Mineo Kojima

Fulminant hepatitis B: Induction by hepatitis B virus mutants defective in the precore region and incapable of encoding E antigen

Clones of hepatitis B virus were propagated from 10 cases of fulminant hepatitis B after amplification by polymerase chain reaction and their nucleotide sequences of the precore region were determined. All 113 clones from 9 cases had a point mutation from guanine to adenine at nucleotide 83 in the precore region, which converted codon 28 for tryptophan (TGG) to a stop codon (TAG) and prohibited the synthesis and secretion of hepatitis B e antigen. Precore-region defects were not detected in any of 23 clones from the remaining 1 case. By contrast, precore-region defects were not found in any of 180 clones from 8 cases of acute hepatitis B without hepatic failure serving as controls. The source of infection was traceable in 3 cases. The same precore-region defect, along with the sequence identity of 435 nucleotides, was observed in clones from the case of a baby and his grandmother, who carried the virus and was implicated in the transmission, and also in clones from two pediatricians and the carrier patients they attended. These findings support the hypothesis that precore-defective mutants have stronger activity to induce fulminant hepatitis than nondefective viruses.

GB Virus C and Hepatitis C Virus Infections in Hemodialysis Patients in Eight Japanese Centers

RNA of a putative non-A to E hepatitis virus, designated GB virus C (GBV-C), was detected in 40 (6.2%) of 645 hemodialysis patients, at a frequency significantly higher than in 3 (0.9%) of 336 blood donors in Japan (p < 0.001). A history of transfusion was more frequent (88 vs. 58%, p < 0.001), the duration of dialysis was longer (13.2 +/- 7.9 vs. 7.9 +/- 6.5 years, p < 0.001), and the detection of hepatitis C virus RNA was more often (38 vs. 18%, p < 0.01) in the 40 patients with GBV-C RNA than in the 605 patients without it. The prevalence of GBV-C RNA varied widely from 0 to 10% among the 8 dialysis centers. These results indicate that hemodialysis patients would be at increased risk of GBV-C transmitted by transfusions. The detection of GBV-C RNA in the 5 patients without a history of transfusion and a high prevalence restricted to certain dialysis centers would reflect nosocomial infection.

High-dose (9 MU) long-term (60 weeks) alfa-interferon therapy for chronic hepatitis patients infected with HCV genotype 1b

SummaryEfficacy of standard regimens (e.g., 3–6 MU for 24 weeks) of alfa-IFN therapy for chronic hepatitis C has been limited, particularly in patients with HCV/1b. To see if higher-dose longer term treatment is more effective, we tried a 9 MU 60-week regimen. HCV/1b-infected chronic hepatitis patients received 9 MU IFNα2a everyday but Sunday for 2 weeks and thrice a week for next 10 weeks, and 76 patients became HCV RNA-negative while 81 remained positive. The RNA-negative patients were then randomized to receive 3 MU (group I, n=37) or 9 MU (group II, n=39) for 48 weeks. Of the RNA-positive patients, only those with normal ALT received another 9 MU 48-week treatment (group III, n=45). Sustained responders (SR) were defined as those with negative RNA and normal ALT 6 months after the therapy. SR rates based on intent-to-treat principle did not differ significantly between groups I and II (30% vs 41%), but those based on the protocol-compatible cases showed a significant difference (32% vs 56%, p=0.034). SR rate in group III was significantly lower than those in group II. Adverse effects of IFN, developed more frequently in groups II and III than in group I, were mostly reversible. In conclusion, our results encourage 9 MU 60-week IFNα treatment in HCV/1b-infected patients with careful attention to adverse effects, and suggest that the treatment should be discontinued if HCV RNA does not disappear within 12 weeks.

Idiopathic facial paralysis may be one of the extrahepatic manifestations in hepatitis C virus infection.

平成6年11月1日より平成11年12月30日までにKクリニックを受診した特発性末梢性顔面神経麻痺 (ベル麻痺) 10名のうちC型慢性肝疾患5名, 糖尿病3名の合併を認め, うち1例は重複例であった. ベル麻痺既往の有無について検討した結果, C型慢性肝疾患患者617名中他に14名にベル麻痺の既往を認めた. 前述の5名のうち調査期間中に来院しなかった1名を除く4名と合わせ, 18名 (2.91%) のHCV抗体陽性者でベル麻痺の既往を認めた. 一方, HCV抗体陰性で糖尿病を合併しない本態性高血圧症患者でベル麻痺の既往を認めた症例は635名中3名 (0.47%) であり, C型慢性肝疾患患者におけるベル麻痺の既往を有する割合は本態性高血圧症患者に比し有意 (P<0.001) に高率であった. 従って, ベル麻痺はHCV感染の肝外病変のひとつである可能性が示唆された.

An epidemiological study of hepatitis B surface antigen subtypes among hepatitis B virus carriers.

岐阜県における献血者でHBs抗原陽性者672名および病院受診のHBVキャリアー122名のHBs抗原subtypeを測定した.献血者672名の検討では,1)年齢別にみると16～19歳ではadwがadrより多数例であったが加齢と共にadrが多数になり年齢によってsubtypeの分布が異なっていた.2)subtype別HBe抗原陽性率はadr 459名中26.8%, adw 192名中10.4%であり有意差を認めた(p<0.001).3)HBe抗原陰性例におけるHBs抗原価は若年者ではadwの方がadrより高い傾向にあるが30歳以降は逆転していた.一方,当院受診のHBVキャリアー122名ではadr 68名中垂直感染69.1%,水平感染30.9%であるのに対してadw 44名中垂直感染29.5%,水平感染70.5%であり,subtypeにより感染様式に差を認めた(p<0.001).小児HBe抗原陽性のadwではHBV-DNA量の高値例が多くみられ児から児への水平感染を来しやすいと考えられ,岐阜地方でのadrとadwのsubtypeのHBVのstrainでの違いが示唆された.

Prognosis of the patients with clinical symptom of acute hepatitis B

昭和50年1月より,52年6月までに入院した輸血の既往のないHBs抗原陽性の急性肝炎様症状により発見された43例につき検討した.対象の肝炎を初診時のHBc抗体価の高低と持続,HBs抗原の持続または一過性により4群に分類した.I群はHBc抗体が陰性もしくは低力価(29>)で経過とともに上昇し,HBs抗原一過性陽性群で35例,II群はHBc抗体価が高く(210<)持続し,HBs抗原一過性の3例,III群はHBc抗体が高力価で持続し,HBs抗原も持続性の5例,IV群はHBc抗体が低力価で経過とともに上昇し,HBs抗原は持続性のものとしたが,この群は認められなかった.3群を比較するとI群10例の肝生検像はいずれも急性肝炎,III群は5例のうち4例が慢性肝炎活動性,1例は急性肝炎であった.またIII群はI群に比しZTT, AFPが有意に高かった.II群の組織像は慢性肝炎活動性,急性肝炎の各1例で,検査所見はI群とIII群のほぼ中間値を示した.6ヵ月以上の経過観察により,III群の4例に,トランスアミナーゼの再上昇がみられた.

Carrier state and infectivity of HBs-Ag

It has recently been clarified by Magnius and others that e antigen and antibody system is closely related to HBV infectivity, i.e., HBsAg-positive sera detected e antigen (e-Ag) have an intensive infectivity, and those detected e antibody are no infective. Therefore, the authors tested e-Ag and e-Ab by the Micro-Ochteronys method in sera from 127 carriers, and, from the data, discussed as to intrafamilial infections with HBV and the clustering of the carriers. The results are as follows. 1. In eleven children of 6 e-Ag-positive carrier mothers, 10 children were positive for HBsAg, and 3 out of 6 children of 2 e-Ag-positive carrier fathers also were HBsAg-positive. Moreover, in one of 3 children living with their e-Ag-positive grandfather, HBsAg was detected in the serum. Accordingly, it can be said that an e-Ag-positive carrier produces new carriers at a high rate in the following generations, and the rate is extremely high in mother-to-child transmission. 2. In 103 asymptomatic carriers, the frequency of e-Ag-positive result was higher in the younger ages (75% in ages of below 10 years and 12% in ages of more than 41 years). On the contrary, the rate of e-Ab-positive carriers was higher in the older ages (17% in ages of below 10 years and 44% in ages of more than 41 years). This result implies that, in the majority of HBsAg carriers, although there are wide differences in the individuals, HBV infectivity declines with years and finally vanishes.

Clinical studies on Au-antigen and antibody

The present study investigated the relationship between Au-antigen (AG) and Au-antibody (AB), and the effect of AB on the blood recipient. Abnormal liver function was observed in four out of 18 recipients. Two of the four cases received both AG. AB negative blood, one received AG (+) AB(--) blood, and the last received undetermined blood. Two of the four cases changed to AG positive after blood transfusion, the third no AG. AB in the blood but showed the transient elevation of S-GOT and GPT, and only the fourth showed AB in the blood. However, the liver damage of the fourth case could be explained by the side effect of the antibiotics he had used. Therefore, the defensive effect of AB on the liver function was suggested from the observation. Comparison of infectious and serum hepatitis showed the rare or seldom appearance and low titer, if present, of AB in the former, and the frequent appearance and high titer of AB in the letter.

[Family survey of nine Australia-antigen positive patients with chronic hepatitis and cirrhosis of the liver].

Au抗原陽性慢性肝炎または肝硬変症を発端者とする家系を調査し,その結果9家系に家族的にAu抗原陽性者が高頻度に発見され,うち5家系には発端者以外にもAu陽性肝疾患患者または肝機能異常者が発見された.これらの家系内の感染様式は母から子へと考えられるものが最も多く,母親がAu抗原陽性であるとその子供は49% Au陽性であつた.また父から子,同胞内,同居における感染,夫婦共に陽性者なども認められた.これらの感染はAu陽性者との接触の機会が多く,かつ若年者であるほど高頻度のように思われた.これらの家系のうちAu陽性者とその両親,同胞,子供計66名を集計してみると, Au陽性者は40名(60%)で陰性者は26名であり, Au陽性の男性は18名中7名(39%),女性22名中11名(50%)に肝機能異常が認められたが, Au陰性男性14名はすべて,女性は12名のうち11名に肝機能は正常であつた.

Various courses of Australia antigen in serum with hepatitis and cirrhosis

Since there have been many discussions about Australian Antigen (AuAg) in hepatic diseases, we will further examine its meaning by long term observation in hepatic diseases. The detection of AuAg was performed by Immuno-adherence method. Its occurrence rate was as follows: inAcute hepatitis 35% (nine out of twenty-six cases) Chronic hepatitis (inactive type) 13% (three out of sixteen cases). Chronic hepatitis (active type )32% (nineteen out of fifty-nine eases) Liver cirrhosis 7% (two out of thirty cases). In acute hepatitis, the occurrence rate was not significantly different between serum hepatitis and infectious hepatitis, and AuAg was disappeared within three weeks after the onset except one. In chronic hepatitis, the occurrence rate was significantly higher in (active type) than in (inactive type). In three out of thirteen cases of chronic hepatitis (active type) AuAg was disappeared after one year coincided with clinical improvement, and in another one case AuAg was disappearecd after large amount of blood transfusion during operation of hepatoma resection, which had been secondally developed. In so far as acute hepatitis and chronic hepatitis are concerned, AuAg does not suggest their prognosis. The authors could not observe the change of AuAg negative to positive, even in acute exacerbation of chronic hepatitis and liver cirrhosis. These results suggest us that the acute exacerbation is not the reinfection of acute hepatitis but one course of chronic hepatitis and liver cirrhosis.