非酒精性脂肪性肝炎的病理學(xué)

    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.

 

    到目前為止，對(duì)于非酒精性脂肪性肝病（nonalcoholic fatty liver disease，NAFLD）評(píng)估的金標(biāo)準(zhǔn)仍然是我們最常用的方式肝活檢。組織學(xué)評(píng)估對(duì)于起始研究中介紹和定義脂肪肝作為一種肝病發(fā)揮了重要作用。目前，肝活檢在NAFLD中具有多個(gè)作用：證實(shí)（或排除）診斷，將單純性脂肪肝與非酒精性脂肪性肝炎區(qū)分開來，評(píng)價(jià)壞死性炎癥活動(dòng)、纖維化和小葉結(jié)構(gòu)改變的程度和范圍。組織病理學(xué)研究忽略了這樣一個(gè)事實(shí)，即并非所有肥胖和/或糖尿病個(gè)體發(fā)生轉(zhuǎn)氨酶升高的患者均為脂肪性肝病所致。如：糖尿病患者中存在的肝糖原累積病和肝血色病或存在其它已知的嚴(yán)重肝病；如同肝活檢在一些不尋常的患者或臨床實(shí)踐中可以在如體型消瘦和轉(zhuǎn)氨酶正常的個(gè)體中發(fā)現(xiàn)脂肪變或脂肪性肝炎一樣。接受一些醫(yī)學(xué)治療的患者，這些患者包括共存血清學(xué)可以診斷的肝病和兒童患者。肝活檢研究顯示NASH可進(jìn)展到或者不進(jìn)展到肝硬化階段。之前肝活檢存在NASH是目前許多發(fā)生隱源性肝硬化患者的一個(gè)重要的標(biāo)記階段，這提示隱源性肝硬化可能是從NAFLD/NASH進(jìn)展而來。肝活檢仍然是描繪NAFLD長(zhǎng)期結(jié)局的一個(gè)重要指標(biāo)，肝活檢顯示為“單純性脂肪肝”并非肯定疾病就不會(huì)進(jìn)展和是良性疾病。最后，研究者注意到NASH的病理生理進(jìn)展過程中具有一些特殊的組織學(xué)特點(diǎn)。

 

    NASH治療性試驗(yàn)的治療效果評(píng)價(jià)依賴于組織學(xué)評(píng)價(jià)，因?yàn)楹笳咦蠲舾星易羁煽俊Ｖ委熜栽囼?yàn)為評(píng)價(jià)組織學(xué)緩解提供了一個(gè)機(jī)會(huì)，這些試驗(yàn)同時(shí)對(duì)于一些特異性的組織學(xué)損傷與特定患者群體之間的臨床和實(shí)驗(yàn)室指標(biāo)的相關(guān)性具有一定價(jià)值。這些研究的類型目前均相對(duì)較少，但一些近來的研究結(jié)果再次強(qiáng)調(diào)了需要一個(gè)統(tǒng)一的診斷標(biāo)準(zhǔn)。

 

    病理上目前討論的問題包括關(guān)于組織學(xué)進(jìn)展的標(biāo)記性損傷，一些可重復(fù)的診斷方法和半定量的損傷積分系統(tǒng)和一些合適的術(shù)語。Matteoni等根據(jù)其長(zhǎng)遠(yuǎn)的臨床結(jié)局不同提出了NAFLD分為1－4型，Brunt等提出了NASH的分期和分級(jí)系統(tǒng)，這為單一NASH患者壞死性炎癥損傷（分級(jí)）和纖維化（分期）與其它形式的非膽管源性慢性肝病進(jìn)行區(qū)分提供了依據(jù)。近來，NIDDK NASH臨床研究網(wǎng)絡(luò)對(duì)NAFLD包括疾病譜從脂肪變到脂肪性肝炎和纖維化提出了一個(gè)全面評(píng)估的系統(tǒng)，以為將來的臨床治療試驗(yàn)提供參考。并且，如同臨床醫(yī)師不能區(qū)分單純性脂肪肝和脂肪性肝炎一樣，病理學(xué)家對(duì)于是否是由于酗酒導(dǎo)致的潛在損傷不能進(jìn)行區(qū)分相類似。已經(jīng)提供的術(shù)語包括如何描述慢性肝病的不同的命名形式；或者采用已經(jīng)獲得的知識(shí)對(duì)潛在病因（如代謝性綜合征）進(jìn)行討論。

 

    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.