The median levels of PRO-C4 (178.9 vs. 151.8 ng/ml; p = 0.009) and C4M (18.9 vs. 16.8 ng/ml; p = 0.004) levels were increased if donor-specific antibodies were present. PRO-C6 had the highest sensitivity (100%), NPV (100%) and negative likelihood-ratio (0) for graft fibrosis. To conclude, ECM biomarkers are helpful in identifying patients at risk of relevant graft fibrosis.

Published
2023
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3. PRO-C3 is a predictor of clinical outcomes in distinct cohorts of patients with advanced liver disease

Author

Mette J. Nielsen, Grace E. Dolman, Rebecca Harris, Peder Frederiksen, Jane Chalmers, Jane I. Grove, William L. Irving, Morten A. Karsdal, Keyur Patel, Diana Julie Leeming, and Indra Neil Guha

Subjects
Cirrhosis, Biomarker, Outcome, Extracellular matrix, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Fibroblast activity is a key feature of fibrosis progression and organ function loss, leading to liver-related complications and mortality. The fibrogenesis marker, PRO-C3, has been shown to have prognostic significance in relation to fibrosis progression and as a treatment efficacy marker. We investigated whether PRO-C3 was prognostic for clinical outcome and mortality in two distinct cohorts of compensated cirrhosis. Methods: Cohort 1 was a rapid fibrosis progression cohort including 104 patients with HCV and biopsy-proven Ishak fibrosis stage ≥3 without prior clinical events. Cohort 2 was a prospective cohort including 172 patients with compensated cirrhosis of mixed aetiology. Patients were assessed for clinical outcomes. PRO-C3 was assessed in serum at baseline in cohorts 1 and 2, and compared with model for end-stage liver disease and albumin–bilirubin (ALBI) scores. Results: In cohort 1, a 2-fold increase in PRO-C3 was associated with 2.7-fold increased hazard of liver-related events (95% CI 1.6–4.6), whereas a one unit increase in ALBI score was associated with a 6.5-fold increased hazard (95% CI 2.9–14.6). In cohort 2, a 2-fold increase in PRO-C3 was associated with a 2.7-fold increased hazard (95% CI 1.8–3.9), whereas a one unit increase in ALBI score was associated with a 6.3-fold increased hazard (95% CI 3.0–13.2). A multivariable Cox regression analysis identified PRO-C3 and ALBI as being independently associated with the hazard of liver-related outcomes. Conclusions: PRO-C3 and ALBI were independent prognostic factors for predicting liver-related clinical outcomes. Understanding the dynamic range of PRO-C3 might enhance its use for both drug development and clinical practice. Impact and Implications: We tested novel proteins of liver scarring (PRO-C3) in two groups of liver patients with advanced disease to see if they could predict clinical events. We found that this marker and an established test called ALBI were both independently associated with future liver-related clinical outcomes.

Published
2023
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4. Nintedanib modulates type III collagen turnover in viable precision-cut lung slices from bleomycin-treated rats and patients with pulmonary fibrosis

Author

Christina Hesse, Valerie Beneke, Sebastian Konzok, Claudia Diefenbach, Jannie Marie Bülow Sand, Sarah Rank Rønnow, Morten Asser Karsdal, Danny Jonigk, Katherina Sewald, Armin Braun, Diana Julie Leeming, and Lutz Wollin

Subjects
Antifibrotic therapy, Collagen, Extracellular matrix, Human lung, Precision-cut lung slices, Neoepitope biomarkers, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Aberrant extracellular matrix (ECM) deposition and remodelling is important in the disease pathogenesis of pulmonary fibrosis (PF). We characterised neoepitope biomarkers released by ECM turnover in lung tissue from bleomycin-treated rats and patients with PF and analysed the effects of two antifibrotic drugs: nintedanib and pirfenidone. Methods Precision-cut lung slices (PCLS) were prepared from bleomycin-treated rats or patients with PF. PCLS were incubated with nintedanib or pirfenidone for 48 h, and levels of neoepitope biomarkers of type I, III and VI collagen formation or degradation (PRO-C1, PRO-C3, PRO-C6 and C3M) as well as fibronectin (FBN-C) were assessed in the culture supernatants. Results In rat PCLS, incubation with nintedanib led to a reduction in C3M, reflecting type III collagen degradation. In patient PCLS, incubation with nintedanib reduced the levels of PRO-C3 and C3M, thus showing effects on both formation and degradation of type III collagen. Incubation with pirfenidone had a marginal effect on PRO-C3. There were no other notable effects of either nintedanib or pirfenidone on the other neoepitope biomarkers studied. Conclusions This study demonstrated that nintedanib modulates neoepitope biomarkers of type III collagen turnover and indicated that C3M is a promising translational neoepitope biomarker of PF in terms of therapy assessment.

Published
2022
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5. A serological biomarker of type I collagen degradation is related to a more severe, high neutrophilic, obese asthma subtype

Author

Sarah Rank Rønnow, Jannie Marie Bülow Sand, Line Mærsk Staunstrup, Thomas Bahmer, Michael Wegmann, Lars Lunding, Janette Burgess, Klaus Rabe, Grith Lykke Sorensen, Oliver Fuchs, Erika V. Mutius, Gesine Hansen, Matthias Volkmar Kopp, Morten Karsdal, Diana Julie Leeming, Markus Weckmann, and the ALLIANCE Study Group as part of the German Center of Lung Research (DZL)

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Asthma is a heterogeneous disease; therefore, biomarkers that can assist in the identification of subtypes and direct therapy are highly desirable. Asthma is a chronic inflammatory disease that leads to changes in the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) degradation causing fragments of type I collagen that is released into circulation. Objective Here, we asked if MMP-generated type I collagen (C1M) was associated with subtypes of asthma. Methods C1M was serologically assessed at baseline in the adult participants of the All Age Asthma study (ALLIANCE) (n = 233), and in The Prospective Epidemiological Risk Factor study (PERF) (n = 283). In addition, C1M was assessed in mice sensitized to ovalbumin (OVA) and challenged with OVA aerosol. C1M was evaluated in mice with and without acute neutrophilic inflammation provoked by poly(cytidylic-inosinic) acid and mice treated with CP17, a peptide inhibiting neutrophil accumulation. Results Serum C1M was significantly increased in asthmatics compared to healthy controls (p = 0.0005). We found the increased C1M levels in asthmatics were related to blood neutrophil and body mass index (BMI) in the ALLIANCE cohort, which was validated in the PERF cohort. When patients were stratified into obese (BMI > 30) asthmatics with high neutrophil levels and uncontrolled asthma, this group had a significant increase in C1M compared to normal-weight (BMI

Published
2022
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6. LPA1 antagonist BMS-986020 changes collagen dynamics and exerts antifibrotic effects in vitro and in patients with idiopathic pulmonary fibrosis

Author

Benjamin E. Decato, Diana Julie Leeming, Jannie Marie Bülow Sand, Aryeh Fischer, Shuyan Du, Scott M. Palmer, Morten Karsdal, Yi Luo, and Anne Minnich

Subjects
LPA1 antagonist, Collagen, Idiopathic pulmonary fibrosis, Fibrosis, Extracellular matrix, Biomarkers, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited treatment options. A phase 2 trial (NCT01766817) showed that twice-daily treatment with BMS-986020, a lysophosphatidic acid receptor 1 (LPA1) antagonist, significantly decreased the slope of forced vital capacity (FVC) decline over 26 weeks compared with placebo in patients with IPF. This analysis aimed to better understand the impact of LPA1 antagonism on extracellular matrix (ECM)-neoepitope biomarkers and lung function through a post hoc analysis of the phase 2 study, along with an in vitro fibrogenesis model. Methods Serum levels of nine ECM-neoepitope biomarkers were measured in patients with IPF. The association of biomarkers with baseline and change from baseline FVC and quantitative lung fibrosis as measured with high-resolution computed tomography, and differences between treatment arms using linear mixed models, were assessed. The Scar-in-a-Jar in vitro fibrogenesis model was used to further elucidate the antifibrotic mechanism of BMS-986020. Results In 140 patients with IPF, baseline ECM-neoepitope biomarker levels did not predict FVC progression but was significantly correlated with baseline FVC and lung fibrosis measurements. Most serum ECM-neoepitope biomarker levels were significantly reduced following BMS-986020 treatment compared with placebo, and several of the reductions correlated with FVC and/or lung fibrosis improvement. In the Scar-in-a-Jar in vitro model, BMS-986020 potently inhibited LPA1-induced fibrogenesis. Conclusions BMS-986020 reduced serum ECM-neoepitope biomarkers, which were previously associated with IPF prognosis. In vitro, LPA promoted fibrogenesis, which was LPA1 dependent and inhibited by BMS-986020. Together these data elucidate a novel antifibrotic mechanism of action for pharmacological LPA1 blockade. Trial registration ClinicalTrials.gov identifier: NCT01766817; First posted: January 11, 2013; https://clinicaltrials.gov/ct2/show/NCT01766817 .

Published
2022
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7. Prolonged Scar-in-a-Jar: an in vitro screening tool for anti-fibrotic therapies using biomarkers of extracellular matrix synthesis

Author

Sarah Rank Rønnow, Rand Qais Dabbagh, Federica Genovese, Carmel B. Nanthakumar, Vikki J. Barrett, Robert B. Good, Sarah Brockbank, Simon Cruwys, Henrik Jessen, Grith Lykke Sorensen, Morten Asser Karsdal, Diana Julie Leeming, and Jannie Marie Bülow Sand

Subjects
Scar-in-a-jar, Fibrogenesis, IPF, Fibroblasts, Collagens, Extracellular matrix, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a rapidly progressing disease with challenging management. To find novel effective therapies, better preclinical models are needed for the screening of anti-fibrotic compounds. Activated fibroblasts drive fibrogenesis and are the main cells responsible for the accumulation of extracellular matrix (ECM). Here, a prolonged Scar-in-a-Jar assay was combined with clinically validated biochemical markers of ECM synthesis to evaluate ECM synthesis over time. To validate the model as a drug screening tool for novel anti-fibrotic compounds, two approved compounds for IPF, nintedanib and pirfenidone, and a compound in development, omipalisib, were tested. Methods Primary human lung fibroblasts from healthy donors were cultured for 12 days in the presence of ficoll and were stimulated with TGF-β1 with or without treatment with an ALK5/TGF-β1 receptor kinase inhibitor (ALK5i), nintedanib, pirfenidone or the mTOR/PI3K inhibitor omipalisib (GSK2126458). Biomarkers of ECM synthesis were evaluated over time in cell supernatants using ELISAs to assess type I, III, IV, V and VI collagen formation (PRO-C1, PRO-C3, PRO-C4, PRO-C5, PRO-C6), fibronectin (FBN-C) deposition and α-smooth muscle actin (α-SMA) expression. Results TGF-β1 induced synthesis of PRO-C1, PRO-C6 and FBN-C as compared with unstimulated fibroblasts at all timepoints, while PRO-C3 and α-SMA levels were not elevated until day 8. Elevated biomarkers were reduced by suppressing TGF-β1 signalling with ALK5i. Nintedanib and omipalisib were able to reduce all biomarkers induced by TGF-β1 in a concentration dependent manner, while pirfenidone had no effect on α-SMA. Conclusions TGF-β1 stimulated synthesis of type I, III and VI collagen, fibronectin and α-SMA but not type IV or V collagen. Synthesis was increased over time, although temporal profiles differed, and was modulated pharmacologically by ALK5i, nintedanib, pirfenidone and omipalisib. This prolonged 12-day Scar-in-a-Jar assay utilising biochemical markers of ECM synthesis provides a useful screening tool for novel anti-fibrotic compounds.

Published
2020
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8. Determining a healthy reference range and factors potentially influencing PRO-C3 – A biomarker of liver fibrosis

Author

Elisabeth Erhardtsen, Daniel G.K. Rasmussen, Peder Frederiksen, Diana Julie Leeming, Diane Shevell, Lise Lotte Gluud, Morten Asser Karsdal, Guruprasad P. Aithal, and Jörn M. Schattenberg

Subjects
Humans, Non-alcoholic fatty liver disease, Collagen type III, Reference values, Ethnic groups, Healthy volunteers, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Progressive fibrosis has been identified as the major predictor of mortality in patients with non-alcoholic fatty liver disease (NAFLD). Several biomarkers are currently being evaluated for their ability to substitute the liver biopsy as the reference standard. Recent clinical studies in NAFLD/NASH patients support the utility of PRO-C3, a marker of type III collagen formation, as a marker for the degree of fibrosis, disease activity, and effect of treatment. Here we establish the healthy reference range, optimal sample handling conditions for both short- and long-term serum storage, and robustness for the PRO-C3 assay. Methods: PRO-C3 was measured in 269 healthy volunteers and in 222 NAFLD patients. Robustness of the PRO-C3 assay was measured according to Clinical and Laboratory Standards Institute standards and included validation of interference, precision, and reagent stability, whilst sample stability was defined for storage at different temperatures and for 3 freeze-thaw cycles. Fibrosis scoring was based on histological assessments and used as a reference for the diagnostic ability of PRO-C3 to discriminate between patients with different levels of fibrosis. Results: Robustness of the PRO-C3 analysis validated by interference, precision, and reagent stability was found to be within the predefined acceptance criteria. The healthy reference range was determined to be 6.1–14.7 ng/ml. Levels of PRO-C3 were not affected by sex, age, BMI, or ethnicity. Levels of PRO-C3 were able to identify patients with clinically significant fibrosis and advanced fibrosis (AUC = 0.83 (95% CI [0.77–0.88], p

Published
2021
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9. Endotrophin, a pro-peptide of Type VI collagen, is a biomarker of survival in cirrhotic patients with hepatocellular carcinoma

Author

Diana Julie Leeming, Signe Holm Nielsen, Roslyn Vongsuvanh, Pruthviraj Uchila, Mette Juul Nielsen, Alexander L Reese-Petersen, David van der Poorten, Mohammed Eslam, Detlef Schuppan, Morten Asser Karsdal, and Jacob George

Subjects
biomarkers, collagen, endotrophin, extracellular matrix, hepatocellular carcinoma, Diseases of the digestive system. Gastroenterology, RC799-869, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Aim: Type VI collagen, is emerging as a signaling collagen originating from different types of fibroblasts. A specific fragment of Type VI collagen, the pro-peptide, is also known as the hormone endotrophin. We hypothesized that this fibroblast hormone would be of particular relevance in cancer types with a high amount of fibrosis activity, namely for outcome in hepatocellular carcinoma (HCC) cirrhotic patients. Patients & methods: Plasma C6M, PRO-C6 and alphafeto-protein (AFP) were assessed in 309 patients with mixed etiologies (hepatitis C, hepatitis B, alcohol and nonalcoholic fatty liver) diagnosed as cirrhotics, cirrhotics with HCC, noncirrhotics and healthy controls. Progression-free survival and overall survival (OS) data were collected up to 6120 days after diagnosis. The ability of each marker to predict survival was investigated. Results & conclusion: The level of endotrophin assessed by PRO-C6 was able to separate healthy controls, noncirrhotics and cirrhotics from HCC (p

Published
2021
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10. Type IV collagen turnover is predictive of mortality in COPD: a comparison to fibrinogen in a prospective analysis of the ECLIPSE cohort

Author

Sarah Rank Rønnow, Jannie Marie Bülow Sand, Lasse Løcke Langholm, Tina Manon-Jensen, Morten Asser Karsdal, Ruth Tal-Singer, Bruce E. Miller, Jørgen Vestbo, and Diana Julie Leeming

Subjects
COPD, Biomarkers, Basement membrane, Collagen type IV, ECLIPSE, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Identifying subjects with chronic obstructive pulmonary disease (COPD) at high risk of exacerbation and mortality is key to aid individual management of COPD. The only FDA approved blood-based drug development biomarker for patients at high risk of mortality, is plasma fibrinogen. In this study, we benchmarked two biomarkers of basement membrane remodeling, a characteristic of COPD, against plasma fibrinogen alone and as a combination. The biomarkers of basement membrane remodeling are two neoepitopes from of the alpha 3 chain of type IV collagen (COL4A3). Materials and methods COL4A3 degradation was assessed by the biomarkers C4Ma3 and tumstatin (TUM) in year 1 plasma samples in 984 COPD subjects, 95 non-smoking controls and 95 smoking controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. They were measured by competitive ELISA using monoclonal antibodies recognizing two specific MMP-generated cleavage site within COL4A3. The level of fibrinogen was previously assessed in year 1 plasma. Results In COPD subjects, plasma C4Ma3 levels were significantly correlated with plasma fibrinogen levels (0.389 (P

Published
2019
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11. Serological Assessment of Activated Fibroblasts by alpha-Smooth Muscle Actin (α-SMA): A Noninvasive Biomarker of Activated Fibroblasts in Lung Disorders

Author

Signe Holm Nielsen, Nicholas Willumsen, Diana Julie Leeming, Samuel Joseph Daniels, Susanne Brix, Morten Asser Karsdal, Federica Genovese, and Mette Juul Nielsen

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

OBJECTIVES: Remodeling of the extracellular matrix (ECM) is a key event in different lung disorders, such as fibrosis and cancer. The most common cell type in the connective tissue is fibroblasts, which transdifferentiate into myofibroblasts upon activation. All myofibroblasts express α-SMA, which has been found to be upregulated in lung fibrosis and cancer. We evaluated the potential of α-SMA as a noninvasive biomarker of activated fibroblasts in lung fibrosis and cancer. METHODS: A monoclonal antibody was raised against the N-terminal of α-SMA, and a novel competitive enzyme-linked immunosorbent assay (ELISA) measuring α-SMA was developed and technically characterized. Levels of α-SMA were measured in the fibroblast model, “scar-in-a-jar”, and in serum from patients with idiopathic pulmonary fibrosis (IPF), chronic obstructive lung disorder (COPD) and non–small cell lung cancer (NSCLC) belonging to two different cohorts. RESULTS: The novel α-SMA assay was developed and validated as technically robust. Based on the scar-in-a-jar results, α-SMA was only present in the fibroblasts activated by TGF-β. In cohort 1, levels of α-SMA were significantly higher in IPF, COPD and NSCLC patients compared to healthy controls (P = 0.04, P = 0.001 and P

Published
2019
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12. Biomarkers of Clot Activation and Degradation and Risk of Future Major Cardiovascular Events in Acute Exacerbation of COPD: A Cohort Sub-Study in a Randomized Trial Population

Author

Peter Kamstrup, Jannie Marie Bülow Sand, Charlotte Suppli Ulrik, Julie Janner, Christian Philip Rønn, Sarah Rank Rønnow, Diana Julie Leeming, Sidse Graff Jensen, Torgny Wilcke, Alexander G. Mathioudakis, Marc Miravitlles, Therese Lapperre, Elisabeth Bendstrup, Ruth Frikke-Schmidt, Daniel D. Murray, Theis Itenov, Apostolos Bossios, Susanne Dam Nielsen, Jørgen Vestbo, Tor Biering-Sørensen, Morten Karsdal, Jens-Ulrik Jensen, and Pradeesh Sivapalan

Subjects
COPD exacerbation, major cardiovascular events, coagulation, biomarkers, von Willebrand factor, cross-linked fibrin degradation, Biology (General), QH301-705.5
Abstract

Cardiovascular diseases are common in patients with chronic obstructive pulmonary disease (COPD). Clot formation and resolution secondary to systemic inflammation may be a part of the explanation. The aim was to determine whether biomarkers of clot formation (products of von Willebrand Factor formation and activation) and clot resolution (product of fibrin degeneration) during COPD exacerbation predicted major cardiovascular events (MACE). The cohort was based on clinical data and biobank plasma samples from a trial including patients admitted with an acute exacerbation of COPD (CORTICO-COP). Neo-epitope biomarkers of formation and the activation of von Willebrand factor (VWF-N and V-WFA, respectively) and cross-linked fibrin degradation (X-FIB) were assessed using ELISAs in EDTA plasma at the time of acute admission, and analyzed for time-to-first MACE within 36 months, using multivariable Cox proportional hazards models. In total, 299/318 participants had samples available for analysis. The risk of MACE for patients in the upper quartile of each biomarker versus the lower quartile was: X-FIB: HR 0.98 (95% CI 0.65–1.48), VWF-N: HR 1.56 (95% CI 1.07–2.27), and VWF-A: HR 0.78 (95% CI 0.52–1.16). Thus, in COPD patients with an acute exacerbation, VWF-N was associated with future MACE and warrants further studies in a larger population.

Published
2022
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13. Biomarkers reflecting pericellular fibrosis improve together with liver histology after bariatric surgery in early non-alcoholic fatty liver disease

Author

Ida Lønsmann, Julie Steen Pedersen, Aleksander Krag, Torben Hansen, Morten Karsdal, Diana Julie Leeming, Mette Juul Nielsen, and Flemming Bendtsen

Subjects
Clinical Biochemistry, General Medicine
Abstract

Non-invasive tests for non-alcoholic fatty liver disease (NAFLD) are needed for assessing disease stage, prognosis and treatment efficacy. Extracellular matrix biomarkers, such as PRO-C3, are useful as biomarkers of advanced liver fibrosis. However, non-invasive biomarkers of early-stage NAFLD, characterized by pericellular fibrosis, are lacking. Here, we measured serological biomarkers of type IV and VIII collagens reflecting the remodeling of the pericellular basement membrane to explore the effect of bariatric surgery on pericellular fibrosis in patients with early NAFLD.Seventy patients with severe obesity underwent bariatric surgery. The cohort consisted of 61% females who had a mean age of 44. Patients had a median NAFLD activity score of 3 and mild-to-moderate fibrosis F0 (3%), F1 (86%), and F2 (11%). Blood samples were taken at baseline, three, six and 12 months after surgery. At 12 months, 40 patients had a follow-up liver biopsy. The biomarkers PRO-C3, PRO-C4, C4M, and PRO-C8 were measured using indirect competitive ELISAs.Twelve months after surgery patients had significantly lower levels of ALT, GGT, HbA1c, fasting glucose, and CRP. The pericellular fibrosis biomarkers, C4M, PRO-C4, and PRO-C8 decreased by 24%, 18% and 44%, respectively (p0.0001), while the interstitial matrix fibrosis marker PRO-C3 remained unchanged. Furthermore, baseline C4M was associated with histologically assessed hepatocyte ballooning and lobular inflammation in patients with (p=0.032) and without (p=0.032) steatosis, respectively.Biomarkers of pericellular fibrosis decrease in early-stage NAFLD after patients undergo bariatric surgery and potentially reflect an improvement in liver histology.

Published
2023
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14. Comprehensive assessment of ECM turnover using serum biomarkers establishes PBC as a high-turnover autoimmune liver disease

Author

Mette Vesterhus, Mette Juul Nielsen, Johannes Roksund Hov, Francesca Saffioti, Tina Manon-Jensen, Diana Julie Leeming, Bjørn Moum, Kirsten Muri Boberg, Massimo Pinzani, Tom Hemming Karlsen, Morten Asser Karsdal, and Douglas Thorburn

Subjects
Biomarker, Fibrosis, Primary sclerosing cholangitis, Primary biliary cholangitis, PRO-C3, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are phenotypically distinct autoimmune liver diseases that progress to cirrhosis and liver failure; however, their histological fibrosis distribution differs. We investigated the extracellular matrix (ECM) profiles of patients with PSC, PBC, and AIH to establish whether the diseases display differential patterns of ECM turnover. Methods: Serum samples were retrospectively collected from the UK (test cohort; PSC n = 78; PBC n = 74; AIH n = 58) and Norway (validation cohort; PSC n = 138; PBC n = 28; AIH n = 27). Patients with ulcerative colitis without liver disease (n = 194) served as controls. We assessed specific serological biomarkers of ECM turnover: type III and V collagen formation (PRO-C3, PRO-C5), degradation of type III and IV collagen (C3M, C4M), biglycan (BGM) and citrullinated vimentin (VICM). Results: Most of the ECM markers showed elevated serum levels in PBC compared with PSC or AIH (p

Published
2021
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15. Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells

Author

Eveline Gart, Wim van Duyvenvoorde, Karin Toet, Martien P. M. Caspers, Lars Verschuren, Mette Juul Nielsen, Diana Julie Leeming, Everton Souto Lima, Aswin Menke, Roeland Hanemaaijer, Jaap Keijer, Kanita Salic, Robert Kleemann, and Martine C. Morrison

Subjects
butyrate, obesity, non-alcoholic steatohepatitis, liver fibrosis, collagen, hepatic stellate cells, Biology (General), QH301-705.5
Abstract

In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remain unclear. Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared with a HFD-control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). HFD-fed mice developed obesity, insulin resistance, increased plasma leptin levels, adipose tissue inflammation, gut permeability, dysbiosis, and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels, and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 levels and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways Rho-like GTPases and PI3K/AKT and other important pro-fibrotic regulators (e.g., YAP/TAZ, MYC) by butyrate, providing a potential rationale for its antifibrotic effects. In conclusion, butyrate protects against obesity development, insulin resistance-associated NASH, and liver fibrosis. These antifibrotic effects are at least partly attributable to a direct effect of butyrate on collagen production in hepatic stellate cells, involving inhibition of non-canonical TGF-β signaling pathways.

Published
2021
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16. Systemic inflammation is linked to liver fibrogenesis in patients with advanced chronic liver disease

Author

Benedikt Simbrunner, Ida Falk Villesen, Philipp Königshofer, Bernhard Scheiner, David Bauer, Rafael Paternostro, Philipp Schwabl, Gerald Timelthaler, Dariga Ramazanova, Katharina Wöran, Judith Stift, Ernst Eigenbauer, Albert Friedrich Stättermayer, Rodrig Marculescu, Matthias Pinter, Søren Møller, Michael Trauner, Morten Karsdal, Diana Julie Leeming, Thomas Reiberger, and Mattias Mandorfer

Subjects
Inflammation, Liver Cirrhosis, Hepatology, Interleukin-6, cirrhosis, extracellular matrix, Liver Diseases, portal hypertension, Tissue Inhibitor of Metalloproteinases, Complement C3, HSC, Actins, Liver, gut-liver-axis, Humans, bacterial translocation, Collagen, Procalcitonin, Biomarkers
Abstract

Background & Aims: Experimental evidence indicates that systemic inflammation (SI) promotes liver fibrogenesis. This study investigated the potential link between SI and fibrogenesis in patients with advanced chronic liver disease (ACLD). Methods: Serum biomarkers of SI (CRP, IL-6, procalcitonin [PCT]) and extracellular matrix (ECM) turnover (i.e., fibrogenesis/fibrolysis) were analysed in 215 prospectively recruited patients with ACLD (hepatic venous pressure gradient [HVPG] ≥6 mm Hg) undergoing hepatic vein catheterization. Patients with non-elective hospitalization or bacterial infection were excluded. Histological alpha-smooth muscle actin (α-SMA) area was quantified on full biopsy scans by automated morphometric quantification in a subset of 34 patients who underwent concomitant transjugular liver biopsy. Results: Histological α-SMA proportionate area correlated with enhanced liver fibrosis (ELF) score (Spearman's ρ = 0.660, p

Published
2022
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17. Machine learning algorithm improves the detection of NASH (NAS-based) and at-risk NASH: A development and validation study

Author

Jenny, Lee, Max, Westphal, Yasaman, Vali, Jerome, Boursier, Salvatorre, Petta, Rachel, Ostroff, Leigh, Alexander, Yu, Chen, Celine, Fournier, Andreas, Geier, Sven, Francque, Kristy, Wonder, Dina, Tiniako, Pierre, Bedossa, Mike, Allison, Georgios, Papatheodoridi, Helena, Cortez-Pinto, Raluca, Pai, Jean-Francois, Dufour, Diana Julie, Leeming, Stephen, Harrison, Jeremy, Cobbold, Adriaan G, Holleboom, Hannele, Yki-Järvinen, Javier, Crespo, Mattias, Ekstedt, Guruprasad P, Aithal, Elisabetta, Bugianesi, Manuel, Romero-Gomez, Richard, Torstenson, Morten, Karsdal, Carla, Yuni, Jörn M, Schattenberg, Detlef, Schuppan, Vlad, Ratziu, Clifford, Bra, Kevin, Duffin, Koos, Zwinderman, Michael, Pavlide, Quentin M, Anstee, Patrick M, Bossuyt, Anstee, Quentin M., Daly, Ann K., Govaere, Olivier, Cockell, Simon, Tiniakos, Dina, Bedossa, Pierre, Burt, Alastair, Oakley, Fiona, Cordell, Heather J., Day, Christopher P., Wonders, Kristy, Missier, Paolo, Mcteer, Matthew, Vale, Luke, Oluboyede, Yemi, Breckons, Matt, Bossuyt, Patrick M., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Nieuwdorp, Max, Holleboom, Adriaan G., Verheij, Joanne, Ratziu, Vlad, Clément, Karine, Patino-Navarrete, Rafael, Pais, Raluca, Paradis, Valerie, Schuppan, Detlef, Schattenberg, Jörn M., Surabattula, Rambabu, Myneni, Sudha, Straub, Beate K., Vidal-Puig, Toni, Vacca, Michele, Rodrigues-Cuenca, Sergio, Allison, Mike, Kamzolas, Ioanni, Petsalaki, Evangelia, Campbell, Mark, Lelliott, Chris J., Davies, Susan, Orešič, Matej, Hyötyläinen, Tuulia, Mcglinchey, Aiden, Mato, Jose M., Millet, Óscar, Dufour, Jean-Françoi, Berzigotti, Annalisa, Masoodi, Mojgan, Pavlides, Michael, Harrison, Stephen, Neubauer, Stefan, Cobbold, Jeremy, Mozes, Ferenc, Akhtar, Salma, Olodo-Atitebi, Seliat, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Andersson, Anneli, Wigley, Ioan, Romero-Gómez, Manuel, Gómez-González, Emilio, Ampuero, Javier, Castell, Javier, Gallego-Durán, Rocío, Fernández, Isabel, Montero-Vallejo, Rocío, Karsdal, Morten, Guldager Kring Rasmussen, Daniel, Leeming, Diana Julie, Sinisi, Antonia, Musa, Kishwar, Sandt, Estelle, Tonini, Manuela, Bugianesi, Elisabetta, Rosso, Chiara, Armandi, Angelo, Marra, Fabio, Gastaldelli, Amalia, Svegliati, Gianluca, Boursier, Jérôme, Francque, Sven, Vonghia, Luisa, Driessen, Ann, Ekstedt, Mattia, Kechagias, Stergio, Yki-Järvinen, Hannele, Porthan, Kimmo, Arola, Johanna, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Rodrigues, Cecilia M. P., Valenti, Luca, Pelusi, Serena, Petta, Salvatore, Pennisi, Grazia, Miele, Luca, Geier, Andrea, Trautwein, Christian, Aithal, Guruprasad P., Francis, Susan, Hockings, Paul, Schneider, Moritz, Newsome, Philip, Hübscher, Stefan, Wenn, David, Rosenquist, Christian, Trylesinski, Aldo, Mayo, Rebeca, Alonso, Cristina, Duffin, Kevin, Perfield, James W., Chen, Yu, Yunis, Carla, Tuthill, Theresa, Harrington, Magdalena Alicia, Miller, Melissa, Chen, Yan, Mcleod, Euan Jame, Ross, Trenton, Bernardo, Barbara, Schölch, Corinna, Ertle, Judith, Younes, Ramy, Oldenburger, Anouk, Ostroff, Rachel, Alexander, Leigh, Biegel, Hannah, Skalshøi Kjær, Mette, Mørch Harder, Lea, Davidsen, Peter, Mikkelsen, Lars Frii, Balp, Maria-Magdalena, Brass, Clifford, Jennings, Lori, Martic, Miljen, Löffler, Jürgen, Applegate, Dougla, Shankar, Sudha, Torstenson, Richard, Fournier-Poizat, Céline, Llorca, Anne, Kalutkiewicz, Michael, Pepin, Kay, Ehman, Richard, Horan, Gerald, Ho, Gideon, Tai, Dean, Chng, Elaine, Patterson, Scott D., Billin, Andrew, Doward, Lynda, Twiss, Jame, Thakker, Paresh, Landgren, Henrik, Lackner, Carolin, Gouw, Annette, Hytiroglou, Prodromos, Luca, Miele (ORCID:0000-0003-3464-0068), Jenny, Lee, Max, Westphal, Yasaman, Vali, Jerome, Boursier, Salvatorre, Petta, Rachel, Ostroff, Leigh, Alexander, Yu, Chen, Celine, Fournier, Andreas, Geier, Sven, Francque, Kristy, Wonder, Dina, Tiniako, Pierre, Bedossa, Mike, Allison, Georgios, Papatheodoridi, Helena, Cortez-Pinto, Raluca, Pai, Jean-Francois, Dufour, Diana Julie, Leeming, Stephen, Harrison, Jeremy, Cobbold, Adriaan G, Holleboom, Hannele, Yki-Järvinen, Javier, Crespo, Mattias, Ekstedt, Guruprasad P, Aithal, Elisabetta, Bugianesi, Manuel, Romero-Gomez, Richard, Torstenson, Morten, Karsdal, Carla, Yuni, Jörn M, Schattenberg, Detlef, Schuppan, Vlad, Ratziu, Clifford, Bra, Kevin, Duffin, Koos, Zwinderman, Michael, Pavlide, Quentin M, Anstee, Patrick M, Bossuyt, Anstee, Quentin M., Daly, Ann K., Govaere, Olivier, Cockell, Simon, Tiniakos, Dina, Bedossa, Pierre, Burt, Alastair, Oakley, Fiona, Cordell, Heather J., Day, Christopher P., Wonders, Kristy, Missier, Paolo, Mcteer, Matthew, Vale, Luke, Oluboyede, Yemi, Breckons, Matt, Bossuyt, Patrick M., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Nieuwdorp, Max, Holleboom, Adriaan G., Verheij, Joanne, Ratziu, Vlad, Clément, Karine, Patino-Navarrete, Rafael, Pais, Raluca, Paradis, Valerie, Schuppan, Detlef, Schattenberg, Jörn M., Surabattula, Rambabu, Myneni, Sudha, Straub, Beate K., Vidal-Puig, Toni, Vacca, Michele, Rodrigues-Cuenca, Sergio, Allison, Mike, Kamzolas, Ioanni, Petsalaki, Evangelia, Campbell, Mark, Lelliott, Chris J., Davies, Susan, Orešič, Matej, Hyötyläinen, Tuulia, Mcglinchey, Aiden, Mato, Jose M., Millet, Óscar, Dufour, Jean-Françoi, Berzigotti, Annalisa, Masoodi, Mojgan, Pavlides, Michael, Harrison, Stephen, Neubauer, Stefan, Cobbold, Jeremy, Mozes, Ferenc, Akhtar, Salma, Olodo-Atitebi, Seliat, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Andersson, Anneli, Wigley, Ioan, Romero-Gómez, Manuel, Gómez-González, Emilio, Ampuero, Javier, Castell, Javier, Gallego-Durán, Rocío, Fernández, Isabel, Montero-Vallejo, Rocío, Karsdal, Morten, Guldager Kring Rasmussen, Daniel, Leeming, Diana Julie, Sinisi, Antonia, Musa, Kishwar, Sandt, Estelle, Tonini, Manuela, Bugianesi, Elisabetta, Rosso, Chiara, Armandi, Angelo, Marra, Fabio, Gastaldelli, Amalia, Svegliati, Gianluca, Boursier, Jérôme, Francque, Sven, Vonghia, Luisa, Driessen, Ann, Ekstedt, Mattia, Kechagias, Stergio, Yki-Järvinen, Hannele, Porthan, Kimmo, Arola, Johanna, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Rodrigues, Cecilia M. P., Valenti, Luca, Pelusi, Serena, Petta, Salvatore, Pennisi, Grazia, Miele, Luca, Geier, Andrea, Trautwein, Christian, Aithal, Guruprasad P., Francis, Susan, Hockings, Paul, Schneider, Moritz, Newsome, Philip, Hübscher, Stefan, Wenn, David, Rosenquist, Christian, Trylesinski, Aldo, Mayo, Rebeca, Alonso, Cristina, Duffin, Kevin, Perfield, James W., Chen, Yu, Yunis, Carla, Tuthill, Theresa, Harrington, Magdalena Alicia, Miller, Melissa, Chen, Yan, Mcleod, Euan Jame, Ross, Trenton, Bernardo, Barbara, Schölch, Corinna, Ertle, Judith, Younes, Ramy, Oldenburger, Anouk, Ostroff, Rachel, Alexander, Leigh, Biegel, Hannah, Skalshøi Kjær, Mette, Mørch Harder, Lea, Davidsen, Peter, Mikkelsen, Lars Frii, Balp, Maria-Magdalena, Brass, Clifford, Jennings, Lori, Martic, Miljen, Löffler, Jürgen, Applegate, Dougla, Shankar, Sudha, Torstenson, Richard, Fournier-Poizat, Céline, Llorca, Anne, Kalutkiewicz, Michael, Pepin, Kay, Ehman, Richard, Horan, Gerald, Ho, Gideon, Tai, Dean, Chng, Elaine, Patterson, Scott D., Billin, Andrew, Doward, Lynda, Twiss, Jame, Thakker, Paresh, Landgren, Henrik, Lackner, Carolin, Gouw, Annette, Hytiroglou, Prodromos, and Luca, Miele (ORCID:0000-0003-3464-0068)

Abstract

Background and aims: Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD. Approach and results: Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS ≥ 4;53%), at-risk NASH (NASH with F ≥ 2;35%), significant (F ≥ 2;47%), and advanced fibrosis (F ≥ 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82). Conclusions: Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis.

Published
2023

18. Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study

Author

Yasaman Vali, Jenny Lee, Jerome Boursier, Salvatore Petta, Kristy Wonders, Dina Tiniakos, Pierre Bedossa, Andreas Geier, Sven Francque, Mike Allison, Georgios Papatheodoridis, Helena Cortez-Pinto, Raluca Pais, Jean-Francois Dufour, Diana Julie Leeming, Stephen A Harrison, Yu Chen, Jeremy F Cobbold, Michael Pavlides, Adriaan G Holleboom, Hannele Yki-Jarvinen, Javier Crespo, Morten Karsdal, Rachel Ostroff, Mohammad Hadi Zafarmand, Richard Torstenson, Kevin Duffin, Carla Yunis, Clifford Brass, Mattias Ekstedt, Guruprasad P Aithal, Jörn M Schattenberg, Elisabetta Bugianesi, Manuel Romero-Gomez, Vlad Ratziu, Quentin M Anstee, Patrick M Bossuyt, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, Graduate School, Gastroenterology and Hepatology, Vascular Medicine, ACS - Diabetes & metabolism, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Hepatology, Gastroenterology, 610 Medicine & health
Abstract

BACKGROUND The reference standard for detecting non-alcoholic steatohepatitis (NASH) and staging fibrosis-liver biopsy-is invasive and resource intensive. Non-invasive biomarkers are urgently needed, but few studies have compared these biomarkers in a single cohort. As part of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) project, we aimed to evaluate the diagnostic accuracy of 17 biomarkers and multimarker scores in detecting NASH and clinically significant fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) and identify their optimal cutoffs as screening tests in clinical trial recruitment. METHODS This was a comparative diagnostic accuracy study in people with biopsy-confirmed NAFLD from 13 countries across Europe, recruited between Jan 6, 2010, and Dec 29, 2017, from the LITMUS metacohort of the prospective European NAFLD Registry. Adults (aged ≥18 years) with paired liver biopsy and serum samples were eligible; those with excessive alcohol consumption or evidence of other chronic liver diseases were excluded. The diagnostic accuracy of the biomarkers was expressed as the area under the receiver operating characteristic curve (AUC) with liver histology as the reference standard and compared with the Fibrosis-4 index for liver fibrosis (FIB-4) in the same subgroup. Target conditions were the presence of NASH with clinically significant fibrosis (ie, at-risk NASH; NAFLD Activity Score ≥4 and F≥2) or the presence of advanced fibrosis (F≥3), analysed in all participants with complete data. We identified thres holds for each biomarker for reducing the number of biopsy-based screen failures when recruiting people with both NASH and clinically significant fibrosis for future trials. FINDINGS Of 1430 participants with NAFLD in the LITMUS metacohort with serum samples, 966 (403 women and 563 men) were included after all exclusion criteria had been applied. 335 (35%) of 966 participants had biopsy-confirmed NASH and clinically significant fibrosis and 271 (28%) had advanced fibrosis. For people with NASH and clinically significant fibrosis, no single biomarker or multimarker score significantly reached the predefined AUC 0·80 acceptability threshold (AUCs ranging from 0·61 [95% CI 0·54-0·67] for FibroScan controlled attenuation parameter to 0·81 [0·75-0·86] for SomaSignal), with accuracy mostly similar to FIB-4. Regarding detection of advanced fibrosis, SomaSignal (AUC 0·90 [95% CI 0·86-0·94]), ADAPT (0·85 [0·81-0·89]), and FibroScan liver stiffness measurement (0·83 [0·80-0·86]) reached acceptable accuracy. With 11 of 17 markers, histological screen failure rates could be reduced to 33% in trials if only people who were marker positive had a biopsy for evaluating eligibility. The best screening performance for NASH and clinically significant fibrosis was observed for SomaSignal (number needed to test [NNT] to find one true positive was four [95% CI 4-5]), then ADAPT (six [5-7]), MACK-3 (seven [6-8]), and PRO-C3 (nine [7-11]). INTERPRETATION None of the single markers or multimarker scores achieved the predefined acceptable AUC for replacing biopsy in detecting people with both NASH and clinically significant fibrosis. However, several biomarkers could be applied in a prescreening strategy in clinical trial recruitment. The performance of promising markers will be further evaluated in the ongoing prospective LITMUS study cohort. FUNDING The Innovative Medicines Initiative 2 Joint Undertaking.

Published
2023
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19. No effect of rifaximin on soluble CD163, mannose receptor or type III and IV neoepitope collagen markers in decompensated cirrhosis: Results from a randomized, placebo controlled trial.

Author

Nina Kimer, Natasja Stæhr Gudmann, Julie Steen Pedersen, Søren Møller, Mette Juul Nielsen, Diana Julie Leeming, Morten Asser Karsdal, Holger Jon Møller, Flemming Bendtsen, and Henning Grønbæk

Subjects
Medicine, Science
Abstract

BACKGROUND AND AIMS:Macrophages play a significant role in chronic liver disease as reflected by elevated soluble (s)CD163 and mannose receptor (sMR) levels and associated with liver disease severity and prognosis. Extracellular matrix remodelling associated with fibrogenesis may be affected by systemic inflammation induced by bacterial translocation. Therefore, we aimed to investigate the effect of rifaximin-α, an antibiotic with effect on gut bacteria, on sCD163, sMR, and collagen metabolites. METHODS:Fifty-four clinically stable patients with decompensated cirrhosis were randomized to 4 weeks treatment with rifaximin-α (n = 36) or placebo (n = 18). Macrophage markers sCD163, sMR and markers of collagen fibrogenesis (C3M and C4M) and formation (PRO-C3 and P4NPS7) were analysed in plasma before and after treatment. RESULTS:sCD163 and sMR levels were associated with liver disease severity (MELD score, sCD163 rho = 0.47, p 5.9 μg/ml, 38 patients) there was no effect of rifaximin-α on sCD163 (p = 0.49) or sMR levels (p = 0.32). CONCLUSION:We confirmed that macrophage activation markers sCD163 and sMR are directly associated to liver disease severity (MELD score). However, rifaximin-α has no effect on sCD163, sMR or collagen markers in decompensated cirrhosis and does therefore not seem to interfere with macrophage activation or fibrogenesis.

Published
2018
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20. PRO‐C3 and ADAPT algorithm accurately identify patients with advanced fibrosis due to alcohol‐related liver disease

Author

Maria Kjærgaard, Mette Juul Nielsen, Maja Thiele, Diana Julie Leeming, Jonel Trebicka, Aleksander Krag, Bjørn Stæhr Madsen, Morten A. Karsdal, Sönke Detlefsen, Linda Maria Sevelsted Møller, and Natasja Stæhr Gudmann

Subjects
Liver Cirrhosis, Biopsy, Disease, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, medicine, Humans, Pharmacology (medical), Alcohol-related liver disease, Prospective Studies, Prospective cohort study, 030304 developmental biology, 0303 health sciences, Hepatology, medicine.diagnostic_test, business.industry, Fatty liver, Gastroenterology, Complement C3, medicine.disease, 3. Good health, Liver, Elasticity Imaging Techniques, Biomarker (medicine), 030211 gastroenterology & hepatology, business, Algorithm, Algorithms, Biomarkers
Abstract

BACKGROUND: Alcohol is a main cause of preventable deaths and frequently leads to the development of alcohol-related liver disease. Due to the lack of diagnostics, patients are commonly diagnosed after developing clinical manifestations. Recently, the biomarker PRO-C3 was shown to accurately identify fibrosis due to non-alcoholic fatty liver disease.AIM: To assess the diagnostic accuracy of PRO-C3, the ADAPT score and best-performing non-patented serological test to detect advanced alcohol-related liver fibrosis.METHODS: We enrolled 426 patients with alcohol overuse in a prospective biopsy-controlled study. We evaluated the accuracy of PRO-C3 and the PRO-C3-based algorithm ADAPT to detect advanced liver fibrosis.RESULTS: The accuracy of PRO-C3 was good with an AUROC of 0.85 (95% CI 0.79-0.90). The best-performing non-patented test was the Forns index with an AUROC of 0.83 (95% CI 0.78-0.89). The ADAPT algorithm performed better as compared to both the Forns index and PRO-C3 alone with an AUROC = 0.88 (95% CI 0.83-0.93).CONCLUSION: PRO-C3 is a new marker with high accuracy to detect advanced alcohol-related liver fibrosis. The diagnostic accuracy of PRO-C3 can be further improved by using the ADAPT algorithm in which the test outperforms currently available non-patented serological fibrosis markers. The study is registered in the Odense Patient Data Exploratory Network (OPEN) under study identification numbers OP_040 (https://open.rsyd.dk/OpenProjects/da/openProject.jsp?openNo=40) and OP_239 (https://open.rsyd.dk/OpenProjects/openProject.jsp?openNo=239&lang=da).

Published
2021
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21. PRO‐C3, a Serological Marker of Fibrosis, During Childhood and Correlations With Fibrosis in Pediatric NAFLD

Author

Miriam B. Vos, Diane E. Shevell, Diana Julie Leeming, Rebecca Cleeton, Catherine C. Cohen, Morten A. Karsdal, Shelley A. Caltharp, Alton B. Farris, Elizabeth M. Sinclair, Mette Juul Nielsen, and Eduardo Castillo‐Leon

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Adolescent, Osteocalcin, RC799-869, Chronic liver disease, Severity of Illness Index, Gastroenterology, Collagen Type I, Bone remodeling, N-terminal telopeptide, Non-alcoholic Fatty Liver Disease, Fibrosis, Interquartile range, Internal medicine, Nonalcoholic fatty liver disease, medicine, Humans, Child, Hepatology, medicine.diagnostic_test, business.industry, Puberty, Age Factors, Original Articles, Complement C3, Diseases of the digestive system. Gastroenterology, medicine.disease, Cross-Sectional Studies, Liver biopsy, Original Article, Female, Bone Remodeling, Peptides, business, Biomarkers
Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease in children and may lead to cirrhosis requiring liver transplant. Thus, prompt diagnosis of advanced fibrosis is essential. Our objectives were to examine PRO‐C3 (a neo‐epitope pro‐peptide of type III collagen formation) levels across childhood/adolescence and associations with advanced fibrosis in pediatric NAFLD. This cross‐sectional study included 88 children and adolescents with biopsy‐proven NAFLD (mean age: 13.9 ± 2.9 years, 71% male) and 65 healthy participants (11.8 ± 4.5 years, 38% male). PRO‐C3, and the bone remodeling biomarkers C‐terminal telopeptide of type I collagen (CTX‐I; bone resorption) and osteocalcin (N‐MID; bone formation), were measured in serum by enzyme‐linked immunosorbent assay. Fibrosis was assessed by liver biopsy in participants with NAFLD, who were categorized as having advanced (Ishak score ≥ 3) or none/mild fibrosis (Ishak score ≤ 2). Overall, PRO‐C3 was similar in participants with NAFLD (median [interquartile range]: 20.6 [15.8, 25.9] ng/mL) versus healthy participants (19.0 [13.8, 26.0] ng/mL), but was significantly lower in older adolescents ≥ 15 years old (16.4 [13.0, 21.2] ng/mL) compared with children ≤ 10 years old (22.9 [18.1, 28.4] ng/mL; P

Published
2021
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22. N-terminal propeptide of type 3 collagen-based sequential algorithm can identify high-risk steatohepatitis and fibrosis in MAFLD

Author

Liang-Jie Tang, Gang Li, Mohammed Eslam, Pei-Wu Zhu, Sui-Dan Chen, Howard Ho-Wai Leung, Ou-Yang Huang, Grace Lai-Hung Wong, Yu-Jie Zhou, Morten Karsdal, Diana Julie Leeming, Pei Jiang, Cong Wang, Hai-Yang Yuan, Christopher D. Byrne, Giovanni Targher, Jacob George, Vincent Wai-Sun Wong, and Ming-Hua Zheng

Subjects
Metabolic dysfunction-associated fatty liver disease, Hepatology, Fibrosis staging, Sequential algorithm, Steatohepatitis
Abstract

With metabolic dysfunction-associated fatty liver disease (MAFLD) incidence and prevalence sharply increasing globally, there is an urgent need for non-invasive diagnostic tests to accurately screen high-risk MAFLD patients for liver inflammation and fibrosis. We aimed to develop a novel sequential algorithm based on N-terminal propeptide of type 3 collagen (PRO-C3) for disease risk stratification in patients with MAFLD.A derivation and independent validation cohort of 327 and 142 patients with biopsy-confirmed MAFLD were studied. We compared the diagnostic performances of various non-invasive scores in different disease states, and a novel sequential algorithm was constructed by combining the best performing non-invasive scores.For patients with high-risk progressive steatohepatitis (i.e., steatohepatitis + NAFLD activity score ≥ 4 + F ≥ 2), the AUROC of FAST score was 0.801 (95% confidence interval (CI): 0.739-0.863), and the negative predictive value (NPV) was 0.951. For advanced fibrosis (≥ F3) and cirrhosis (F4), the AUROCs of ADAPT and Agile 4 were 0.879 (95%CI 0.825-0.933) and 0.943 (95%CI 0.892-0.994), and the NPV were 0.972 and 0.992. Sequential algorithm of ADAPT + Agile 4 combination was better than other combinations for risk stratification of patients with severe fibrosis (AUROC = 0.88), with similar results in the validation cohort. Meanwhile, in all subgroup analyses (stratifying by sex, age, diabetes, NAS, BMI and ALT), ADAPT + Agile 4 had a good diagnostic performance.The new sequential algorithm reliably identifies liver inflammation and fibrosis in MAFLD, making it easier to exclude low-risk patients and recommending high-risk MAFLD patients for clinical trials and emerging pharmacotherapies.

Published
2022

23. Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

Author

Natasja Stæhr Gudmann, Richard P. Marshall, Jeni Luckett, Rebecca F. Rogers, Robert J. Slack, Simon J. F. Macdonald, Diana Julie Leeming, Rachel C. Chambers, Joelle Le, Pauline T. Lukey, Anthony Habgood, Paul F. Mercer, Rachel A. Burgoyne, Ben S. Barksby, Lloyd I. Bibby, Yim Man, Maryam Hafeji, Andrew J. Fisher, David J. Flint, Toby M. Maher, Louise Organ, Susan Pyne, Lee A. Borthwick, James A. Roper, Valerie S. Morrison, Alison E. John, Giovanni Vitulli, Rebecca H. Graves, Rochelle C. Edwards-Pritchard, R. Gisli Jenkins, John Barrett, Josie Morrell, K. Tao Pun, Elaine Gower, Rory Barnes, Ellen J. Forty, Chitra Joseph, and National Institute for Health Research

Subjects
Male, 0301 basic medicine, Integrins, Pyrrolidines, General Physics and Astronomy, Pharmacology, INTEGRIN-ALPHA-V-BETA-6, NINTEDANIB, Translational Research, Biomedical, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Transforming Growth Factor beta, Fibrosis, Medicine, lcsh:Science, Internalization, media_common, Multidisciplinary, PIRFENIDONE, respiratory system, Small molecule, Multidisciplinary Sciences, Molecular Docking Simulation, Butyrates, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Collagen, TYROSINE KINASE INHIBITOR, media_common.quotation_subject, Science, MODELS, Article, General Biochemistry, Genetics and Molecular Biology, RS, Small Molecule Libraries, Bleomycin, 03 medical and health sciences, Mediator, Antigen, Antigens, Neoplasm, Administration, Inhalation, Animals, Humans, Naphthyridines, Tomography, Emission-Computed, Single-Photon, Respiratory tract diseases, Science & Technology, Lung, business.industry, Epithelial Cells, General Chemistry, EFFICACY, medicine.disease, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Pharmacodynamics, Pyrazoles, lcsh:Q, business, Transforming growth factor
Abstract

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy., The αvβ6 integrin is key in activating the pro-fibrotic cytokine TGFβ in idiopathic pulmonary fibrosis. Here, the authors show an inhaled small molecule αvβ6 inhibitor GSK3008348 induces prolonged inhibition of TGFβ signaling pathways in human and murine models of lung fibrosis via αvβ6 degradation.

Published
2020

24. Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: A systematic review and meta-analysis

Author

Kevin L. Duffin, Patrick M.M. Bossuyt, Diana Julie Leeming, Jürgen Löffler, Ann K. Daly, Yasaman Vali, Koos H. Zwinderman, René Spijker, Detlef Schuppan, Pablo Ortiz, Guido Hanauer, Tim Bauer, Mohammad Hadi Zafarmand, Yu Chen, Jérôme Boursier, Matej Orešič, Craig L. Hyde, Peter Nissen Bjerring, Zsolt Böcskei, Christina Levick, Michael Pavlides, Pierre Bedossa, Joanne Verheij, M. Julia Brosnan, Jenny Lee, Quentin M. Anstee, Rémy Hanf, Elizabeth Shumbayawonda, University of Denver, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Julius Center for Health Sciences and Primary Care, University Medical Center [Utrecht], University Hospital of Würzburg, VU University Medical Center [Amsterdam], SANOFI Recherche, Newcastle University [Newcastle], University of Amsterdam [Amsterdam] (UvA), Epidemiology and Data Science, Graduate School, APH - Methodology, Pathology, APH - Personalized Medicine, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, and ACS - Atherosclerosis & ischemic syndromes

Subjects
Liver Cirrhosis, 0301 basic medicine, medicine.medical_specialty, Biopsy, [SDV]Life Sciences [q-bio], Enhanced liver fibrosis test, Cochrane Library, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Fibrosis, Internal medicine, medicine, Humans, Blood test, Hyaluronic Acid, ComputingMilieux_MISCELLANEOUS, Non-alcoholic steatohepatitis, Tissue Inhibitor of Metalloproteinase-1, Hepatology, medicine.diagnostic_test, business.industry, Fatty liver, Biomarker, Reference Standards, medicine.disease, Peptide Fragments, 3. Good health, Meta-analysis, 030104 developmental biology, Liver, Liver biopsy, Disease Progression, Biomarker (medicine), 030211 gastroenterology & hepatology, business, Algorithms, Biomarkers, Procollagen, Non-alcoholic fatty liver disease
Abstract

BACKGROUND & AIMS:The enhanced liver fibrosis (ELF) test has been proposed for the non-invasive assessment of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). We performed a systematic review to estimate the accuracy of this test against biopsy. METHODS:In this systematic review, we searched MEDLINE, Embase, Web of Science and the Cochrane Library for studies that included patients with NAFLD and that used both liver biopsy (as the reference standard) and the ELF test. Two authors independently screened the references, extracted the data and assessed the quality of included studies. Due to the variation in reported thresholds, we used a multiple thresholds random effects model for meta-analysis (diagmeta R-package). RESULTS:The meta-analysis of 11 studies reporting advanced fibrosis and 5 studies reporting significant fibrosis showed that the ELF test had a sensitivity of >0.90 for excluding fibrosis at a threshold of 7.7. However, as a diagnostic test at high thresholds, the test only achieved specificity and positive predictive value >0.80 in very high prevalence settings (>50%). To achieve a specificity of 0.90 for advanced and significant fibrosis, thresholds of 10.18 (sensitivity: 0.57) and 9.86 (sensitivity: 0.55) were required, respectively. CONCLUSION:The ELF test showed high sensitivity but limited specificity to exclude advanced and significant fibrosis at low cut-offs. The diagnostic performance of the test at higher thresholds was found to be more limited in low-prevalence settings. We conclude that clinicians should carefully consider the likely disease prevalence in their practice setting and adopt suitable test thresholds to achieve the desired performance. LAY SUMMARY:The enhanced liver fibrosis test has been suggested as a non-invasive blood test to aid the diagnosis of severe liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Our study results showed that the test has a high negative predictive value, especially in populations with low disease prevalence (likely encountered in primary care); so, it can exclude advanced fibrosis in patients with NAFLD. However, when prevalence is low, the positive predictive value of the enhanced liver fibrosis test is low, suggesting that additional strategies may be needed to make a positive diagnosis in such settings.

Published
2020
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25. Review article: the signalling and functional role of the extracellular matrix in the development of liver fibrosis

Author

Samuel Joseph Daniels, Diana Julie Leeming, Mette Juul Nielsen, Ida Villesen, and Morten A. Karsdal

Subjects
Liver Cirrhosis, Hepatology, business.industry, Gastroenterology, Disease, Bioinformatics, medicine.disease, Extracellular Matrix, Review article, Extracellular matrix, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Signalling, Fibrosis, Hepatic stellate cell, Humans, Medicine, 030211 gastroenterology & hepatology, Pharmacology (medical), 030212 general & internal medicine, Signal transduction, business, Signal Transduction
Abstract

Background Patients with liver fibrosis show a large heterogeneity, and for that reason effective treatments are still lacking. Emerging data suggest that there is more to fibrosis than previously understood. Opposed to earlier belief of being a passive scaffold for cells to reside in, the extracellular matrix (ECM) is now known to hold both signalling and functional properties important for the development of fibrosis. The interaction between the ECM and the collagen-producing cells determines the course of the disease but is still poorly understood. Exploring the dynamics of this interplay will aid in the development of effective treatments. Aim To summarise and discuss the latest advances in the pathogenesis of liver fibrosis as well as key mediators of early disease progression. Methods Through literature search using databases including PubMed and Google Scholar, manuscripts published between 1961 and 2019 were included to assess both well-established and recent theories of fibrosis development. Both pre-clinical and clinical studies were included. Results Fibrosis alters the structure of the ECM releasing signalling fragments with the potential to escalate disease severity. In a diseased liver, hepatic stellate cells and other fibroblasts, together with hepatocytes and sinusoidal cells, produce an excessive amount of collagens. The cell-to-collagen interactions are unique in the different liver aetiologies, generating ECM profiles with considerable patient-monitoring potential. Conclusions The local milieu in the injured area affects the course of fibrosis development in a site-specific manner. Future research should focus on the dissimilarities in the ECM profile between different aetiologies of liver fibrosis.

Published
2020
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26. Collagen biology and non‐invasive biomarkers of liver fibrosis

Author

Rose C. Christian, Mette Juul Nielsen, Daniel Guldager Kring Rasmussen, Cecilie L. Bager, Diana Julie Leeming, Jacob George, Natasja Stæhr Gudmann, Rambabu Surabattula, Yi Luo, Ida Villesen, Morten A. Karsdal, Signe Holm Nielsen, Samuel Joseph Daniels, Rohit Loomba, Diane E. Shevell, and Detlef Schuppan

Subjects
Liver Cirrhosis, Liver injury, Cirrhosis, Hepatology, Fatty liver, Disease, Biology, Bioinformatics, medicine.disease, Chronic liver disease, 03 medical and health sciences, 0302 clinical medicine, Liver, Non-alcoholic Fatty Liver Disease, Fibrosis, 030220 oncology & carcinogenesis, medicine, Humans, Biomarker (medicine), 030211 gastroenterology & hepatology, Collagen, Biomarkers, Tissue homeostasis
Abstract

There is an unmet need for high-quality liquid biomarkers that can safely and reproducibly predict the stage of fibrosis and the outcomes of chronic liver disease (CLD). The requirement for such markers has intensified because of the high global prevalence of diseases such as non-alcoholic fatty liver disease (NAFLD). In particular, there is a need for diagnostic and prognostic tools, as well as predictive biomarkers that reflect the efficacy of interventions, as described by the BEST criteria (Biomarkers, EndpointS, and other Tools Resource). This review covers the various liver collagens, their functional role in tissue homeostasis and delineates the common nomenclature for biomarkers based on BEST criteria. It addresses the common confounders affecting serological biomarkers, and describes defined collagen epitope biomarkers that originate from the dynamic processes of extracellular matrix (ECM) remodelling during liver injury.

Published
2020
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27. Addition of trans fat and alcohol has divergent effects on atherogenic diet-induced liver injury in rodent models of steatohepatitis

Author

Sarah Brockbank, Maria Fuglsang Bruun, Morten A. Karsdal, Kim Henriksen, Peter Hein, Samuel Joseph Daniels, Sönke Detlefsen, Sara Toftegaard Hjuler, Simon Cruwys, Diana Julie Leeming, Aleksander Krag, and Mette Juul Nielsen

Subjects
Male, medicine.medical_specialty, Alcoholic liver disease, Physiology, Chronic liver disease, Binge Drinking, Rats, Sprague-Dawley, chemistry.chemical_compound, Liver disease, Liver Cirrhosis, Alcoholic, Non-alcoholic Fatty Liver Disease, Physiology (medical), Internal medicine, Nonalcoholic fatty liver disease, medicine, Animals, Aspartate Aminotransferases, Obesity, Nonalcoholic, Dyslipidemias, Steatohepatitis, Hepatology, business.industry, Cholesterol, Gastroenterology, Alanine Transaminase, Trans Fatty Acids, Lipid Metabolism, Alcoholic, medicine.disease, Peptide Fragments, Disease Models, Animal, Oxidative Stress, Rodent models, Endocrinology, Liver, chemistry, Diet, Atherogenic, Metabolic, Steatosis, business, Biomarkers, Procollagen, Dyslipidemia, Fatty Liver, Alcoholic, Hepatomegaly
Abstract

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essential for drug discovery. We aimed to characterize several models of steatohepatitis (SH) and to investigate whether the pathology could be modulated. Sprague-Dawley rats were fed a high-fat diet (HFD) for 9 wk, followed by either a high-fat, high-cholesterol and cholate diet (HFC) or a HFC diet containing 13% trans fat (HFC-TF). A subset received 15% ethanol-water twice a week for 12 wk. Serum triglycerides, cholesterol, LDL, HDL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and rodent NH2-terminal propeptide of type III collagen (rPRO-C3) were assessed. The liver was weighed and evaluated using modified Nonalcoholic Steatohepatitis Clinical Research Network histological score system criteria. All diets induced hepatomegaly, but only HFC-TF increased the size of visceral adipose tissue. Trans fat augmented HFC-induced dyslipidemia, and cholesterol was higher and HDL was lower in the HFC-TF groups. Alcohol lowered triglycerides in both dietary groups. HFC elevated ALT and AST, which were lowered by trans fat. All diets induced histological SH, addition of trans fat induced more steatosis but less inflammation. Inclusion of alcohol augmented the HFC-induced inflammation. All diets induced mild fibrosis. Inclusion of trans fat and alcohol significantly increased rPRO-C3. The addition of trans fat reduced the HFC-induced inflammation but augmented steatosis and dyslipidemia. Inclusion of alcohol induced a more inflammatory and fibrogenic phenotype. NEW & NOTEWORTHY Alcoholic liver disease and nonalcoholic liver disease share significant overlap, which suggests the existence of metabolic steatohepatitis. Trans fat has been implicated in steatohepatitis development. Here, we show that the addition of trans fat to an atherogenic diet results in a more steatotic but less inflammatory phenotype, whereas the addition of alcohol to an atherogenic diet augments the inflammatory and fibrogenic properties of the diet.

Published
2020
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28. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Author

Raluca Pais, Rachel Ostroff, Stephen Harrison, Lars Friis Mikkelsen, Elisabeth Erhardtsen, Sudha Shankar, Kimmo Porthan, Jérôme Boursier, Antonia Sinisi, Michael Kalutkiewicz, Sven Francque, Miljen Martic, Vanessa Pellegrinelli, Phil N. Newsome, Guido Hanauer, Hannele Yki-Järvinen, Rebecca Darlay, Joel Myers, Carla Yunis, Salvatore Petta, Mette Skalshøi Kjær, Pablo Ortiz, Ann K. Daly, James H. Clark, Dina Tiniakos, Yasaman Vali, Hadi Zafarmand, Matej Orešič, Maurizio Parola, Estelle Sandt, Lori L. Jennings, Matt Kelly, Tuulia Hyötyläinen, Detlef Schuppan, Céline Fournier, Chiara Rosso, Diane E. Shevell, Maria Manuela Tonini, Paul Hockings, Aidan McGlinchey, Salma Akhtar, Mette Juul Fisker, Morten A. Karsdal, Diane Whalley, Melissa R. Miller, Aldo Trylesinski, Mattias Ekstedt, Stefan Neubauer, Jeremy M. Palmer, Partho Sen, Michael Pavlides, Per Qvist, Isabel Fernández, Luca Miele, Fabio Marra, Stergios Kechagias, Richard Torstenson, Katherine Johnson, Jean-François Dufour, Elisabetta Bugianesi, M. Julia Brosnan, George V. Papatheodoridis, Kay M. Pepin, Daniel Guldager Kring Rasmussen, Henrik Landgren, Rachel Queen, Simon Cockell, Michael Allison, Patrick M.M. Bossuyt, Rocío Gallego-Durán, Christian Rosenquist, Leigh Alexander, Elizabeth Shumbayawonda, Michele Vacca, Antonio Vidal-Puig, David Wenn, Rémy Hanf, Oscar Millet, Michalina Zatorska, R. Myers, José M. Mato, Jenny Lee, Theresa Tuthill, James Twiss, Ramy Younes, Peter Leary, Lynda Doward, Kristy Wonders, Guruprasad P. Aithal, Sarah Charlton, Vlad Ratziu, Cecília M. P. Rodrigues, Christian Trautwein, Helena Cortez-Pinto, Gideon Ho, Matt J. Barter, Judith Ertle, Jörn M. Schattenberg, Maria-Magdalena Balp, Yang-Lin Liu, Clifford A. Brass, Olivier Govaere, Amalia Gastaldelli, Sergio Rodriguez Cuenca, Pierre Chaumat, Fiona Oakley, Luca Valenti, Simon J. Cockell, Saskia W.C. van Mil, Ferenc E. Mózes, Andreas Geier, Timothy Hardy, Pierre Bedossa, Andrea Dennis, Richard L. Ehman, Charlotte Erpicum, Karine Clément, Jeremy F. L. Cobbold, Christopher P. Day, Rajarshi Banerjee, Manuel Romero-Gómez, Quentin M. Anstee, Adriaan G. Holleboom, Heather J. Cordell, Kevin L. Duffin, Diana Julie Leeming, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Graduate School, Investigators, LITMUS Consortium, Johnson K., Leary P.J., Govaere O., Barter M.J., Charlton S.H., Cockell S.J., Tiniakos D., Zatorska M., Bedossa P., Brosnan M.J., Cobbold J.F., Ekstedt M., Aithal G.P., Clement K., Schattenberg J.M., Boursier J., Ratziu V., Bugianesi E., Anstee Q.M., Daly A.K., Clark J., Cordell H.J., Darlay R., Day C.P., Hardy T., Liu Y.-L., Oakley F., Palmer J., Queen R., Wonders K., Bossuyt P.M., Holleboom A.G., Zafarmand H., Vali Y., Lee J., Pais R., Schuppan D., Allison M., Cuenca S.R., Pellegrinelli V., Vacca M., Vidal-Puig A., Hyotylainen T., McGlinchey A., Oresic M., Sen P., Mato J., Millet O., Dufour J.-F., Harrison S., Neubauer S., Pavlides M., Mozes F., Akhtar S., Banerjee R., Kelly M., Shumbayawonda E., Dennis A., Erpicum C., Romero-Gomez M., Gallego-Duran R., Fernandez I., Karsdal M., Leeming D., Fisker M.J., Erhardtsen E., Rasmussen D., Qvist P., Sinisi A., Sandt E., Tonini M.M., Parola M., Rosso C., Marra F., Gastaldelli A., Francque S., Kechagias S., Yki-Jarvinen H., Porthan K., van Mil S., Papatheodoridis G., Cortez-Pinto H., Valenti L., Petta S., Miele L., Geier A., Trautwein C., Hockings P., Newsome P., Wenn D., Pereira Rodrigues C.M., Hanf R., Chaumat P., Rosenquist C., Trylesinski A., Ortiz P., Duffin K., Yunis C., Miller M., Tuthill T., Ertle J., Younes R., Alexander L., Ostroff R., Kjaer M.S., Mikkelsen L.F., Brass C., Jennings L., Balp M.-M., Martic M., Hanauer G., Shankar S., Torstenson R., Fournier C., Ehman R., Kalutkiewicz M., Pepin K., Myers J., Shevell D., Ho G., Landgren H., Myers R., Doward L., Whalley D., Twiss J., Miller, Melissa, Tuthill, Theresa, Ertle, Judith, Younes, Ramy, Alexander, Leigh, Ostroff, Rachel, Kjær, Mette Skalshøi, Mikkelsen, Lars Friis, Brass, Clifford, Jennings, Lori, Balp, Maria-Magdalena, Martic, Miljen, Hanauer, Guido, Shankar, Sudha, Torstenson, Richard, Fournier, Céline, Ehman, Richard, Kalutkiewicz, Michael, Pepin, Kay, Myers, Joel, Shevell, Diane, Ho, Gideon, Landgren, Henrik, Myers, Rob, Doward, Lynda, Whalley, Diane, Twiss, James, Clark, James, Cordell, Heather J., Darlay, Rebecca, Day, Christopher P., Hardy, Tim, Liu, Yang-Lin, Oakley, Fiona, Palmer, Jeremy, Queen, Rachel, Wonders, Kristy, Bossuyt, Patrick M., Holleboom, Adriaan G., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Clement, Karine, Pais, Raluca, Schuppan, Detlef, Allison, Michael, Cuenca, Sergio Rodriguez, Pellegrinelli, Vanessa, Vacca, Michele, Vidal-Puig, Antonio, Hyötyläinen, Tuulia, McGlinchey, Aidan, Orešič, Matej, Sen, Partho, Mato, Jose, Millet, Óscar, Dufour, Jean-Francois, Harrison, Stephen, Neubauer, Stefan, Pavlides, Michael, Mozes, Ferenc, Akhtar, Salma, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Erpicum, Charlotte, Romero-Gomez, Manuel, Gallego-Durán, Rocío, Fernández, Isabel, Karsdal, Morten, Leeming, Diana, Fisker, Mette Juul, Erhardtsen, Elisabeth, Rasmussen, Daniel, Qvist, Per, Sinisi, Antonia, Sandt, Estelle, Tonini, Maria Manuela, Parola, Maurizio, Rosso, Chiara, Marra, Fabio, Gastaldelli, Amalia, Francque, Sven, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Valenti, Luca, Petta, Salvatore, Miele, Luca, Geier, Andreas, Trautwein, Christian, Hockings, Paul, Newsome, Phil, Wenn, David, Pereira Rodrigues, Cecília Maria, Hanf, Rémy, Chaumat, Pierre, Rosenquist, Christian, Trylesinski, Aldo, Ortiz, Pablo, Duffin, Kevin, and Yunis, Carla

Subjects
SCORING SYSTEM, CPM, counts per million, AUROC, area under the receiver operating characteristic, RC799-869, AST, aspartate aminotransferase, MicroRNA, Non-alcoholic fatty liver disease, Biomarker, Sequencing, TGF-β, transforming growth factor-beta, Gastroenterology, STEATOHEPATITIS, Liver disease, 0302 clinical medicine, Fibrosis, miRNA, microRNA, logFC, log2 fold change, FIBROSIS, Immunology and Allergy, 0303 health sciences, education.field_of_study, NAS, NAFLD activity score, medicine.diagnostic_test, Fatty liver, GTEx, Genotype-Tissue Expression, Diseases of the digestive system. Gastroenterology, 3. Good health, Real-time polymerase chain reaction, Biomarker, MicroRNA, Non-alcoholic fatty liver disease, Sequencing, Liver biopsy, ACID, Biomarker (medicine), 030211 gastroenterology & hepatology, Life Sciences & Biomedicine, Research Article, EXPRESSION, medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steatohepatitis, Population, Gastroenterology and Hepatology, SAF, steatosis–activity–fibrosis, VALIDATION, ER, endoplasmic reticulum, 03 medical and health sciences, cDNA, complementary DNA, Internal medicine, ALT, alanine aminotransferase, Gastroenterologi, Internal Medicine, medicine, NAFL, non-alcoholic fatty liver, ALGORITHM, FIB-4, fibrosis-4, education, 030304 developmental biology, PCA, principal component analysis, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, FC, fold change, medicine.disease, digestive system diseases, FLIP, fatty liver inhibition of progression, Ct, cycle threshold, Steatosis, qPCR, quantitative PCR, business
Abstract

Background & Aims Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. Lay summary MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy., Graphical abstract, Highlights • Serum miRNA was sequenced in 183 NAFLD cases of varying severity and 10 population controls. • Plasma levels of miR-193a-5p were significantly increased in patients with advanced fibrosis, high NAS scores, or high SAF scores. • Other miRNAs including miR378d and miR378e were also significantly increased in certain comparisons. • The findings for miR-193a-5p were replicated in a cohort of 372 additional NAFLD cases.

Published
2022
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29. Crosstalk between Irisin Levels, Liver Fibrogenesis and Liver Damage in Non-Obese, Non-Diabetic Individuals with Non-Alcoholic Fatty Liver Disease

Author

Angelo Armandi, Chiara Rosso, Aurora Nicolosi, Gian Paolo Caviglia, Maria Lorena Abate, Antonella Olivero, Daphne D’Amato, Marta Vernero, Melania Gaggini, Giorgio Maria Saracco, Davide Giuseppe Ribaldone, Diana Julie Leeming, Amalia Gastaldelli, and Elisabetta Bugianesi

Subjects
irisin, insulin resistance, non-invasive biomarkers, liver fibrosis, liver fibrogenesis, PRO-C3, PRO-C6, NAFLD, Medicine, General Medicine, Insulin resistance, Irisin, Liver fibrogenesis, Liver fibrosis, Non-invasive biomarkers
Abstract

Background: Insulin resistance plays a relevant role in the onset of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH) and fibrosis. Irisin is an exercise-induced myokine involved in the regulation of energy homeostasis and glucose metabolism. Additionally, pre-clinical models have shown a potential role of irisin in the pathogenesis of NAFLD. The aim of this study is to explore the association between irisin, histological features and biomarkers of liver fibrogenesis in non-diabetic, non-obese, biopsy-proven NAFLD individuals. Methods: Forty-one patients with histological evidence of NAFLD were included. Circulating irisin and direct markers of fibrogenesis N-terminal type III collagen propeptide (PRO-C3) and type VI collagen cleavage product (PRO-C6) were measured by ELISA. Results: Median age of the cohort was 45 years (41–51) and 80.4% were male. Significant fibrosis (stage ≥ 2) was present in 36.6% of cases. Circulating irisin, PRO-C3 and PRO-C6 levels were significantly higher in subjects with fibrosis stage ≥ 2 when compared to those with fibrosis stage < 2 (5.96 ng/mL (95% CI = 4.42–9.19) vs. 2.42 ng/mL (95% CI = 1.73–5.95), p = 0.033; 9.5 ng/mL (95% CI = 7.7–13.6) vs. 6.2 ng/mL (95% CI = 4.9–8.9), p = 0.016; 6.6 ng/mL (95% CI = 5.6–7.9) vs. 5.1 ng/mL (95% CI = 4.2–5.4), p = 0.013, respectively). Irisin levels were similarly distributed between the features of NASH. Circulating irisin positively correlated with both PRO-C3 and PRO-C6 levels (r = 0.47, p = 0.008 and r = 0.46, p = 0.002). Conclusions: Increased circulating irisin levels may identify a more aggressive phenotype of liver disease with increased fibrogenesis and more severe liver damage.

Published
2022

30. Among simple non-invasive scores, Pro-C3 and ADAPT best exclude advanced fibrosis in Asian patients with MAFLD

Author

Liang-Jie Tang, Hong-Lei Ma, Mohammed Eslam, Grace Lai-Hung Wong, Pei-Wu Zhu, Sui-Dan Chen, Diana Julie Leeming, Morten Karsdal, Gang Li, Ou-Yang Huang, Howard Ho-Wai Leung, Yu-Jie Zhou, Qian Feng, Pei Jiang, Li-Mei Gao, Christopher D. Byrne, Giovanni Targher, Jacob George, Vincent Wai-Sun Wong, and Ming-Hua Zheng

Subjects
Metabolic dysfunction-associated fatty liver disease, Endocrinology, Endocrinology, Diabetes and Metabolism, NASH, Liver Fibrosis staging, N-terminal propeptide of type 3 collagen, ADAPT, Pro-C3
Abstract

Background: With metabolic dysfunction-associated fatty liver disease (MAFLD) incidence and prevalence increasing, it is necessary to identify patients with advanced fibrosis (F3-F4 stages). We evaluated the performance of new biomarkers and algorithms for diagnosing advanced fibrosis in an Asian population. Methods: Data from two Asian cohorts (including 851 biopsy-proven MAFLD [578 from Wenzhou, 273 from Hong Kong]) were studied. The association between N-terminal propeptide of type 3 collagen (PRO-C3) and the histologic stage of liver fibrosis was analyzed by multivariable linear regression. The area under the receiver operating characteristic curve (AUROC) was used to test the diagnostic performance of serum PRO-C3 and the ADAPT score for advanced fibrosis and compared them to other established non-invasive tests. Results: Serum PRO-C3 levels increased progressively across liver fibrosis stages and correlated with advanced fibrosis (P < 0.001). The ADAPT score had an AUROC of 0.865 (95% confidence interval 0.829–0.901) for advanced fibrosis; the accuracy, sensitivity and negative predictive values were 81.4%, 82.2% and 96.1%, respectively. This result was better compared to that of PRO-C3 alone or other non-invasive fibrosis biomarkers (aspartate aminotransferase-to-platelet ratio index, Fibrosis-4, BARD, and NAFLD fibrosis score). In subgroup analyses (including sex, age, diabetes, NAFLD activity score, body mass index or serum alanine aminotransferase levels), the ADAPT score had good diagnostic performance. Conclusion: PRO-C3 and the ADAPT score reliably exclude advanced fibrosis in MAFLD patients and reduce the need for liver biopsy.

Published
2022

31. Heat-Inactivated Akkermansia muciniphila Improves Gut Permeability but Does Not Prevent Development of Non-Alcoholic Steatohepatitis in Diet-Induced Obese Ldlr−/−.Leiden Mice

Author

Martine C. Morrison, Eveline Gart, Wim van Duyvenvoorde, Jessica Snabel, Mette Juul Nielsen, Diana Julie Leeming, Aswin Menke, and Robert Kleemann

Subjects
Prebiotic, Type IV collagen, Probiotic, digestive system, Catalysis, Inorganic Chemistry, Bioint Diagnostics, Obesity, Physical and Theoretical Chemistry, Molecular Biology, Bioint Diagnostics, Food Safety & Phyt. Research, Gut permeability, Spectroscopy, Non-alcoholic steatohepatitis, VLAG, non-alcoholic steatohepatitis, fibrosis, diet-induced, obesity, gut permeability, Akkermansia muciniphila, prebiotic, probiotic, microbiota, type IV collagen, Microbiota, Organic Chemistry, Diet-induced, nutritional and metabolic diseases, General Medicine, Fibrosis, Computer Science Applications, Food Safety & Phyt. Research, Human and Animal Physiology, Fysiologie van Mens en Dier
Abstract

The development of non-alcoholic steatohepatitis (NASH) has been associated with alterations in gut microbiota composition and reduced gut barrier function. Akkermansia muciniphila is a gut microbe that is thought to have health-promoting properties, including the ability to improve gut barrier function and host metabolism, both when administered live and after heat-inactivation. We questioned whether heat-inactivated A. muciniphila may reduce NASH development. Ldlr−/−.Leiden mice, a translational, diet-induced model for NASH, were fed a NASH-inducing high-fat diet (HFD) supplemented with heat-inactivated A. muciniphila. After 28 weeks, effects of the treatment on obesity and associated metabolic dysfunction in the gut (microbiota composition and permeability), adipose tissue, and liver were studied relative to an untreated HFD control. Treatment with heat-inactivated A. muciniphila did not affect body weight or adiposity and had no effect on plasma lipids, blood glucose, or plasma insulin. Heat-inactivated A. muciniphila had some minor effects on mucosal microbiota composition in ileum and colon and improved gut barrier function, as assessed by an in vivo functional gut permeability test. Epidydimal white adipose tissue (WAT) hypertrophy and inflammation were not affected, but heat-inactivated A. muciniphila did reduce hypertrophy in the mesenteric WAT which is in close proximity to the intestine. Heat-inactivated A. muciniphila did not affect the development of NASH or associated fibrosis in the liver and did not affect circulating bile acids or markers of liver fibrosis, but did reduce PRO-C4, a type IV collagen synthesis marker, which may be associated with gut integrity. In conclusion, despite beneficial effects in the gut and mesenteric adipose tissue, heat-inactivated A. muciniphila did not affect the development of NASH and fibrosis in a chronic disease setting that mimics clinically relevant disease stages.

Published
2022

32. Binge drinking induces an acute burst of markers of hepatic fibrogenesis (PRO-C3)

Author

Morten A. Karsdal, Torben Hansen, Ida Villesen, Maja Thiele, Nikolaj Torp, Mette Juul Nielsen, Claus Philip Åstrand, Camilla Dalby Hansen, Stine Johansen, Pernille Juhl, Mads Israelsen, Diana Julie Leeming, Aleksander Krag, and Bjørn Stæhr Madsen

Subjects
medicine.medical_specialty, Cirrhosis, extracellular matrix, Binge drinking, Gastroenterology, Binge Drinking, Liver disease, Interstitial matrix, Fibrosis, Non-alcoholic Fatty Liver Disease, Internal medicine, medicine, Humans, acute intoxication, Hepatology, Ethanol, business.industry, cirrhosis, Fatty liver, fibrosis, Complement C3, medicine.disease, Pathophysiology, Biomarker (medicine), biomarker, business
Abstract

Background & Aims: Binge drinking is associated with an increased risk of liver disease. Morbidity and mortality of alcohol-related liver disease (ALD) is associated with collagen deposition in the hepatic extracellular matrix (ECM). However, the acute effects of binge drinking on ECM turnover are unknown. We aimed to investigate the effects on hepatic ECM turnover following a binge drinking episode. Methods: We performed a pathophysiological intervention study with 15 non-alcoholic fatty liver disease (NAFLD) patients, 15 ALD patients and 10 healthy controls. We used 40% ethanol in 9 mg/mL NaCl administered through a nasogastric tube to simulate binge drinking. Hepatic vein catheterisation allowed simultaneous hepatic- and systemic vein sampling. Markers of ECM formation and degradation were measured with competitive ELISA. Results: The interstitial matrix formation marker PRO-C3 increased by 1.2 ng/mL (10%, P

Published
2022
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33. Global multi-stakeholder endorsement of the MAFLD definition

Author

Nahum Méndez-Sánchez, Elisabetta Bugianesi, Robert G Gish, Frank Lammert, Herbert Tilg, Mindie H Nguyen, Shiv K Sarin, Núria Fabrellas, Shira Zelber-Sagi, Jian-Gao Fan, Gamal Shiha, Giovanni Targher, Ming-Hua Zheng, Wah-Kheong Chan, Shlomo Vinker, Takumi Kawaguchi, Laurent Castera, Yusuf Yilmaz, Marko Korenjak, C Wendy Spearman, Mehmet Ungan, Melissa Palmer, Mortada El-Shabrawi, Hans-Juergen Gruss, Jean-François Dufour, Anil Dhawan, Heiner Wedemeyer, Jacob George, Luca Valenti, Yasser Fouad, Manuel Romero‐Gomez, Mohammed Eslam, Maria Lorena Abate, Bahaa Abbas, Ahmed Amr Abbassy, Waleed Abd El Ghany, Amira Abd Elkhalek, Emad Abd ElMajeed, Mohammad Abdalgaber, Mohamed AbdAllah, Marwa Abdallah, Nourhan Abdallah, Shereen Abdelaleem, Yasser Abdelghani, Wael Abdelghany, Safaa Mohamed Abdelhalim, Wafaa Abdelhamid, Nehal Abdelhamid, Nadia A. Abdelkader, Elsayed Abdelkreem, Aly Mohamed Abdelmohsen, Awny Ali Abdelrahman, Sherief M Abd-elsalam, Doaa Abdeltawab, Abdulbaset Abduh, Nada Abdulhakam, Maheeba Abdulla, Navid Abedpoor, Ludovico Abenavoli, Fredrik Åberg, Omala Ablack, Mostafa Abo elftouh, Yousry Esam-Eldin Abo-Amer, Ashraf Aboubkr, Alaa Aboud, Amr M. Abouelnaga, Galal A. Aboufarrag, Ashraf Aboutaleb, Leticia Abundis, Gupse Adalı, Enrique Adames, Leon Adams, Danjuma Adda, Noor Adel, Nada Adel, Muhammad Adel Sayed, Taiba Jibril Afaa, Nawal Afredj, Gulnara Aghayeva, Alessio Aghemo, Carlos A. Aguilar-Salinas, Golo Ahlenstiel, Walid Ahmady, Wafaa Ahmed, Amira Ahmed, Samah Nasser Ahmed, Heba Mostafa Ahmed, Rasha Ahmed, Elmar Aigner, Mesut Akarsu, Maisam Akroush, Umit Akyuz, Mamun Al Mahtab, Tahani Al Qadiri, Yusriya Al Rawahi, Razzaq AL rubaee, Muna Al Saffar, Shahinul Alam, Zaid Al-Ani, Agustín Albillos, Mohamed Alboraie, Said Al-Busafi, Mohamed Al-Emam, Jawaher Alharthi, Kareem Ali, Basma Abdelmoez Ali, Mohammad Ali, Raja Affendi Raja Ali, Anna Alisi, Ali Raad AL-Khafaji, Maryam Alkhatry, Rocio Aller, Yahya Almansoury, Khalid Al-Naamani, Alaa Alnakeeb, Anna Alonso, Saleh A. Alqahtani, Leina Alrabadi, Khalid Alswat, Mahir Altaher, Turki Altamimi, Jose Altamirano, Mario R. Alvares-da-Silva, Elsragy Adel M. Aly, Amgad Alzahaby, Ahmed Alzamzamy, Keisuke Amano, Maysa A. Amer, Mona A. Amin, Sayed A. Amin, Ashraf A. Amir, Javier Ampuero, Noha Anas, Pietro Andreone, Soa Fy Andriamandimby, Mahmoud Anees, Peltec Angela, Manal Antonios, Wael Arafat, Jose Moreno Araya, Juan Armendariz-Borunda, Matthew J. Armstrong, Hassan Ashktorab, Patricia Aspichueta, Fathia Assal, Mira Atef, Dina Attia, Hoda Atwa, Reham Awad, Mohyeldeen Abd Elaziz Awad, Sally Awny, Obafemi Awolowo, Yaw Asante Awuku, Ibrahim Ayada, Than Than Aye, Sherif Ayman, Hedy Ayman, Hesham Ayoub, Hosny M. Azmy, Romiro P. 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Khalaf, Rofida Khalefa, Sherin Khamis, Doaa Khater, Hamed khattab, Anatoly Khavkin, Olga Khlynova, Nabil Khmis, Nazarii Kobyliak, Apostolos Koffas, Kazuhiko Koike, Kenneth Y.Y. Kok, Tomas Koller, Narcisse Patrice Komas, Nataliya V. Korochanskaya, Yannoula Koulla, Shunji Koya, Colleen Kraft, Bledar Kraja, Marcin Krawczyk, Mohammad Shafi Kuchay, Anand V Kulkarni, Ashish Kumar, Manoj Kumar, Sulaiman Lakoh, Philip Lam, Ling Lan, Naomi F. Lange, Kamran Bagheri Lankarani, Nicolas Lanthier, Kateryna Lapshyna, Sameh A. Lashen, Konang Nguieguia Justine Laure, Leonid Lazebnik, Didier Lebrec, Samuel S. 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Hasan, F, Hashim, A, Hassan, I, Hassan, A, Hassan, E, Hassan, M, Hassanin, F, Hassnine, A, Haukeland, J, Hawal, A, He, J, He, Q, He, Y, He, F, Hegazy, M, Hegazy, A, Henegil, O, Hernandez, N, Hernandez-Guerra, M, Higuera-de-la-Tijera, F, Hindy, I, Hirota, K, Ho, L, Hodge, A, Hosny, M, Hou, X, Huang, J, Huang, Y, Huang, Z, Huang, A, Huang, X, Hui-ping, S, Hunyady, B, Hussein, M, Hussein, O, Hussien, S, Ibanez-Samaniego, L, Ibdah, J, Ibrahim, L, Ibrahim, M, Ibrahim, I, Icaza-Chavez, M, Idelbi, S, Idilman, R, Ikeda, M, Indolfi, G, Invernizzi, F, Irshad, I, Isa, H, Iskandar, N, Ismaiel, A, Ismail, M, Ismail, Z, Ismail, F, Iwamoto, H, Jack, K, Jacob, R, Jafarov, F, Jafri, W, Jahshan, H, Jalal, P, Jancoriene, L, Janicko, M, Jayasena, H, Jefferies, M, Jha, V, Ji, F, Ji, Y, Jia, J, Jiang, C, Jiang, N, Jiang, Z, Jin, X, Jin, Y, Jing, X, Jingyu, Q, Jinjolava, M, Jong, F, Jucov, A, Julius, I, Kaddah, M, Kamada, Y, Kamal, A, Kamal, E, Kamel, A, Kao, J, Karin, M, Karlas, T, Kashwaa, M, Katsidzira, L, Kaya, E, Kayasseh, M, Keenan, B, Keklikkiran, C, Keml, W, Khalaf, D, Khalefa, R, Khamis, S, Khater, D, Khattab, H, Khavkin, A, Khlynova, O, Khmis, N, Kobyliak, N, Koffas, A, Koike, K, Kok, K, Koller, T, Komas, N, Korochanskaya, N, Koulla, Y, Koya, S, Kraft, C, Kraja, B, Krawczyk, M, Kuchay, M, Kulkarni, A, Kumar, A, Kumar, M, Lakoh, S, Lam, P, Lan, L, Lange, N, Lankarani, K, Lanthier, N, Lapshyna, K, Lashen, S, Laure, K, Lazebnik, L, Lebrec, D, Lee, S, Lee, W, Lee, Y, Leeming, D, Leite, N, Leon, R, Lesmana, C, Li, J, Li, Q, Li, Y, Li, L, Li, M, Liang, H, Lijuan, T, Lim, S, Lim, L, Lin, S, Lin, H, Lin, R, Lithy, R, Liu, Y, Liu, X, Liu, W, Liu, S, Liu, K, Liu, T, Lonardo, A, Lopez, M, Lopez-Benages, E, Lopez-Jaramillo, P, Lu, H, Lu, L, Lu, Y, Lubel, J, Lui, R, Lupasco, I, Luzina, E, Lv, X, Lynch, K, Ma, H, Machado, M, Maduka, N, Madzharova, K, Magdaong, R, Mahadeva, S, Mahfouz, A, Mahmood, N, Mahmoud, E, Mahrous, M, Maiwall, R, Majeed, A, Majumdar, A, Mak, L, Maklouf, M, Malekzadeh, R, Mandato, C, Mangia, A, Mann, J, Mansour, H, Mansouri, A, Mantovani, A, Mao, J, Maramag, F, Marchesini, G, Marcus, C, Marinho, R, Martinez-Chantar, M, Martins, A, Marwan, R, Mason, K, Masoud, G, Massoud, M, Matamoros, M, Mateos, R, Mawed, A, Mbanya, J, Mbendi, C, Mccolaugh, L, Mcleod, D, Medina, J, Megahed, A, Mehrez, M, Memon, I, Merat, S, Mercado, R, Mesbah, A, Meskini, T, Metwally, M, Metwaly, R, Miao, L, Micah, E, Miele, L, Milivojevic, V, Milovanovic, T, Mina, Y, Mishkovik, M, Mishriki, A, Mitchell, T, Mohamed, A, Mohamed, M, Mohamed, S, Mohammed, S, Mohammed, A, Mohan, V, Mohie, S, Mokhtar, A, Moniem, R, Montilla, M, Morales, J, Morata, M, Moreno-Planas, J, Morise, S, Mosaad, S, Moselhy, M, Mostafa, A, Mostafa, E, Mouane, N, Mousa, N, Moustafa, H, Msherif, A, Muller, K, Munoz, C, Munoz-Urribarri, A, Murillo, O, Mustapha, F, Muzurovic, E, Nabil, Y, Nafady, S, Nagamatsu, A, Nakajima, A, Nakano, D, Nan, Y, Nascimbeni, F, Naseef, M, Nashat, N, Natalia, T, Negro, F, Nersesov, A, Neuman, M, Ng'Wanasayi, M, Ni, Y, Nicoll, A, Niizeki, T, Nikolova, D, Ningning, W, Niriella, M, Nogoibaeva, K, Nordien, R, O Sullivan, C, O'Beirne, J, Obekpa, S, Ocama, P, Ochwoto, M, Ogolodom, M, Ojo, O, Okrostsvaridze, N, Oliveira, C, Omana, R, Omar, O, Omar, H, Omar, M, Omran, S, Omran, R, Osman, M, Owise, N, Owusu-Ansah, T, Padilla- Machaca, P, Palle, S, Pan, Z, Pan, X, Pan, Q, Papaefthymiou, A, Paquissi, F, Par, G, Parkash, A, Payawal, D, Peltekian, K, Peng, X, Peng, L, Peng, Y, Pengoria, R, Perez, M, Perez, J, Perez, N, Persico, M, Pessoa, M, Petta, S, Philip, M, Plaz Torres, M, Polavarapu, N, Poniachik, J, Portincasa, P, Pu, C, Purnak, T, Purwanto, E, Qi, X, Qian, Z, Qiang, Z, Qiao, Z, Qiao, L, Queiroz, A, Rabiee, A, Radwan, M, Rahetilahy, A, Ramadan, Y, Ramadan, D, Ramli, A, Ramm, G, Ran, A, Rankovic, I, Rao, H, Raouf, S, Ray, S, Reau, N, Refaat, A, Reiberger, T, Remes-Troche, J, Reyes, E, Richardson, B, Ridruejo, E, Riestra Jimenez, S, Rizk, I, Roberts, S, Roblero, J, Robles, J, Rockey, D, Rodriguez, M, Rodriguez Hernandez, H, Roman, E, Romeiro, F, Romeo, S, Rosales-Zabal, J, Roshdi, G, Rosso, N, Ruf, A, Ruiz, P, Runes, N, Ruzzenente, A, Ryan, M, Saad, A, Sabbagh, E, Sabbah, M, Saber, S, Sabrey, R, Sabry, R, Saeed, M, Said, D, Said, E, Sakr, M, Salah, Y, Salama, R, Salama, A, Saleh, H, Saleh, A, Salem, A, Salifou, A, Salih, A, Salman, A, Samouda, H, Sanai, F, Sanchez-Avila, J, Sanker, L, Sano, T, Sanz, M, Saparbu, T, Sawhney, R, Sayed, F, Sayed, S, Sayed, A, Sayed, M, Sebastiani, G, Secadas, L, Sediqi, K, Seif, S, Semida, N, Senates, E, Serban, E, Serfaty, L, Seto, W, Sghaier, I, Sha, M, Shabaan, H, Shalaby, L, Shaltout, I, Sharara, A, Sharma, V, Shawa, I, Shawkat, A, Shawky, N, Shehata, O, Sheils, S, Shewaye, A, Shi, G, Shi, J, Shimose, S, Shirono, T, Shou, L, Shrestha, A, Shui, G, Sievert, W, Sigurdardottir, S, Sira, M, Siradj, R, Sison, C, Smyth, L, Soliman, R, Sollano, J, Sombie, R, Sonderup, M, Sood, S, Soriano, G, Stedman, C, Stefanyuk, O, Stimac, D, Strasser, S, Strnad, P, Stuart, K, Su, W, Su, M, Sumida, Y, Sumie, S, Sun, D, Sun, J, Suzuki, H, Svegliati-Baroni, G, Swar, M, Taharboucht, S, Taher, Z, Takamura, S, Tan, L, Tan, S, Tanwandee, T, Tarek, S, Tatiana, G, Tavaglione, F, Tecson, G, Tee, H, Teschke, R, Tharwat, M, Thong, V, Thursz, M, Tine, T, Tiribelli, C, Tolmane, I, Tong, J, Tongo, M, Torkie, M, Torre, A, Torres, E, Trajkovska, M, Treeprasertsuk, S, Tsutsumi, T, Tu, T, Tur, J, Turan, D, Turcan, S, Turkina, S, Tutar, E, Tzeuton, C, Ugiagbe, R, Uygun, A, Vacca, M, Vajro, P, Van der Poorten, D, Van Kleef, L, Vashakidze, E, Velazquez, C, Velazquez, M, Vento, S, Verhoeven, V, Vespasiani-Gentilucci, U, Vethakkan, S, Vilaseca, J, Vitek, L, Volkanovska, A, Wallace, M, Wan, W, Wang, Y, Wang, X, Wang, C, Wang, M, Wangchuk, P, Weltman, M, White, M, Wiegand, J, Wifi, M, Wigg, A, Wilhelmi, M, William, R, Wittenburg, H, Wu, S, Wubeneh, A, Xia, H, Xiao, J, Xiao, X, Xiaofeng, W, Xiong, W, Xu, L, Xu, J, Xu, W, Xu, K, Xu, Y, Xu, S, Xu, M, Xu, A, Xu, C, Yan, H, Yang, J, Yang, R, Yang, Y, Yang, Q, Yang, N, Yao, J, Yara, J, Yaras, S, Yilmaz, N, Younes, R, Younes, H, Young, S, Youssef, F, Yu, Y, Yu, M, Yuan, J, Yue, Z, Yuen, M, Yun, W, Yurukova, N, Zakaria, S, Zaky, S, Zaldastanishvili, M, Zapata, R, Zare, N, Zerem, E, Zeriban, N, Zeshuai, X, Zhang, H, Zhang, X, Zhang, Y, Zhang, W, Zhang, Z, Zhao, J, Zhao, R, Zhao, H, Zheng, C, Zheng, Y, Zheng, R, Zheng, T, Zheng, K, Zhou, X, Zhou, Y, Zhou, H, Zhou, L, Zhu, L, Zhu, Y, Zhu, P, Ziada, E, Ziring, D, Ziyi, L, Zou, S, Zou, Z, Zou, H, Zuart Ruiz, R, and Global Multi-Stakeholder Consensus on the Redefinition of Fatty Liver Disease

Subjects
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Hepatology, Non-alcoholic Fatty Liver Disease, NAFLD, consensu, Gastroenterology, MAFLD, definition, Humans, MAFLD, NAFLD, Human medicine
Abstract

Contains fulltext : 252162.pdf (Publisher’s version ) (Closed access)

Published
2022
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34. Heat-Inactivated

Author

Martine C, Morrison, Eveline, Gart, Wim van, Duyvenvoorde, Jessica, Snabel, Mette Juul, Nielsen, Diana Julie, Leeming, Aswin, Menke, and Robert, Kleemann

Subjects
Inflammation, Liver Cirrhosis, Male, Hot Temperature, Mice, Obese, Akkermansia, Diet, High-Fat, Permeability, Gastrointestinal Microbiome, Mice, Adipose Tissue, Liver, Receptors, LDL, Non-alcoholic Fatty Liver Disease, Animals, Obesity, Intestinal Mucosa
Abstract

The development of non-alcoholic steatohepatitis (NASH) has been associated with alterations in gut microbiota composition and reduced gut barrier function.

Published
2021

35. Fibrogenesis marker PRO-C3 is higher in advanced liver fibrosis and improves in patients undergoing bariatric surgery

Author

Pierre Bel Lassen, Nicole Nori, Pierre Bedossa, Laurent Genser, Judith Aron-Wisnewsky, Christine Poitou, Rambabu Surabattula, Mette Juul Nielsen, Morten Asser Karsdal, Diana Julie Leeming, Detlef Schuppan, Karine Clément, Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], Nordic Bioscience [Herlev, Denmark], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Liver Cirrhosis, Non-alcoholic Fatty Liver Disease (NAFLD), Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Bariatric Surgery, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Non-alcoholic Fatty Liver Disease, Humans, Obesity, Non-alcoholic steatohepatitis (NASH), 030304 developmental biology, 0303 health sciences, Biochemistry (medical), Complement C3, Biomarker, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Fibrosis, Obesity, Morbid, Liver, Adipose Tissue, 030211 gastroenterology & hepatology, Collagen, Biomarkers
Abstract

Context Serum propeptides of type III and type VI collagen (PRO-C3 and PRO-C6) are elevated in advanced nonalcoholic fatty liver disease (NAFLD), but their value in patients with severe obesity and their evolution after bariatric surgery (BS) is unknown. It is unclear if these markers of fibrogenesis are affected by adipose tissue fibrosis (ATF). Objective We studied the association of PRO-C3 and PRO-C6 with liver fibrosis before BS, examined their evolution after BS, and evaluated how much patients’ ATF contribute to their levels. Methods Serum PRO-C3 and PRO-C6 were measured in 158 BS patients and compared with liver, subcutaneous, and omental adipose tissue histology obtained during surgery. PRO-C3 and PRO-C6 levels of 63 patients were determined in follow-up at 3 and 12 months post-BS. Results Patients in the highest quartile of PRO-C3 had a higher risk of advanced liver fibrosis (stage F3-4; odds ratio 5.8; 95% CI [1.5-29.9]; P = 0.017) vs the lowest quartile (adjustment for age, gender, and BMI). PRO-C3 was positively correlated with markers of insulin resistance and liver enzymes. After BS, PRO-C3 levels decreased in patients with high baseline liver fibrosis. This decrease correlated with improvement of metabolic and liver parameters. PRO-C6 was not related to stage of liver fibrosis. ATF did not correlate with PRO-C3 or PRO-C6 levels at baseline or after BS. Conclusion PRO-C3 was associated with advanced liver fibrosis in patients with severe obesity, and decreased after BS, without being affected by ATF. These data suggest that BS prominently eliminates drivers of hepatic fibrogenesis in NAFLD.

Published
2021
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37. Nintedanib modulates type III collagen turnover in viable precision-cut lung slices from bleomycin-treated rats and patients with pulmonary fibrosis

Author

Christina Hesse, Valerie Beneke, Sebastian Konzok, Claudia Diefenbach, Jannie Marie Bülow Sand, Sarah Rank Rønnow, Morten Asser Karsdal, Danny Jonigk, Katherina Sewald, Armin Braun, Diana Julie Leeming, Lutz Wollin, and Publica

Subjects
Precision-cut lung slices, Indoles, Nintedanib, Pulmonary Fibrosis, Antifibrotic therapy, Neoepitope biomarkers, Extracellular matrix, Complement C3, Pirfenidone, Idiopathic Pulmonary Fibrosis, Human lung, Rats, Bleomycin, Collagen Type III, Animals, Collagen, Lung, Biomarkers
Abstract

Respiratory research 23, 201 (2022). doi:10.1186/s12931-022-02116-4, Published by BioMed Central, London

Published
2021
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40. Longitudinal serological assessment of type VI collagen turnover is related to progression in a real-world cohort of idiopathic pulmonary fibrosis

Author

Jannie M.B. Sand, Nils Hoyer, Morten A. Karsdal, Thomas Skovhus Prior, Saher B. Shaker, Elisabeth Bendstrup, Peder Frederiksen, Diana Julie Leeming, Henrik Jessen, and Sarah Rønnow

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Idiopathic pulmonary fibrosis, Enzyme-Linked Immunosorbent Assay, Collagen Type VI, Gastroenterology, chemistry.chemical_compound, Diseases of the respiratory system, Stable Disease, Internal medicine, medicine, Humans, Longitudinal Studies, Prospective Studies, Aged, Aged, 80 and over, RC705-779, business.industry, Research, Pirfenidone, Extracellular matrix, Middle Aged, medicine.disease, chemistry, Cohort, Type VI collagen, Disease Progression, Linear Models, Biomarker (medicine), Nintedanib, Female, Antifibrotic Agents, business, Cohort study, Progressive disease, Biomarkers, medicine.drug
Abstract

Background Remodeling of the extracellular matrix (ECM) is a central mechanism in the progression of idiopathic pulmonary fibrosis (IPF), and remodeling of type VI collagen has been suggested to be associated with disease progression. Biomarkers that reflect and predict the progression of IPF would provide valuable information for clinicians when treating IPF patients. Methods Two serological biomarkers reflecting formation (PRO-C6) and degradation (C6M) of type VI collagen were evaluated in a real-world cohort of 178 newly diagnoses IPF patients. All patients were treatment naïve at the baseline visit. Blood samples and clinical data were collected from baseline, six months, and 12 months visit. The biomarkers were measured by competitive ELISA using monoclonal antibodies. Results Patients with progressive disease had higher (P = 0.0099) serum levels of PRO-C6 compared to those with stable disease over 12 months with an average difference across all timepoints of 12% (95% CI 3–22), whereas C6M levels tended (P = 0.061) to be higher in patients with progressive disease compared with stable patients over 12 months with an average difference across all timepoints of 12% (95% CI − 0.005–27). Patients who did not receive antifibrotic medicine had a greater increase of C6M (P = 0.043) compared to treated patients from baseline over 12 months with an average difference across all timepoints of 12% (95% CI − 0.07–47). There were no differences in biomarker levels between patients receiving pirfenidone or nintedanib. Conclusions Type VI collagen formation was related to progressive disease in patients with IPF in a real-world cohort and antifibrotic therapy seemed to affect the degradation of type VI collagen. Type VI collagen formation and degradation products might be potential biomarkers for disease progression in IPF.

Published
2021
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41. Basement membrane remodeling is related to disease progression and severity in idiopathic pulmonary fibrosis

Author

Morten A. Karsdal, Jannie M.B. Sand, Saher B. Shaker, Thomas Skovhus Prior, Henrik Jessen, Peder Frederiksen, Nils Hoyer, Elisabeth Bendstrup, and Diana Julie Leeming

Subjects
Basement membrane, Pathology, medicine.medical_specialty, Idiopathic pulmonary fibrosis, medicine.anatomical_structure, business.industry, Disease progression, medicine, business, medicine.disease
Published
2021
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42. Neutrophil activity assessed using a novel serological marker of human neutrophil elastase degraded calprotectin is elevated in patients with COPD or IPF

Author

Sarah Rønnow, Morten A. Karsdal, Diana Julie Leeming, Jannie M.B. Sand, Anne-Christine Bay-Jensen, Annika Hummersgaard Hansen, and Joachim Høg Mortensen

Subjects
COPD, Human neutrophil, business.industry, Elastase, Immunology, Medicine, In patient, Calprotectin, business, medicine.disease, Serology
Published
2021
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43. Longitudinal serological assessment of neutrophil activity is related to disease progression in idiopathic pulmonary fibrosis

Author

Thomas Skovhus Prior, Peder Frederiksen, Henrik Jessen, Jannie M.B. Sand, Diana Julie Leeming, Saher B. Shaker, Nils Hoyer, Elisabeth Bendstrup, and Morten A. Karsdal

Subjects
medicine.medical_specialty, Idiopathic pulmonary fibrosis, business.industry, Internal medicine, Disease progression, medicine, medicine.disease, business, Gastroenterology, Serology
Published
2021
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45. Comparison of ADAPT, FIB4 and APRI as non-invasive predictors of liver fibrosis and NASH within the CENTAUR Screening Population

Author

Laurent Fischer, Star Seyedkazemi, Daniel Guldager Kring Rasmussen, Diana Julie Leeming, Mette Juul Nielsen, Morten A. Karsdal, Zachary Goodman, Richard Torstenson, Scott L. Friedman, Eric Lefebvre, Vlad Ratziu, Peder Frederiksen, Pamela Vig, Arun J. Sanyal, Nordic Bioscience [Herlev, Denmark], Department of Medicine [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Liver Cirrhosis, Male, Biopsy, CENTAUR, Severity of Illness Index, Gastroenterology, Liver disease, 0302 clinical medicine, Fibrosis, Mass Screening, PRO-C3, 0303 health sciences, education.field_of_study, medicine.diagnostic_test, type III collagen, Fatty liver, Complement C3, Middle Aged, 3. Good health, Liver, Area Under Curve, Biomarker (medicine), Female, 030211 gastroenterology & hepatology, non-alcoholic steatohepatitis, ADAPT, medicine.medical_specialty, extracellular matrix, Population, Enzyme-Linked Immunosorbent Assay, digestive system, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, education, Retrospective Studies, 030304 developmental biology, neoepitope, Hepatology, business.industry, nutritional and metabolic diseases, non-alcoholic fatty liver disease, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, digestive system diseases, serological markers, Logistic Models, ROC Curve, Steatohepatitis, Steatosis, business, Biomarkers
Abstract

BACKGROUND & AIMS The development of accurate non-invasive tests to detect and measure the extent of fibrosis and disease activity in patients with non-alcoholic steatohepatitis (NASH) - the progressive phenotype of non-alcoholic fatty liver disease (NAFLD) - is of great clinical importance. Herein, we aimed to validate the performance of PRO-C3 and ADAPT for the detection of moderate/severe fibrosis within the CENTAUR screening population. METHODS PRO-C3 was assessed in plasma from the screening population of the phase IIb CENTAUR study (NCT02217475) in adults with NASH and liver fibrosis. The relation between PRO-C3 and histologic features of NASH was evaluated, as well as the demographics of patients with high and low levels of PRO-C3. The diagnostic ability of PRO-C3, as a standalone marker or incorporated into ADAPT, to identify patients with F≥2 and NASH was estimated using receiver-operating characteristic analysis and logistic regression models. RESULTS A total of 517 individuals with matched biopsy and PRO-C3 measurements were included. Patients with PRO-C3 levels ≥20.2 ng/ml showed increased levels of insulin, HOMA-IR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and platelet count compared to patients with low PRO-C3 (p

Published
2021
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46. LPA

Author

Benjamin E, Decato, Diana Julie, Leeming, Jannie Marie Bülow, Sand, Aryeh, Fischer, Shuyan, Du, Scott M, Palmer, Morten, Karsdal, Yi, Luo, and Anne, Minnich

Subjects
Adult, Aged, 80 and over, Male, Vital Capacity, Respiratory System Agents, In Vitro Techniques, Middle Aged, Models, Biological, Idiopathic Pulmonary Fibrosis, Epitopes, Humans, Female, Collagen, Receptors, Lysophosphatidic Acid, Biomarkers, Aged
Abstract

Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited treatment options. A phase 2 trial (NCT01766817) showed that twice-daily treatment with BMS-986020, a lysophosphatidic acid receptor 1 (LPASerum levels of nine ECM-neoepitope biomarkers were measured in patients with IPF. The association of biomarkers with baseline and change from baseline FVC and quantitative lung fibrosis as measured with high-resolution computed tomography, and differences between treatment arms using linear mixed models, were assessed. The Scar-in-a-Jar in vitro fibrogenesis model was used to further elucidate the antifibrotic mechanism of BMS-986020.In 140 patients with IPF, baseline ECM-neoepitope biomarker levels did not predict FVC progression but was significantly correlated with baseline FVC and lung fibrosis measurements. Most serum ECM-neoepitope biomarker levels were significantly reduced following BMS-986020 treatment compared with placebo, and several of the reductions correlated with FVC and/or lung fibrosis improvement. In the Scar-in-a-Jar in vitro model, BMS-986020 potently inhibited LPABMS-986020 reduced serum ECM-neoepitope biomarkers, which were previously associated with IPF prognosis. In vitro, LPA promoted fibrogenesis, which was LPA

Published
2021

47. High turnover of types III and VI collagen in progressive idiopathic pulmonary fibrosis

Author

Jannie M.B. Sand, Morten A. Karsdal, Elisabeth Bendstrup, Gustav K M Vangsgaard, Thomas Skovhus Prior, Diana Julie Leeming, Nils Hoyer, Saher B. Shaker, Emilia K.A. Åttingsberg, and Henrik Jessen

Subjects
Pulmonary and Respiratory Medicine, collagen, medicine.medical_specialty, extracellular matrix, Gastroenterology, Pulmonary function testing, Extracellular matrix, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Disease severity, Internal medicine, medicine, cohort study, Humans, 030212 general & internal medicine, High turnover, business.industry, Disease progression, Hazard ratio, biomarkers, medicine.disease, idiopathic pulmonary fibrosis, Idiopathic Pulmonary Fibrosis, Extracellular Matrix, Respiratory Function Tests, 030228 respiratory system, Collagen, prognosis, business, Biomarkers, Cohort study
Abstract

Background and objective: Prediction of idiopathic pulmonary fibrosis (IPF) progression is vital for the choice and timing of treatment and patient follow-up. This could potentially be achieved by prognostic blood biomarkers of extracellular matrix (ECM) remodelling. Methods: Neoepitope biomarkers of types III and VI collagen turnover (C3M, C6M, PRO-C3 and PRO-C6) were measured in 185 patients with newly diagnosed IPF. Disease severity at baseline and progression over 6 months was assessed by lung function tests and 6-min walk tests. All-cause mortality was assessed over a 3-year follow-up period. Results: High baseline levels of C3M, C6M, PRO-C3 and PRO-C6 were associated with more advanced disease at the time of diagnosis. Baseline levels of C6M and PRO-C3 were also associated with mortality over 3 years of follow-up (hazard ratio [HR]: 2.3, 95% CI: 1.3–3.9, p = 0.002 and HR: 1.8, 95% CI: 1.1–3.0, p = 0.03). Patients with several increased biomarkers at baseline, representing a high ECM remodelling phenotype, had more advanced disease at baseline, higher risk of progression or death at 6 months (OR: 1.4, 95% CI: 1.1–1.8, p = 0.002) and higher mortality over 3 years of follow-up (HR: 2.4, 95% CI: 1.3–4.5, p = 0.007). Conclusion: Blood biomarkers of types III and VI collagen turnover, assessed at the time of diagnosis, are associated with several indices of disease severity, short-term progression and long-term mortality. These biomarkers can help to identify patients with a high ECM remodelling phenotype at high risk of disease progression and death.

Published
2021
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48. Enhanced processing of von Willebrand factor reflects disease severity and discriminates severe portal hypertension in cirrhosis

Author

Diana Julie Leeming, Lasse Langholm, Tina Manon-Jensen, Flemming Bendtsen, Morten A. Karsdal, and Sören Möller

Subjects
Liver Cirrhosis, Male, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Cirrhosis, Blood Pressure, Enzyme-Linked Immunosorbent Assay, Severity of Illness Index, Gastroenterology, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Von Willebrand factor, hemic and lymphatic diseases, Internal medicine, Hypertension, Portal, von Willebrand Factor, Severity of illness, Humans, Medicine, Endothelial dysfunction, Aged, Retrospective Studies, Aged, 80 and over, Hemostasis, Hepatology, biology, business.industry, Area under the curve, Retrospective cohort study, Middle Aged, medicine.disease, Liver, 030220 oncology & carcinogenesis, cardiovascular system, biology.protein, Portal hypertension, Female, 030211 gastroenterology & hepatology, business, Biomarkers, Follow-Up Studies, circulatory and respiratory physiology
Abstract

OBJECTIVES Portal hypertension in cirrhosis is associated with endothelial dysfunction, impaired wound healing, and decreased platelet count. Increased von Willebrand factor (VWF) formation has been suggested as a compensatory mechanism, but the role of VWF processing has not been directly assessed. The aim was to measure the processing of activated VWF (VWF-A) in addition to VWF release (VWF-N) to investigate the association of primary hemostasis with disease activity and portal hypertension in liver cirrhosis. PARTICIPANTS AND METHODS Plasma samples from 105 participants undergoing liver vein catheterization and with liver cirrhosis of varying severity were included in the study together with 20 controls without liver disease. Competitive enzyme-linked immunosorbent assay format was used to estimate biomarkers of VWF turnover using neo-epitope-specific monoclonal antibodies. RESULTS VWF-N levels and VWF-A levels were significantly elevated in cirrhotic patients compared with controls (P

Published
2019
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49. Use of Plasma Fragments of Propeptides of Type III, V, and VI Procollagen for the Detection of Liver Fibrosis in Type 2 Diabetes

Author

Morten A. Karsdal, Diana Barb, Diana Julie Leeming, Jinping Lai, Kenneth Cusi, Fernando Bril, Srilaxmi Kalavalapalli, and Matthew Rabe

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Biopsy, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Collagen Type VI, Type 2 diabetes, Sensitivity and Specificity, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Predictive Value of Tests, Fibrosis, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Aspartate Aminotransferases, Longitudinal Studies, 030212 general & internal medicine, Aged, Advanced and Specialized Nursing, Receiver operating characteristic, medicine.diagnostic_test, Platelet Count, business.industry, Type 2 Diabetes Mellitus, Alanine Transaminase, Middle Aged, medicine.disease, Peptide Fragments, Procollagen peptidase, Collagen Type III, Diabetes Mellitus, Type 2, Liver biopsy, Female, business, Collagen Type V, Biomarkers, Procollagen
Abstract

OBJECTIVE This study assessed the utility of plasma fragments of propeptides of type III (PRO-C3), V (PRO-C5), and VI (PRO-C6) procollagen for the detection of liver fibrosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Patients with T2DM (n = 191) underwent an oral glucose tolerance test, a liver 1H-MRS, and a liver biopsy when indicated. PRO-C3, PRO-C5, and PRO-C6 were blindly assessed. RESULTS PRO-C3 performed well for the diagnosis of moderate-to-advanced (area under the receiver operating characteristic curve [AUROC] 0.81 [95% CI 0.74–0.88]) and advanced (AUROC 0.88 [0.80–0.95]) fibrosis in T2DM patients. Its performance was similar to that of AST to platelet ratio index (APRI) (AUROC 0.83 and 0.87, respectively) and Fibrosis-4 (FIB-4) (AUROCs 0.83 and 0.86, respectively) scores. Use of PRO-C5 and PRO-C6 did not improve the accuracy to detect liver fibrosis. After 18 months, PRO-C3 changes were associated with changes in fibrosis stages. CONCLUSIONS PRO-C3 performed well for the detection of fibrosis in T2DM patients and showed promising results for prediction of histological changes in fibrosis stage with treatment.

Published
2019
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50. Collagen type IV remodelling gender‐specifically predicts mortality in decompensated cirrhosis

Author

Jonel Trebicka, Søren Møller, Flemming Bendtsen, Morten A. Karsdal, Christian P. Strassburg, Daniel Thomas, Michael Praktiknjo, Jennifer Lehmann, Mette Juul Nielsen, Robert Schierwagen, Carsten H. Meyer, Francesco Violi, Diana Julie Leeming, and Aleksander Krag

Subjects
Liver Cirrhosis, Male, Cirrhosis, medicine.medical_treatment, acute‐on‐chronic liver failure, Gastroenterology, extracellular matrix remodelling, Collagen Type III, 0302 clinical medicine, ACLF, Ascites, gender, Prospective Studies, Aged, 80 and over, portal hypertension, Middle Aged, Cirrhosis and Liver Failure, 030220 oncology & carcinogenesis, Portal hypertension, Female, 030211 gastroenterology & hepatology, acute-on-chronic liver failure, medicine.symptom, Transjugular intrahepatic portosystemic shunt, Adult, Collagen Type IV, medicine.medical_specialty, liver, collagen type IV, 03 medical and health sciences, Sex Factors, Internal medicine, Hypertension, Portal, transjugular intrahepatic portosystemic shunt, medicine, Humans, Decompensation, Aged, Hepatology, Proportional hazards model, business.industry, cirrhosis, acute decompensation, medicine.disease, Survival Analysis, Renal sodium excretion, Multivariate Analysis, Portasystemic Shunt, Transjugular Intrahepatic, business, Biomarkers
Abstract

BACKGROUND & AIMS: Remodelling of extracellular matrix is crucial in progressive liver fibrosis. Collagen type III desposition has been shown in acute decompensation. Extratracellular matrix is compiled of deposition of various components. The role of basement membrane collagen type IV in advanced cirrhosis and acute decompensation is unclear and investigated in this study.METHODS: Patients with decompensated cirrhosis from the prospective NEPTUN cohort (ClinicalTrials.gov Identifier: NCT03628807), who underwent transjugular intrahepatic portosystemic shunt procedure were included. Clinical and laboratory parameters, PRO-C4 and C4M levels were measured in blood samples from portal and hepatic veins just before transjugular intrahepatic portosystemic shunt placement.RESULTS: Levels of C4M and PRO-C4 are significantly lower in patients with massive ascites and impaired renal sodium excretion. C4M and PRO-C4 show gender-specific profiles with significantly lower levels in females compared to males. Females with higher C4M levels show higher mortality. By contrast, males with higher C4M levels show lower mortality. In multivariate Cox regression analysis, C4M is an independent predictor of survival in female patients.CONCLUSION: This study shows that markers of collagen type IV remodelling do not accumulate in severe renal dysfunction. Although collagen type IV degradation markers derive from the liver, portal venous C4M levels are relevant for survival. Moreover, it demonstrates that circulating C4M shows gender-specific profiles, which can independently predict survival in female patients with decompensated cirrhosis.

Published
2019
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