**4. Discussion**

68 Hepatocellular Carcinoma – Basic Research

Fig. 4. OCT in NASH patients with a normal range of ALT. Forty-two patients had a normal rage of ALT, among these 42 patients, 13 (31%) had OCT over 43.2ng/mL. Of these 13

Fig. 5. Variations between the serum levels of OCT, OCT/ALT, DCP, and AFP in patients with HCC pre- and post-treatment. Serum level of OCT and OCT/ALT ratio were

patients, eight had F3 or F4 fibrosis

significantly decreased in HCC after a therapy

An ideal biomarker should be simple, accurate, specific, inexpensive and readily available.

In this study, both the ratios of OCT/ALT and OCT/AST were increased in LC induced by NASH or HCV. Further, the significant association with fibrosis grade in NASH was confirmed. These data suggested that even without liver biopsy, we are able to speculate about the progression of various liver diseases by routine laboratory examinations. Concerning to the relationship between aminotransferase and the progression of liver diseases, serum AST and ALT levels do not necessarily reflect the activity and progression of NASH. It was reported that more than half of NASH patients with persistently normal ALT have a potentially progressive liver disease (Fracanzani et al., 2008). In our study, about 30% of NASH patients with a normal range of ALT show the elevation of OCT. In addition, the majority of these patients had severe fibrosis. It was reported that serum ALT levels in severe fibrosis of NASH were decreased (Hashimoto et al., 2009). Taken together, in NASH patients with normal range of ALT and severe fibrosis, OCT might be a normal useful marker. It is unclear why OCT is frequently elevated in NASH patients with a normal range of ALT and severe fibrosis.

In addition, serum OCT and both ratios were increased in HCC compared to LC. In the previous study, we reported that the ratios were increased in HCC with NASH (Tokushige et al., 2009). In the present study, the increase in the ratios was confirmed in HCC on chronic liver dieases infected by HCV. These data suggested that the ratios were common tumor markers in HCC based on various liver diseases. In addition, we confirmed that OCT and OCT/ALT ratio were decreased after therapy. These data suggested that OCT and OCT/ALT ratio might be useful for monitoring HCC during follow-up. Especially, in HCC with NASH, the positive percentage of DPC was higher than that of AFP. However, DCP can be affected by certain medications such as warfarin, or by the condition of the patients with severe liver failure or with bile acid outflow obstruction. As some of the NASH patients were complicated with cardiovascular diseases, they required warfarinization. Also, in about 25% of HCC patients, AFP and DCP were negative (Okuda et al.,, 2001). In these cases, OCT and OCT/ALT ratio might be useful as new HCC tumor markers for diagnosis and monitoring. We need to compare the sensitivity and specificity of these ratios and AFP or DCP in much greater numbers of samples. Recently, the association of DCP with tumor invasion and pathological grading was reported (Sakon et al., 1992; Koike et al., 2001). In the future, we need to investigate the association between OCT, OCT/ALT ratio and pathological grading or the condition of HCC.

The reason why the ratio of OCT/ALT was increased in HCC is still unclear. This increase could not be explained by the distribution of OCT and ALT, since both are located in the periportal region. One possibility is that cancer cells, expressing Fas-Ligand, might have induced apoptosis of hepatocytes (Shiraki et al., 1997). Then, in apoptotic cell death, mitochondoria-related proteins were released. Another possibility is that the expression of enzymes might change in HCC.

As for comparison with several liver diseases, serum OCT levels, OCT/ALT and OCT/AST ratios in ALD were significantly higher than those of other liver diseases. ALD

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#### **5. Conclusion**

Serum OCT levels and the ratios of OCT/ALT and OCT/AST are useful for monitoring the progression of liver diseases. Moreover, the possibility was suggested that serum OCT level and the OCT/ALT ratio might represent a new tumor marker of HCC and be a potent indicator for evaluation of the post-treatment HCC status. To confirm this possibility, we need validation study in much greater numbers of HCC samples.

#### **6. References**


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**5. Conclusion** 

**6. References** 


**4** 

*Italy* 

**New Molecular Biomarkers Candidates for the** 

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, showing a rapid progressive clinical course, poor response to pharmacological treatment and a severe prognosis (Colombo, 2003; Sherlock & Dooley, 2002). HCC generally develops from chronic liver injury, which leads to inflammation, hepatocyte regeneration, liver matrix remodeling, fibrosis, and finally, cirrhosis. The main risk factors for HCC are hepatitis B (HBV) or C virus (HCV) infection, alcohol-induced liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis and exposure to environmental carcinogens (particularly aflatoxin), and genetic metabolic diseases. (Chuang et al., 2009; Di Bisceglie, 1995; Kato et al, 1994; Malaguarnera et al., 2006; Malaguarnera et al., 2009; Seitz & Becker, 2007; Takano et al., 1995). Obesity has also been identified as an independent risk factor for developing HCC in patients with alcoholic or cryptogenic cirrhosis (Nair et al, 2002). Actually, HCV-related cirrhosis is considered the major risk factor since many HCV chronically infected patients remain asymptomatic for a long period, with liver cirrhosis developing after approximately 30 years (Yano et al., 1996; Poynard et al., 1997). The lack of predictive markers that makes unforeseeable the insurgence of liver cirrhosis in chronic HCV patients may also contribute to HCC late diagnosis, progression and poor prognosis. Currently, alpha-fetoprotein (AFP) is the most common marker for early malignancy used in clinical practice, in combination with hepatic echography, to detect HCC in patients suffering from cirrhosis. Nevertheless, most episodes of AFP elevation were transient and closely correlated with the presence of bridging hepatic necrosis, without subsequent development of HCC (Liaw et al., 1986). Since an early diagnosis of HCC is extremely important in improving the survival of patients, the identification of new and more reliable biological markers of HCC insurgence, recurrence and metastasis is essential for the proper management of this malignancy. Once hepatic cancer develops, one of the main reasons for the high mortality rate in patients with HCC is the lack of effective treatment options, especially for those with advanced disease. Although surgery and percutaneous ablation can achieve long-

**1. Introduction** 

**Development of Multiparametric Platforms** 

**for Hepatocellular Carcinoma Diagnosis,** 

**Prognosis and Personalised Therapy** 

Annalucia Serafino and Pasquale Pierimarchi

 *National Research of Council of Italy (CNR), Rome* 

*Institute of Translational Pharmacology,* 

hepatitis C. *Journal of Gastroentelorogy,* Vol.45, No.9, (September 2010) pp.960-7. ISSN 0944-1174

World Health Organization. Mortality database. (2010) www.who.int/whosis/en. Accessed February 2010
