Clinical Utility of Serum Dickkopf-1 in the Diagnosis and Prognosis of Hepatocellular Carcinomaا

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common neoplasm worldwide and the third most frequent cause of cancer-related death. The major risk factor associated with HCC is liver cirrhosis, which is predominantly caused by chronic HBV and/or HCV infections, aflatoxin B1 exposure, and alcoholic liver disease. It is estimated that HBV and HCV account for approximately 75%-80% of HCC cases worldwide. The diagnosis of HCC is mainly based on a combination of abdominal ultrasound and serum alpha-fetoprotein level. However, tumors that are too small will be missed by abdominal ultrasound, and serum alpha fetoprotein level has a low sensitivity particularly in early-stage disease. Clearly, the available screening methods are inadequate for early detection and follow up of HCC. So there is a need for a higher sensitivity aiming at early diagnosis of HCC as well as a better specificity aiming at differentiation between HCC and benign lesions. DKK-1 is a secreted protein that has been defined as a direct inhibitor of Wnt/β-catenin signaling pathway. DKK-1 is a critical mediator of osteoblastogenesis. It regulates the formation of the skeleton during the development of the embryo. DKK-1 expression was confirmed in several cancer cell lines derived from breast and other common cancers. DKK-1 protein secretion was documented in breast, prostate and lung cancers. It was frequently found to be overexpressed in patients with Wilms’tumor, hepatoblastoma and multiple myeloma, indicating a potential role of DKK-1 in carcinogenesis. In this regard, our study aimed to evaluate the clinical utility of DKK-1 in the diagnosis and prognosis of HCC and to correlate its levels with AFP, the routinely used serological marker, for diagnosis of the disease nowadays. This study was conducted at the Tropical Medicine and Clinical Pathology Departments of Ain Shams University Hospitals on 65 patients in addition to 20 apparently healthy age-matched controls. Patients were divided into two groups according to their diagnosis. Group I included 35 HCC patients who were further subdivided into three subgroups based on the stage of the disease, as determined by the BCLC Staging System(subgroup Ia: 9 patients in stage B, subgroup Ib: 18 patients in stage C, subgroup Ic: 8 patients in stage D). Group II included 30 patients with liver cirrhosis. All patients in the study were subjected to full history taking, thorough clinical examination, radiological investigations including abdominal U/S and CT scan, routine laboratory investigations (ALT, AST, serum albumin, ALP, GGT, total bilirubin, direct bilirubin and INR)in addition to serum AFP and serum DKK-1 assay by ELISA technique. Serum AFP was significantly higher in patients with liver cirrhosis when compared to the healthy control group. Moreover, a highly significant increase was recorded in the HCC group when compared to the liver cirrhosis group or the healthy control group, respectively. Our results revealed anon-significant difference regarding serum DKK-1 in patients with liver cirrhosis when compared to the healthy control group.However, it was highly significantlyincreased in the HCC group when compared to either the liver cirrhosis group or the healthy control group. Furthermore, our results showed a non-significant difference between serum DKK-1 levels of HCC patients in BCLC stage B as compared to those in stages C and D, respectively. Our correlation study within the HCC group revealed a non-significant correlation between serum DKK-1 and all of the other studied parameters (serum AFP, serum AST, ALT, ALP, total and direct bilirubin, INR and serum albumin). Assessment of the diagnostic performance of serum DKK-1 and AFP when used individually for discriminating HCC patients from liver cirrhosis patients and the healthy control group, collectively,revealed that the best ROC cutoff of DKK-1 was 1,480 pg/mL with a diagnostic sensitivity of 68.6%, specificity 84.0%, PPV 75.0%, NPV 79.2%, diagnostic efficacy 77.6%, and AUC was 0.790. Concerning serum AFP, the best ROC cutoff was 8.2 IU/mL, with a diagnostic sensitivity of 77.1%, specificity 82.0%, PPV 75.0%, NPV 83.7%, diagnostic efficacy 70.0%, and AUC was 0.882.