Elevated Serum Level of Cytokeratin 18 M65ED Is an Independent Indicator of Cardiometabolic Disorders

Abstract

Background. Recent studies have suggested that cell death might be involved in the pathophysiology of metabolic disorders. The cytokeratin 18 (CK18) fragment, as a cell death marker, plays an important role in nonalcoholic fatty liver disease (NAFLD). However, only a limited number of studies have found elevated serum levels of CK18 in patients with type 2 diabetes. Moreover, no studies have been conducted yet to investigate the role of CK18 in hypertension or dyslipidemia. In particular, CK18 M65ED is a more sensitive marker of cell death, and its role in cardiometabolic disorders has not been revealed yet. Methods. A total of 588 subjects were enrolled from the local communities of Shanghai. Serum CK18 M65ED were determined using the enzyme-linked immunosorbent assay. A cardiometabolic disorder was identified by the presence of at least one of the components including overweight or central obesity, diabetes, dyslipidemia, and hypertension. Results. Subjects with cardiometabolic disorders exhibited significantly higher serum levels of CK18 M65ED than those without cardiometabolic disorders (197.36 (121.13–354.50) U/L versus 83.85 (52.80–153.75) U/L, respectively, P<0.001). Increased serum CK18 M65ED quartiles were associated with the increased prevalence of cardiometabolic disorders and its components (P<0.001 for all components). Multiple stepwise regression analysis also revealed that diastolic blood pressure, glycated hemoglobin A1c, alanine transaminase, and high-density lipoprotein cholesterol were independently correlated with serum CK18 M65ED levels (all P<0.01). In addition, logistic regression analysis showed that the serum CK18 M65ED levels were positively correlated with cardiometabolic disorders and in an independent manner. Further, CK18 M65ED was revealed to be an indicator of cardiometabolic disorders in a NAFLD-independent manner. Conclusions. Elevated levels of CK18 M65ED, a sensitive cell death marker, were independently and positively correlated with cardiometabolic disorders, even after the adjustment for the presence of NAFLD and other cardiovascular risk factors.

Serum Level of Cytokeratin 18 (M65) as a Prognostic Marker of High Cardiovascular Disease Risk in Individuals with Non-Alcoholic Fatty Liver Disease

“…The second important finding of this work is that total CK18 (M65) was found to be associated with a very high CVD risk according to the SCORE2, both particularly in individuals with an FLI ≥ 60. Consistent with previous studies [25,29,46], our linear regression and Spearman analyses showed that M30 and M65 were independently associated with the FLI and with several cardiometabolic parameters, especially in the overall study population where M30 and M65 were significantly associated with almost all the parameters studied and with both CVD risk scores, while when considering the same associations in participants with FLI ≥ 60, M30 and M65 were significantly associated only with liver function enzymes (ALT, AST, and GGT) and only M65 was associated with FRS.…”

“…Extending previous observations reporting higher levels of CK18 (M30 and M65) in NAFLD subjects compared to healthy subjects [25,29,46] and even more in steatohepatitis [41], this is, to our knowledge, the first demonstration indicating that CK18 (M30) predicts FLI-suspected NAFLD, except for a very recently shown relationship of CK (M30) with the FLI as a continuous parameter [47], and that CK-18 (M65) predicts 10-year CVD risk independently of FLI if the SCORE2 algorithm is used for CVD risk stratification purposes.…”

“…A recent study by Quian and colleagues showed that CK18 (M65) was independently and positively associated with cardiometabolic disorders, even after adjustment for the presence of NAFLD and other cardiovascular risk factors [29]. Notably, limited data are available regarding the ability of CK18 to predict NAFLD in the general population and to predict CVD risk among NAFLD subjects.…”

Plasma Cytokeratin-18 Fragment Level Reflects the Metabolic Phenotype in Obesity

“…The strong correlations of CK-18 with ALT were also observed in other studies, and changes in CK-18 M65 levels after the 12 weeks of exercise were significantly correlated with changes in alanine aminotransferase activity (r = 0.62) [ 29 ]. A study on a population of 688 subjects showed, by regression analysis, that the total CK-18 (M65) plasma levels positively correlated with cardiometabolic disorder components, including obesity, blood pressure, glycated hemoglobin A1c, ALT and HDL [ 34 ]. In this Chinese population, total CK-18 levels were significantly increased in subjects with multiple cardiometabolic factors and were an independent risk factor for cardiometabolic disorders after accounting for general cardiometabolic risk parameters or the presence of NAFLD.…”