Short-term complications of retrograde transvenous obliteration of gastric varices in patients with portal hypertension: effects of obliteration of major portosystemic shunts.

The type, incidence, and severity of complications of balloon-occluded retrograde transvenous obliteration (B-RTO) for gastric varices should be precisely estimated. Complications were evaluated in 38 patients who had fundic gastric varices and 43 B-RTO procedures during injection of ethanolamine oleate (phase 1), within 4 h after injection (phase 2), 24 h after injection (phase 3), and from 24 h to 10 days after injection (phase 4). Endoscopic evaluation at 8 weeks showed resolution of gastric varices in 35 of 38 patients (92%) and smaller varices in the remaining three (8%). B-RTO caused transient hypertension in 35% of patients, hemoglobinuria in 49%, and fever in 33% during phases 1, 2, and 3, respectively. Pleural effusion, pulmonary infarction, ascites, gastric ulcers with unique appearance, localized mosaic-like change of gastric mucosa, and hemorrhagic portal hypertensive gastropathy were noted in phase 4. There were no fatalities. Lactate dehydrogenase, aspartate aminotransferase, and bilirubin increased on day 1. Each datum was retrieved within 7 days. The severity of lactate dehydrogenase elevation correlated significantly with the volume of infused ethanolamine oleate. Thus, B-RTO is a safe and effective management of fundic varices. However, short-term hemodynamic change after B-RTO may cause gastric mucosal damage. Pulmonary infarction and pleural effusion are potential complications.

Effects of antioxidative agents on apoptosis induced by ischaemia-reperfusion in rat intestinal mucosa.

BACKGROUND AND AIM: We have previously demonstrated that ischaemia-reperfusion induces apoptosis in the intestinal mucosa. To evaluate that reactive oxygen species enhanced intestinal apoptosis after ischaemia-reperfusion, we examined whether antioxidants reduced apoptosis. METHODS: Rats were infused through a duodenal tube with antioxidative agents, glutathione, rebamipide and dymethylsulfoxide during 2 h before an ischaemic insult. The superior mesenteric artery was occluded for 60 min, followed by 60 min reperfusion. Apoptosis was evaluated by percentage fragmented DNA (fragmented DNA/total DNA) and immunochemical staining. RESULTS: Increase in apoptosis in the intestinal mucosa after ischaemia-reperfusion was attenuated by intraduodenal infusion of antioxidative agents, but was not completely abolished. CONCLUSION: Scavenging effects of the antioxidative agents attenuated increases in intestinal apoptosis, indicating that oxidative stress after ischaemia-reperfusion plays an important role in induction of apoptosis in the intestinal mucosa.

Induction of apoptosis in cells by cadmium: quantitative negative correlation between basal or induced metallothionein concentration and apoptotic rate.

Metallothionein (MT) often reduces the adverse effects of cadmium (Cd), but how it may alter Cd-induced apoptosis is unclear. The goal of this study was to define the role of MT in Cd-induced apoptosis using cell lines with widely varying sensitivity to Cd. Effects of Cd on growth of human hepatocellular carcinoma cell lines (HepG2 and PLC/PRF/5) were investigated and compared with Chang cells. These cells were cultured with 0, 5, 10, 20, 40, 80, and 120 microM of Cd for 3, 6, 12, and 24 h. Significant cytolethality was observed in HepG2 and PLC/PRF/5 cells in a time- and concentration-dependent manner, with LC(50) values of 24 microM and 13 microM, respectively. However, Chang cells were much less sensitive to Cd-induced cytotoxicity (LC(50), 64 microM). Apoptotic cell death occurring at cytolethal concentrations was demonstrated in all cell lines by DNA fragmentation on agarose gel electrophoresis or by ELISA. When MT was measured, there was a highly significant negative linear correlation between the basal cellular MT concentration or Cd-induced MT and the rate of apoptosis induced by Cd in these cell lines. Treating HepG2 cells with zinc (Zn) made the relatively sensitive HepG2 cell line resistant to Cd-induced apoptosis, likely due to Zn-induced MT. In fact, there was also a significant negative linear correlation between the amount of Zn-induced MT in HepG2 cells and the rate of Cd-induced apoptosis. These findings revealed that basal or induced MT perturbs Cd-induced apoptotic cell death in various cell lines, and a strong negative correlation exists between cellular MT content and the rate of apoptosis induced by Cd.

Prevalence of hepatitis G virus in liver disease.

The prevalence of hepatitis G virus (HGV) in liver disease of non-A, -B, -C viral hepatitis, hepatitis B and hepatitis C was determined. Two of 44 patients (4.5%) with liver injury without any hepatitis A, B or C marker were positive for HGV. One of five cases of hepatocellular carcinoma was positive for HGV. One of three cases with fulminant hepatitis was positive for HGV. This case was negative at the onset of fulminant hepatitis and became positive after plasmapheresis. No patient with acute (n=8) or chronic (n=5) hepatitis or liver cirrhosis (n=8) was positive for HGV in non-A, -B, -C liver disease. One of 30 patients with various HBV-positive liver diseases and nine (17.3) of 52 patients with type C liver disease were positive for HGV. In patients with hepatitis C, four (28.6%) of 14 HGV-co-infected patients were complicated with diabetes mellitus compared with four (10.5%) of 38 single hepatitis C virus (HCV)-infected patients (not significant). In 12 HGV-positive patients, eight of 10 (80%) had a history of blood transfusion. In HCV-positive patients, co-infection with HGV was not a risk factor in patients with diabetes mellitus as a complication. HGV appeared to cause non-A, -B, -C hepatitis rarely, and its main route of infection was blood transfusion.

Accidental transmission of HCV and treatment with interferon.

Accidental transmission of contagious pathogens, especially hepatitis C virus (HCV), by needlestick or other means as an occupational hazard for medical staff is of concern. We retrospectively analysed cases of work-related accidental injury with pathogens such as hepatitis B virus (HBV), HCV, syphilis and human immunodeficiency virus (HIV) reported to the centres for disease control at 15 hospitals (total 5776 beds) in the Gunma prefecture, Japan, from December 1990 to August 1993 (24.7 months). There were 416 such cases (16.8 cases/month), with an incidence of 0.2-3.5 accidents per month per hospital. Such accidents occurred in 297 (71.2%) nurses, 98 (23.5%) medical doctors, 13 (3%) laboratory technicians, four (1.0%) hospital maintenance workers, one (0.2%) assistant nurse, one secretary and two others. There were 323 (77.6%) injuries caused by needlestick, 42 (10.1%) from suture needles or surgical knife cuts, 17 (4.1%) from blood splatters from patients into the eyes or mouth, 10 (2.4%) from contact with injured skin and 24 (5.8%) simple skin contacts. Of the pathogens, 60.3% were HCV, 22.6% HBV, 5.8% syphilis, 0.7% HIV and 10.6% were of unknown origin. Four cases (1.6%) of HCV infection were found and treated with one or two courses of interferon therapy, and HCV was subsequently cleared. All four patients were cured with interferon therapy. None of the HBV-injured cases resulted in infection, possibly because of prophylaxis with HB immunoglobulin and HB vaccine. No HIV or syphilis infection was contracted. In summary, chronic HCV infection acquired as an occupational hazard can be cured by appropriate treatment, such as with interferon, after early detection of the infection.

Quantitative analysis of hepatitis B virus precore mutant in hepatitis type B.

Active liver disease has been detected in chronic hepatitis B after seroconversion from positive HBe antigen to positive anti-HBe antibody. Active replication of HB virus (HBV) containing a precore stop-codon mutation has been implicated in this condition. The usual methods, such as direct sequencing, to characterize the responsible mutant of HBV are not suitable for routine clinical use. Here we employed the competitive mutation site specific assay (CMSSA) to detect precore mutant HBV-DNA in patients with positive HB surface antigen. In patients with HBe antigen, precore mutant HBV-DNA was significantly higher than in patients with HBe antibody. The level of precore mutant HBV-DNA in patients with elevated serum ALT was significantly higher than in patients with normal serum ALT. Sex, age and the level of serum HBV-associated DNA polymerase levels were not correlated with levels of precore mutant HBV-DNA. Ten of 11 negative patients for the precore mutant by polymerase chain reaction followed by restriction fragment length polymorphism assay (PCRRFLP) were positive for the precore mutant by CMSSA. These results suggest that the precore mutant has already emerged in the HBeAg-positive phase as determined by CMSSA, which is more sensitive than PCR-RFLP and is useful for evaluating the clinical course of patients with chronic hepatitis B.

Prediction of effect of interferon on chronic hepatitis C.

Clinical, pathological, and virological analysis including hypervariable region-1 of hepatitis C virus (HCV) was performed to predict the effect of interferon (IFN) on 41 patients with chronic hepatitis type C. The low virus load, low frequency of the mutation in the hypervariable region-1 as the change of amino acid and high level of serum aminotransferase make one estimate the good effect of IFN on patients with HCV. Mutation in the hypervariable region-1 of HCV measured by fast assay fluorescence single-stranded conformational polymorphism was more frequent in nonresponders to IFN than responders. The most frequently mutated position was amino acid number 406. This indicates that the specific mutation site might affect the response of IFN.

The possible role of zinc and metallothionein in the liver on the therapeutic effect of IFN-alpha to hepatitis C patients.

We have studies zinc deficiency in hepatitis C patients (complete responder [CR] 22, nonresponder [NR] 25) with relation to the therapeutic effect of interferon-alpha (IFN-alpha). Circadian variations in serum zinc levels were high in the morning (basal level) and then gradually decreased during the day in both chronic hepatitis C patients and healthy controls. Basal zinc levels in serum were significantly lower in chronic hepatitis C patients (73 +/- 3 micrograms/dL, n = 12) than in controls (93 +/- 5 micrograms/dL). An injection of 10 MU of IFN-alpha to hepatitis C patients augmented the serum zinc reductions, up to 40% in 8 h. Serum cortisol levels were significantly elevated 8 h (25.6 +/- 2.3 micrograms/dL) after IFN-alpha dose. Forty-seven chronic hepatitis C patients were treated with IFN-alpha for 24 wk, and serum zinc and copper levels were determined 12 and 24 wk during and after the completion of IFN-alpha therapy. Serum zinc levels and zinc/copper ratio were higher in CRs than in NRs to IFN therapy at each time-point. Hepatic metallothionein staining became prominent after IFN therapy in most of CRs, whereas it diminished NRs. These data suggest that nutritional status of zinc influences the effect of IFN on hepatitis C patients.

Flow-injection analysis of cobalt(II) utilizing enhanced lophine chemiluminescence with hydroxylammonium chloride.

A rapid and convenient flow-injection method is described for the determination of Co(II). The method utilized the phenomenon that the lophine-Co(II)-H2O2 chemiluminescence (CL) reaction is enhanced in alkaline media by the addition of hydroxylammonium chloride. The calibration curve was linear over the range 2 x 10(-7) to 2 x 10(-5) M with a detection limit of 4.5 x 10(-8) M (0.9 pmol) at a signal-to-noise ratio of 2. The method was applied to the assay of cyanocobalamin in commercially available eye lotions.

Hepatocellular carcinoma with pleural metastasis complicated by hemothorax.

Hemothorax can be caused by rupture of hepatocellular carcinoma (HCC). Hemoperitoneum is a well-known cause of death caused by rupture of a primary HCC lesion. Rupture of a HCC metastasis has not been adequately described. This is the first report of a HCC patient who died of hemothorax due to rupture of a pleural metastasis. The patient, a woman, died in respiratory failure 2 wk after rupture of her HCC metastasis in the pleura. Autopsy revealed moderately differentiated HCC in the liver, lung, and pleura. We discuss treatment options for ruptured pleura-based HCC metastases.

Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis.

8-Hydroxydeoxyguanosine (oh8dG) is a promutagenic DNA lesion produced by oxygen radicals. We examined alterations in the oh8dG level in human livers which have chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The oh8dG content in livers with chronic hepatitis was significantly higher than the oh8dG content in normal livers (P < 0.05). There was also a significant correlation between the oh8dG content in noncancerous liver tissues with individual serum alanine aminotransferase concentration (r = 0.515; P < 0.001). Thus, chronic inflammation in the liver produces oxidative DNA damage, which may increase the risk for genomic alterations causing hepatocarcinogenesis.

Evaluation of the therapeutic effect of TAE on primary liver cancer.

The therapeutic effect of transcatheter arterial chemoembolization (TAE) performed on 31 patients with primary liver cancer was evaluated using the following procedures: (1) the alpha-fetoprotein (AFP) reduction rates and prognoses were analyzed according to the tumor reduction rates (TR), and (2) the AFP reduction rates and prognoses were also analyzed according to the tumor necrosis rates (TN) estimated by regarding every region with Lipiodol retention as being necrotic. The following results were obtained. The AFP level was 400 ng/ml or higher in 15 patients (48%). Their AFP reduction rates were as favorably high as 65.4%-99.8% (mean, 88.1%), and the AFP level was normalized in 3 patients. The cumulative survival rates after the initial treatment were relatively high, i.e., 78.4% in the 1st year, 58.1% in the 2nd year, and 38.7% in the 3rd year. These results suggested the effectiveness of the TAE treatment undertaken in this study. Regarding the TR, the tumor was reduced in size by 50% or more in only 5 patients (16%), and most patients had a TR of less than 25%. On the other hand, the majority, 25 patients (81%), had a TN ranging between 50% and less than 100%, including 7 who had a TN ranging between 50% and less than 90% and 18 who had a TN ranging between 90% and less than 100%. There was no significant correlation between the AFP reduction rate and the TN or TR. Regarding evaluation of the cumulative survival rates by TR and TN, the 1-year survival rate was lower in patients having a TR of less than 25% than in those having a TR of 25% or more. Patients having a TN of less than 50% showed a poor outcome as compared with those having a TN of 50% or more. Although the TR was found to be less than 50% in a majority of the patients when the therapeutic effect of TAE on the liver cancer was evaluated according to the TR, many of these patients showed a good outcome. Thus, the conventional efficacy evaluation, in which a tumor reduction of 50% or more is considered to be effective, should be reconsidered. On the other hand, the TN was found to be 50% or more in most of the patients, suggesting the necessity of a more detailed classification of TN. In relation to the survival rate, patients having a TN of less than 50% showed a poor outcome.