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Serum asialoglycoproteins (desialylated glycoproteins) concentration was reported to be elevated in patients with hepatic disease as compared with that of normal subjects. In this study, we measured serum asialo-alpha(1) acid glycoprotein (AsAGP) level by a solid-phase sandwich assay in which monoclonal antibody (mAb) to alpha(1)-acid glycoprotein and galactose-binding lectin, ricinus communis (RCA), have been employed as capture protein and probe protein, respectively. The mAb-RCA sandwich assay was sensitive (0.02 μg/ml) and specific for AsAGP. We have determined AsAGP concentration of 869 serum specimens and analyzed the results using l.38 and 2.24 μg/ml (AsAGP) as cut-off values, respectively. AsAGP level was 0.80+/-0.29 μg/ml (mean+/-S.D.) with 97 normal serum specimens and elevated primarily in patients with liver cirrhosis (LC) or hepatocellular carcinoma (HCC). Using 1.38 μg/ml as a cutoff, 4/97 normal subjects, 11/39 acute hepatitis and 26/159 non-hepatic disease exhibited a slight elevation, whereas, AsAGP level was significantly elevated in 182/230 LC and 63/72 HCC. Meanwhile, a cutoff of 2.24 μg/ml allowed significant differentiation of LC or HCC from chronic hepatitis. Serum AsAGP level appeared to increase progressively with increasing severity of liver disease in cirrhotic patients. Thus, serum AsAGP concentration, as measured by the new mAb-RCA sandwich assay, may be a useful differential marker as a diagnostic aid for LC or HCC.

It has been suggested that genetic changes in cancers are related to genomic instability. To evaluate a possible correlation between growth-regulatory genes and genomic instability in HCC, we investigated microsatellite instability and mutations of TGF-beta type II receptor (TGF-beta RII) and E2F-4 genes in each pair of tumor and surrounding nontumor liver tissues, collected from 19 patients with HCC. By the identification of mutations in six different genetic loci (D1S170, D2S123, D4S395, D13S126, D13S260, and D16S402), one or more alterations in microsatellite markers were identified in 13/19 (68%) hepatocellular carcinoma specimens. When two repeated sequences of TGF-beta RII gene, poly(A)(10) tract in exon 8 and poly(GT)(3) tract in exon 9, were analyzed by polymerase chain reaction-single strand conformational polymorphism, none of the 19 hepatocellular carcinoma specimens showed mutations. When amplicons of poly(AGC)(13) tract of E2F-4 were analyzed by cloning and automated sequencing, 5/19 (36%) hepatocellular carcinomas showed deletion mutation in one or two AGC repeats and such mutations were identified only among cases with microsatellite instability. These results suggest that both microsatellite instability and mutations of E2F-4 occur commonly in hepatocellular carcinoma and play an important role in hepatocarcinogenesis.