Studies on the pathogenesis and pathophysiology of alcoholic liver cirrhosis and cancer.

为了分析酒精性肝病（ALD）的病理生理学，可靠的ALD诊断标准是必不可少的。首先，我们获得了ALD的可靠诊断标准，特别是其与丙型肝炎病毒（HCV）感染相关的病原学诊断。根据新的标准，重度饮酒者的肝脏疾病可以分为3种病因类别：单纯酒精（AL），酒精和病毒联合（AL+HCV），以及其他（可能是病毒单独）。基于这些标准，在日本使用询问函进行的ALD全国调查显示，在60%的患者中发现AL型，在其余40%的患者中发现AL+HCV型。AL+HCV型在慢性肝炎和肝细胞癌（HCC）患者中的患病率很高。AL和AL+HCV型患者的肝脏组织学特征有很大不同。AL型以纤维化为主，AL+HCV型以圆形细胞浸润为主。在随访研究中，HCV标志物阳性患者发生HCC的频率高于阴性患者，提示HCV标志物阳性患者发生HCC的风险较高。对不同病因、不同年龄的肝癌患者进行多因素Logistic回归分析。AL+HCV型的估计相对危险度显著高于AL型。计算出的HCV和酒精之间的相互作用对肝癌的发展是显着的统计学，表明酗酒可能会增加与HCV感染相关的肝癌的发展。少量饮酒引起的ALD发生在乙醛脱氢酶-2基因杂合子患者中。细胞色素P4502 E1基因c2基因在所有ALD患者中均有表达，而在无ALD的重度饮酒者中均无表达。这些结果表明，ALD的发展是由遗传控制的。

For analysis of the pathophysiology of alcoholic liver disease (ALD), reliable criteria for the diagnosis of ALD are essential. First, we obtained reliable diagnostic criteria for ALD, especially for its etiological diagnosis related to hepatitis C virus (HCV) infection. With the new criteria, liver disease in heavy drinkers can be classified into 3 etiological categories: alcohol alone (AL), alcohol and virus combined (AL+HCV), and others(probably virus alone). Based on these criteria, a national survey of ALD in Japan using a letter of inquiry revealed that the AL type was found in 60 % of patients and the AL+HCV type was found in the remaining 40%. The prevalence of the AL+HCV type was very high in patients with chronic hepatitis and hepatocellular carcinoma (HCC). Histological features of livers in patients classified with the AL or AL+HCV type were quite different. Fibrosis in the AL type and round cell infiltration in the AL+HCV type were characteristic. In follow-up studies, HCC developed more frequently in HCV marker-positive patients than in negative patients, suggesting a high risk for development of HCC in HCV marker-positive patients. Multiple logistic-regression analysis for the development of HCC was performed in cirrhotic patients with different etiologies and different ages. The estimated relative risk was significantly higher in the AL+HCV type than in the AL type. The calculated interaction between HCV and alcohol for development of HCC was significant statistically, indicating that alcohol abuse may increase development of HCC related to HCV infection. ALD caused by smaller amounts of alcohol consumption occurred in patients heterozygous for the aldehyde dehydrogenase-2 gene. The c2 gene of cytochrome P4502E1 gene was found in all patients with ALD, but not in any heavy drinkers without ALD. These results indicate that the development of ALD is controlled genetically.