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Background Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. The utility of serum alpha-fetoprotein (α-FP) in its detection is questionable. Over-expression and high circulating levels of insulin-like growth factor-II (IGF-II) were reported in tissue and in serum of patients with HCC. We investigated the diagnostic application of IGF-II in the diagnosis of HCC. Methods Serum IGF-II and α-FP levels were measured in 178 patients (82 with HCC and 96 with liver cirrhosis) and in 30 healthy controls. Spearman test, non parametric combination test and confidence interval analysis were used for statistical evaluation of data. Results The best cut-off values selected by ROC curves were 796 ng/ml for IGF-II and 132 ng/ml for α-FP. IGF-II mean values were higher in patients with HCC than in those with liver cirrhosis (LC) ( p = 0.0001) but lower in LC than in controls ( p = 0.0001). Serum IGF-II levels above cut-off were found in 22% of patients with HCC, in 9.3% of those with cirrhosis and in 20% of controls. α-FP serum levels > 132 ng/ml were observed in 48% of HCC, in 3.1% of LC and in none of control group. By correlation study, serum IGF-II levels were significantly correlated with serum α-FP levels ( r = 0.427, p = 0.0001) and with nodules' diameter ( r = 0.252, p = 0.0130) but not with nodules' number ( p > 0.050). Finally, IGF-II showed lower sensitivity, specificity and predictive values than α-FP. Conclusion Circulating IGF-II is not a useful marker for HCC. Further researches are however needed to evaluate its diagnostic accuracy before and after nutritional adjustment.

AIM The utility of serum alpha-fetoprotein (alpha-FP) in the detection of hepatocellular carcinoma (HCC) is questionable. Very high circulating levels of nociceptin/orphanin FQ (N/OFQ), a ligand for a novel opioid receptor, have recently been reported in HCC. The aim of this study was to assess the role of plasma N/OFQ in the diagnosis of HCC arising in patients with liver cirrhosis. METHODS Plasma N/OFQ levels were measured by ELISA in 58 patients (28 HCC and 30 liver cirrhosis) and in 25 healthy controls. The values were correlated with clinical and laboratory features including alpha-FP. Spearman index, biserial correlation coefficient, non parametric combination (NPC) test and discriminant stepwise analysis were used for statistical evaluation of data. RESULTS The upper normal limit of nociceptin was 122 pg/mL. Plasma levels above this cut-off were found in 21.4% of patients with HCC, in 23.3% of those with cirrhosis and in 8% of healthy subjects. alpha-FP serum levels > 200 ng/mL were found in 46.4% of the patients with HCC and in none of those with cirrhosis. No correlation was found between N/OFQ levels and any of the clinical and laboratory features, including alpha-FP. By NPC test, HCC and cirrhotic patients were different with regard to alpha-FP (P = 0.000) but not in terms of nociceptin (P = 0.595). By point biserial correlation, HCC presence was positively correlated with alpha-FP (rpb = 0.52, P = 0.000) but not with N/OFQ (rpb = 0.16, P = 0.157). In a discriminant analysis, alpha-FP was significant in the Wilks test (Y = -0.709 + 0.03 alpha-FP) and properly classified 81% of all patients and 61% of HCC. N/OFQ had lower sensitivity, specificity and predictive values than alpha-FP. CONCLUSION Nociceptin is increased in patients with chronic liver disease, independently of the presence of HCC, although the underlying mechanism has yet to be clarified. We conclude it is not a useful marker for HCC.

Viral infection may play a role in alcoholic liver disease with histological features of chronic active hepatitis (CAH). Human leucocyte antigen (HLA) hepatocellular display is supposed to allow HLA-restricted T-lymphocyte cytotoxicity in chronic viral hepatitis. We studied the presence of serum anti-hepatitis C virus (HCV) antibodies, the hepatic HLA display and the composition of the mononuclear cell infiltrate in 16 patients with alcoholic liver disease and histological features of CAH and in 11 patients with alcohol-related degenerative changes. All patients were negative for hepatitis B virus (HBV) markers. Anti-HCV were tested by microplate ELISA. Class I HLA A, B, class II HLA DR, lymphocytes pan T, T helper/inducer, T suppressor/cytotoxic, B, and K NK cells were stained on liver cryostat sections by monoclonal antibodies and double indirect immunoperoxi-dase. Anti-HCV were present in all the patients with features of CAH and absent in those with only degenerative changes. In livers with features of CAH the mononuclear cell infiltrate consisted largely of T lymphocytes with marked prevalence of suppressor/cytotoxic cells in periportal and lobular areas. K NK cells were rare. Class I HLA, diffusely displayed on bile duct epithelium and on sinusoidal cells, also appeared on liver cells in the areas of periportal and lobular necrosis, namely on the hepatocytes in close contact with suppressor/cytotoxic T cells. In livers with only degenerative changes class I HLA were diffusely displayed on bile duct epithelium and on sinusoidal cells but absent on the hepatocytes. In all the specimens HLA DR antigens were expressed on sinusoidal and inflammatory cells. In alcoholic liver disease with features of CAH the presence of anti-HCV and the close contact of T-cytotoxic cells to hepatocytes expressing class I HLA suggest a pathogenetic role of HCV and an HLA-restricted T-cytotoxic mechanism of hepatocellular necrosis.