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We have discovered that non-A, non-B, non-C, non-D, non-E (so-called type F) acute and chronic hepatitis is caused by a hepatitis B virus (HBV) variant with mutations in the X open reading frame. This silent HBV mutant does not induce immunoserological markers. In the present investigation we attempted to elucidate the putative mechanism of hepatocellular necrosis and expression patterns of hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) in biopsied liver tissue. The subjects consisted of 14 patients with acute hepatitis, 11 with chronic hepatitis and eight with liver cirrhosis, all of whom had been previously diagnosed as having so-called hepatitis F. Nine of the 14, 10 of the 11 and all eight, respectively, of the above patients exhibited significant positive immunostaining for HBsAg within their hepatocellular cytoplasm, diffusely or focally. HBcAg stained in a few hepatocellular nuclei in 24.2% of the patients. Histological features were characterized by necroinflammation, indicating immune-mediated hepatocellular necrosis. Despite the serological-marker negativity, the results of immunostaining for HBsAg and HBcAg support replication and expression of HBV DNA, though weak.

Although less common than oesophageal varices in portal hypertension, gastric fundal varices carry a higher mortality rate when they rupture. They are less amenable to sclerotherapy. We have developed a minimally invasive balloon-occluded retrograde transverse obliteration (B-RTO) procedure to treat gastric fundal varices. B-RTO involves inserting a balloon catheter into an outflow shunt (gastric-renal or gastric-vena caval inferior) via the femoral or internal jugular vein. Blood flow is then blocked by inflating the balloon, and 5% ethanolamine oleate iopamidol is injected in a retrograde manner. The embolized gastric varix subsequently disappears. B-RTO was performed in 32 patients with gastric varices. Follow-up endoscopies were performed at intervals of 2-4 months for an average observation period of 14 months. Eradication of the varices has been confirmed in 31 of 32 patients. No recurrence occurred in any patients in the follow-up period. There were no significant changes in liver function after the procedure. We conclude that B-RTO is a safe and effective procedure for the treatment of gastric fundal varices.

A pathogenic role of precore-defective mutation in the onset of fulminant hepatitis B has been suggested. However, precore-defective mutants do not always cause fulminant hepatitis B and are not always isolated from affected patients. These findings strongly suggest the presence of some additional important mutations outside the precore region in fulminant hepatitis. In the present investigation an attempt was made to sequence the X open reading frame of hepatitis B virus DNA isolated from seven patients with fulminant hepatitis B and five patients with acute hepatitis B. The latter were used as controls. Since the X open reading frame encodes the X protein and contains the core promoter/enhancer II complex, some critical mutations may enhance or disrupt the replication and expression of hepatitis B virus DNA leading to fulminant hepatitis. A C-to-T substitution was found at nucleotide (nt) 1655, an A-to-T substitution at nt 1764 and a G-to-A substitution at nt 1766 in 4, 5 and 5 patients, respectively, out of the seven with fulminant hepatitis. These substitutions were not recognized in the patients with acute hepatitis. These mutations might change the function of the X protein and core promoter/enhancer II complex. It is suggested, therefore, that these mutations, as well as the precore-defective mutation, may play an important role in the pathogenesis of fulminant hepatitis.

We analyzed the evolution of the precore/core gene of hepatitis B virus (HBV) over a period of 6 to 11 years in seven patients with chronic HBV infection, who exhibited a variety of clinical features. Sequence analysis revealed the following results: (1) HBeAg to anti-HBe seroconversion was correlated roughly with the occurrence of precore-defective mutants, and several years appeared to be required for complete replacement of wild types by mutants; (2) core gene mutations preceded precore-defective mutations and tended to increase with time, although not cumulatively. They occurred not only during serum alanine aminotransferase (ALT) elevations but also after ALT returned to normal; (3) ALT fluctuations appeared to subside with complete replacement of the wild type by the mutant type and/or substantial accumulation of core gene mutations; (4) unexpectedly, the anti-HBe-positive “healthy” carrier was found to harbor the wild type precore gene, as did the HBeAg-positive “healthy” carrier; however, the core gene of the former evolved at a rapid rate; and (5) a partial deletion was recognized in the core gene at the onset of fatal hepatic failure in one patient. Thus, the precore/core mutation was closely related with the clinical features in the patients. © 1994 Wiley-Liss, Inc.