Weltman M D, Farrell G C, Hall P, Ingelman-Sundberg M, Liddle C
Department of Gastroenterology and Hepatology, University of Sydney at Westmead Hospital, NSW, Australia.
Hepatology. 1998 Jan;27(1):128-33. doi: 10.1002/hep.510270121.
Nonalcoholic steatohepatitis (NASH) has multiple etiologic associations, but the pathogenesis is poorly understood. Cytochrome P450 (CYP) 2E1 is induced in the liver of patients who drink alcohol to excess and is important in the pathogenesis of alcoholic liver disease (ALD). We have previously shown that hepatic CYP2E1 is also increased in a rat dietary model of steatohepatitis. The aim of the present study was to test the hypothesis that hepatic CYP2E1 is induced in the liver of patients with NASH, defined on the basis of compatible liver histology and the exclusion of excessive alcohol intake. Sections of paraffin-embedded liver biopsy material from 31 subjects with NASH were evaluated and compared with sections from 10 histologically normal livers and 6 patients with ALD. Hepatic CYP2E1 and CYP3A were detected in liver sections by immunohistochemistry using specific anti-human CYP2E1 and CYP3A antibodies. As expected, normal livers showed CYP2E1 immunostaining confined to a rim, two to three cells thick, around terminal hepatic venule, while livers from alcoholic hepatitis patients showed increased CYP2E1 staining. CYP2E1 immunostaining was also increased in livers from patients with NASH, irrespective of the etiologic association. Further, the pattern of CYP2E1 distribution was similar to ALD, with increased perivenular intensity and more extensive acinar distribution of staining. As in the rat model, the hepatic distribution of CYP2E1 corresponded to that of steatosis. In contrast to CYP2E1, CYP3A immunostaining was decreased in patients with NASH. We conclude that hepatic CYP2E1 is increased in patients with NASH compared with normal livers. Thus, despite many possible etiologic factors for NASH, the pathogenetic mechanisms may be similar and, like alcoholic steatohepatitis, may involve induction of CYP2E1.
非酒精性脂肪性肝炎（NASH）有多种病因关联，但发病机制尚不清楚。细胞色素P450（CYP）2E1在过量饮酒患者的肝脏中被诱导，在酒精性肝病（ALD）的发病机制中起重要作用。我们之前已经表明，在脂肪性肝炎的大鼠饮食模型中，肝脏中的CYP2E1也会增加。本研究的目的是检验以下假设：在基于肝脏组织学相符且排除过量饮酒的NASH患者肝脏中，肝脏CYP2E1会被诱导。对31例NASH患者石蜡包埋的肝活检材料切片进行评估，并与10例组织学正常肝脏的切片和6例ALD患者的切片进行比较。使用特异性抗人CYP2E1和CYP3A抗体，通过免疫组织化学在肝脏切片中检测肝脏CYP2E1和CYP3A。正如预期的那样，正常肝脏显示CYP2E1免疫染色局限于终末肝小静脉周围一层两到三个细胞厚的边缘，而酒精性肝炎患者的肝脏显示CYP2E1染色增加。NASH患者的肝脏中CYP2E1免疫染色也增加，与病因关联无关。此外，CYP2E1分布模式与ALD相似，终末肝小静脉周围强度增加，腺泡染色分布更广泛。与大鼠模型一样，CYP2E1的肝脏分布与脂肪变性相对应。与CYP2E1相反，NASH患者的CYP3A免疫染色减少。我们得出结论，与正常肝脏相比，NASH患者肝脏中的CYP2E1增加。因此，尽管NASH有许多可能的病因，但发病机制可能相似，并且与酒精性脂肪性肝炎一样，可能涉及CYP2E1的诱导。
