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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.

To assess the efficacy of ursodeoxycholic acid (UDCA) in autoimmune hepatitis we administered UDCA (600 mg/day, orally) to four patients who had autoimmune hepatitis refractory to treatment with prednisolone alone (20 mg every other day). During the treatment, serum levels of alanine aminotransferase (ALT) normalized and we were able to taper the dose of prednisolone to 5 mg every other day. The results indicate that UDCA administered concomitantly with very low doses of prednisolone may prove effective in patients who have autoimmune 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.

To confirm the possibility that some hepatitis B virus (HBV) variants do not induce HB s antigen (HBsAg), anti-HB core antibody (anti-HBc) and anti-HBc IgM in a transient infection, polymerase chain reaction (PCR) was performed in 20 patients with acute hepatitis and 7 patients with fulminant hepatitis. Patients were diagnosed with non-A, non-B hepatitis by serological markers at admission. PCR successfully amplified the precore/core gene in 5 (25%) of the patients with acute hepatitis and 2 (29%) of the patients with fulminant hepatitis. Subsequent sequencing revealed frequent mutations including precore-defects in the precore/core gene.

Leukocyte cell-derived chemotoxin 2 (LECT2) is a recently isolated protein and has been shown to be synthesized by human hepatocytes. All hepatocytes show diffuse immunostaining for LECT2 within the cytoplasm. In the present study, an attempt was made to clarify the expression pattern of LECT2 in nine cases of low-grade malignant hepatocellular carcinoma (LGM-HCC) and five cases of advanced HCC and 19 cases of premalignant lesion, termed atypical hyperplasia (AH), using the indirect immunoperoxidase technique. Variable spotty to coarsely diffuse staining in the majority of cells, a mixture of positively staining and negatively staining areas, and essentially negative staining was observed within the cellular cytoplasm of AH, LGM-HCC and advanced HCC, respectively. The expression of LECT2 became weaker with the progression of multistep hepatocarcinogenesis. The data clearly demonstrate that LECT2 becomes essentially negative in full-blown HCC cells and that the histological distinction between AH and LGM-HCC is valid. It also seems likely that LECT2 is related to hepatocyte growth.

The nucleotide sequences of the precore/core and X open reading frames (ORFs) of hepatitis B virus (HBV) were studied in four subjects who were serologically negative for anti-hepatitis B core antibody. These subjects were positive for serum hepatitis B surface antigen and were considered to be asymptomatic HBV carriers. Sequencing of the precore/core ORF revealed precore wild type and 3 to 8 nucleotide substitutions (replacing 0 to 2 amino acids) in the core region compared with the sequence of subtype adr. These substitutions were not considered to have changed the epitope of the core antigen, resulting in the absence of anti-HBc as determined by a conventional diagnostic kit. The X ORF showed 1 to 5 nucleotide substitutions (replacing 1 to 3 amino acids) and the structure of the X protein and the core promoter/enhancer II complex appeared to be conserved. These findings strongly suggest that the absence of serum anti-HBc is not due to mutation of the HBV DNA but to an aberrant immune reaction of the host to HBV.

Variations of the hepatitis B virus (HBV) precore/core sequence has been shown to play a role in the development of active liver disease in chronic hepatitis B. Whether this is also an important viral factor in the pathogenesis of acute and fulminant hepatitis B is unknown. To determine the precore/core gene sequence in patients with acute and fulminant hepatitis B, 11 patients with fulminant hepatitis B and seven patients with acute hepatitis B were studied. The sequences of precore/core gene were determined by direct sequencing of the polymerase chain reaction amplicons generated from the HBV isolated from patients' serum. For the 11 patients with fulminant hepatitis B, the precore/core regions were successfully amplified in 10 patients. Eight patients exhibited precore stop codon mutations. In addition, nine of the 10 fulminant hepatitis B patients had frequent nucleotide substitutions with corresponding changes in the predicted amino acid sequences in the mid-core and the 5′ terminus region of the core gene. In contrast, precore stop codon mutants were not detected, and variations of the HBV core gene were minimal in patients with acute hepatitis B. The association of HBV precore mutants and HBV core gene variations with fulminant hepatitis B and not acute hepatitis B suggested that these variations may be important in modulating the clinical course of HBV infection.

Hepatocellular carcinoma (HCC) is rather rare in the Western Hemisphere and in Europe, however, it is far more prevalent in the Orient and Africa and is indeed one of the most common causes of cancer death in these areas [1–3].

肝癌のhigh risk groupを対象に昭和56年11月から超音波を主体とした肝癌の集団検診を実施した.対象者はHBVキャリアおよび肝疾患歴のあるものを主体とし,GOT, GPT, LDH, ALP, Ch-E, r-GTP, TTT, ZTTなどの肝機能検査,HBs抗原抗体系,AFPその他の腫瘍マーカーの検索と超音波検診を併用した.昭和59年4月までの2年6ヵ月間に,札幌,函館,帯広,旭川の道内主要都市を中心に計9回の検診を行い,受診者は延べ2,028名を数えた.受診者は30～60代を主体とし,男女比は1:0.49であり,なんらかの肝機能検査異常を呈したものは60.9%に上り,HBs抗原の陽性率は23.2%を示した.肝癌は21名,1.04%に発見されたが,19名は超音波検査のみによりスクリーニングされ,他はAFP高値例の追跡により診断しえた.その他,肝血管腫22名,1.1%,肝嚢胞52名,2.6%,胆石症91名,4.5%, FNH 1名も発見された.

原発性胆汁性肝硬変症は自己免疫症と考えられるが,臓器特異抗原を含有すると推定される肝内胆管上皮の単離が困難なため,本症成立に関する免疫学的検討を著しく困難にしている.今回家兎-抗人胆汁蛋白血清を用い,蛍光抗体間接法によって人胆汁中には,胆管上皮由来の蛋白が存在することを明らかにした.又二元免疫拡散法により,人胆汁中には胆管上皮由来抗原を含めて,少くとも3種類の抗原蛋白が存在することを明らかにした.これら抗原蛋白は何れもSephadex G-200によるゲル濾過で第1峰に溶出される高分子群に含有されると推定された.又これらの抗原蛋白は臓器特異性の高いものであることを明らかにし得た.原発性胆汁性肝硬変症患者は人胆汁蛋白のSephadex G-200第1峰を添加抗原としたLMTで陽性反応を示し,この抗原に対する細胞性免疫の成立が本症発現に重要な役割を演じていることが示唆された.

From a human fetal liver cDNA library, a new cDNA clone (lambda HFL10) was isolated using an antiserum to P450 HFLa, which has been isolated from livers of human fetuses. Cytochrome P450 cDNAs, namely lambda hPA6, lamda hP2-1, and lambda hPD4 which were highly homologous to cDNA clones, pHY13, Hp1-1, and phP450j, respectively, were also isolated from the cDNA library of human adult livers. Using these cDNA clones as probes together with Lambda HFL10, Northern blot analysis was conducted to determine whether all of these cytochromes were expressed in human fetal livers. The results clearly showed that only P450 HFL10 mRNA was detected in human fetal livers. This result supports the allegation that there is a much more limited number of forms of cytochrome P450 in human fetal livers than in adult livers.