Letter to the Editor: Evaluating cytokeratin 18 fragment as a non-invasive marker of fibrosis and lipid alterations in steatotic liver disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) arises from the interplay between disordered lipid metabolism, hepatocellular injury, and systemic inflammation. Ichikawa et al published a study in the recent issue of the World Journal of Hepatology, explored the clinical value of circulating cytokeratin 18 fragment (CK18F), a marker of hepatocyte apoptosis, among individuals with steatotic liver disease. The study found that CK18F concentrations were closely linked to biochemical indicators of liver injury and lipid abnormalities-most notably elevated triglycerides and reduced high-density lipoprotein; cholesterol-while showing little association with conventional fibrosis scores such as fibrosis-4 index or liver stiffness measurements. Conversely, CK18F demonstrated strong alignment with integrative non-invasive indices, including the FibroScan-aspartate aminotransferase and Steatosis-Associated Fibrosis Estimator scores. These results indicate that CK18F primarily reflects active hepatic injury and metabolic stress rather than established fibrosis. Incorporating CK18F into existing non-invasive evaluation frameworks could improve the early detection of metabolically active MASLD, refine patient risk stratification, and support targeted lifestyle and therapeutic interventions aimed at preventing disease progression.

Key Words: Cytokeratin 18 fragment; Steatotic liver disease; Metabolic dysfunction-associated steatotic liver disease; Hepatocyte apoptosis; FibroScan-aspartate aminotransferase score; Steatosis-Associated Fibrosis Estimator score; Non-invasive biomarkers; Lipid metabolism; Liver injury; Metabolic dysfunction

Core Tip: Ichikawa et al examined the diagnostic utility of serum cytokeratin 18 fragment (CK18F) in patients with steatotic liver disease (SLD). Their findings demonstrated that CK18F-a marker of hepatocyte apoptosis-shows a strong relationship with liver injury markers and lipid disturbances, particularly elevated triglycerides, but not with conventional fibrosis indices. Notably, CK18F correlated closely with non-invasive composite scores such as FibroScan-aspartate aminotransferase and Steatosis-Associated Fibrosis Estimator, emphasizing its ability to reflect active hepatic inflammation and metabolic stress rather than fibrotic burden. These results suggest that incorporating CK18F into existing non-invasive assessment tools could enhance early detection and clinical stratification of individuals at metabolic and hepatic risk within the spectrum of metabolic dysfunction-associated SLD.

TO THE EDITOR

We read with interest the recent study by Ichikawa et al[1] published in the World Journal of Hepatology, which explored the clinical relevance of serum cytokeratin 18 fragment (CK18F) in steatotic liver disease (SLD). The authors demonstrated that CK18F-a circulating marker of hepatocyte apoptosis-correlates closely with biochemical indices of hepatic injury [aspartate aminotransferase (AST), alanine aminotransferase] and lipid abnormalities, particularly hypertriglyceridemia[1]. Of note, CK18F showed strong concordance with the FibroScan-AST (FAST) and Steatosis-Associated Fibrosis Estimator (SAFE) scores, but not with traditional fibrosis metrics such as fibrosis-4 index (FIB-4) or liver stiffness measurements[1]. These findings suggest that CK18F may capture the inflammatory and steatotic elements characteristic of early metabolic dysfunction-associated SLD (MASLD). Furthermore, the observation that CK18F levels rose in the setting of both high triglycerides and reduced high-density lipoprotein (HDL) cholesterol reinforces the interplay between lipid dysregulation and hepatocellular injury in MASLD[1].

Clinical relevance of CK18F

CK18F has long been recognized as a non-invasive indicator of hepatocyte apoptosis and necroinflammation, previously proposed as a surrogate marker for non-alcoholic steatohepatitis (NASH). Beyond summarizing prior evidence, this Letter critically contextualizes CK18F within the modern framework of MASLD by integrating both metabolic and elastography-derived indicators. This conceptual synthesis highlights an underexplored dimension-namely, the role of CK18F as a biochemical mediator that bridges metabolic dysregulation with hepatocellular apoptosis, a connection that has not been explicitly delineated in previous studies. Alhinai et al[2] demonstrated that coupling controlled attenuation parameter (CAP) measurements with CK18F enhanced non-invasive diagnostic accuracy for NASH, achieving up to 82% concordance with histology[2]. Ichikawa et al[1] build upon this by integrating CK18F with composite clinical indices such as FAST and SAFE, which are increasingly used for patient triage in nonalcoholic fatty liver disease (NAFLD)/MASLD. Their finding that CK18F concentrations above 260 U/L were almost universally associated with elevated FAST and SAFE scores[1] highlights CK18F’s potential incorporation into simplified diagnostic algorithms. This is consistent with prior data from Alkhouri et al[3], who reported that a FAST score below 0.35 effectively ruled out advanced fibrosis in NAFLD patients. Hence, a combined approach using CK18F alongside established non-invasive tools could optimize patient stratification and guide referrals to hepatology specialists.

Methodological strengths

The study by Ichikawa et al[1] is notable for its robust design and comprehensive evaluation. The investigators examined 125 well-characterized SLD patients, applying multiple non-invasive tests (CK18F, FibroScan, FAST, SAFE, FIB-4, among others) to enable rigorous comparative analyses. Their results revealed that CK18F aligned with transaminase elevations and dyslipidemic profiles, but not with fibrosis-related indices, supporting its specificity for ongoing hepatocellular injury rather than chronic scarring[1]. This distinction is critical since, as Huang et al[4] have emphasized, no single biomarker currently substitutes for biopsy in differentiating NASH from simple steatosis. The inclusion of multivariable analyses further strengthened their findings, identifying the combination of hypertriglyceridemia and low HDL as the strongest predictors of CK18F elevation-underscoring the tight metabolic-liver axis in MASLD progression.

Contribution to non-invasive testing literature

Ichikawa et al[1] meaningfully extend prior work in the World Journal of Hepatology by situating CK18F within the broader landscape of metabolic and imaging-based markers. Priego-Parra et al[5] recently reviewed the triglyceride-glucose-waist circumference index as a reliable predictor of MASLD risk and outcomes across populations. Similar to that approach, Ichikawa et al[1] bridge metabolic parameters and liver-specific injury biomarkers, demonstrating that CK18F correlates with integrated risk models such as FAST and SAFE. Together, these findings suggest that embedding CK18F into composite algorithms could enhance early detection of the metabolically “active” or “high-risk” MASLD phenotype. Importantly, their results also reaffirm that conventional fibrosis indices like FIB-4 and elastography, while useful for staging fibrosis, do not reflect active hepatocyte injury[1].

Implications for MASLD risk assessment and management

The evolving MASLD framework underscores early metabolic risk identification and intervention. As Samanta and Sen Sarma[6] recently discussed, reframing NAFLD as MASLD prioritizes metabolic dysfunction as the core driver of disease and highlights lifestyle optimization as the therapeutic cornerstone. Within this paradigm, Ichikawa et al[1] propose a practical biomarker that aligns with these goals: Elevated CK18F, particularly in the context of hypertriglyceridemia, may identify patients in an early, metabolically active phase of liver injury. Combining high FAST or SAFE scores with elevated CK18F could help clinicians recognize individuals at risk of transitioning to steatohepatitis or progressive fibrosis-those who may benefit from intensive lipid and glucose management. Conversely, low CK18F in conjunction with low-risk non invasive test scores might safely exclude advanced disease, reducing unnecessary referrals. Importantly, as dyslipidemia is modifiable, the demonstrated link between triglycerides, HDL, and CK18F implies that targeted metabolic therapy might mitigate hepatocellular stress. Once validated in larger cohorts, CK18F could become part of an integrated MASLD biomarker panel linking metabolic status with direct measures of hepatocyte injury.

This finding aligns with current consensus statements emphasizing the central contribution of metabolic dysfunction to MASLD pathogenesis and its incorporation into emerging non-invasive diagnostic frameworks[7,8].

Key observations

The authors found that CK18F elevation paralleled biochemical evidence of liver injury and metabolic disturbance[1]. Elevated CK18F values corresponded closely with FAST and steatosis associated fibrosis estimator; SAFE scores but not with fibrosis surrogates such as FIB-4 or stiffness values[1]. These results suggest CK18F provides unique and complementary information about dynamic hepatocellular injury rather than cumulative fibrotic burden.

Integration with existing non-invasive tools

Ichikawa et al[1] have effectively positioned CK18F as an adjunct to established non-invasive markers. Alhinai et al[2] previously showed that combining CK18 with CAP improved diagnostic precision for NASH, while Huang et al[4] highlighted the absence of a single definitive non-invasive biomarker. The current work integrates biochemical (CK18F) and imaging-based (FAST, SAFE) modalities to achieve a balanced and clinically feasible risk assessment framework.

Clinical and research implications

As highlighted by Priego-Parra et al[5] incorporating metabolic markers such as triglycerides and glucose into diagnostic models strengthens MASLD risk prediction. Ichikawa et al[1] extend this rationale by demonstrating that CK18F-an indicator of hepatocyte apoptosis-rises in parallel with these metabolic abnormalities. Clinically, patients presenting with obesity, diabetes, high triglycerides, low HDL, and elevated CK18F could represent an actionable high-risk group requiring intensive metabolic intervention, consistent with the recent call for earlier MASLD recognition and management[6]. Additionally, serial CK18F monitoring could offer a convenient means of tracking therapeutic response in both clinical practice and interventional trials, addressing a major gap in current MASLD monitoring strategies.

In summary, Ichikawa et al[1] have contributed an important piece to the evolving MASLD diagnostic framework. By validating CK18F against modern non-invasive indices and elucidating its metabolic associations, they advance a multimodal, mechanism-driven approach to disease assessment. Their work reinforces an emerging principle echoed throughout the World Journal of Hepatology literature: No single test sufficiently captures the multifactorial nature of MASLD. Instead, combining metabolic indices (e.g., triglyceride-glucose index, lipid ratios)[5], elastography-based scores (FAST, SAFE)[3], and cell-injury biomarkers (CK18F)[1] may provide a more holistic and actionable assessment. This integrated viewpoint expands the scope of the original study by positioning CK18F as a mechanistic link connecting metabolic stress, lipid dysregulation, and hepatocellular damage throughout the MASLD spectrum. Future research should aim to confirm these findings in larger, longitudinal cohorts and evaluate whether CK18F-guided algorithms translate into improved patient outcomes in the MASLD continuum.

ACKNOWLEDGEMENTS

We thank Cairo University for their continuous support.