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

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

doi:10.2337/dc18-2578

Cited by 43 publications

(61 citation statements)

References 15 publications

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“…Future studies must develop algorithms in this setting. This is also our own personal experience in patients recruited in diabetes clinics . A recent study compared several plasma biomarkers and diagnostic panels in 213 patients with T2DM not recruited from hepatology clinics .…”

Section: The Challenge Of Diagnosing Nash In Patients With T2dmmentioning

confidence: 75%

“…This is also our own personal experience in patients recruited in diabetes clinics. [23][24][25][26] A recent study compared several plasma biomarkers and diagnostic panels in 213 patients with T2DM not TA B L E 1 Potential mechanisms by which chronic hyperglycemia may play a role in NASH • Hepatic inflammation and oxidative stress with formation of hydrogen peroxide/hydroxyl radicals leading to hepatocyte lipid peroxidation. • Accelerate the production of advanced glycosylation endproducts (AGEs) and development of inflammation in Kupffer and hepatic stellate cells (both have receptors for AGE).…”

Section: The Challeng E Of D Iag Nos Ing Na S H In Patients With T2dmmentioning

confidence: 99%

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A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

Cusi

2020

Liver International

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There is a close link between steatohepatitis (NASH) and Type 2 diabetes (T2DM). Recently, the American Diabetes Association (ADA) recommended screening for NASH and advanced fibrosis in patients with diabetes and hepatic steatosis or elevated plasma alanine aminotransferase (ALT). This is because as many as ~30% to 40% may have NASH and ~10% to 15% advanced fibrosis. The role of hyperglycemia and the natural history of NASH in diabetes remain poorly understood, as well as which diagnostic algorithm or interventions are most cost‐effective. There is significant clinical inertia and most patients today are still not receiving adequate lifestyle intervention or pharmacological treatment with diabetes agents known to be effective against NASH. Lifestyle intervention improves steatohepatitis in proportion to the magnitude of weight loss, but this trend is not as consistent for regression of fibrosis. This limited success supports the need for concomitant pharmacological therapy. Pioglitazone has been shown to consistently induce resolution of NASH in both patients with or without diabetes in a total of 498 participants in five randomized controlled trials (RCTs), but with modest effects on liver fibrosis. Proof‐of‐concept studies suggest a potential role for GLP‐1RAs and SGLT2 inhibitors. Combination therapy is on the horizon. Treating diabetes and NASH with a combination of pioglitazone, GLP‐1RAs or SGLT2i, could be a cost‐effective strategy to treat both diseases while reducing their high cardiovascular risk. Future combination therapies will likely combine existing diabetes agents with novel NASH‐spechfic drugs under development. This review highlights current knowledge gaps and proposes future directions for the treatment of NASH in diabetes.

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Section: The Challenge Of Diagnosing Nash In Patients With T2dmmentioning

confidence: 75%

Section: The Challeng E Of D Iag Nos Ing Na S H In Patients With T2dmmentioning

confidence: 99%

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

Cusi

2020

Liver International

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“…Cytokeratin (CK) 18, an intermediate filament protein that is cleaved during cell death to CK18 M30 and CK18 M65, has been intensively investigated as a surrogate of NASH-associated liver cell damage, but a recent meta-analysis of 25 studies reported a maximum sensitivity of 0.75 for NASH diagnosis [76] and suboptimal diagnostic value was shown in T2DM [75]. The ECM turnover marker, type III procollagen, can offer a diagnostic efficacy of 0.81 and 0.88 to detect moderate and advanced liver fibrosis in T2DM, respectively [77].…”

Section: Current Biomarkers and Indicesmentioning

confidence: 99%

Metabolic liver disease in diabetes – From mechanisms to clinical trials

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) comprises fatty liver (steatosis), non-alcoholic steatohepatitis (NASH) and fibrosis/cirrhosis and may lead to end-stage liver failure or hepatocellular carcinoma. NAFLD is tightly associated with the most frequent metabolic disorders, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). Both multisystem diseases share several common mechanisms. Alterations of tissue communications include excessive lipid and later cytokine release by dysfunctional adipose tissue, intestinal dysbiosis and ectopic fat deposition in skeletal muscle. On the hepatocellular level, this leads to insulin resistance due to abnormal lipid handling and mitochondrial function. Over time, cellular oxidative stress and activation of inflammatory pathways, again supported by multiorgan crosstalk, determine NAFLD progression. Recent studies show that particularly the severe insulin resistant diabetes (SIRD) subgroup (cluster) associates with NAFLD and its accelerated progression and increases the risk of diabetes-related cardiovascular and kidney diseases, underpinning the critical role of insulin resistance. Consequently, lifestyle modification and certain drug classes used to treat T2DM have demonstrated effectiveness for treating NAFLD, but also some novel therapeutic concepts may be beneficial for both NAFLD and T2DM. This review addresses the bidirectional relationship between mechanisms underlying T2DM and NAFLD, the relevance of novel biomarkers for improving the diagnostic modalities and the identification of subgroups at specific risk of disease progression. Also, the role of metabolism-related drugs in NAFLD is discussed in light of the recent clinical trials. Finally, this review highlights some challenges to be addressed by future studies on NAFLD in the context of T2DM.

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“…Patients with high ECM formation (and thus disease activity) progress more when compared to those with normal levels 114,115 . In addition, patients with high fibrotic levels respond better to anti‐fibrotic therapies, indicating that only patients with active progressive disease will respond to therapy targeting fibrosis formation 114,116 . Consequently, the rate of ECM turnover is important for patient stratification and treatment efficacy 117 .…”

Section: The Future—ecm Profiling For Identification Of Patient Hetermentioning

confidence: 99%

Review article: the signalling and functional role of the extracellular matrix in the development of liver fibrosis

Villesen

Leeming

Karsdal

et al. 2020

Aliment Pharmacol Ther

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Summary 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.

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

Cited by 43 publications

References 15 publications

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

Metabolic liver disease in diabetes – From mechanisms to clinical trials

Review article: the signalling and functional role of the extracellular matrix in the development of liver fibrosis

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