Toshitsugu Oda

Effects of Subchronic Treatment with Natural Human Interferons on Antipyrine Clearance and Liver Function in Patients with Chronic Hepatitis

To determine whether natural human interferon administered under the usual therapeutic dosing scheme would inhibit the hepatic drug metabolism, we performed an antipyrine test in eight patients with chronic B or non‐A, non‐B hepatitis before and after a subchronic interferon therapy (6 megaunits/day for 17 ± 4 days, mean ± SD). Six patients received interferon‐β and 2 received interferon‐α. To circumvent a possible influence of interferon‐induced fever on the hepatic drug metabolism, the antipyrine test during the interferon therapy was performed at least 14 days after the interferon‐induced fever disappeared. The kinetic parameters of antipyrine were obtained from seven saliva samples over 32 hours postdose. There were no significant differences in any kinetic parameters of antipyrine observed before and during the interferon therapy. With the sample size of the study, there was only a 20% chance (i.e., β‐power = 0.8 at α = 0.05) that we might have missed a 17% reduction in antipyrine clearance by the interferon therapy (type II error). On the other hand, the subchronic interferon therapy lowered serum aminotransferases and DNA polymerase activity significantly (P < .05) compared with the respective baseline values. Our results suggest that the subchronic therapeutic dosing scheme of interferon as conducted in the present study does not cause the inhibitory effect on the oxidative drug metabolism to a statistically significant or clinically relevant degree in patients with chronic hepatitis, while it improves their liver function. Further studies are required for determining if different types of interferons administered under the different dosing schemes would alter the hepatic drug metabolism and the inhibitory effect would be time‐dependent.

Double Cardia An Unusual Sequela of Reflux Esophagitis with Ulcer

SummaryWe report a patient with acquired “double cardia” (esophagogastric fistula). She was a 76-year-old farmers widow with severe kyphosis. She presented with postprandial heartburn one month after the initiation of nifedipine and isosorbide dinitrate. Radiologic and endoscopic examinations revealed an esophagogastric fistula, short esophagus with hiatal hernia, Barretts esophagus with reflux esophagitis, and ulcer. This case shows that repeated reflux esophagitis and esophageal ulcer, complicated with short esophagus and hiatal hernia, can predispose to the formation of esophagogastric fistula.

ULTRASTRUCTURAL STUDIES ON LIVER CELL NECROSIS AND LYMPHOCYTES IN EXPERIMENTAL HEPATITIS B

Ultrastructural studies on liver cell necrosis and the interaction of lymphocyte and liver cell were carried out in experimental hepatitis B in chimpanzees. Two types of liver cell necrosis were identified. One was a lytic necrosis, and the other was a coagulation necrosis. Both types of liver cell necrosis were closely associated with the apposition of lymphocytes. The interaction (or close contact) of lymphocyte and non‐necrotic liver cell infected with HBV was also detected. There were two distinct patterns of the contact. One was the direct contact, and the other was the contact with the intervention of electron‐dense fuzzy material containing 20 to 22 mu spherical particles and 51 to 55 mu double‐layered spherical particles. The ultrastructural characteristics of lymphocytes in each pattern of the contact were different. The results suggested that the pathogenesis of liver cell necrosis in hepatitis B was closely associated with the action of lymphocytes, and two modes of lymphocytic reaction were conceivable. ACTA PATHOL. JPN. 35 : 1359 ‐1374, 1985.

HBV‐ASSOCIATED ULTRASTRUCTURES IN THE CHIMPANZEES’LIVERS WITH EXPERIMENTAL HEPATITIS B

An electron‐microscopic study was carried out using chimpanzees’livers infected with experimental hepatitis B for the elucidation of intracellular development of HBV‐associated ultrastructures and extracellular release of HBV. Core particles were first detected in the nucleus of liver cells at around the time of the first seropositiveness for HBsAg, and then in the cytoplasm. Subsequently, their budding into endoplasmic reticular cisterna was seen together with other core particles in the surrounding cytoplasm. Dane‐like particles were seen in the cisterna, and also extracellularly nearby a liver cell with a marked proliferation of microvilli at the onset of liver cell injury. Thereafter, core‐like particles were seen within electrondense amorphous material at the site of the contact between liver cell and lymphocyte. The above sequence of features suggested us the assembly of core particles and surface envelope at the cisternal membrane of endoplasmic reticulum, and a reversed pinocytosis whereby Dane or HBV particles were released extracellularly. The filamentous structures within endoplasmic reticular cisternae, which were thought to be HBsAg, were never detected. ACTA PATHOL. JPN. 35: 1333–1342, 1985.

ULTRASTRUCTURAL CHANGES OF THE BILE SECRETORY APPARATUS AND BILE DUCTULE IN EXPERIMENTAL HEPATITIS B WITH NEITHER APPARENT BIOCHEMICAL NOR LIGHT‐MICROSCOPIC CHOLESTASIS

An ultrastructural study on the hepatic bile secretory apparatus and bile ductules was carried out using liver biopsy specimens of six chimpanzees with experimental hepatitis B. Although biochemical cholestasis was very mild or lacking and light‐microscopic evidence of cholestasis was not evident, various ultrastructural changes which had been described in association with cholestasis were detected. The significance of these ultrastructural changes in relevance to cholestasis was difflcult to determine, nevertheless electron‐microscopic examination could possibly be the most sensitive means for the diagnosis of cholestasis. These ultrastructural changes appeared to be indifferent to the necrotizing process of liver cells in experimental hepatitis B. ACTA PATHOL. JPN. 35 : 1343–1358, 1985.

Something Perhaps Unique to the 1993 ISVHLD: Statistics and Acknowledgments

A total of 847 abstracts were submitted, and only one was rejected. Of the hepatitis viruses, C was the most frequent topic of these abstracts, with D the least frequent (C:D = 19:1). Of 1459 registrants and/or abstract-submitters from 60 countries, 1332 from 52 countries were able to reach the symposium site, overcoming a strong head wind (subacute ¥ hypertension). A total of 252 papers were presented orally in Plenary Sessions, Breakfast Workshops, Specialty Sessions, and Satellite Symposia, with 726 in Poster Sessions. The most attractive session seemed to be the Plenary Session: ‘Treatment of Hepatitis C with Interferon’, according to purchase orders for session videos. Around 200 papers included in this Book cited about 1600 papers as references: the most frequently cited journal, edited work, and paper were Lancet, Viral Hepatitis and Liver Disease (1991, Williams & Wilkins), and Choo et al. (1989) Science 244:359–62, respectively. The 5-day meeting cost ¥ 180 million.

Phenotypes of α1-antitrypsin in liver diseases

肝疾患患者761名の血清α1-アンチトリプシン表現型の分布を正常者648名を対照として新しい方法であるpolyacrylamide gel slab isoelectric focusingを用いて検討した.正常者群で,MMが99.2%, rare variants 0.8%,肝疾患患者群で,MMが98.8%, rare variants 1.2%であった.欧米と比較しMMが圧倒的に多く,また欠乏症を呈するZ遣伝子が検出されなかった.このようにα1-アンチトリプシン表現型の分布には民族差が認められた.慢性肝疾患患者中に欧米では稀であり,α1-アンチトリプシン濃度が低値を示すPのheterozygotesが4名認められた.この患者の肝生検組織にはα1-アンチトリプシンの蓄積は認められなかった.Isoelectric focusingによりMMがさらに3つの亜型,M1M1, M1M2, M2M2に分類され,3群間に血中濃度差(M1M1＞M1M2＞M2M2)が認められた.低値群のM2M2の出現頻度が正常者群で4.9%であるのに対し,慢性肝疾患患者群に10.8%と有意に高頻度に観察された(p＜0.001).

CASES OF LINDAU'S DISEASE FOUND IN A FAMILY

中枢神経系に多発するhemangioblastomaを主病変とする疾患は, 1926年Lindauにより一つの疾患単位としてまとめられている.この疾患は濃厚な遺伝性が認められているが,本邦ではその家系は現在迄6家系報告されているに過ぎない.われわれが経験したLindau病は父と長男の2症例であり,家系調査より優性遣伝と考えられる.長男例は家族歴,右眼底血管腫,脊髄hemangioblastomaと考えられる血管像,右腎の腫瘍,父親例は両側眼底血管腫,組織学的に確認された小脳hemangioblastomaを診断根拠としてLindau病と診断した. Lindau病の歴史,疾患概念からは遺伝性,中枢神経のhemangioblastoma,内臓病変が本疾患の基本となるが,臨床診断基準は中枢神経のhemangioblastomaの存在または遺伝性を重視する考え方に分かれるがいずれも広義に解釈されており,われわれの診断根拠は確実なものと考えられた.また,長男例は脊髄hemangioblastomaと考えられる血管像の認められた症例であるが,臨床所見で第IX胸髄以下の知覚障害,錐体路症状のほか小脳症状が見られており,椎骨動脈撮影では後頭蓋窩に異常所見は認められなかつたが,今後の経過で再検討の必要があると考えられる

A CASE OF ACUTE RENAL FAILURE CAUSED BY EXERTIONAL MYOGLOBINURIA

20才の男性.家族歴に筋疾患はなく,筋痙〓,脱力などの既往も無い.マラソン中6～7km走つた後,大腿部の脱力をきたし譫妄状態となり入院.入院時,発熱,頻脈,脱水を認め大腿伸筋の筋痛を訴えた.尿は暗褐色,混濁し顆粒円柱が多数存在. GOT, GPT, LDH, CPK等諸酵素値の上昇,低K血症を認めた.褐色尿は3日,筋痛は1週間で消失し,諸酵素値も第7病日GOT 683 K-Unit, GPT 179K-Unit, LDH 3,904UV. Unitに達し以後正常化した.一方,急性腎不全が急速に進行し, BUNを上まわるcreatinineの上昇が認められた.第9病日BUN 136mg/dl, creatinine 19.3mg/dlに達し腹膜潅流を開始.第20病日より利尿期となり約40日の経過で改善をみた.発症初期の尿および血清より免疫沈降反応によりmyoglobinを検出.第49病日の筋組織像では,筋線維の再生過程と思われる変化を認めただけであつた.以上よりexertional myoglobinuriaと診断したが, idiopathic paroxysmal myoglobinuria, heat stroke等, entityの明確でない類縁疾患との鑑別は現在のところ必ずしも明瞭でない.本症の発症機転として入院時みられた低K血症と脱水が,筋血流の相対的欠乏を来たし,それにより筋破壊をもたらした可能性が考えられた.本症,とりわけ腎不全を合併した例の報告は本邦では極めて少ない.しかし,潜血反応陽性で顆粒円柱を含む褐色尿,筋由来の血清諸酵素値の上昇と共に, BUNを上廻るcreatinineと, K等の上昇を示す原因不明の急性腎不全に対して, myoglobinuriaの可能性を疑つてみる必要を示唆する症例である.

Utilization of Glutathione for BSP Conjugation in the rat liver

肝の抱合排泄機構を解明するため,ラットを用い,放射性グルタチオン(GSH)と,その構成アミノ酸であるグリシン,システインとBSPを静注し,胆汁中へ排泄される,これらの物質を検討することにより,BSPの抱合排泄機構に関して検討した.特に二重標識法による検討より,外来性GSHの肝細胞膜透過性,BSP抱合に対する利用性,誘導作用を含めて,BSPによる肝細胞の代謝変動に関して検討した.外来性GSHは肝細胞膜をそのままの形で通過し,BSPのグルタチオン抱合に利用される.BSPがGSHあるいはグリシンの水素交換反応を亢進し,肝細胞におけるGSH合成を亢進させていることを推測させる成績が得られた.