Hepatol Res. 2005 Oct 5;

    Pathology of nonalcoholic steatohepatitis.

 

    Brunt EM.

 

    Saint Louis University Liver Center, Saint Louis University School of Medicine, 3635 Vista Avenue, St. Louis, MO 63110, USA.

 

    到目前为止，对于非酒精性脂肪性肝病（nonalcoholic fatty liver disease，NAFLD）评估的金标准仍然是我们最常用的方式肝活检。组织学评估对于起始研究中介绍和定义脂肪肝作为一种肝病发挥了重要作用。目前，肝活检在NAFLD中具有多个作用：证实（或排除）诊断，将单纯性脂肪肝与非酒精性脂肪性肝炎区分开来，评价坏死性炎症活动、纤维化和小叶结构改变的程度和范围。组织病理学研究忽略了这样一个事实，即并非所有肥胖和/或糖尿病个体发生转氨酶升高的患者均为脂肪性肝病所致。如：糖尿病患者中存在的肝糖原累积病和肝血色病或存在其它已知的严重肝病；如同肝活检在一些不寻常的患者或临床实践中可以在如体型消瘦和转氨酶正常的个体中发现脂肪变或脂肪性肝炎一样。接受一些医学治疗的患者，这些患者包括共存血清学可以诊断的肝病和儿童患者。肝活检研究显示NASH可进展到或者不进展到肝硬化阶段。之前肝活检存在NASH是目前许多发生隐源性肝硬化患者的一个重要的标记阶段，这提示隐源性肝硬化可能是从NAFLD/NASH进展而来。肝活检仍然是描绘NAFLD长期结局的一个重要指标，肝活检显示为“单纯性脂肪肝”并非肯定疾病就不会进展和是良性疾病。最后，研究者注意到NASH的病理生理进展过程中具有一些特殊的组织学特点。

 

    NASH治疗性试验的治疗效果评价依赖于组织学评价，因为后者最敏感且最可靠。治疗性试验为评价组织学缓解提供了一个机会，这些试验同时对于一些特异性的组织学损伤与特定患者群体之间的临床和实验室指标的相关性具有一定价值。这些研究的类型目前均相对较少，但一些近来的研究结果再次强调了需要一个统一的诊断标准。

 

    病理上目前讨论的问题包括关于组织学进展的标记性损伤，一些可重复的诊断方法和半定量的损伤积分系统和一些合适的术语。Matteoni等根据其长远的临床结局不同提出了NAFLD分为1－4型，Brunt等提出了NASH的分期和分级系统，这为单一NASH患者坏死性炎症损伤（分级）和纤维化（分期）与其它形式的非胆管源性慢性肝病进行区分提供了依据。近来，NIDDK NASH临床研究网络对NAFLD包括疾病谱从脂肪变到脂肪性肝炎和纤维化提出了一个全面评估的系统，以为将来的临床治疗试验提供参考。并且，如同临床医师不能区分单纯性脂肪肝和脂肪性肝炎一样，病理学家对于是否是由于酗酒导致的潜在损伤不能进行区分相类似。已经提供的术语包括如何描述慢性肝病的不同的命名形式；或者采用已经获得的知识对潜在病因（如代谢性综合征）进行讨论。

 

    To date, histologic evaluation, most commonly in the form of liver biopsy, remains the gold standard in evaluation of nonalcoholic fatty liver disease (NAFLD). Histologic evaluation was fundamental to the initial studies that introduced and defined the concept of fatty liver as a liver disease. Currently, liver biopsy in NAFLD serves multiple roles: confirmation (or exclusion) of the diagnosis; distinction of steatohepatitis from "simple steatosis"; assessment of extent of necroinflammatory activity, fibrosis, and architectural alterations. Histopathologic studies have underscored the fact that not all obese and/or diabetic individuals with elevated liver tests have fatty liver disease; for example, hepatic glycogenosis and hepatosclerosis have been described in diabetics, and other significant liver diseases have been documented. Likewise biopsy studies have documented lesions of steatosis or steatohepatitis in unusual patient groups or clinical settings, such as lean individuals, individuals with normal liver tests, patients taking certain medications, patients with co-existent serologically-diagnosed liver disease, and pediatric patients. Biopsy studies have shown that the lesions of NASH may or may not persist in cirrhosis; prior evidence of NASH on liver biopsy serves as a benchmark for the concept that many cases of otherwise cryptogenic cirrhosis developed from NAFLD/NASH. Liver biopsy remains a significant feature of studies delineating long-term outcome of NAFLD, some of which have shown that "simple steatosis" is not always non-progressive and benign. Finally, investigators have noted correlations of proposed pathophysiologic processes in NASH with particular histologic features. Therapeutic trials for NASH rely on histologic evaluation as the most sensitive analysis to document effects of treatment. Treatment trials afford an opportunity to evaluate histologic features of resolution, and these trials have also provided an opportunity for correlations of particular histologic lesions with clinical and laboratory features in well-characterized patient populations. These kinds of studies are currently relatively few, but results of a recent study have reinforced the concept of necessary criteria for diagnosis. Current discussions in pathology include identification of lesions of concern for progression, reproducible methods of diagnosis and semiquantification of lesions, and appropriate nomenclature. Matteoni et al. proposed NAFLD types 1-4 based on long-term outcome studies; Brunt et al. proposed a system of grading and staging for NASH that follows methods of separate assessment for necroinflammatory lesions (grade) and fibrosis (stage) accepted in other forms of non-biliary chronic liver disease. Recently, the Pathology Committee of the NIDDK NASH Clinical Research Network has proposed a system of evaluation that encompasses the entire spectrum of NAFLD from steatosis to steatohepatitis with fibrosis for use in upcoming treatment trials. And, just as the clinician cannot distinguish steatosis and steatohepatitis, the pathologist cannot discern if alcohol abuse may be an underlying cause of the lesions. Proposed nomenclature to align with either extant terminology in other forms of chronic liver disease, or to align with our knowledge of underlying cause(s) (such as metabolic syndrome) will be discussed.