Soluble CD46 as a diagnostic biomarker for steatotic liver disease

Background and Aims: Steatotic liver disease (SLD) is a major driver of chronic liver damage and early detection is crucial to improve the patients’ prognosis. Currently, there is a lack of accurate diagnostic options for screening the general population and monitoring treatment responses. Here, we have identified soluble CD46 (sCD46) as an accurate marker to non-invasively detect SLD.

Methods: sCD46 was measured in plasma and serum samples of patients from two independent patient cohorts (n=156 and n=91) using two newly developed assays, a flow cytometry-based immuno-competition assay and an ELISA. Studies to identify the underlying mechanism were performed using HepaRG cells and primary hepatocytes in combination with intrahepatic lymphocytes.

Results: Patients with SLD showed an overrepresentation of IL-4+iNKT cells within intrahepatic lymphocytes. The preferred development of IL-4+iNKT cells was also evident in an in-vitro fat-loading model. Here, the induction of matrix metalloproteases was revealed, which led to an indiscriminate cleavage of immune receptors. The loss of CD46 on the cell surface led to a disinhibited IL-4+iNKT cell differentiation. Analyses of patient samples showed an increase of sCD46 in the blood of SLD patients. By determining discriminatory cut-off values, patients could be correctly classified according to histological steatosis grades with a correct classification rate of 97.8% for high-grade steatosis.

Conclusion: sCD46 is a promising clinical marker that can non-invasively and reliably detect SLD which can complement and improve existing diagnostic options.

Publication History

Article published online:
20 January 2025