Non-Invasive Biomarkers in Liver Disease Diagnostics

Non-invasive biomarkers have emerged as critical tools for the early detection, staging and monitoring of liver disease, offering an alternative to invasive biopsy. Research over the past decade has focused on circulating proteins, lipids and nucleic acids that reflect hepatocellular injury, apoptosis, inflammation and fibrogenesis. Among these, cytokeratin-18 fragments, fibroblast growth factor 21 and novel monocyte-derived markers such as perilipin-2 and RAB14 have shown strong potential to discriminate simple steatosis from steatohepatitis and to stratify fibrosis severity. Advances in imaging adjuncts, including transient elastography and shear-wave elastography, have been integrated with serum panels to enhance diagnostic accuracy. The global burden of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, coupled with the cardiometabolic risks of advanced fibrosis, underscores the urgent need for reliable, cost-effective and widely accessible non-invasive tests. The convergence of proteomic profiling, multiplex immunoassays and machine-learning algorithms promises to refine risk prediction, personalise patient management and accelerate drug development by providing robust endpoints in clinical trials.

Research from Nature Portfolio

Seminal work has demonstrated that circulating levels of fibroblast growth factor 21 and cytokeratin-18 fragments serve complementary roles across the spectrum of fatty liver disease. Early elevation of FGF21 independently predicts the onset of steatosis in at-risk populations, whereas specific CK18 fragments (M30 and total cell-death marker M65ED) forecast progression to non-alcoholic steatohepatitis. Logistic regression and receiver-operating characteristic analyses in large prospective cohorts have confirmed that FGF21 identifies simple steatosis, while CK18 metrics stratify patients according to inflammatory and fibrotic activity, providing a non-invasive framework for longitudinal monitoring.

Non-Invasive Biomarkers in Liver Disease Diagnostics publication trend

The graph below shows the total number of articles in non-invasive biomarkers in liver disease diagnostics across all publications each year (not limited to Nature Index journals).

Technical terms

Non-alcoholic fatty liver disease (NAFLD): A spectrum of liver disorders characterised by lipid accumulation in hepatocytes, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH).

Non-alcoholic steatohepatitis (NASH): An aggressive form of NAFLD marked by inflammation, hepatocyte injury and varying degrees of fibrosis.

Cytokeratin-18 (CK18): An intermediate filament protein in hepatocytes; circulating fragments (M30, M65ED) reflect apoptosis and total cell death.

Fibroblast growth factor 21 (FGF21): A hormone-like protein regulating lipid and glucose metabolism, elevated in early steatosis.

Perilipin-2 (PLIN2) and Ras-related protein 14 (RAB14): Monocyte-associated proteins identified by proteomics, serving as markers of inflammation and fibrogenesis in liver disease.

Transient elastography: An imaging technique that measures liver stiffness as a surrogate for fibrosis severity.

References

1. Performance of Noninvasive Tests for Metabolic Dysfunction-Associated Steatohepatitis and Liver Fibrosis Resolution after Bariatric Surgery. Clinical Chemistry (2024).
2. Visceral Obesity and Cytokeratin-18 Antigens as Early Biomarkers of Liver Damage. International Journal of Molecular Sciences (2023).
3. Accurate liquid biopsy for the diagnosis of non-alcoholic steatohepatitis and liver fibrosis. Gut (2022).
4. Complementary Role of Fibroblast Growth Factor 21 and Cytokeratin 18 in Monitoring the Different Stages of Nonalcoholic Fatty Liver Disease. Scientific Reports (2017).