Randomized controlled trial of lymphoblastoid interferon alpha for chronic hepatitis C (comparison of 9-MU and 6-MU doses). IFN Treatment Group of Affiliated Hospitals of the Third Department of Internal Medicine at Nagoya University School of Medicine.

OBJECTIVE: We conducted a randomized controlled trial to compare the efficacy of two different dosages of lymphoblastoid interferon alpha (IFN) for the treatment of chronic hepatitis C. METHODS: Eighty-four patients with chronic hepatitis C were enrolled and randomly assigned into the two groups; group A was treated with 6 million units (MU) and group B with 9 MU daily for the first 2 wk, and then thrice weekly for an additional 14 or 22 wk. RESULTS: Eighty patients were evaluated (39 patients in group A and 41 in group B); 14 patients in group A (35.9%) and 15 in group B (36.6%) obtained sustained response. The percentages of patients who became negative for HCV RNA at the end of the second wk differed slightly between the groups, without statistical significance (56.4% and 68.3%). When assessed in detail, patients with genotype 1 and < 1 Meq/ml of viral load became negative for HCV RNA significantly more frequently in group B (eight of eight) than in group A (three of seven) (p < 0.05) at the end of the second week, whereas the sustained response rate was similar between the groups (five of eight and four of seven). Predictors of sustained response by multivariate analysis were low viral load (< 1.0 Meq/ml) and negativity of HCV RNA at the end of the second wk of IFN. CONCLUSIONS: The results indicated that there was no difference in sustained response rate between the 6-MU and 9-MU doses. The earlier disappearance of HCV RNA, at the end of the second wk or at least by the end of the fourth week, is an essential condition for sustained response.

Analyses on lipid-rich organelles of the rat liver after bile duct ligation.

A fraction of lipid-rich organelles of rat livers was analyzed to study the effect of bile duct ligation on lipid metabolism. The lipid fraction of the control rats consisted mainly of Golgi-derived dense bodies. Three days after the ligation, myelin-like figures and increased phospholipids and cholesterol were characteristic of the fraction. Two weeks ligation resulted in proliferation of lysosomal electron dense bodies. As their volume density expanded, phospholipids and cholesterol increased. Electrophoresis indicated a reduced rate of VLDL assembly after ligation. The Golgi-dominant phase is converted to the lysosomal phase in the heavy subfraction after the bile duct ligation. This subcellular change could be a consequence of secondary lipidosis: hepatocyte lysosomes have been exhausted in sorting accumulated lipids into secretory lipoproteins.

A copper-sulfur complex in the liver of a patient with Wilson's disease.

An asymptomatic 16-year-old boy was found to have Wilson's disease without Kayser-Fleischer rings. Liver biopsy showed chronic active hepatitis with 1025 micrograms copper/g dry weight. After 19 months of d-penicillamine therapy, the liver histology became almost normal and the copper content decreased to 238 micrograms/g dry weight. The liver specimens obtained before and after treatment were studied by X-ray probe microanalysis. After treatment, both copper and sulfur decreased in hepatocellular lysosomes. The estimated molar ratio of the decreased copper to the decreased sulfur was 32/100. These figures suggest that lysosomal copper exists in the form of metallothionein.

A role of the heavy subfraction of the floating lipids in acute alcoholic fatty liver of rats.

Two subfractions of floating lipids were studied to clarify the subcellular pathogenesis of ethanol-induced acute fatty liver in the rat. The main lipid in both the heavy and light subfraction was triglyceride, but the heavy subfraction was richer in phospholipids than the light subfraction. After ethanol-treatment of the animals, not only triglyceride but also phospholipids increased significantly in the light subfraction. The similarity of the phospholipid species in the two subfractions suggests a possible exchange of lipids between them. The heavy subfraction consisted of membrane-free lipid droplets of very low density lipoprotein (VLDL) size plus membrane-bound, vacuolated organelles; the light subfraction consisted of membrane-free lipid globules larger than 1000 nm in diameter. Occasionally adherent particles, 40 to 100 nm in diameter, were detected on the surface of the lipid globules. After ethanol treatment, the ratio of adherent particles to lipid globules increased significantly. These observations suggest that the biogenesis of acute alcoholic fatty liver in rats involves first the formation of membrane-free lipoproteins of VLDL size in the cytoplasm and subsequently their fusion to pre-existing lipid globules.

An association of mercury with selenium in inorganic mercury intoxication.

Energy dispersive X-ray analysis was performed on the renal tubular cells of two patients with inorganic mercury intoxication. Some lysosomes of these cells consisted of unusual matrices of aggregated electron-dense grains which were positive for mercury, selenium and sulphur. Though maps of the specific X-rays of both mercury and selenium coincided exactly with these lysosomes, the molecular ratio of selenium to mercury ranged between zero and 2.9. It is unlikely that the trace element of selenium and exogenous inorganic mercury are deposited in the lysosomes independent of each other, but rather their coexistence in the characteristic lysosomes strongly suggests a compound formed by binding mercury to the SeH residues of selenoprotein.

Electron probe X-ray analysis on human hepatocellular lysosomes with copper deposits: copper binding to a thiol-protein in lysosomes.

Livers of eight patients with chronic liver diseases were investigated by energy dispersive x-ray analysis. First, three kinds of preparations (osmium-Epon sections, glutaraldehyde-frozen sections, and unfixed-frozen sections) were compared for element detectability at a subcellular level. The glutaraldehyde-frozen sections were satisfactory as far as copper, sulfur, and phosphorus were concerned. Five patients (one patient with Wilson's disease, one chronic cholestasis, one chronic hepatitis, and two asymptomatic primary biliary cirrhosis) yielded x-ray images of copper and sulfur consistent with hepatocellular lysosomes. Second, the glutaraldehyde-frozen sections were utilized for a study of copper deposits in the patients' livers. There was a significant correlation between copper and sulfur contents in the lysosomes of all patients studied but no correlation in the remainder of the cytoplasm. Zinc was not detected in the lysosomes. Whatever the content of copper in the lysosomes, the ratio of delta copper to phosphorus (weight/weight) to delta sulfur to phosphorus was 0.60. These data indicate that most lysosomal copper binds to a thiol protein, probably metallothionein, in the liver.