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BACKGROUND Many studies have demonstrated in animal experiments that persistent inflammation may accelerate the development of carcinoma. In this article, the question of whether the persistent elevation of serum alanine aminotransferase (ALT) levels (which represents the inflammatory necrosis of hepatocytes) correlates with the development of hepatocellular carcinoma (HCC) was studied in patients with early stage hepatitis C virus (HCV)‐associated cirrhosis. METHODS Sixty‐nine consecutive patients with biopsy proven HCV‐associated cirrhosis (mostly Child's Stage A) who had been followed for >5 years for the development of HCC were studied. They were subdivided into 3 groups according to their serum ALT levels: Group A was comprised of 28 patients whose annual average serum ALT level was persistently high (≥ 80 IU) (high ALT group), Group B was comprised of 28 patients whose annual average serum ALT level was persistently low (< 80 IU) (low ALT group), and Group C was comprised of 13 unclassified patients. The patients had been studied prospectively with frequent ultrasonography and magnetic resonance imaging or computed tomography for > 5 years. RESULTS In the high ALT group HCC developed in 71.4% of patients compared with 25.0% in the low ALT group over the observation period (P < 0.005). The 5‐year rate of incidence of HCC in the high ALT group was as high as 53.6% compared with only 7.1% in the low ALT group (P < 0.001). The expected interval between the diagnosis of cirrhosis and the development of HCC was 6.0 ± 0.7 years (mean ± standard error) in the high ALT group and 12.7 ± 1.2 years in the low ALT group (P < 0.001). CONCLUSIONS The results of the current study demonstrated that the development of HCC was more rapid in the high ALT group with HCV‐associated cirrhosis. Cancer 1999;86:589–95. © 1999 American Cancer Society.

BACKGROUND The relationship between the recurrence of hepatocellular carcinoma (HCC) and the serum alanine aminotransferase (ALT) level was studied in hepatectomized patients with hepatitis C virus (HCV)‐associated cirrhosis and HCC. METHODS Twenty‐six hepatectomized patients with HCV‐associated cirrhosis and HCC whose resected specimens showed neither portal vein nor hepatic vein invasion by HCC histologically were divided into 2 groups: 15 patients who had no recurrence 3 years after surgery (Group A) and 11 patients whose disease recurred 1‐3 years after surgery (Group B). The patients' serum ALT levels during this period were examined. RESULTS In Group A, serum ALT generally showed sustained low levels < 80 international units (INU) in 12 patients (80%). In contrast, ALT levels in Group B showed several peaks or plateaus > 80 INU in all patients except 2. The recurrence rate of HCC in the hepatectomized patients with sustained low levels of ALT was 14.3% (2 of 14 patients) at 3 years, and was significantly lower (P < 0.01) than that in those patients whose ALT levels showed several peaks or plateaus > 80 INU (9 of 12 patients; 75.0%). The average level of mode of ALT in Group A (48.8 ± 26.0 INU) was significantly smaller than that in Group B (101.1 ± 47.3 INU) (P < 0.005). CONCLUSIONS The importance of hepatocytic necrosis in the recurrence of HCC in hepatectomized patients with cirrhosis and HCC of HCV origin was demonstrated and the significance of subsiding hepatic necroinflammatory process in the prevention of HCC recurrence suggested. Cancer 1997; 79:688‐94. © 1997 American Cancer Society.

Background. There is a hypothesis explaining the pathogenesis of carcinoma that increased proliferation of tissue cells correlates with the development of carcinoma, presumably by increased rate of random muta‐tions and by promotion. In this study, the significance of hepatocellular proliferation in the development of human hepatocellular carcinoma (HCC) from anti‐hepatitis C virus (HCV)‐positive cirrhotic patients was studied. Method. Twenty‐eight Child A cirrhotic patients who were anti‐HCV (C‐100 antibody) positive were studied. At the beginning of the study, the in vitro uptake of bromodeoxyuridine (BrdU, a thymidine analogue) by he‐patocytes in biopsied liver specimens was investigated as labeling indices (LIs), and they were divided into high‐DNA synthetic (BrdU LI 2 1.5%) and low‐DNA synthetic (BrdU LI < 1.5%) groups. The patients were then surveyed prospectively with frequent ultrasonography (every 3 months) for the development of HCC for 3 years. Result. The mean BrdU LI plus or minus standard deviation for 14 cirrhotic patients with high‐DNA synthesis activity (BrdU LI 2 1.5%) was 2.7 kO.8%, and this was significantly (P < 0.001) higher than that for 14 cirrhotic patients with low‐DNA synthesis activity (BrdU LI < 1.5%, 0.5 k 0.3%). Nine of 14 (64.3%) of the cirrhotic patients with high‐DNA synthesis activity developed HCC in the 3‐year period, in contrast to only 2 of 14 (14.3%) of the cirrhotic patients with low‐DNA synthesis activity (P < 0.05). Conclusions. Proliferation of hepatocytes is important in HCC development from anti‐HCV‐positive cir‐rhotic patients.

BACKGROUND. Multicentric development of hepatocellular carcinoma (HCC) is a characteristic feature of hepatitis C virus (HCV)-associated cirrhosis (HCV-LC). In this study, the objective was to determine whether the persistent elevation of the serum alanine aminotransferase (ALT) level, which represents the inflammatory necrosis of hepatocytes, is correlated with the multicentric development of hepatocellular carcinoma (HCC) in patients with early-stage HCV-LC. METHODS. Ninety-three consecutive patients with biopsy proven HCV-LC (Child Stage A) who had been followed for Ͼ 5 years for the development of HCC were studied. They were subdivided into three groups according to their serum ALT level: Group A included 33 patients with annual average serum ALT levels that were persistently high (Ն 80 IU; high ALT group), Group B included 41 patients with annual average serum ALT levels that were persistently low (Ͻ 80 IU; low ALT group), and Group C included 19 unclassified patients. The patients had been studied prospectively with frequent ultrasonography and magnetic resonance imaging or computed tomography (CT) scans for Ͼ 5years. When the development of HCC was suspected, angiography, infusion of lipiodol into the hepatic artery, and lipiodol-CT scans were performed in all patients to determine the number of HCC nodules. RESULTS. In Group A, 27 patients (81.8%) developed HCC. Seventeen of 27 patients (63.0%) had multiple nodules. In contrast, in Group B, only 12 patients (29.3%) developed HCC, and only 1 of these 12 patients (8.3%) had multiple nodules. There was a significant difference between Groups A and B in the incidence of developing HCC (P Ͻ 0.001) and developing multiple nodules (P ϭ 0.006). In addition, among the male patients, the incidence of developing multiple HCC nodules in Group A (12 of 19 patients; 63.2%) was significantly higher (P Ͻ 0.05) compared with the incidence in Group B (0 of 6 patients; 0%). The same tendency was observed among the female patients. CONCLUSIONS. These results showed a close correlation between multicentric hepatocarcinogenesis and sustained necroinflammation of the liver in patients