Sukeo Yamamoto's research while affiliated with Osaka General Medical Center and other places

Most hepatocellular carcinomas (HCC) arise in patients with cirrhosis, in whom its incidence is high. The prevention of HCC in patients with cirrhosis is important. A prospective, randomized, nonblind controlled study was performed to evaluate the preventive effect of Sho-saiko-to (TJ-9) on HCC development. TJ-9 is a Chinese herbal medicine that contains crude extracts of seven herbs; it has antitumor effects in experimental animals. Two hundred sixty patients with cirrhosis were randomly assigned to two groups, matched for age, sex, presence of hepatitis B surface antigen, and the severity of liver damage. The patients in the trial group were given TJ-9 at a daily oral dose of 7.5 g in addition to the conventional drugs given to the control patients. The patients were prospectively monitored for 60 months and the cumulative incidence of HCC and the survival rate in the two groups were calculated. The cumulative incidence curve for 5 years of the trial group was lower than that of the control group (P = 0.071). For the patients without HBs antigen, the difference was significant (P = 0.024). The survival curve for 5 years of the trial group was higher than that of the control group (P = 0.053). For the patients without HBs antigen, the difference was significant (P = 0.043). TJ-9 helped to prevent the development of HCC in patients with cirrhosis, particularly in patients without HBs antigen.

The usefulness of measurements of serum alpha-fetoprotein elevation for diagnosis of the development of hepatocellular carcinoma was evaluated by a prospective study of 260 patients with cirrhosis. Hepatocellular carcinoma was found in 55 patients during the 5-yr follow-up, excluding 7 found to have hepatocellular carcinoma in the first 6 mo. The cumulative incidence of hepatocellular carcinoma was 26% in the 185 patients who had alpha-fetoprotein levels below 20 ng/ml at the time of entry and 46% in the 68 patients who had alpha-fetoprotein levels of 20 ng/ml or more but below 200 ng/ml. In 169 of the patients, serum levels of alpha-fetoprotein were assayed regularly for at least 2 yr. The incidence of hepatocellular carcinoma development in the 36 patients who had repeated transient increases in alpha-fetoprotein to above 100 ng/ml was 36%. This was significantly higher than the incidence in the 99 patients who had alpha-fetoprotein levels consistently below 20 ng/ml. Thus patients who had alpha-fetoprotein levels of 20 ng/ml or more, who had transient increases in alpha-fetoprotein or who had both should be treated as being in a super-high-risk group for hepatocellular carcinoma. Frequent and careful examination by ultrasonography of such patients is recommended.

A comparative study of three different high-dose regimens of interferon--2b (IFN) was conducted in patients with chronic hepatitis C to determine which was better at obtaining a sustained remission. A total of 126 patients were assigned randomly to one of three groups: group A was given 10 million international units (MIU) of IFN six times a week for eight weeks; group B was given 10 MIU IFN six times a week for four weeks followed by three times a week for an additional eight weeks; group C was given 10 MIU IFN six times a week for two weeks followed by three times a week for 12 weeks. The total dose administered to each group was 480 MIU/patient. Only the dosing schedule varied among the three groups. Among 98 efficacy-evaluable patients, a sustained alanine aminotransferase (ALT) response, defined as persistent normalization of the ALT for greater than six months after the termination of treatment, was achieved in 21.2% (7/33) of group A, 42.3% (11/26) of group B, and 54.5% (18/33) of group C patients. Similarly, a sustained loss of measurable serum hepatitis C virus RNA was observed in 28.6% (8/28) of group A, 40.9% (9/22) of group B, and 48.3% (14/29) of group C patients. Based upon these data, it can be concluded that 10 MIU of IFN administered six days a week for two weeks followed by three times a week for an additional 12 weeks produces the highest rate of both biochemical and virological responses to IFN therapy in patients with chronic HCV.

The relationship between alcoholic liver disease and hepatitis C virus was studied in 80 patients by searching for hepatitis C virus RNA with the polymerase chain reaction and by measuring hepatitis C virus antibodies. By C-100 enzyme-linked immunosorbent assay, hepatitis C virus antibodies were found in 2 of 10 patients with fibrosteatosis, 8 of 20 patients with alcoholic hepatitis, 14 of 19 patients with chronic hepatitis and 19 of 31 patients with cirrhosis. Percentages of patients with antibodies found by C-100 radioimmunoassay and by enzyme-linked immunosorbent assay based on sequence peptide 42 were lower; of the 16 patients with a low titer by C-100 enzyme-linked immunosorbent assay, 10 were negative by radioimmunoassay and 6 were negative by sequence peptide 42. By a second-generation recombinant immunoblot assay, hepatitis C virus antibodies were found in 1 of 10 patients with fibrosteatosis, 2 of 20 patients with alcoholic hepatitis, 15 of 19 patients with chronic hepatitis and 18 of 31 patients with cirrhosis. Hepatitis C virus RNA was found in 1 of 10 patients with fibrosteatosis, 3 of 20 patients with alcoholic hepatitis, 13 of 19 patients with chronic hepatitis and 20 of 31 patients with cirrhosis. Of the 37 patients with hepatitis C virus RNA, 31 had antibodies by C-100 enzyme-linked immunosorbent assay (25 patients at a high titer [cut-off index greater than 6]), and 31 had antibodies by second-generation recombinant immunoblot assay. Patients with cirrhosis and hepatitis C virus RNA had higher ALT activity than such patients without hepatitis C virus RNA (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of interleukin-1 (IL-1) and arachidonic acid metabolites, prostaglandin (PG) E1, leukotriene (LT) B4 and LTC4, on the amount of platelet activating factor (PAF) produced and released by mouse hepatic sinusoidal endothelial cells were investigated. When hepatic sinusoidal endothelial cells were incubated with 1 microgram/mL of calcium ionophore (CaI) A23187, PAF production increased until 20 min after the start of incubation, but when the cells were incubated with PGE1 and CaI A23187, PAF production was significantly suppressed. On the other hand, when hepatic sinusoidal endothelial cells were incubated with IL-1 beta, LTB4 or LTC4 alone, PAF production significantly increased compared with that of the cells incubated without these substances. However, when the cells were incubated with PGE1 alone or with IL-1 beta, LTB4 or LTC4 and CaI A23187, these effects were not observed. These results indicated that PAF produced by hepatic sinusoidal endothelial cells is affected by IL-1 and arachidonic acid metabolites, suggesting that immune and inflammatory reactions in these cells may be regulated by chemical mediators produced by the cells themselves.

最近,著者らは,実験的に誘導した急性肝不全がロイコトリエン(LT)の特異的阻害剤によって著明に軽減されること,および,LTC4がin vitroで直接,肝細胞障害を誘導することを見いだし,肝細胞障害の誘導にLTが関与する可能性を示した.このLTの肝細胞障害誘導に関与する機構を解析するために,著者らはラット肝から肝細胞を分離して,LTB4およびLTC4に対するレセプターを検討した.その結果,ラット肝細胞にはLTB4レセプターの存在は認められなかったが,LTC4と特異的に結合するレセプターの存在が確認された.このことは,LTC4が肝細胞のLTC4レセプターに結合することによって肝細胞に対して何らかの作用をすることを示しており,今後,LTと肝細胞に関わりを考えていく上で非常に興味ある知見と考えられた.

肝類洞内皮細胞から産生される血小板活性化因子(PAF)およびインターロイキン1 (IL1)が四塩化炭素肝障害にどのような影響を受けるかについて検討した.四塩化炭素を投与したマウスの肝類洞内皮細胞を経時的に調製し,calcium ionophore A23187刺激でPAFを誘導し,またlipopolysaccharide刺激でIL1を誘導した.その結果,大量投与群(0.05%四塩化炭素・オリーブ油混合液を0.15ml投与)ではPAFおよびIL1の活性は投与48時間で最も低下し,72時間後でも低下したままであり,72時間後の肝組織像は広範な出血性壊死像が認められた.一方,少量投与群(同混合液を0.05ml投与)ではPAFおよびIL1活性は投与48時間で最も低下したが,72時間後には活性は回復し,72時間後の肝組織像は肝組織内に単核細胞が認められた.以上の結果は,肝類洞内皮細胞の機能と肝組織像の変化には密接な関係がある可能性を示唆した.

著者らはPropionibacterium acnes (P. acnes)およびlipopolysaccharide (LPS)を用いる急性肝不全モデルの誘導においてLPSの多糖部分が重要な意義を有することを報告した.そこで,急性肝不全の誘導に及ぼすLPSの糖鎖の影響について解析するため,P. acnes処理後のマウスから分離した肝粘着性細胞をin vitroで糖鎖の異なったLPSまたはlipid Aで刺激し,tumor necrosis factor (TNF), interleukin 1 (IL1)およびhepatocytotoxic factorの産生に及ぼす影響について検討した.その結果,TNFおよびhepatocytotoxic factorの産生量はSalmonella minnesota (SM) R345由来のLPS投与群の方がSMR5投与群より有意に高かった.しかし,IL1については両者の有意差は見られなかった.この結果から急性肝不全の誘導にはTNFおよびhepatocytotoxic factorがより深く関与しており,IL1はあまり重要な役割を果たしていない可能性が示唆された.