Cytokeratin-18 fragments and biomarkers of the metabolic syndrome in nonalcoholic steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) remains a leading cause of chronic liver disease. In the context of NAFLD, the presence of nonalcoholic steatohepatitis (NASH) portends an adverse prognosis with greater risk of liver fibrosis and cirrhosis. Although liver biopsy is the keystone of patient management in NAFLD, it is also increasingly clear that such evaluation has its limitations. The availability of biochemical markers of NAFLD and NASH has tremendous potential to radically alter management strategies for these conditions, as well as to monitor disease activity. Our article provides an overview of biomarker discovery and selection in the setting of NAFLD and highlights future directions in the field.

Nonalcoholic fatty liver disease: Diagnostic biomarkers

“…During the apoptosis process, cytokeratin-18 (CK-18) is fragmented by caspase 3[135] and hepatocytes which leads to cell death through the apoptosis process and release fragments of CK-18 into the blood stream, so that the blood level of the fragmented CK-18 is associated with the presence of hepatic fibrosis[133]. Indeed, this substance has been shown to be significantly higher in patients with NASH[120].…”

Knowledge-Based Identification of Soluble Biomarkers: Hepatic Fibrosis in NAFLD as an Example

“…More often than not, initial exploratory studies aimed at the discovery of biomarkers are performed using high-throughput proteomics-based platforms, for example, the label-free mass spectrometry [1], the antibody arrays [2] and the reverse phase protein arrays [3]. The high-throughput approach described above is also known as so-called “unbiased” approach as it may uncover truly novel biomarker molecules reflecting yet unknown pathological mechanisms for given condition [4]. This, most strong, advantage of “unbiased” strategies is mirrored by its weakness as lack of bias comes in hand with its lack of connection to known pathophysiological processes, thus, being bound to produce at least some spurious results.…”

“…One way around this issue is to use knowledge-based, or systems biology approaches that involve the analysis of integrated data, predominantly, molecular pathways and networks already known to be implicated in given condition [4], [5]. If the systems biology model in use truly reflects the real state of the organism of study, one should be able to infer quantitative changes in the levels of biomolecules not included by the given assay from the levels of the analytes profiled.…”

Systematic Analysis of the Gene Expression in the Livers of Nonalcoholic Steatohepatitis: Implications on Potential Biomarkers and Molecular Pathological Mechanism

“…The first hit corresponds to the fat accumulation in liver and the second hit consists of an oxidative stress leading to liver injury and inflammation. What is more, a number of studies showed that apoptosis [11], [12], mitochondrial dysfunction [13], [14], [15], [16], [17], insulin resistance [18], [19], [20], [21], immune response [21], [22], alcohol metabolism [23], lipid peroxidation [5], [24], lipid metabolism [25], and many other factors like endoplasmic reticulum's response to stress [9] are all involved in or related to the development of NASH. However, the complex interplay among these observations and the molecular pathological mechanism of NASH remains unknown [26].…”