Close association between high serum ALT and more rapid recurrence of hepatocellular carcinoma in hepatectomized patients with HCV-associated liver cirrhosis and hepatocellular carcinoma.

We investigated whether or not a high serum alanine aminotransferase (ALT) level is associated with a more rapid recurrence of hepatocellular carcinoma (HCC) in hepatectomized patients with hepatitis C virus (HCV)-associated liver cirrhosis (LC) (HCV-LC) and HCC. Thirty-three hepatectomized patients with HCV-LC and HCC of a single nodule who had no histologic evidence of portal or hepatic vein invasion and who had been followed up for more than 3 years were included in the study. They were subdivided into two groups according to their serum ALT levels, ALT being a well-known marker of inflammatory necrosis in the liver. Seventeen patients whose serum ALT levels showed several peaks or plateaus above 80 international units (IU) were designated as the high ALT group, and 16 patients whose serum ALT levels showed a sustained low level below 80 IU until the first recurrence were designated as the low ALT group, and the interval between hepatectomy and the first recurrence was observed. In the high ALT group, HCC recurred within 3 years in 70.6% of the patients. In contrast, it recurred in only 18.8% of the low ALT group within the same period (p < 0.05). There was a significant difference (p = 0.0201) between the two groups in the cumulative nonrecurrence rate. The mean interval in recurrent patients between hepatectomy and the first recurrence in the high ALT group (23.6 +/- 2.8 months; mean +/- SE) was significantly (p < 0.02) shorter than that in the low ALT group (49.3 +/- 9.7 months). The expected interval between hepatectomy and recurrence was as short as 2.8 +/- 0.5 years (mean +/- SE) in the high ALT group, compared with 5.8 +/- 0.7 years in the low ALT group (p < 0.05). These results showed that the recurrence of HCC was accelerated in the high ALT group, suggesting that suppression of the rise in ALT level after hepatectomy by treatment with anti-inflammatory drugs may prolong the interval until recurrence by about 2 years in hepatectomized patients with HCC and HCV-LC.

Association between high serum alanine aminotransferase levels and more rapid development and higher rate of incidence of hepatocellular carcinoma in patients with hepatitis C virus-associated cirrhosis.

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.

Relationship between the recurrence of hepatocellular carcinoma (HCC) and serum alanine aminotransferase levels in hepatectomized patients with hepatitis C virus-associated cirrhosis and HCC.

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.

[Endoscopic mucosal resection of the stomach using a ligating device (EMRL)--experimental study for the purpose of establishing reliable and safe technique].

We confirmed a new reliable and safe technique for endoscopic mucosal resection of the stomach using a ligating device (EMRL), which was used for endoscopic ligation of esophageal varices. We resected the gastric mucosa by this procedure in 6 mongrel dogs, and examined resected specimens histopathologically. It is concluded that EMRL can take a mucosal specimen 15 x 12mm in size on the average, be performed almost all the site which was previously difficult to resect endoscopically, and the submucosal local injection of physiological saline solution is necessary to perform EMRL. Based on these conclusion, we experimented to establish the safe and reliable technique of the divided mucosal resection, too. EMRL procedure is an easy and valuable treatment modality.

[Effects of lactitol on fecal bacterial flora in patients with liver cirrhosis and hepatic encephalopathy].

Lactitol, a non-absorbable synthetic disaccharide, was administered at a dose of 36g/day for 3-4 weeks to 8 patients with liver cirrhosis and hepatic encephalopathy in order to investigate its effects on fecal bacterial flora and clinical symptoms of hepatic encephalopathy. Lactitol significantly increased occupation ratio (ratio to total bacterial number) of anaerobic Bifidobacterium (before administration 7.1% --> after 4 weeks 46.0% (p < 0.05) as well as bacterial count of Lactobacillus. On the other hand, bacterial counts of Bacteroides and Clostridium, which are considered to be NH3-producing bacteria, and that of total aerobic bacteria were not markedly changed, but their occupation ratio were decreased after the administration. Further, tendencies toward decreased fecal pH, increased frequency of defecation and soft stools were observed. As for clinical efficacy, a decrease in blood ammonia concentration, improvement in mental state and flapping tremor were also observed.

Patients with ultrasonic coarse-nodular cirrhosis who are anti-hepatitis C virus-positive are at high risk for hepatocellular carcinoma.

BACKGROUND: The relationship between echosonographic patterns of patients with cirrhosis who are antihepatitis C virus (HCV)-positive, the DNA synthesis of hepatocytes, and the risk for HCC were studied. METHODS: Thirty-eight patients with anti-C-100 antibody-positive and Child's grade A posthepatitic cirrhosis were studied. DNA synthesis activity was measured by a bromodeoxyuridine (BrdU, a thymidine analogue)-labeling index (LI), using the BrdU-anti-BrdU in vitro method, and the patients were followed prospectively by frequent liver ultrasonography for 3 years. The ultrasound patterns were classified into fine, coarse, and coarse-nodular (CN) patterns, and the reproducibility of the classification in practical use also was confirmed. RESULTS: Of the 21 patients with high DNA synthesizing cirrhosis (BrdU LI > or = 1.5%), 10 (48%) showed coarse-nodular, 5 (24%) coarse, and 6 (29%) fine pattern in ultrasonography. Conversely, of the 17 patients with low DNA synthesizing LC (BrdU LI < 1.5%), only 1 (6%) showed coarse-nodular, 2 (12%) coarse, and 14 (82%) fine pattern. A significant relationship was found between the two groups of BrdU LI and ultrasound imaging patterns (P < 0.05). The incidence of CN pattern was significantly higher (P < 0.01) in the high DNA synthesizing group than in low DNA synthesizing group. Of the 11 patients with CN pattern by ultrasound imaging, 10 (91%) were in the high DNA synthesizing group, and 9 (82%) developed HCC during the follow-up period, compared with 3 of 7 (43%) with coarse, and only one of 20 (5%) with fine pattern developed HCC. The incidence of HCC was significantly higher (P < 0.01) in patients with a CN cirrhosis pattern than in those with a fine pattern. CONCLUSIONS: In patients with cirrhosis who are anti-HCV-positive, the CN pattern by ultrasound imaging indicates increased DNA synthesis of hepatocytes and a high risk for developing HCC.

Portal vein aneurysm in the liver associated with multiple vascular malformations.

Portal vein aneurysm (PVA) includes focal dilatation of the portal vein, and was formerly thought to be a rare disease. We report a 46-year-old man with chronic aggressive hepatitis and intrahepatic portal vein aneurysm communicating with the hepatic vein. Hemangiomas in the liver and intracranial arteriovenous malformation (AVM) were also found. To our knowledge, this is the first report of a case of PVA in a patient with congenital intracranial AVM. As the PVA in this patient communicated with the hepatic vein, and as hemangiomas in the liver and intracranial AVM were also present, the pathogenesis in this patient seems to have been congenital anomaly of the vasculature.

Role of increased DNA synthesis activity of hepatocytes in multicentric hepatocarcinogenesis in residual liver of hepatectomized cirrhotic patients with hepatocellular carcinoma.

To examine whether the marked increase in DNA synthesis of hepatocytes in cirrhotic liver might elicit multicentric hepatocarcinogenesis, we examined the relationship between new development of hepatocellular carcinoma (HCC) and the bromodeoxyuridine (BrdU) labeling index (LI) of hepatocytes in the residual liver of hepatectomized patients with liver cirrhosis (LC) and HCC. Eighteen hepatectomized patients with LC and HCC, whose resected liver revealed neither portal nor hepatic vein invasion by histologic examination, were studied (to exclude cases with intrahepatic metastasis). DNA synthesis activity of hepatocytes from the residual cirrhotic liver was measured by a BrdU/anti-BrdU in vitro method. The incidence of HCC recurrence was studied during a 3-year follow-up period. Among 18 patients, 9 patients had recurrence and 9 did not. The average BrdU LI in the recurrent patients was 2.6 +/- 1.3% and was significantly higher than that in patients without recurrence (1.4 +/- 0.5%, P < 0.05). All five patients who had a BrdU LI of 2.4% or above showed recurrence within 3 years, as compared with 4 of 13 (30.8%) patients with BrdU LI of less than 2.4% (P < 0.05). Our data indicate that abnormally high DNA synthesis in hepatocytes in the background cirrhosis might lead to the development of multicentric carcinogenesis in human cirrhotic liver, and in the residual cirrhotic liver of hepatectomized patients with HCC and LC, it may be a predictor of new development of HCC.

Significance of hepatocellular proliferation in the development of hepatocellular carcinoma from anti-hepatitis C virus-positive cirrhotic patients.

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 mutations 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. METHODS: 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 hepatocytes in biopsied liver specimens was investigated as labeling indices (LIs), and they were divided into high-DNA synthetic (BrdU LI > or = 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. RESULTS: The mean BrdU LI plus or minus standard deviation for 14 cirrhotic patients with high-DNA synthesis activity (BrdU LI > or = 1.5%) was 2.7 +/- 0.8%, 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 +/- 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).

[A case of hepatocellular carcinoma with portal invasion and right adrenal gland metastasis showing marked contraction of primary tumor and metastasis with treated by UFT alone].

A 79-year-old female with hepatocellular carcinoma with portal invasion and right adrenal gland metastasis was treated by low dose UFT (200 mg/day). Two months after the initiation of UFT administration, CT scan revealed marked contraction of the primary liver tumor and right adrenal metastasis. Serum AFP and PIVKA-II were also reduced, and right flank pain disappeared. Six months later, CT scan and MRI study were performed. The findings of liver and metastatic lesion were the same as in the earlier study, and the liver function and the patient condition were well controlled. This case is probably rare, but suggestive in the choice of treatment for advanced hepatocellular carcinoma.

The male preponderance in incidence of hepatocellular carcinoma in cirrhotic patients may depend on the higher DNA synthetic activity of cirrhotic tissue in men.

BACKGROUND: The relationship between the DNA synthetic activity of hepatocytes from cirrhotic liver tissue and the incidence of hepatocellular carcinoma (HCC) during a 3-year follow-up period was studied in male and female patients with posthepatitic cirrhosis. METHODS: The bromodeoxyuridine labeling index (BrdU LI) of hepatocytes was estimated in 38 cirrhotic patients (Child A stage, 23 men and 15 women) using a BrdU/anti-BrdU in vitro method. The incidence of HCC was compared between male and female cirrhotic patients during a 3-year follow-up period. RESULTS: Sixteen of 23 (69.6%) male patients belonged to the high-DNA synthesis group (BrdU LI > or = 1.5%), and only 7 (30.4%) were in the low-DNA synthesis group (BrdU LI < 1.5%). Among female patients, only 5 of 15 (33.3%) were in the high-DNA synthesis group, and 10 of 15 (66.7%) were in the low-DNA synthesis group (P < 0.05). Eleven of 23 (47.8%) male patients and 3 of 15 (20.0%) female patients had HCC develop. In the high-DNA synthesis group, 10 of 16 (62.5%) of the men and 3 of 5 (60.0%) of the women had HCC develop during the follow-up period. In contrast, only one of seven (14.3%) male patients and none of ten (0%) female patients in the low-DNA synthesis group had HCC develop. CONCLUSIONS: It was concluded that HCC developed frequently (about 60% of the time within 3 years) in patients of both sexes who were in a high-DNA synthesis group. Thus, the larger proportion of men in the high-DNA synthesis group compared with the number of women in the group (69.6% versus 33.3%) might be one possible reason for the male predominance in the development of HCC in cirrhotic patients.

DNA synthesis activities of hepatocytes from noncancerous cirrhotic tissue and of hepatocellular carcinoma (HCC) cells from cancerous tissue can predict the survival of hepatectomized patients with HCC.

BACKGROUND: There is a concept that a cancer often maintains some of the traits of the background tissue cells. Thus, the possibility exists that the DNA synthetic activity of the hepatocytes in cirrhotic tissue affects that of hepatocellular carcinoma (HCC) cells. METHODS: DNA synthesis activity of hepatocytes from background cirrhotic tissue and HCC cells from cancerous tissue was studied in 30 patients with liver cirrhosis (LC) and HCC who had undergone hepatectomy; the study was done using the bromodeoxyuridine (BrdU)-anti-BrdU in vitro method. The correlation between the BrdU labeling index (LI) of hepatocytes from noncancerous cirrhotic tissue and that of HCC cells was studied. The relationship between both BrdU LI values and the survival after hepatectomy also was studied. RESULTS: A significant correlation (r = 0.572; P < 0.001) was identified between the BrdU LI for HCC and that for noncancerous cirrhotic tissue. A significant correlation (r = -0.572; P < 0.05) was found between the BrdU LI of HCC cells and the survival after hepatectomy. A significant correlation (r = -0.678; P < 0.01) was observed between the BrdU LI of the noncancerous cirrhotic tissue and the survival. CONCLUSIONS: It was concluded that a significant correlation existed between DNA synthesis of hepatocytes from the background cirrhotic tissue and that of HCC cells and that DNA synthesis activity of hepatocytes from noncancerous cirrhotic tissue and that of HCC cells from cancerous tissue could predict the survival of patients with HCC who had undergone hepatectomy.

Development of hepatocellular carcinoma associated with increases in DNA synthesis in the surrounding cirrhosis.

The relationship between DNA synthesis activity in hepatocytes from cirrhotic tissue and development of hepatocellular carcinoma was studied in 33 posthepatitic patients with Child's grade A cirrhosis. DNA synthesis activity was measured by a bromodeoxyuridine (a thymidine analogue) labeling index, using the bromodeoxyuridine-antibromodeoxyuridine in vitro method, and the patients were followed up prospectively with frequent liver ultrasonography for 2 years. During the 2-year follow-up, 11 of the 33 cirrhotic patients developed hepatocellular carcinoma; they included 8 of the 15 patients (53%) in the high labeling index (greater than 1.5%) group compared with only 3 of the 18 patients (17%) in the low labeling index (less than 1.5) group (P less than 0.05). Five of the latter 18 subsequently had increased synthesis activity. Of these 20 patients who showed high synthesis activities either initially or subsequently, 10 (50%) developed hepatocellular carcinoma, in contrast to 1 of 13 (8%) with persistently low activities (P less than 0.05). Thus, hepatocellular carcinoma seems to develop or may become detectable when DNA synthesis in the background cirrhosis is increasing or remains high.

In vitro uptake of bromodeoxyuridine by human hepatocellular carcinoma and its relation to histopathologic findings and biologic behavior.

The in vitro uptake of bromodeoxyuridine (BrdU) by hepatocellular carcinoma (HCC) cells was studied in 30 hepatectomized patients. Labeling of the nuclei by BrdU expressed as labeling index (LI) was 5.6 +/- 3.2% (mean +/- standard deviation), with a considerable variation from case to case. The mean LI in Grade III to IV cancers (less differentiated, by Edmondson and Steiner's classification, 11.1 +/- 2.1%) was significantly larger (P less than 0.001) than that in Grade I to II cancers (more differentiated, 4.5 +/- 2.0%). Capsule formation was found in all 17 patients except one (94%) with a low DNA synthetic HCC (LI less than 6.0%) compared with seven of 13 (54%) with a high DNA synthetic HCC (LI greater than or equal to 6.0%, P less than 0.02). The 2-year survival rate after surgery was significantly higher (P less than 0.02), and intrahepatic metastasis was significantly less (P less than 0.05) in the former group than in the latter. The BrdU LI of HCC tumors showed a strong correlation with histopathologic findings and the biologic behavior of HCC.

Evidence of sex difference in DNA synthesis in hepatocellular carcinoma.

To clarify sex differences in DNA synthesis in hepatocellular carcinoma (HCC), bromodeoxyuridine labeling indices (BrdU LI) of HCC cells included in tumor biopsy specimens from 12 consecutive male patients and from 5 consecutive female patients all with liver cirrhosis and HCC were examined using an in vitro labeling technique. The mean BrdU LI +/- SE of HCC from male patients (7.7 +/- 0.8%) was significantly (P less than 0.05) higher than that from female patients (4.4 +/- 1.0%). While 7 of the 12 male HCC patients belonged to the high DNA synthesis group (BrdU LI greater than or equal to 7.0%), none of the 5 female HCC patients showed high DNA synthesis (P less than 0.05). We conclude that DNA synthesis in HCC was higher in males than in females.