Serum Cytokeratin 18 M30 Levels in Chronic Hepatitis B Reflect Both Phase and Histological Activities of Disease.
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ABSTRACT:
SUBMITTER: Swiderska M
PROVIDER: S-EPMC5554581 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:Caspase-cleaved cytokeratin 18 (CK18-Asp396) is a potential clinically useful biomarker in liver disease as it is released from hepatocytes during apoptosis. In this study, we investigated serum CK18-Asp396 levels in chronic hepatitis B (CHB).Overall, 163 patients with CHB were included. Serum CK18-Asp396 levels were determined by enzyme-linked immunosorbent assay (ELISA), and results were related to steatosis grade, histological activity index, inflammation score, and METAVIR fibrosis grade as well as to viral load, serum levels of liver enzymes, and albumin. Receiver operating characteristic analysis was used to evaluate the diagnostic performance of serum CK18-Asp396 levels for assessing disease activity.A higher level of serum CK 18 concentrations was found in patients with significant inflammation vs no significant inflammation (378.5 [interquartile range {IQR}: 173.2-629.6] vs 137.3 [87.5-197.7], P < 0.05; approximately threefold increase) and in patients with significant fibrosis vs no significant fibrosis (177.8 [IQR: 120.8-519.1] vs 142.7 [IQR: 88.8-214.4], P < 0.05; 1.25-fold increase). There was no differential CK 18 level by degree of steatosis. CK 18 was an independent predictor of significant inflammation with an 82% specificity and a 94% negative predictive value. We found the strongest correlation of CK 18 with alanine aminotransferase and aspartate aminotransferase (both r = 0.52; P < 0.001), but less with albumin (r = -0.24; P < 0.05) and viral load (log) (r = 0.19; P < 0.05).CHB appears to be accompanied by continuous high levels of hepatocyte apoptosis as judged from serum CK 18, suggesting that elimination of the infected compartment constitutes a defensive strategy against disease. Accordingly, CK 18 works as an independent predictor of significant inflammation with a high specificity.
| S-EPMC5560566 | biostudies-other
Project description:Cytokeratin (CK)-18 is the major intermediate filament protein in the liver and during hepatocyte apoptosis is cleaved by the action of caspases; the resulting fragments are released into the blood as caspase-cleaved cytokeratin (CCCK)-18. Higher circulating levels of CCCK-18 have been found in patients with hepatocellular carcinoma (HCC) than in healthy controls and than in cirrhotic patients. However, it is unknown whether serum CCCK-18 levels before liver transplantation (LT) in patients with HCC could be used as a prognostic biomarker of one-year survival, and this was the objective of our study with 135 patients. At one year after LT, non-survivors showed higher serum CCCK-18 levels than survivors (p = 0.001). On binary logistic regression analysis, serum CCCK-18 levels >384 U/L were associated with death at one year (odds ratio = 19.801; 95% confidence interval = 5.301-73.972; p < 0.001) after controlling for deceased donor age. The area under the receiver operating characteristic (ROC) curve of serum CCCK-18 levels to predict death at one year was 77% (95% CI = 69%-84%; p < 0.001). The new finding of our study was that serum levels of CCCK-18 before LT in patients with HCC could be used as prognostic biomarker of survival.
| S-EPMC5037799 | biostudies-literature
Project description:BackgroundHepatocytes infected by hepatitis B virus (HBV) produce different HBV RNA species, including pregenomic RNA (pgRNA), which is reverse transcribed during replication. Particles containing HBV RNA are present in serum of infected individuals, and quantification of this HBV RNA could be clinically useful.MethodsIn a retrospective study of 95 patients with chronic HBV infection, we characterised HBV RNA in serum in terms of concentration, particle association and sequence. HBV RNA was detected by real-time PCR at levels almost as high as HBV DNA.ResultsThe HBV RNA was protected from RNase and it was found in particles of similar density as particles containing HBV DNA after fractionation on a Nycodenz gradient. Sequencing the epsilon region of the RNA did not reveal mutations that would preclude its binding to the viral polymerase before encapsidation. Specific quantification of precore RNA and pgRNA by digital PCR showed almost seven times lower ratio of precore RNA/pgRNA in serum than in liver tissue, which corresponds to poorer encapsidation of this RNA as compared with pgRNA. The serum ratio between HBV DNA and HBV RNA was higher in genotype D as compared with other genotypes.ConclusionsThe results suggest that HBV RNA in serum is present in viral particles with failing reverse transcription activity, which are produced at almost as high rates as viral particles containing DNA. The results encourage further studies of the mechanisms by which these particles are produced, the impact of genotype, and the potential clinical utility of quantifying HBV RNA in serum.
| S-EPMC5952638 | biostudies-literature
Project description:Background & aimsIn autoimmune hepatitis (AIH), normal levels of transaminases and IgG define biochemical remission and are considered the best surrogate markers for histological remission. This study assessed whether this also applies to patients with AIH cirrhosis.MethodsIn this European multicentric study, we included 125 biopsies from 113 patients with AIH and histologically proven cirrhosis; 105 biopsies from 104 patients with AIH without cirrhosis served as controls. Biochemical parameters were available within 4 weeks of biopsy. AIH activity was graded according to the modified Hepatitis Activity Index (mHAI), with mHAI ≥4/18 considered to indicate risk of disease progression.ResultsIn total, 47 out of 125 liver biopsies were obtained from patients with AIH cirrhosis and normal ALT levels at time of biopsy. Only 26% (12/47) of those livers showed histological remission (mHAI <4/18), whereas 36% (17/47) showed moderate to high histological activity (mHAI ≥6/18). In patients with noncirrhotic AIH, 88% (46/52 biopsies) of cases with normal ALT levels had histological remission and only 4% (2/52) had an mHAI ≥6/18 (p <0.001). The addition of IgG to define complete biochemical remission only slightly improved the association with histological remission in the limited number of patients with AIH cirrhosis available for analysis [29% (5/17) of biopsies with mHAI <4/18]. ALT correlated closely with mHAI in AIH without cirrhosis but poorly in AIH with cirrhosis.ConclusionsIn contrast to patients with noncirrhotic AIH, in patients with AIH cirrhosis, who are at risk of disease progression, normal ALT levels and potentially also complete biochemical remission are poor surrogate markers of histological remission. Thus, new biomarkers are needed to monitor disease activity and progression in patients with AIH cirrhosis.Lay summaryAutoimmune hepatitis (AIH) is an inflammatory disease of the liver that usually responds to immunosuppressive therapy. Serum transaminases and IgG levels within the normal ranges define complete biochemical remission and are considered as surrogate markers for histological disease activity. Here, we show that those biochemical markers are not sufficient to indicate low disease activity in patients with AIH and already established cirrhosis. Consequently, until better biomarkers for disease activity are found, only liver biopsy can reliably indicate disease activity in the presence of cirrhosis. Additional investigations, such as measurements of liver stiffness, should be undertaken to monitor non-invasively for disease progression in patients with AIH and established cirrhosis.
| S-EPMC8333110 | biostudies-literature
Project description: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.
| S-EPMC7150704 | biostudies-literature
Project description:BackgroundProinflammatory cytokines play a critical role in antiviral immune responses. Large-scale genome studies have found correlations between single-nucleotide polymorphisms (SNPs) in the interleukin (IL) 18 promoter and spontaneous control of hepatitis C virus (HCV), suggesting a role in clearance.MethodsPlasma IL-18, IL-1β, IL-6, IL-8, IL-12, interferon-γ, tumor necrosis factor-α, alanine aminotransferase (ALT), and HCV RNA levels were assessed longitudinally in subjects with known dates of HCV acquisition and analyzed according to IL-18 SNPs and outcome, either spontaneous clearance (SC) (n = 13) or persistent infection (PI) (n = 25).ResultsNo significant change in plasma proinflammatory cytokine expression was observed with the exception of IL-18, which increased in every subject with initial detection of HCV RNA. In every SC subject, IL-18 returned to the preinfection baseline concomitant with HCV control. In PI subjects, IL-18 declined following the acute phase of infection but remained above the preinfection baseline throughout chronic infection and did not correlate with HCV RNA or ALT levels.ConclusionsPlasma IL-18 was an early and the most reliably detected host response to HCV infection measured in blood. Reduced IL-18 production with transition to chronic infection without correlation with HCV RNA or ALT levels suggests modulation of the innate response with persistent infection.
| S-EPMC3203233 | biostudies-literature
Project description:Background: Gastrointestinal cancer is one of the most common neoplasms. Cytokeratin 18(CK18) is widely expressed in many different organs and cancers. Emerging data suggested conflicting results about the role of CK18 during carcinogenesis. The aim of this study is to systematically review the prognostic value of circulating CK18 (M65) and caspase-Cleaved CK18 (M30) in digestive cancers. Materials and Methods: We searched major database for manuscripts reporting the effect of pretreatment CK18 on survival of digestive cancer patients. Revman5.3 and R were the software used for analysis. Pooled multivariable-adjusted hazard ratios (HR) for overall survival (OS) were calculated in all patients and many different subgroup analyses by stratifying on tumor type, metastasis stage, and ethnicity. Results: 11 original studies were included for analysis. A low level of M30 and M65 were shown to be a protective factor for all cancer patients (HR 0.49, 95%CI 0.33-0.73, P=0.0003; HR 0.48, 95% CI 0.32-0.70, P =0.0001, respectively). The low M30 remained to be a protective factor for metastasized cancer patients while M65 had no statistically significant correlation with prognosis. Conclusions: Non-invasive total and cleaved CK18 level detection by ELISA could be potentially a useful predictor of prognosis of digestive cancer patients. Further studies are warranted to investigate the molecular mechanisms of CK18.
| S-EPMC6775513 | biostudies-literature
Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) seem common after liver transplantation.AimTo investigate incidence and predictors of NAFLD and NASH by employing noninvasive testing in liver transplant recipients, namely controlled attenuation parameter (CAP) and the serum biomarker cytokeratin 18 (CK-18). We also evaluated the diagnostic accuracy of CK-18 and CAP compared to liver histology.MethodsWe prospectively recruited consecutive adult patients who received liver transplant at the McGill University Health Centre between 2015-2018. Serial measurements of CK-18 and CAP were recorded. NAFLD and NASH were diagnosed by CAP ≥ 270 dB/m, and a combination of CAP ≥ 270 dB/m with CK-18 > 130.5 U/L, respectively. Incidences and predictors of NAFLD and NASH were investigated using survival analysis and Cox proportional hazards.ResultsOverall, 40 liver transplant recipients (mean age 57 years; 70% males) were included. During a median follow-up of 16.8 mo (interquartile range 15.6-18.0), 63.0% and 48.5% of patients developed NAFLD and NASH, respectively. On multivariable analysis, after adjusting for sex and alanine aminotransferase, body mass index was an independent predictor of development of NAFLD [adjusted hazard ratio (aHR): 1.21, 95% confidence interval (CI): 1.04-1.41; P = 0.01] and NASH (aHR: 1.26, 95%CI: 1.06-1.49; P < 0.01). Compared to liver histology, CAP had a 76% accuracy to diagnose NAFLD, while the accuracy of CAP plus CK-18 to diagnose NASH was 82%.ConclusionNAFLD and NASH diagnosed non-invasively are frequent in liver transplant recipients within the first 18 mo. Close follow-up and nutritional counselling should be planned in overweight patients.
| S-EPMC8727200 | biostudies-literature
Project description:OBJECTIVE:Cytokeratin 5/6 and Cytokeratin 8/18 are basal and luminal markers of breast cancer and they have pathological and prognostic significance in breast cancer. We performed Cytokeratin 5/6 and CK8/18 immunohistochemistry on 150 cases of triple negative breast cancers and association with various clinicopathological features was evaluated. RESULTS:Positive CK5/6 expression was noted in 8% (12 cases) of TNBC while 2.4% (4 cases) showed focal positive (<?10%) and 89.3% (134) were negative with CK5/6. Complete loss of CK8/18 expression was seen in 4.7% (7 cases) while 32.7% (49 cases) revealed focal loss of CK8/18 and 62.7% (94 cases) showed intact normal expression of CK8/18. No significant association of CK5/6 and CK8/18 with various clinicopathological parameters was observed. We found a low expression of basal cytokeratin (CK5/6) in TNBC our studied population, while loss/altered expression of CK8/18 in approximately 38% of TNBC. Although no prognostic relevance of these finding was noted in our study, however these findings are different from those reported in literature in other parts of the world. Therefore we suggest a more through immunohistochemical and genomic profiling of TNBC in our population for better understanding of this disease in this part of the world.
| S-EPMC5994131 | biostudies-literature
Project description:This study aimed to investigate the correlation between serum microRNA levels and histological stages of liver fibrosis in patients with chronic hepatitis B (CHB). A total of 28 patients with CHB who received liver biopsy at China Medical University Hospital between October 2012 and April 2013 were included in the study. The patients were divided into four groups according to the histological stages of liver fibrosis by using the METAVIR score. Serum microRNA levels were tested using quantitative real-time PCR after microRNA extraction from patients' serum. Of all the tested microRNAs, miR-21, miR-29, and miR-221 were expressed in the serum. The expression levels of serum miR-21 were significantly correlated with liver fibrosis stages (r = 0.420, P = 0.026). The expression levels of serum miR-21 were significantly correlated with cirrhosis (METAVIR F4 vs. F1-F3, r = 0.386, P = 0.043). The grades of serum miR-21 showed significant ordered differences among different stages of liver fibrosis (P = 0.019). However, miR-21 exhibited an inferior predictive performance for liver fibrosis F2-F4 (AUROC = 0.69) compared with other noninvasive markers of liver fibrosis, namely the aspartate aminotransferase (AST) to platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score (AUROC = 0.83 and 0.86, respectively). Serum miR-21 correlated with the histological stage of liver fibrosis in patients with CHB. The predictive performance of serum miR-21 for the histological stage of liver fibrosis tended to be inferior to those of the APRI and FIB-4 score.
| S-EPMC6949750 | biostudies-literature