Differentiation between Cell Death Modes Using Measurements of Different Soluble Forms of Extracellular Cytokeratin 18

BackgroundThe mechanism by which SARS-CoV-2 triggers cell damage and necrosis are yet to be fully elucidated. We sought to quantify epithelial cell death in patients with COVID-19, with an estimation of relative contributions of apoptosis and necrosis.MethodsBlood samples were collected prospectively from adult patients presenting to the emergency department. Circulating levels of caspase-cleaved (apoptosis) and total cytokeratin 18 (CK-18) (total cell death) were determined using M30 and M65 enzyme assays, respectively. Intact CK-18 (necrosis) was estimated by subtracting M30 levels from M65.ResultsA total of 52 COVID-19 patients and 27 matched sick controls (with respiratory symptoms not due to COVID-19) were enrolled. Compared with sick controls, COVID-19 patients had higher levels of M65 (p = 0.046, total cell death) and M30 (p = 0.0079, apoptosis). Hospitalised COVID-19 patients had higher levels of M65 (p= 0.014) and intact CK-18 (p= 0.004, necrosis) than discharged patients. Intensive care unit (ICU)-admitted COVID-19 patients had higher levels of M65 (p= 0.004), M30 (p= 0.004) and intact CK-18 (p= 0.033) than hospitalised non-ICU admitted patients. In multivariable logistic regression, elevated levels of M65, M30 and intact CK-18 were associated with increased odds of ICU admission (OR=22.05, p=0.014, OR=19.71, p=0.012 and OR=14.12, p=0.016, respectively).ConclusionNecrosis appears to be the main driver of hospitalisation, whereas apoptosis and necrosis appear to drive ICU admission. Elevated levels CK-18 levels are independent predictors of severe disease, and could be useful for risk stratification of COVID-19 patients and in assessment of therapeutic efficacy in early-phase COVID-19 clinical trials.

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Urinary acrolein metabolite levels in severe acute alcoholic hepatitis patients

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00209.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. G115-G122 ◽

Cited By ~ 7

Author(s):

Vatsalya Vatsalya ◽

Maiying Kong ◽

Leila Gobejishvili ◽

Wei-Yang Chen ◽

Sanjay Srivastava ◽

...

Keyword(s):

Cell Death ◽

Liver Disease ◽

Proinflammatory Cytokines ◽

Alcoholic Hepatitis ◽

Pathogenic Role ◽

Cytokeratin 18 ◽

Acute Alcoholic Hepatitis ◽

Noninvasive Biomarker ◽

Liver Cell Death

Alcohol-associated liver disease (ALD) remains a major health concern worldwide. Alcohol consumption gives rise to reactive/toxic acrolein, a pathogenic mediator of liver injury in experimental ALD. Elevated acrolein adducts and metabolites are detectable in blood and urine. This study evaluates the major urinary acrolein metabolite, 3-hydroxypropylmercapturic acid (HPMA), in patients with acute alcoholic hepatitis (AAH) and examines its association with disease severity and markers of hepatic inflammation and injury. Urine HPMA was significantly higher in patients with severe [model for end-stage liver disease (MELD) ≥ 20] AAH compared with nonsevere AAH (MELD ≤ 19) or non-alcohol-consuming controls, suggesting that urine HPMA is a novel noninvasive biomarker in severe AAH. The association between HPMA and MELD in patients with AAH was nonlinear. In patients with nonsevere AAH, there was a positive trend, although not significant, whereas in severe AAH the association was negative, indicative of extensive injury and glutathione depletion. Consistent with the multifactorial etiology of ALD, our data identified strong combined effects of HPMA and proinflammatory cytokines on hepatocyte cell death, thereby supporting the pathogenic role of acrolein in liver injury. HPMA, together with IL-1β, showed robust associations with cytokeratin 18 caspase-cleaved fragment (CK18-M30; adjusted R2 = 0.812, P = 0.016) and cytokeratin 18 full-length protein (CK18-M65; adjusted R2 = 0.670, P = 0.048); similarly, HPMA, with IL-8, correlated with CK18-M30 (adjusted R2 = 0.875, P = 0.007) and CK18-M65 (adjusted R2 = 0.831, P = 0.013). The apoptosis index (CK18-M30:CK18-M65 ratio) strongly correlated with HPMA, together with IL-1β (adjusted R2 = 0.777, P = 0.022) or tumor necrosis factor-α (TNFα; adjusted R2 = 0.677, P = 0.046). In patients with severe AAH, IL-1β, IL-8, and TNFα are the predominant proinflammatory cytokines that interact with HPMA and play important mediating roles in influencing the extent/pattern of liver cell death. NEW & NOTEWORTHY This is the first study to examine the urinary acrolein metabolite 3-hydroxypropylmercapturic acid (HPMA) in alcoholic liver disease. HPMA was higher in patients with severe acute alcoholic hepatitis (AAH) compared with controls or nonsevere AAH and may be a novel selective, noninvasive biomarker for severe AAH. Consistent with the multifactorial etiology of alcohol-associated liver disease, we identified strong combined effects of HPMA and proinflammatory cytokines (IL-1β, IL-8, and TNFα) on the extent/pattern of liver cell death, thereby supporting the pathogenic role of acrolein.

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Commentary on “Cytokeratin 18, a Marker of Cell Death, is Increased in Children With Suspected Nonalcoholic Fatty Liver Disease”

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/mpg.0b013e3181a2bb50 ◽

2009 ◽

Vol 49 (3) ◽

pp. 371

Author(s):

Yusuf Yilmaz ◽

Enver Dolar ◽

Engin Ulukaya

Keyword(s):

Cell Death ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Cytokeratin 18 ◽

Nonalcoholic Fatty Liver

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Soluble cytokeratin 18 biomarkers may provide information on the type of cell death during early ischemia and reperfusion periods of liver transplantation

Clinical Transplantation ◽

10.1111/j.1399-0012.2009.01177.x ◽

2010 ◽

Vol 24 (6) ◽

pp. 848-854 ◽

Cited By ~ 7

Author(s):

Sezgin Ulukaya ◽

Engin Ulukaya ◽

Isik Alper ◽

Arzu Yilmaztepe-Oral ◽

Murat Kilic

Keyword(s):

Liver Transplantation ◽

Cell Death ◽

Ischemia And Reperfusion ◽

Cytokeratin 18

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

Journal of Diabetes Research ◽

10.1155/2020/5198359 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Lingling Qian ◽

Lei Zhang ◽

Liang Wu ◽

Jing Zhang ◽

Qichen Fang ◽

...

Keyword(s):

Cell Death ◽

Regression Analysis ◽

Elevated Serum ◽

Density Lipoprotein ◽

Serum Levels ◽

Enzyme Linked Immunosorbent Assay ◽

Cytokeratin 18 ◽

Independent Manner ◽

Nonalcoholic Fatty Liver ◽

Cardiometabolic Disorders

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.

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