Introduction: Metabolic-associated fatty liver disease is common, with fibrosis the major determinant of adverse outcomes. Population-based screening tools with high diagnostic accuracy for the staging of fibrosis are lacking. Methods: Three independent cohorts, 2 with both liver biopsy and liver s...
November 26, 2020
Journal:
Am J Physiol Gastrointest Liver Physiol
Author:
Eslam M, Wong GL, Hashem AM, Chan HL, Nielsen MJ, Leeming DJ, Chan AW, Chen Y, Duffin KL, Schattenberg JM, George J, Wong VW, Karsdal MA
Purpose: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis is present in 80-90% of HCC patients. Cirrhosis is characterized by deposition and cross-linking of collagens that have crucial roles in HCC initiation and progression. We eva...
November 20, 2020
Journal:
J Hepatocell Carcinoma
Author:
Jensen C, Holm Nielsen S, Eslam M, Genovese F, Nielsen MJ, Vongsuvanh R, Uchila R, van der Poorten D, George J, Karsdal MA, Leeming DJ, Willumsen N.
Purpose: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis is present in 80-90% of HCC patients. Cirrhosis is characterized by deposition and cross-linking of collagens that have crucial roles in HCC initiation and progression. We eva...
November 20, 2020
Journal:
J Hepatocell Carcinoma
Author:
Jensen C, Holm Nielsen S, Eslam M, Genovese F, Nielsen MJ, Vongsuvanh R, Uchila R, van der Poorten D, George J, Karsdal MA, Leeming DJ, Willumsen N.
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...
September 3, 2020
Journal:
JHEP Rep
Author:
Vesterhus M, Nielsen MJ, Hov JR, Saffioti F, Manon-Jensen T, Leeming DJ, Moum B, Boberg KM, Pinzani M, Karlsen TH, Karsdal MA, Thorburn D
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 liv...
April 9, 2020
Journal:
Liver Int
Author:
Karsdal MA, Daniels SJ, Nielsen SH, Bager CL, Rasmussen DGK, Loomba R, Surabattula R, Villesen IF, Luo Y, Shevell D, Gudmann NS, Nielsen MJ, George J, Christian R, Leeming DJ, Schuppan D
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 essenti...
January 6, 2020
Journal:
Am J Physiol Gastrointest Liver Physiol
Author:
Daniels SJ, Leeming DJ, Detlefsen S, Bruun MF, Hjuler ST, Henriksen K, Hein P, Krag A, Karsdal MA, Nielsen MJ, Brockbank S, Cruwys S
Is liver fibrosis just liver fibrosis? Or do the subtype of collagen, its spatial localization in the liver, its cell of origin, and the time point at which it is synthesized also matter? It is important, since the various collagen subtypes hold different informative values regarding reparative proc...
December 18, 2019
Journal:
Hepatology
Author:
Karsdal MA, Detlefsen S, Daniels SJ, Nielsen MJ, Krag A, Schuppan D
Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups...
October 25, 2019
Journal:
Nat Med
Author:
Moroni F, Dwyer BJ, Graham C, Pass C, Bailey L, Ritchie L, Mitchell D, Glover A, Lauire A, Doig S, Hargreaves E, Fraser AR, Turner ML, Cambpell JDM, McGowan NWA, Barry J, Moore JK, Hayes PC, Leeming DJ, Nielsen MJ, Musa K, Fallowfield JA, Forbes SJ
Following liver transplantation (LT), 10-30% of patients develop recurrent cirrhosis (RC). There is an urgent need for predictive non-invasive markers for improved monitoring of these patients. Here we studied extracellular matrix biomarkers as predictors of RC after LT. Forty-seven LT patients were...
October 16, 2019
Journal:
Sci Rep
Author:
Nielsen MJ, Villesen IF, Gudmann NS, Leeming DJ, Krag A, Karsdal MA, Zimmermann T, Schuppan D
Background and aims: Although combined antiretroviral treatment (cART) has improved overall survival of HIV infected patients, liver fibrosis and liver related-mortality still constitute major challenges in HIV positive patients. Collagen accumulates in the liver during fibrogenesis. Recent studies ...
July 11, 2019
Journal:
PLoS One
Author:
Dold L, Nielsen MJ, Praktiknjo M, Schwarzer-Zander C, Boesecke C, Schierwagen R, Mohr R, Wasmuth JC, Jansen C, Bischoff J, Rockstroh J, Karsdal MA, Trebicka J, Leeming DJ
There is an unmet need for non-invasive biomarkers in non-alcoholic fatty liver disease (NAFLD) that can diagnose advanced disease and identify patients suitable for clinical trials. The PRO-C3 collagen neo-epitope is a putative direct marker of fibrogenesis. We assessed the performance of PRO-C3 in...
July 4, 2019
Journal:
JHEP Rep
Author:
Boyle M, tiniakos D, Schattenberg JM, Ratziu V, Bugianessi E, Petta S, Oliveira CP, Govaere O, Yournes R, McPherson S, Bedossa P, Nielsen MJ, Oersnes-Leeming DJ, Kendrick, Anstee QM, Karsdal MA
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 h...
February 12, 2019
Journal:
Transl Oncol
Author:
Holm Nielsen S, Willumsen N, Leeming DJ, Daniels SJ, brix s, Karsdal MA, Genovese F, Nielsen MJ
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 cir...
February 9, 2019
Journal:
Liver Int
Author:
Lehmann J, Praktiknjo M, Nielsen MJ, Schierwagen R, Meyer C, Thomas D, Violi F, Strassburg CP, Bendtsen F, Møller S, Krag A, Leeming DJ, Trebicka J, Karsdal MA
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 sys...
September 5, 2018
Journal:
PLoS One
Author:
kimer N, Gudmann NS, Pedersen JS, Møller S, Nielsen MJ, Leeming DJ, Karsdal MA, Møller HJ, Bedtsen F, Grønbæk H
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 sys...
September 5, 2018
Journal:
PLoS One
Author:
kimer N, Gudmann NS, Pedersen JS, Møller S, Nielsen MJ, Leeming DJ, Karsdal MA, Møller HJ, Bendtsen F, Grønbæk H
OBJECTIVE: There is a need for non-invasive biomarkers that can identify patients with progressive liver fibrosis and monitor response to anti-fibrotic therapy. An equally important need is identification of patients with spontaneous fibrosis regression, since they may not need treatment nor be incl...
August 30, 2018
Journal:
Am J Physiol Gastrointest Liver Physiol
Author:
Karsdal MA, Hjuler ST, Luo Y, Rasmussen DG, Nielsen MJ, Nielsen SH, Leeming DJ, Goodman ZD, Arch RH, Patel K, Schuppan D
OBJECTIVE: There is a need for non-invasive biomarkers that can identify patients with progressive liver fibrosis and monitor response to anti-fibrotic therapy. An equally important need is identification of patients with spontaneous fibrosis regression, since they may not need treatment nor be incl...
August 30, 2018
Journal:
Am J Physiol Gastrointest Liver Physiol.
Author:
Karsdal MA, Hjuler ST, Luo Y, Rasmussen DG, Nielsen MJ, Holm Nielsen S, Leeming DJ, goodman Z, Arch RH, Patel K, Schuppan D
BACKGROUND AND AIM: Given the high global prevalence of non-alcoholic fatty liver disease (NAFLD), the need for relevant non-invasive biomarkers and algorithms to accurately stage disease severity is a critical unmet medical need. Identifying those with advanced fibrosis (≥F3) is the most crucial, a...
July 16, 2018
Journal:
Hepagology
Author:
Daniels SJ, Leeming DJ, Eslam M, Hashem AM, Nielsen MJ, Krag A, Karsdal MA, Grove JI, Guha IN, Kawaguchi T, Torimura T, McLeod D, Akiba J, Kaye P, de Boer B, Aithal GP, Adams LA, George J
BACKGROUND: Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Biomarkers of disease activity or prognostic models predicting outcome at an individual level are currently not established. AIM: To evaluate the prognostic utility of four biomarkers of bas...
July 16, 2018
Journal:
Alimentary pharmacology therapeutics
Author:
Nielsen MJ, Thorburn D, Leeming DJ, Hov JR, Nygård S, Moum B, Saffioti F, Gilja OH, Boberg KM, Mazza G, Røsjø H, Pinzani M, Karlsen TH, Karsdal MA, Vesterhus M
Patients with end-stage liver disease develop acute decompensation (AD) episodes, which become more frequent and might develop into acute-on-chronic liver failure (ACLF). However, it remains unknown how AD induces acceleration of liver disease. We hypothesized that remodeling of collagen type III pl...
January 18, 2018
Journal:
Hepatol Commun
Author:
Praktiknjo M, Lehmann J, Nielsen MJ, Schierwagen R, Uschner FE, Meyer C, Thomas D, Strassburg CP, Bendtsen F, Møller S, Krag A, Karsdal MA, Leeming DJ, Trebicka J
Usually the dense extracellular structure in fibrotic tissues is described as extracellular matrix (ECM) or simply as collagen. However, fibrosis is not just fibrosis, which is already exemplified by the variant morphological characteristics of fibrosis due to viral versus cholestatic, autoimmune or...
July 21, 2017
Journal:
Adv Drug Deliv Rev
Author:
Karsdal MA, Nielsen SH, Leeming DJ, Langholm LL, Nielsen MJ, Manon-Jensen T, Siebuhr AS, Gudmann NS, Rønnow S, Sand JM, Daniels SJ, Mortensen JH, Schuppan D
There are no approved treatments for liver fibrosis. To aid development of antifibrotic therapies, noninvasive biomarkers that can identify patients with progressive fibrosis and that permit monitoring of the response to antifibrotic therapy are much needed. Samples from a phase II antifibrotic tria...
October 20, 2016
Journal:
Am J Physiol Gastrointest Liver Physiol
Author:
Karsdal MA, Henriksen K, Nielsen MJ, Byrjalsen I, Leeming DJ, Gardner SD, Goodman ZD, Patel K, Krag A, Christiansen C, Schuppan D
BACKGROUND: While morphological patterns differ, the molecular phenotype of liver fibrosis is considered a stereotypical response to chronic liver injury. However, with different cellular triggers and networks regulating fibrosis, the molecular responses of the injured liver may not be identical. A...
October 3, 2016
Journal:
Aliment Pharmacol Ther.
Author:
Nielsen MJ, Karsdal MA, Kazankov K, Krag A, Grønbæk H, Leeming DJ, Schuppan D, George J
AIMS/HYPOTHESIS:The treatment of type 2 diabetes with full peroxisome proliferator-activated receptor gamma (PPARγ) agonists improves insulin sensitivity, but is associated with weight gain, heart failure, peripheral oedema and bone loss. Endotrophin, the C-terminal fragment of the α3 chain of proco...
September 8, 2016
Journal:
Diabetologia
Author:
Karsdal MA, Henriksen K, Genovese F, Leeming DJ, Nielsen MJ, Riis BJ, Christiansen C, Byrjalsen I, Schuppan D
AIMS/HYPOTHESIS: The treatment of type 2 diabetes with full peroxisome proliferator-activated receptor gamma (PPARγ) agonists improves insulin sensitivity, but is associated with weight gain, heart failure, peripheral oedema and bone loss. Endotrophin, the C-terminal fragment of the α3 chain of proc...
September 8, 2016
Journal:
Diabetologia
Author:
Karsdal MA, Henriksen K, Genovese F, Leeming DJ, Nielsen MJ, Riis BJ, Christiansen C, Byrjalsen I, Schuppan D
Background and aim: Detection of advanced fibrosis (Metavir F≥3) is important to identify patients with a high urgency of antiviral treatments vs. those whose treatment could be deferred (F≤2). The aim was to assess the diagnostic value of novel serological extracellular matrix protein fragments as ...
September 25, 2015
Journal:
PLoS One
Author:
Nielsen MJ, Kazankov K, Leeming DJ, Karsdal MA, Krag A, Barrera F, McLeod D, George J, Grønbæk H
Background and aims: Progressive fibrosis increases hepatic resistance and causes portal hypertension with complications. During progressive fibrosis remodeling and deposition of collagens and elastin occur. Elastin remodeling is crucially involved in fibrosis progression in animal models and human ...
July 3, 2015
Journal:
Dig Dis Sci
Author:
Nielsen MJ, Lehmann J, Leeming DJ, Schierwagen R, Klein S, Jansen C, Strassburg CP, Bendtsen F, Møller S, Sauerbruch T, Karsdal MA, Krag A, Trebicka J
Emerging evidence suggests that altered components and posttranslational modifications of proteins in the extracellular matrix (ECM) may both initiate and drive disease progression. The ECM is a complex grid consisting of multiple proteins, most of which play a vital role in containing the essential...
May 15, 2015
Journal:
Am J Physiol Gastrointest Liver Physiol
Author:
Karsdal MA, Manon-Jensen T, Genovese F, Kristensen JH, Nielsen MJ, Sand JM, Brandt-Hansen NU, Bay-Jensen AC, Bager CL, Krag A, Blanchard A, Krarup H, Leeming DJ, Schuppan D
Background and aims: The hepatic venous pressure gradient (HVPG) is an important but invasive diagnostic and prognostic marker in cirrhotic patients. The aim of the study was to evaluate a novel biochemical plasma marker of true type V collagen formation (Pro-C5) for describing HVPG. Methods: Ninet...
May 1, 2015
Journal:
Scand J Gastroenterol
Author:
Leeming DJ, Veidal SS, Karsdal MA, Nielsen MJ, Trebicka J, Busk T, Bendtsen F, Krag A, Møller S
Fibrogenesis results in release of certain extracellular matrix protein fragments into the circulation. We evaluated the diagnostic and prognostic performance of two novel serological markers, the precisely cleaved N-terminal propeptide of type III collagen (Pro-C3) and a peptide of helical collagen...
February 1, 2015
Journal:
Liver Int
Author:
Nielsen MJ, Veidal SS, Karsdal MA, Leeming DJ, Vainer B, Gardner SD, Hamatake R, Goodman ZD, Schuppan D, Patel K
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