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Peptic ulcer in the human stomach causes localized destruction of the gastric wall, which may be associated with focal vascular insufficiency. Endothelin-1, an extremely potent vasoconstrictor peptide, modulates regional blood flow in the vasculature of stomach, suggesting a role for endothelin-1 in peptic ulcer. We examined the relationship among endogenous plasma and mucosal endothelin-1 concentrations and the severity and area of ulcer in 19 patients with gastric ulcers and eight healthy adults. Endothelin-1 concentrations were measured by enzyme immunoassay in plasma and gastric mucosal specimens from ulcer margins, corpus, and antrum. The severity and area of ulcer were assessed endoscopically. Plasma endothelin-1 concentrations in active (P < 0.01 compared with normal) and healing (P < 0.05) stages of ulcer were significantly greater than those in normal subjects. Plasma endothelin-1 concentrations, but not mucosal endothelin-1 concentrations in the ulcer margin, were significantly associated with the severity of the ulcer. There was a significant positive correlation between plasma endothelin-1 concentrations and area of ulcer (r = 0.70, P < 0.01). In conclusion, locally increased endothelin-1 may be an important mediator contributing to the pathogenesis of peptic ulcer.

To determine the long-term response to interferon-alpha, 134 patients with chronic hepatitis C were followed for more than a year after therapy. Follow-up was stopped for 14 patients and 43 patients received retreatment. The remaining 77 patients were followed for 26-46 months, and 39 of them achieved long-term sustained alanine aminotransferase (ALT) normality. This normality was achieved in 35/38 short-term sustained responders, which was significantly higher (P < 0.001) than in the short-term relapsers (2/38) and the short-term nonresponders (2/44). Hepatitis C virus (HCV) RNA remained negative in 27 (73%) of 37 patients in the long-term sustained ALT normality group. However, only one (1.6%) of 63 long-term responders was negative for HCV RNA. The results of HCV RNA testing for the long-term period agreed with those at three to six months after therapy. Serum ALT levels during the first six months after therapy and HCV RNA testing at three to six months after therapy are important for predicting long-term sustained ALT normality and HCV RNA negativity.

Hepatocyte growth factor (HGF) stimulates the growth of hepatocytes and other epithelial cells. A gene for the HGF receptor, c-met, is detected in the intestinal tract and the liver, as well as in gastric carcinoma cells. However, the role of HGF in the regeneration of the normal gastric mucosa is not known. The purpose of the present study was to elucidate the effects of HGF on the morphogenesis of cultured gastric mucosal cells and to evaluate the role of HGF and c-met in the healing process in rat gastric mucosa. The cultured gastric mucosal cells developed a branching morphology in a collagen matrix supplemented with HGF or fetal calf serum. They did not form this morphology on a plastic dish or in the collagen without HGF or the serum. In an in vivo study, total RNA was extracted from rat gastric mucosa 6, 24, 48, and 96 hr after the exposure to a solution of 0.6 M HCl. HGF messenger RNA was not detected, but c-met was expressed in the mucosa. The increased expression of c-met was followed by healing of the mucosal injury. These results indicate that HGF plays important roles in the morphogenesis of gastric mucosal cells and that the HGF receptor gene participates in the healing process of gastric mucosa.

We classified 53 Japanese patients with chronic hepatitis C who were treated with natural interferon-alpha into genotypes and also tested the amounts of hepatitis C virus (HCV) RNA. The rate of the long-term complete response group, whose alanine aminotransferase levels remained within the normal range during the six months after therapy, was significantly higher (P < 0.01) in the type-III patients (4/5, 80.0%) than in type-II patients (4/43, 9.3%). For these long-term complete responders, the amounts of HCV RNA was less than 10(7) copies/ml serum in type-II patients, whereas two type-III patients with relatively high amounts of HCV RNA responded completely. These results confirm that the genotype of HCV is an important factor for predicting the response to interferon therapy. The amounts of HCV RNA can also predict its efficacy in type-II patients.

We measured des-gamma-carboxyprothrombin (DCP) (prothrombin induced by vitamin K absence or antagonist-II, abbreviated as PIVKA-II) by a newly developed enzyme immunoassay using an anti-DCP monoclonal antibody in 665 human subjects, of which 112 were patients with hepatocellular carcinoma (HCC). PIVKA-II was elevated to more than 0.1 AU/ml in 54 of the 112 patients (48.2%) with HCC, while it was positive only in 7.1% of those with liver cirrhosis and 3.1% of those with chronic hepatitis. Three patients with elevated PIVKA-II greater than 0.1 AU/ml who had been diagnosed as having liver cirrhosis by ultrasonography and computed tomography at the start of this study developed a diffuse type of HCC three or six months later, which was detected by angiography. No obvious correlation was observed between plasma PIVKA-II concentration and serum alpha-fetoprotein (AFP) level in HCC patients. Of the 112 HCC patients, 40.2% showed an increase in AFP to above 200 ng/ml. In the remaining patients, 32.8% had a PIVKA-II concentration greater than 0.1 AU/ml. In these patients with a negative or low serum AFP concentration, PIVKA-II proved to be a valuable tumor marker for laboratory diagnosis of HCC. Among them, 59.8% tested positive for PIVKA-II and/or AFP. Thus, combination assay with PIVKA-II and AFP seems useful for increasing the accuracy of laboratory diagnosis of HCC. None of patients with a solitary tumor smaller than 2 cm had elevated PIVKA-II. In patients with larger-sized and multiple HCC, positive results of elevated PIVKA-II were more frequent than those of increased AFP.(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the prevalence of hepatitis C virus (HCV) RNA and antibody (anti-HCVcore) to the putative HCV core protein in Japanese patients with chronic liver disease. Sera were screened by solid-phase enzyme immunoassay with a recombinant HCV core protein and by the reverse transcription-polymerase chain reaction (RT-PCR) test which directly detects the HCV genome. Anti-HCV core was detected with high titers in 95% (69/73) of chronic non-A, non-B hepatitis, and 94% (65/69) of anti-HCVcore-positive patients had the genome. Anti-HCVcore was also found with lower titers in 24% (10/41) of chronic hepatitis B virus carriers, and three of them had the genome. Only one (3%) of the 35 patients negative for anti-HCVcore tested positive to RT-PCR. These findings indicate the overwhelming prevalence of HCV infection in Japanese patients with chronic non-A, non-B hepatitis and a close relationship between the presence of anti-HCVcore and chronic hepatitis C in this population.

Interferon therapy is useful for decreasing the serum ALT level and improving liver histology in patients with chronic non-A, non-B hepatitis. This study examined the effect of interferon therapy in acute cases of posttransfusion hepatitis C. We report on three cases in which interferon alpha was administered at 100-220.5 million units. HCV RNA became undetectable during interferon administration and the ALT level declined to the normal range. However, after the cessation of the therapy, the ALT level began to fluctuate and HCV RNA reappeared in two patients. We concluded that interferon therapy for the acute phase of posttransfusion hepatitis is useful for suppressing viral replication and quickly improving the ALT level, but it can not always prevent the development of chronic hepatitis. Furthermore, there was a close correlation between the profile of HCV RNA and that of the ALT level, indicating that the replication of HCV plays an important role in liver injury.

Sera from Japanese patients with chronic liver disease were tested for hepatitis B virus (HBV) markers and antibodies to hepatitis C virus (anti-HCV), and the results were correlated to the presence of hepatocellular carcinoma. In chronic non-A, non-B liver disease, anti-HCV prevalence was high both in patients with hepatocellular carcinoma (78/89, 88%) and without it (66/84, 79%), while previous HBV infection was more common in patients with hepatocellular carcinoma (65/89, 73%) than in those without it (46/84, 55%) (P less than 0.05). Coexistence of anti-HCV and antibodies to HBV was observed frequently in patients with hepatocellular carcinoma (56/89, 63%) compared with patients without it (39/84, 46%) (P less than 0.05). In chronic HBV carriers, anti-HCV was more common in patients with hepatocellular carcinoma (12/38, 32%) than in those without it (3/62, 5%) (P less than 0.01). These results suggest that infection with the two viruses may be a risk factor for more serious liver disease.

The prevalence of Helicobacter pylori (HP) in the gastric mucosa of patients with chronic atrophic gastritis has been reported to be significantly higher than in normal mucosa. To clarify the role of HP in the etiology of chronic atrophic gastritis, we assessed the effect of ammonia on the gastric mucosal structure in rats, since HP has a strong urease activity and produces abundant amounts of ammonia. Ammonia administered orally at 0.01% and 0.1% as drinking water for two to four weeks decreased the mucosal thickness and the parietal cell number and oxyntic gland number in a dose- and time-dependent manner. The decrease of mucosal thickness was significantly greater in the antral mucosa than in the body mucosa. The border between the antral and body mucosa shifted toward the cardia, reflecting the decrease in oxyntic gland numbers. Furthermore, intracellular mucin was also decreased in a dose- and time-dependent manner, especially in the antral mucosa. Thus, ammonia chronically administered orally in rats led to changes in gastric mucosal structures and functions. The results suggest that the ammonia produced by HP partly plays an etiologic role in chronic atrophic gastritis.

Peripheral and intrahepatic lymphocyte subsets were analyzed in 22 patients with chronic hepatitis by two-dimensional flow cytometry. Activated T cells in the liver significantly increased compared with those in the peripheral blood. Helper T cells increased, but the CD4+ cells decreased due to a marked decrease of suppressor inducer T cells. CD8+ cells increased due to a increase of both cytotoxic T and suppressor T cells. Fc-receptor-positive cells, which increased significantly, were not NK cells but Fc-receptor-bearing T cells. In comparison with immunohistochemical methods, flow cytometric analysis enables more objective quantitation and simpler two-color staining of intrahepatic lymphocytes. Our findings using this method suggest that activated T cells and helper T cells have important roles in hepatitis and that hepatocellular injury may be generated not only by cytotoxic T cells but also by Fc-receptor-bearing T cells.

The influence of the intravenous injection of ranitidine (50 mg) on hepatic hemodynamics was investigated in normal subjects and patients with chronic liver disease. Using the organ-reflectance spectrophotometer, the regional hepatic blood hemoglobin concentration (delta Er569-650), an indicator of the regional hepatic blood flow, and the oxygen saturation of hemoglobin in the regional hepatic tissue (So2) were measured in patients with chronic liver disease after ranitidine injection under peritoneoscopy. With the pulse-Doppler ultrasonic flowmeter, the portal blood flow was measured in patients with chronic liver disease and normal subjects. There were no significant changes in the regional hepatic blood flow, the oxygen saturation of hemoglobin, and the portal blood flow after the intravenous injection of ranitidine. Thus, it is concluded that usual dose of ranitidine has no significant influence on the hepatic blood flow and that it can be prescribed without reducing the hepatic blood flow.