Midkine Increases Diagnostic Yield in AFP Negative and NASH-Related Hepatocellular Carcinoma

• Published in: PloS one 2016-05, Vol.11 (5), p.e0155800-e0155800
• Main Authors: Vongsuvanh, Roslyn, van der Poorten, David, Iseli, Tristan, Strasser, Simone I, McCaughan, Geoffrey W, George, Jacob
• Format: Article
• Language: English
• Subjects: Aged; alpha-Fetoproteins - metabolism; Biocompatibility; Biology and Life Sciences; Biomarkers; Biomarkers, Tumor - blood; Biomedical materials; Cancer diagnosis; Carcinoma, Hepatocellular - blood; Carcinoma, Hepatocellular - diagnosis; Carcinoma, Hepatocellular - metabolism; Case-Control Studies; Cirrhosis; Cross-Sectional Studies; Diagnosis; Diagnostic systems; Disease control; Dkk1 protein; Female; Gastroenterology; Gene expression; Genetic aspects; Hepatitis; Hepatocellular carcinoma; Hospitals; Humans; Intercellular Signaling Peptides and Proteins - blood; Liver; Liver cancer; Liver cirrhosis; Liver diseases; Liver Neoplasms - blood; Liver Neoplasms - diagnosis; Liver Neoplasms - metabolism; Longitudinal Studies; Male; Medical diagnosis; Medicine and Health Sciences; Methods; Middle Aged; Midkine; Nerve Growth Factors - blood; Non-alcoholic Fatty Liver Disease - complications; Osteopontin; Osteopontin - blood; Patients; ROC Curve; Sensitivity and Specificity; Serum levels; Surveillance; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0155800

Robust biomarkers for population-level hepatocellular carcinoma (HCC) surveillance are lacking. We compared serum midkine (MDK), dickkopf-1 (DKK1), osteopontin (OPN) and AFP for HCC diagnosis in 86 HCC patients matched to 86 cirrhotics, 86 with chronic liver disease (CLD) and 86 healthy controls (HC). Based on the performance of each biomarker, we assessed a separate longitudinal cohort of 28 HCC patients, at and before cancer diagnosis. Serum levels of MDK and OPN were higher in HCC patients compared to cirrhosis, CLD and HC groups. DKK1 was not different between cases and controls. More than half of HCC patients had normal AFP. In this AFP-negative HCC cohort, 59.18% (n = 29/49) had elevated MDK, applying the optimal cut-off of 0.44 ng/ml. Using AFP ≥ 20 IU/ml or MDK ≥ 0.44 ng/ml, a significantly greater number (76.7%; n = 66/86) of HCC cases were detected. The area under the receiver operating curve for MDK was superior to AFP and OPN in NASH-HCC diagnosis. In the longitudinal cohort, MDK was elevated in 15/28 (54%) of HCC patients at diagnosis, of whom 67% had elevated MDK 6 months prior. AFP and MDK have a complementary role in HCC detection. MDK increases the diagnostic yield in AFP-negative HCC and has greater diagnostic performance than AFP, OPN and DKK-1 in the diagnosis of NASH-HCC. Additionally, MDK has a promising role in the pre-clinical diagnosis of HCC.