Accuracy of cytokeratin 18 (M30 and M65) in detecting non-alcoholic steatohepatitis and fibrosis: A systematic review and meta-analysis

Abstract

Introduction Association between elevated cytokeratin 18 (CK-18) levels and hepatocyte death has made circulating CK-18 a candidate biomarker to differentiate non-alcoholic fatty liver from non-alcoholic steatohepatitis (NASH). Yet studies produced variable diagnostic performance. We aimed to provide summary estimates with increased precision for the accuracy of CK-18 (M30, M65) in detecting NASH and fibrosis among non-alcoholic fatty liver disease (NAFLD) adults. Methods We searched five databases to retrieve studies evaluating CK-18 against a liver biopsy in NAFLD adults. Reference screening, data extraction and quality assessment (QUADAS-2) were independently conducted by two authors. Meta-analyses were performed for five groups based on the CK-18 antigens and target conditions, using one of two methods: linear mixed-effects multiple thresholds model or bivariate logit-normal random-effects model. Results We included 41 studies, with data on 5,815 participants. A wide range of disease prevalence was observed. No study reported a pre-defined cutoff. Thirty of 41 studies provided sufficient data for inclusion in any of the meta-analyses.

Systematic Review with Meta-Analyses: Diagnostic Accuracy of FibroMeter Tests in Patients with Non-Alcoholic Fatty Liver Disease

“…The search strategy was developed in collaboration with an experienced medical librarian, whereby input from the study investigators was used. The details of the search strategy are included in the Supplementary Table S2 [20,21]. The search was updated in October 2020 specifically for FibroMeter.…”

“…With these, we calculated predictive values. We defined the minimal acceptable performance levels of sensitivity, specificity and AUC estimates for any FibroMeter version as ≥ 0.80 [21]. Summary receiver operating characteristic (SROC) curves were constructed to represent the overall diagnostic accuracy of the index test.…”

Epigenetics of Hepatic Insulin Resistance

“…Bloodborne biomarkers offer a potential non-invasive diagnostic. For example, circulating levels of cytokeratin 18, which is seen following hepatocyte death, has been reported as a strong candidate for distinguishing NASH patients ( 245 ). In terms of the epigenome, circulating liver-specific miRNAs may also provide rapid and non-invasive biomarkers of liver damage ( 246 ) and IR/NAFLD ( 247 ).…”

Nonalcoholic Fatty Liver Disease: Focus on New Biomarkers and Lifestyle Interventions

“…CK18-M30 and CK18-M65 are antigens of the same protein, in particular M30 measures the caspase-cleaved CK-18 revealed during apoptosis, while M65 measures both caspase-cleaved and intact CK-18, which is released from cells undergoing necrosis [ 83 ]. In patients with NAFLD, a significant positive association was detected between serum levels of CK-18 and serum Alanine aminotransferase (ALT), suggesting that CK-18 can be a convenient biomarker for making the diagnosis of NAFLD [ 84 ]. Similarly, throughout the hepatocyte apoptosis, the cleaved pieces of CK-18 can be used to differentiate the stages of liver disease [ 84 , 85 ].…”

“…In patients with NAFLD, a significant positive association was detected between serum levels of CK-18 and serum Alanine aminotransferase (ALT), suggesting that CK-18 can be a convenient biomarker for making the diagnosis of NAFLD [ 84 ]. Similarly, throughout the hepatocyte apoptosis, the cleaved pieces of CK-18 can be used to differentiate the stages of liver disease [ 84 , 85 ].…”