The application of cytokeratin-18 as a biomarker for drug-induced liver injury

Abstract

Drug-induced liver injury (DILI) is a frequent and dangerous adverse effect faced during preclinical and clinical drug therapy. DILI is a leading cause of candidate drug attrition, withdrawal and in clinic, is the primary cause of acute liver failure. Traditional diagnostic markers for DILI include alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Yet, these routinely used diagnostic markers have several noteworthy limitations, restricting their sensitivity, specificity and accuracy in diagnosing DILI. Consequently, new biomarkers for DILI need to be identified.A potential biomarker for DILI is cytokeratin-18 (CK18), an intermediate filament protein highly abundant in hepatocytes and cholangiocytes. Extensively researched in a variety of clinical settings, both full length and cleaved forms of CK18 can diagnose early-stage DILI and provide insight into the mechanism of hepatocellular injury compared to traditionally used diagnostic markers. However, relatively little research has been conducted on CK18 in preclinical models of DILI. In particular, CK18 and its relationship with DILI is yet to be characterised in an in vivo rat model. Such characterization of CK18 and ccCK18 responses may enable their use as translational biomarkers for hepatotoxicity and facilitate management of clinical DILI risk in drug development. The aim of this review is to discuss the application of CK18 as a biomarker for DILI. Specifically, this review will highlight the properties of CK18, summarise clinical research that utilised CK18 to diagnose DILI and examine the current challenges preventing the characterisation of CK18 in an in vivo rat model of DILI.

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

“…In a study of obese children, linear regression showed that CK-18 was associated with WHR, FLI and adiponectin levels, which is consistent with the results of the correlation analysis in our study. Among other candidate markers studied (glutamate dehydrogenase, macrophage colony stimulating factor receptor and osteopontin), CK-18 is more sensitive and specific in diagnosing early-stage drug-induced liver injury and has a demonstrated strong relationship with hepatocellular injury in the clinic [ 37 ]. Recent studies also indicated the association of CK-18 with molecular markers of liver diseases, such as various types of microRNA, in particular miRNA-122 [ 36 , 38 , 39 , 40 ].…”

“…These values were higher than those reported in our study, which is consistent with the fact that participants involved in our study were obese but clinically healthy. Nevertheless, it is worth noting that CK-18 is released excessively from the liver into the circulation not only in NAFLD/NASH, but also in alcoholic liver disease (ALD), hepatitis B and hepatitis C patients and drug-induced liver injury [ 37 , 38 , 42 , 43 , 44 ]. Additionally, in acetaminophen-induced acute liver failure, serum CK-18 levels were associated with liver dysfunction and post-transplant graft failure, with levels > 900 U/L indicating 1-year graft loss [ 45 ].…”

A decellularized matrix enriched collagen microscaffold for a 3D in vitro liver model

“…Its upregulation has been also suggested as a potential biomarker for hepatic injury. 37 Thus, any significant alterations in the levels of CK-18 over the culture days will indicate alteration in the normal levels of the hepatocytes and will indicate progression towards disease states. Fig.…”

Evaluation of diagnostic and prognostic candidate biomarkers in drug‐induced liver injury vs. other forms of acute liver damage

“…It should be pointed out that K18 and ccK18 are not liver-specific proteins and serum levels therefore rise with other organ conditions as well as with a variety of adenocarcinomas. 22 Despite this, K18 and ccK18 could be potentially useful for early DILI detection, particularly during drug development, based on the fact that serum elevations of cytokeratin-18, in particular uncleaved protein, appear earlier than ALT in acetaminophen-induced liver injury and consequently is more sensitive. 23 These candidate biomarkers can also provide mechanistic insights due to their reflection of necrotic and apoptotic cell death.…”