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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.

The relationship between DNA synthesis activities of hepatocytes in biopsied specimens and liver volume was studied in various stages of primary biliary cirrhosis using an in vitro bromodeoxyuridine (a thymidine analogue)-anti-bromodeoxyuridine reaction and computed tomography. The mean bromodeoxyuridine (+/- SE) labeling index for 10 patients in an early histological stage (stage I, 4, and stage II, 6, 3.4% +/- 0.4%) of primary biliary cirrhosis was 17 times that for 6 control subjects (0.2% +/- 0.1%, P less than 0.001), and was significantly higher than that for 19 female patients with chronic aggressive hepatitis (0.9% +/- 0.2%, P less than 0.001), 14 compensated cirrhotic patients of viral origin (all female, 1.1% +/- 0.3%, P less than 0.01), and 5 patients with stage III primary biliary cirrhosis (0.5% +/- 0.1%, P less than 0.001). The mean (+/- SE) liver volume in the early stage of primary biliary cirrhosis (1225 +/- 40 cm3) was about 1.5 times that in control subjects (835 +/- 42 cm3, P less than 0.001). These results suggest that liver volume has already become large in the early stage of primary biliary cirrhosis perhaps because of markedly increased DNA synthesis in hepatocytes.

Endotoxin was measured by the Limulus assay in plasma and ascites in 46 patients with cirrhosis having demonstrable esophageal varices, of whom 29 had ascites and 17 did not. It was positive in ascitic fluid in 23 (79.3%) of the former group. In plasma, a positive test was obtained in 22 (75.9%) in the group with ascites and only 4 (23.5%) without ascites, the difference being significant (P less than 0.01). Of the 23 positive ascites specimens, 17 showed high titers (greater than or equal to 10(-3) microgram per ml). Hepatic uptake of 198Au colloid was markedly reduced in 11 of the 17 patients with endotoxemia who were studied by scanning. Death occurred within 6 months in 47.8% of the patients with a positive endotoxin test, whereas only 16.7% of those with a negative test died in the same period (P less than 0.05). No hypotension was noted in patients with toxemia and only 2 ran a fever above 37.5 degrees C. Development of tolerance to endotoxin is suspected. A follow-up study has demonstrated sustained endotoxemia in some of these patients.