A Secreted Form of the Asialoglycoprotein Receptor, sH2a, as a Novel Potential Noninvasive Marker for Liver Fibrosis

Abstract

Background and AimThe human asialoglycoprotein receptor is a membrane heterooligomer expressed exclusively in hepatocytes. A soluble secreted form, sH2a, arises, not by shedding at the cell surface, but by intracellular cleavage of its membrane-bound precursor, which is encoded by an alternatively spliced form of the receptor H2 subunit. Here we determined and report that sH2a, present at constant levels in serum from healthy individuals is altered upon liver fibrosis, reflecting the status of hepatocyte function.MethodsWe measured sH2a levels in serum using a monoclonal antibody and an ELISA assay that we developed, comparing with routine liver function markers. We compared blindly pretreatment serum samples from a cohort of 44 hepatitis C patients, which had METAVIR-scored biopsies, with 28 healthy individuals.ResultssH2a levels varied minimally for the healthy individuals (150±21 ng/ml), whereas the levels deviated from this normal range increasingly in correlation with fibrosis stage. A simple algorithm combining sH2a levels with those of alanine aminotransferase allowed prediction of fibrosis stage, with a very high area under the ROC curve of 0.86.ConclusionssH2a has the potential to be a uniquely sensitive and specific novel marker for liver fibrosis and function.

Advances on Nanomedicines for Diagnosis and Theranostics of Hepatic Fibrosis

“…For example, the number of the asialoglycoprotein receptor (ASGPR), highly expressed in healthy hepatocytes to remove galactose (Gal)‐ or N ‐acetylgalactosamine (GalNAc)‐terminated glycoproteins during their circulation to remain normal metabolism, [ 86 ] would be significantly decreased in the course of hepatic fibrosis. [ 87 ] In this context, several nuclear medicine contrast agents, such as a fluorine‐18‐labeled galactose derivative [ 18 F]FPGal, [ 88 ] 99m Tc‐p(VLA‐co‐VNI), [ 89 ] 18 F‐FBHGal, [ 90 ] and 111 In‐hexavalent lactoside, [ 91 ] have been introduced as effective imaging probes for the detection of hepatic fibrosis lesions and staging of the disease course. But radiotoxicity of these contrast agents and a high cost of nuclear medicine examinations have significantly hampered their wide application clinically.…”