Serum Cytokeratin-18 Fragment Research Articles

Effects of Continuous Positive Airway Pressure on Nonalcoholic Fatty Liver Disease in Patients with Obstructive Sleep Apnea: A Systematic Review

Background: Nonalcoholic fatty liver disease (NAFLD) is associated with obstructive sleep apnea (OSA). Continuous positive airway pressure (CPAP) is the first-line therapy for OSA. However, the effect of CPAP on NAFLD in patients with concomitant OSA is still unclear. This study aims to identify the use of CPAP on NAFLD in patients with OSA. Method: A systematic literature search was performed using particular keywords and medical subheadings in three journal databases: Cochrane, PubMed, and EBSCOhost. The results were screened and assessed using inclusion and exclusion criteria by three independent authors. The Randomized controlled trial (RCT) quality was evaluated with Jadad scale and the cohort studies quality was assessed with Newcastle-Ottawa quality assessment scale.Results: Two RCTs and three cohort studies were eligible to fulfil the inclusion criteria, consisting of 620 total patients. Two RCTs showed no statistically significant improvement after CPAP treatment in NAFLD based on intrahepatic triglyceride (measured by proton magnetic resonance spectroscopy), liver stiffness measurement, serum cytokeratin-18 fragment, and liver function blood test parameters. Meanwhile, 2 cohort studies in adults and 1 cohort study in children showed significant improvement in ALT, AST, and APRI. However, one cohort study showed no significant improvement in serum fibrosis markers and transient elastography measurement after CPAP treatment.Conclusion: CPAP might be beneficial in some patients with OSA to improve NAFLD, but further research that includes many subjects and longer duration of CPAP therapy is needed to confirm this result.

Chemerin, retinol binding protein-4, cytokeratin-18 and transgelin-2 presence in sera of patients with non-alcoholic liver fatty disease

Background. Chemerin and retinol binding protein-4 (RBP-4) are adipokines which may play a role in the progression of NAFLD. It has been also suggested that cytokeratin-18 (CK-18) could be a marker of hepatocyte caspase-directed death while transgelin-2 production could reflect stage of liver fibrosis. The aim of this study was to evaluate the level of the above adipokines in sera of patients with NAFLD and determine the relation between the level of transgelin-2 and fibrosis-4 index (FIB-4).Material and methods. Ninety-five subjects included initially to the study were divided into four groups: (I) prediabetics, obese with NAFLD and metabolic syndrome (Ms), (II) lean with NAFLD and without MS, (III) obese without NAFLD and MS, and (IV) healthy individuals. We determined the levels of chemerin, RBP-4, transgelin-2 and CK-18 fragments in sera of patients with NAFLD. Moreover, we examined if the levels of CK-18 fragments and transgelin-2 correlates with FIB4 value. Results. Chemerin and RBP-4 were highly expressed in sera of all NAFLD, especially in obese individuals. Chemerin level was also linked to MS. High level of serum CK-18 fragments and transgelin-2 did not correlate with obesity and MS, but seemed to correlate with progression of NAFLD to liver fibrosis.Conclusions. In conclusion, the production of the two adipokines, chemerin and RBP-4, is strongly associated with obesity in patients with NAFLD. Serum concentrations of CK-18 fragments and transgelin-2 correlate with the severity of NAFLD, but not with obesity.

Serum cytokeratin-18 fragment levels as noninvasive marker of nonalcoholic steatohepatitis in the Chilean population

Serum cytokeratin-18 fragment levels as noninvasive marker of nonalcoholic steatohepatitis in the Chilean population

Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients.

Nonobese NAFLD patients tend to have less-severe disease and may have a better prognosis than obese patients. Hypertriglyceridemia and higher creatinine are the key factors associated with advanced liver disease in nonobese patients. (Hepatology 2017;65:54-64).

SY24-4APOPTOTIC MARKERS M65 AND M30 PREDICT SURVIVAL IN ALD

Non-invasive assessment of disease activity in patients with non-alcoholic (NALD) and alcoholic liver disease (ALD) is still unsettled but essential for the evaluation of disease progression. Total (M65) and caspase-cleaved (M30) serum cytokeratin-18 fragments are detectable in the serum and could give new insights into the role of …

Association of Serum Cytokeratin-18 Fragment Concentration in Patients with Different Types of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver diseases worldwide. The prevalence of NAFLD was 15% in the Asian population. In a study, NASH was observed in 42.4% of NAFLD cases in Bangladesh. It is a serious clinical problem because of its worldwide distribution and potential adverse sequel. Cytokeratin-18 fragment is a marker of hepatocyte apoptosis. Measurement of serum cytokeratin-18 fragment concentration is a noninvasive, quick and simple procedure that can be carried out easily in peripheral hospital. It can be very much helpful for early detection and frequent monitoring of disease progression and response to therapy. This cross sectional study was conducted in the Department of Clinical Pathology in collaboration with Department of Hepatology and Department of Pathology, BSMMU, Dhaka from March 2014 to February 2015. Forty patients who fulfilled the criteria of NAFLD were determined in our study. The concentration of serum CK-18 fragment was measured to evaluate its association in different types of NAFLD by enzyme linked immune sorbent assay (ELISA). In this study, we observed that the serum CK-18 fragment concentration was increased in relation to Nonalcoholic fatty liver disease Activity Score (NAS) (r=+0.7134, P<0.05). To assess diagnostic performance of CK-18 fragment were used receiver-operator characteristic (ROC) curve. The area under ROC was 0.918 for identification of NASH. Using a cutoff value of 150 U/L the sensitivity and specificity of CK-18 fragment were 85.7% and 80.8% respectively. The positive predictive value, negative predictive value and accuracy of CK-18 fragment were 66.67%, 90.91% and 80.00% respectively. Our data revealed that serum CK-18 fragment was strongly associated with Nonalcoholic fatty liver disease Activity Score (NAS). Serum CK-18 fragment may be a useful noninvasive tool for assessing NASH in patients with NAFLD.

P0981 : Adaptation of hepatic mitochondrial function in obese humans with or without non-alcoholic steatohepatitis

Background and Aims: Patients with non-alcoholic steatohepatitis (NASH) have increased intestinal permeability and small intestine bacterial overgrowth. We aimed to test the hypothesis that endotoxaemia is associated with fatty liver in the general population and to study dietary factors associated with endotoxaemia. Methods: Community adult subjects were randomly selected from the Hong Kong Government’s census database and underwent proton-magnetic resonance spectroscopy and transient elastography to assess hepatic steatosis and fibrosis, respectively. Intrahepatic triglyceride content (IHTG) of 5% was the cutoff to define fatty liver. Endotoxaemia was assessed using the Limulus Amebocyte Lysate, lipopolysaccharide-binding protein (LBP) and EndoCab immunoglobulin G (IgG) assays. Dietary pattern was recorded by a 7-day food-frequency questionnaire. Results: 920 subjects were included (42% male, age 48±11, 23% body mass index ≥25kg/m and 5% diabetes). 263 (29%) had fatty liver; 60 (7%) had raised serum cytokeratin-18 fragment level (CK-18) suggestive of NASH; 27 of 887 (3%) subjects with reliable liver stiffness measurement had advanced fibrosis or cirrhosis. Compared with those without fatty liver, subjects with fatty liver had higher LBP (13.4±3.2mg/ml vs 11.4±2.7mg/ml; P < 0.001) and EndoCab IgG (228±247 GMU/ml vs 188±137 GMU/ml; P = 0.013) levels. Endotoxin markers also correlated positively with aminotransferases, IHTG, CK-18, insulin resistance and dyslipidaemia. Endotoxaemia was not associated with increased liver stiffness. Fetuin-A, the ligand linking fatty acid and Toll-like receptor 4, correlated with IHTG, insulin resistance and dyslipidaemia but did not have consistent association with endotoxaemia markers. Although total energy consumption and individual macronutrients were not associated with endotoxaemia, current drinkers (median alcohol consumption 20g/week [interquartile range 10–70 g]) had lower endotoxin, EndoCab IgG and fetuin-A levels than non-drinkers. Conclusions: Endotoxaemia is associated with fatty liver and possibly NASH in the general population. People with modest alcohol consumption have lower serum endotoxin. This may partly explain the lower risk of fatty liver and NASH in modest drinkers in previous observational studies. This study was supported by a grant from the Health and Medical Research Fund sponsored by the Hong Kong SAR Government [Ref CUHK-11120621]. P0981 ADAPTATION OF HEPATIC MITOCHONDRIAL FUNCTION IN OBESE HUMANS WITH OR WITHOUT NON-ALCOHOLIC STEATOHEPATITIS C. Koliaki, J. Szendroedi, K. Kaul, T. Jelenik, P. Nowotny, F. Jankowiak, C. Herder, M. Carstensen, M. Krausch, W. Trudo Knoefel, M. Schlensak, M. Roden. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Dusseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Dusseldorf, Germany; Department of Endocrinology and Diabetology, Heinrich Heine University, Dusseldorf, Germany; Institute of Pathology, Heinrich Heine University, Dusseldorf, Germany; Department of General, Visceral and Pediatric Surgery, Heinrich Heine University, Dusseldorf, Germany; General Surgery Department, St. Martinus Hospital, Dusseldorf, Germany, Dusseldorf, Germany E-mail: ckoliaki@yahoo.com

Serum Cytokeratin-18 Fragment Levels Predict Development of Type 2 Diabetes Mellitus in Adult Patients With Nonalcoholic Fatty Liver Disease

Introduction: Nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for the development of type 2 diabetes (DM2). Whether the histologic severity of NAFLD correlates with higher risk of DM2 has not been investigated. Cytokeratin-18 (CK18) serum levels have been extensively validated as a reliable non-invasive marker of NAFLD severity and the presence of nonalcoholic steatohepatitis (NASH). We aimed to investigate baseline CK18 level as predictor of the development of DM2 in patients with NAFLD. Methods: Patients with biopsy-proven NAFLD who had serum CK18 fragment levels measured at the time of liver biopsy and were followed at our institution for at least 2 years were included in the current study. Charts were reviewed for the development of DM2 during the course of their follow-up. The diagnosis of DM was made using the American Diabetes Association (ADA) criteria. CK18 fragment levels at baseline were measured using the M30-Apoptosense ELISA kit. Student’s t tests were used to assess the association between the development of DM2 and CK-18 levels. A p< 0.05 was considered statistically significant. Results: Thirty-nine patients met the criteria for inclusion in the study, out of which 32 (82.1%) were white and 20 (51.3%) were female. At baseline, the mean age was 51.3±11.2 years and the mean BMI was 33.8±5.6 Kg/m2. Patients were followed for a median of 62.4 (38.8, 81.0) months. Fourteen patients had DM2 at baseline. Out of the remaining 25 patients, 6 (24.0%) developed DM during the course of the follow-up and had significantly higher mean values of CK-18 at baseline (768.8±821.4) as compared to the 19 that did not develop DM (285.1±166.5) (p =0.019) (Figure 1). Furthermore, there was a trend toward having higher baseline CK18 levels in patients that developed metabolic syndrome at last followup compared to those who did not (361.3±195.9 versus 195.4±103.1; p=0.077).Figure 1Conclusion: Baseline CK18 level may be a useful marker to predict the development of DM2 in adults with NAFLD. If these findings are validated in larger studies, having higher CK18 level may require a more aggressive approach to lifestyle modifications to prevent the development of DM2.

The cytokeratin-18 fragment level as a biomarker of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus

BackgroundThe serum cytokeratin-18 fragment (CK-18) concentration has been suggested to be a biomarker of nonalcoholic fatty liver disease (NAFLD), although its usefulness in patients with type 2 diabetes mellitus (T2DM) is unknown. MethodsThe study was divided into two parts. In the first cross-sectional study, a total of 200 patients with T2DM and 58 healthy control subjects were recruited. NAFLD was diagnosed using ultrasonography. In the subsequent longitudinal study, we evaluated the three-month change (Δ) in the CK-18 concentration and other parameters in 40 T2DM patients with NAFLD. ResultsThe serum CK-18 values were significantly higher in the NAFLD group than in the nonNAFLD group among both diabetic and nondiabetic subjects. The CK-18 concentration was found to be an independent determinant of NAFLD and was positively correlated with the ultrasonography score and AST and ALT concentrations in the T2DM patients. Positive correlations were also identified between the CK-18 and transaminase concentrations in the T2DM and NAFLD cohorts. ΔCK-18 was found to be significantly associated with ΔBMI in the T2DM patients with NAFLD. ConclusionsA dose effect between the CK-18 concentration and the severity of NAFLD was found in the T2DM patients; thus, the CK-18 concentration is a potentially useful biomarker for assessing the efficacy of treatment and the improvement in NAFLD in patients with T2DM.

NAFLD staging by an improved ELISA for serum cytokeratin-18 fragments

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease, ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. Biomarkers for non-invasively monitoring NAFLD activity and progression are urgently needed. Various studies demonstrated that serological detection of caspase-cleaved cytokeratin (CK)-18 fragments by the M30-ELISA can distinguish between NASH and NAFL patients or healthy individuals, but not between NAFL and healthy persons. There is increasing evidence that NAFL can rapidly progress to NASH. Thus, biomarkers that already allow the identification of NAFL patients that are at risk for disease progression are required. In this study we have evaluated an improved M30-ELISA in patients with NAFLD.

Robust Detection of Liver Steatosis and Staging of NAFLD by an Improved ELISA for Serum Cytokeratin-18 Fragments

Bantel, Heike MD1; John, Katharina MSc1; Schulze-Osthoff, Klaus PhD2 Author Information

Apoptosis and diagnosis of nonalcoholic steatohepatitis

Apoptosis and diagnosis of nonalcoholic steatohepatitis

Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years

BackgroundPatients with non-alcoholic steatohepatitis (NASH) have increased mortality and liver-related complications. In contrast, simple steatosis is considered benign and non-progressive.ObjectiveTo investigate disease progression in patients with different degrees of non-alcoholic...

Serum Cytokeratin-18 Fragment Level: A Noninvasive Biomarker for Not Only Nonalcoholic Steatohepatitis, But Also Alcoholic Steatohepatitis

Serum Cytokeratin-18 Fragment Level: A Noninvasive Biomarker for Not Only Nonalcoholic Steatohepatitis, But Also Alcoholic Steatohepatitis

Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease

Graft-versus-host disease (GVHD) is the main complication of allogeneic stem cell transplantation. However, diagnosis of GVHD and evaluation of response to immunosuppressive treatment is sometimes difficult. Since apoptosis is the histopathologic hallmark in GVHD, we investigated whether active GVHD-induced target organ destruction is mirrored by serum levels of the caspase-cleaved neo-epitope of cytokeratin-18 fragments (CK18Fs). Serum CK18F kinetics was monitored by M30 antibody-based enzyme-linked immunosorbent assay (ELISA) in 50 patients who fulfilled histopathologic and/or clinical criteria diagnostic for GVHD. Both intestinal and hepatic GVHD were consistently associated with significant elevations of CK18F levels over baseline. Responses of GVHD to immunosuppressive therapy were paralleled by CK18F decreases, whereas resistant GVHD was characterized by persistent CK18F rises. Clinical conditions that might represent relevant differential diagnoses, such as toxic mucositis, noncomplicated, infection-related diarrhea, and veno-occlusive disease were not associated with CK18F elevations. In conclusion, CK18F monitoring provides a serum marker for quantitative assessment of GVHD-associated apoptotic activity in intestinal and hepatic GVHD. Although apoptosis is not GVHD-specific, CK18Fs may help to distinguish active GVHD from GVHD-unrelated conditions with similar symptoms, and to monitor response to immunosuppressive treatment. Prospective studies are warranted to evaluate how CK18Fs may assist in the diagnosis, grading, and treatment guidance of GVHD.

Serum apoptotic caspase activity as a marker of severity in HBeAg-negative chronic hepatitis B virus infection

Background and aim:In chronic hepatitis C and non-alcoholic fatty liver disease, apoptotic caspases are activated in liver, and serum caspase activity has been suggested as a sensitive marker of early...

Serum Cytokeratin-18 Fragments as Quantitative Marker of Epithelial Apoptosis in Liver and Intestinal Graft-Versus-Host Disease.

Graft-versus-host disease (GvHD) is the main complication of allogeneic stem cell transplantation (SCT). However, diagnosis and differentiation of GvHD from infectious or toxic clinical conditions as well as evaluation of GvHD response to immunosuppressive treatment remains a challenge. Since apoptosis is a common histopathological finding in GvHD, we investigated whether the caspase-cleaved neo-epitope of cytokeratin 18 fragments (CK18F) might be a serum marker for ongoing GvHD-induced target organ inflammation.Longitudinal monitoring of serum CK18F kinetics by M30 antibody-based ELISA in 49 patients who fulfilled histopathological and/or clinical criteria diagnostic for GvHD following SCT showed that CK18F were highly elevated in hepatic and intestinal GvHD (6.3±3.8 fold and 4.6±0.8 fold, respectively, over baseline). Responses of GvHD to immunosuppressive therapy were paralleled by CK18F decreases. The extent of CK18F increases tended to correlate with serological severity of acute (r=0.96) and chronic (r=0.76) liver GvHD. Differentially relevant clinical conditions, such as non-complicated infection-related diarrhea and toxic hyperbilirubinemia were not associated with significant CK18F rises. In conclusion, CK18F monitoring provides a simple serum marker for quantitative assessment of GvHD-associated apoptotic activity in intestinal and hepatic GvHD and for distinguishing active GvHD from irreversible end organ damage. Prospective studies are warranted to demonstrate the significance of CK18F for diagnosis, differentiation, prognosis, and treatment guidance of GvHD.