Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC (SH-HCC), shows features that resemble non-neoplastic steatohepatitis, and is thought to be strongly associated with underlying NASH. In this report, we review the histopathological features of NAFLD/NASH.     

甲氰咪呱不同作用方式对非酒精性脂肪性肝炎大鼠作用的对比研究

目的探讨不同作用方式的甲氰咪呱对非酒精性脂肪性肝炎（NASH）大鼠的作用。方法雄性SD大鼠40只,随机分为4组,即：对照组、模型组、甲氰咪呱治疗组、甲氰咪呱预防组。对照组普通饲料喂养,模型组喂高脂饮食,甲氰咪呱治疗组在高脂饮食12周后给予甲氰咪呱200 mg.kg-1.d-1）灌胃治疗,甲氰咪呱预防组给予高脂饮食同时进行甲氰咪呱200 mg.kg-1.d-1灌胃。16周末处死各组大鼠,测定血清转氨酶（ALT、AST）及血脂（TG、TC）、血清TNF-α;光镜下观察肝脏组织病理形态学改变,测定肝组织丙二醛（MDA）含量和超氧化物歧化酶（SOD）活性。结果与对照组比较,模型组ALT、AST、TG、TC显著增高（P〈0.05）,甲氰咪呱治疗组及预防组较模型组降低（P〈0.05）,且预防组AST与治疗组比较有显著差异（P〈0.05）;与对照组比较,模型组MDA及血清TNF-α显著增高,SOD活性下降（P〈0.05）;甲氰咪呱治疗组及预防组与模型组比较,MDA显著降低,SOD活性升高,均有显著差异（P〈0.05）;与对照组比较,模型组肝脏脂肪变性程度和炎症活动度均显著增高（P〈0.05）;与模型组比较,甲氰咪呱治疗或预防给药均可促进上述指标恢复（P〈0.05）。结论甲氰咪呱对高脂饮食诱导的大鼠NASH有一定治疗效果,其有效阻遏了自由基引发的氧化应激,保持了氧化/抗氧化平衡,改善NASH大鼠脂肪变性,减轻炎症反应,且甲氰咪呱预防组的效果优于治疗组,说明对NASH的早期治疗更有益于NASH的转归。     

Hepatocyte-specific Pten-deficient mice as a novel model for nonalcoholic steatohepatitis and hepatocellular carcinoma.

Phosphatase and tensin homolog (PTEN) is a multifunctional phosphatase whose substrate is phosphatidylinositol-3,4,5-triphosphate (PIP3), and it is also a ubiquitously expressed tumor suppressor gene that down-regulates phosphatidylinositol-3-kinases (PI3Ks). Although there are a few reports about PTEN related to hepatocellular carcinoma, the role of PTEN in the liver remains unclear. Therefore, to clarify the role of PTEN in the liver, we generated and analyzed hepatocyte-specific Pten-deficient mice (Pten-deficient mice). The liver of 40-week-old Pten-deficient mice revealed macrovesicular steatosis, ballooning hepatocytes, lobular inflammatory cell infiltration, and perisinusoidal fibrosis that are characteristic of human nonalcoholic steatohepatitis (NASH). By 80 weeks of age, 100% of Pten-deficient livers showed adenomas and 66% had hepatocellular carcinomas. Thus, PTEN is important for the prevention of adipogenic and tumorigenic transformation, and Pten-deficient mice are a novel model for NASH and hepatocellular carcinoma. Our results suggest that the controlled blocking of molecules acting downstream of PI3K might provide significant therapeutic benefit to patients predisposed to NASH and hepatocellular carcinoma.     

无创诊断和评估非酒精性脂肪性肝炎研究进展*

非酒精性脂肪性肝病（NAFLD）主要包括单纯性脂肪肝（NAFL)、非酒精性脂肪性肝炎（NASH）、相关肝硬化和肝细胞癌。相对于NAFL,NASH更易发展为肝硬化和肝癌,故早期诊断并对其干预尤为重要。近年来,多项无创诊断方法的出现致力于替代肝脏穿刺活检,主要包括血清学和影像学检查等,本文就无创性诊断和评估NASH作一综述。     

甲氰咪呱对非酒精性脂肪性肝炎(NASH)大鼠肝微粒体细胞色素P450的影响

目的研究甲氰咪呱对非酒精性脂肪性肝炎（NASH）大鼠肝微粒体细胞色素P450的影响。方法通过高脂饮食制作非酒精性指肪性肝炎（NASH）动物模型，给予甲氰咪呱灌胃治疗，观察肝组织病理形态变化，进行炎症活动计分，同时测定细胞色素P450（CYP450）和细胞色素2E1（CYP2EI）含量及ALT、AST，并与对照组比较。结果与正常组比较，模型组大鼠ALT、AST及CYP450和CYP2EI含量明显升高；与模型组比较，甲氰咪呱治疗组CYP450和CYP2EI含量均明显下降，（P〈0．05），ALT、AST及炎症活动计分明显低于模型组（P〈0．05）。结论甲氰咪呱能显著改善NASH大鼠肝脏功能及形态损伤，可能通过抑制肝细胞微粒体CYP450和同功酶CYP2EI的表达发挥作用。     

网络抗氧化剂对非酒精性脂肪性肝炎大鼠氧化应激作用的影响

目的探讨网络抗氧化剂对非酒精性脂肪性肝炎（NASH）大鼠氧化应激作用的影响。方法雄性SD大鼠30只,随机分为3组,正常对照组、模型组、网络抗氧化剂组。正常对照组普通饲料喂养,模型组喂高脂饮食,网络抗氧化剂组在高脂饮食12周后给予维生素E（100mg／kg）、维生素C（100mg／kg）、硫辛酸（40mg／kg）、辅酶Q10（100mg／kg）、还原性谷胱甘肽（100mg／kg）混合灌胃治疗。16周末处死各组大鼠,测定血清转氨酶（ALT、AST）及硒-谷胱甘肽过氧化物酶（Se-GSH-PX）活性,光镜下观察肝脏组织病理形态学改变,测定肝组织丙二醛（MDA）含量及超氧化物歧化酶（SOD）活性。结果与正常对照组比较,模型组大鼠血清ALT、AST显著升高（P〈0．05）;肝组织MDA含量增高（P〈0．05）,SOD及Se-GSH-PX活性下降（P〈0．05）;肝脏脂肪变性程度和炎症活动度均有显著增高（P〈0．05）,与模型组比较,网络抗氧化剂组可促进上述指标恢复（P〈0．05）。结论网络抗氧化剂对高脂饮食诱导的大鼠NASH有一定治疗效果,网络抗氧化剂之间协同增强的抗氧化能力有效阻遏了自由基引发的氧化应激,保持了氧化／抗氧化平衡,改善NASH大鼠脂肪变性,减轻炎症反应。     

慢性胃炎病理诊断的一致性研究

目的探讨采取慢性胃炎病理诊断标准培训并应用直观模拟评分法能否提高病理医师间慢性胃炎病理诊断的一致性。方法8位病理医师对70份慢性萎缩性胃炎病理切片进行两轮读片,第一轮结束后接受《中国慢性胃炎共识意见（2012,上海）》中关于慢性胃炎病理诊断标准的培训,并在第二轮读片过程中运用直观模拟评分法。8位病理医师按工作年限和所在医院进行分组,采用Kappa分析两轮读片的慢性胃炎5项组织学改变诊断的一致性,并行对比分析。结果8位病理医师第二轮读片对慢性胃炎5项组织学改变的总体诊断Kappa值均较第一轮读片有所提高,且5项组织学改变诊断的一致性程度也均有所提高。第二轮读片,高年资组和低年资组5项组织学改变的诊断Kappa值值差在-0．0180-0．0341,但5项组织学改变诊断的一致性程度均相同;同一医院组和不同医院组5项组织学改变的诊断Kappa值值差在0．0122～0．0497,其中幽门螺杆菌感染的诊断一致性程度好于不同医院组,其他4项组织学改变诊断的一致性程度均与不同医院组相同。结论对病理医师进行《中国慢性胃炎共识意见（2012,上海）》中关于慢性胃炎病理诊断标准培训,并在读片时采用直观模拟评分法,可普遍提高病理医师间慢性胃炎病理诊断的一致性。     

非酒精性脂肪性肝炎诊断的研究进展

疾病的诊断均从问病史开始,体检、生物化学指标的检测、影像诊断、组织学检查等.体重指数和腰臀比例可作为NAFLD发生的有效预测指标,血糖、血脂常规检查也有助于诊断,但有200左右的NAFLD患者在确诊时,体重.血脂、血糖均在正常范围.     

非酒精性脂肪性肝炎的临床病理研究

目的：探讨非酒精性脂肪性肝炎（Nonalcoholic steatohepatitis,NASH)的临床和病理学特征。方法：对40例NASH患者的临床资料和穿刺肝组织进行临床和病理学分析,并与酒精性脂肪性肝炎（Alcoholic steatohepatitis,ASH)和丙型肝炎（HCV）患者各20例作对照。结果：90％ NASH患者肥胖（P＜0．01）,血浆总蛋白平均水平高于ASH（P＜0．05）,血清ALT、AST、GGT、TBA、TG平均水平分别是正常范围上限值的2．6、1．5、1．2、1．3倍,但白蛋白水平是正常范围下限值的0．96倍。NASH的组织学改变类似ASH,但有些组织学改变如脂肪变性、汇管区的炎症程度,Mallory小体和空泡状核的出现频率等两者间存在着差异性（P＜0．05或P＜0．01）。NASH有其相对的病理特征：大小泡混合型脂肪变性,以大泡为主;肝组织气球样变性,小叶中央区较常见,气球样变性的细胞胞浆内常常有嗜碱性的细颗粒;肝小叶内炎症,不典型的Mallory小体,汇管区周围易见空泡状核细胞。多数NASH患者的肝小叶中央区（腺泡Ⅲk带）有不同程度的窦周纤维化。结论：结果显示NASH有一些相对的临床和病理学特征,临床、病理及实验室检查相结合能对NASH作出肯定的诊断,其中病理活检仍然是诊断NASH的“金标准”。     

细胞因子在非酒精性脂肪性肝炎发病机制中的作用

随着非酒精性脂肪性肝病发病率的逐年上升及其对健康的危害,包括3种类型:单纯性脂肪肝、脂肪性肝炎和脂肪性肝硬化已受到越来越多的重视,而非酒精性脂肪性肝炎是由单纯性脂肪肝发展为脂肪性肝硬化的必经阶段,了解其发病机制,探讨具有多种生物学效应的细胞因子在非酒精性脂肪性肝炎中的作用,对于弄清其发病机制的多样性有着深刻的意义。     

非酒精性脂肪性肝炎肝硬化发病机制研究进展与展望

正在过去几十年里,非酒精性脂肪性肝病(NAFLD)的发病率迅速增加。NAFLD包括单纯性脂肪肝(SFL)和非酒精性脂肪性肝炎(NASH)两种。SFL一般是指单纯肝细胞的脂肪积累,并无肝组织的炎症和坏死,但随着时间的推移和认识的提高,发现它与代谢综合征及2型糖尿病关系密切。值得注意的是在一定条件下,如肥胖、胰岛素抵抗、细胞因子(脂联素、瘦素、TNF-α、SREBP、MLCK、RBP4、性激     

非酒精性脂肪性肝炎的非侵入性诊断指标

非酒精性脂肪性肝炎(NASH)是非酒精性脂肪性肝病(NAFLD)的慢性进展形式,患病率高.早期诊断NASH并干预可改善预后.肝活检是诊断NASH的金标准,但具有一定局限性.一些代谢因素、炎性反应指标、脂肪细胞因子、肝核素显像等非侵人性实验室和影像学检查单独或联合使用可以较准确的区分NASH和单纯性脂肪肝,但存在一定缺陷,尚需社区大样本研究以证实其诊断价值.     

非酒精性脂肪性肝炎的药物治疗

非酒精性脂肪性肝炎是非酒精性脂肪性肝病的一种,其可以进一步发展为终末期肝病以致肝功能衰竭。非酒精性脂肪性肝炎药物治疗主要包括二甲双胍、过氧化物酶体增殖物-γ激动剂、已酮可可碱、N-乙酰半胱氨酸、血管紧张素Ⅱ受体拮抗剂、熊去氧胆酸、维生素E、降脂药等。近年来,对这些药物治疗非酒精性脂肪性肝炎的疗效也做了相关研究,但均未得出确切的结论。     

Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.     

抵抗素mRNA在非酒精性脂肪性肝炎大鼠肝组织中的表达与定位

目的观察高脂饮食诱导的非酒精性脂肪性肝炎（NASH）大鼠肝组织抵抗素mRNA的表达与定位，探讨其在NASH发病中的作用。方法16只雄性Wistar大鼠被随机分为普通饲料和高脂饲料喂养组，连续18周后处死各组大鼠，测定血清甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、游离脂肪酸（FFA）、肿瘤坏死因子（TNF-α）、空腹血糖（FBS）和空腹胰岛素（FINS），并计算胰岛素敏感指数（ISI），观察肝脏组织病理变化和炎症活动度计分；应用原位杂交和半定量RT—PCR技术检测各组大鼠肝脏组织抵抗素mRNA的表达及定位。结果模型组肝组织抵抗素mRNA表达较正常组显著性升高，其阳性颗粒主要分布于小叶内及汇管区炎细胞浸润区的巨噬细胞胞浆中。模型组肝组织抵抗素和血清TNF-α水平、肝脏炎症活动度计分成显著性正相关（r=0．873，0．892，P〈0．01），但与ISI无相关。结论NASH模型大鼠肝脏抵抗素定位于小叶内及汇管区炎细胞浸润区的巨噬细胞胞浆中，参与NASH的炎症发病机制。     

Liver fibrosis markers of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.     

二甲双胍干预大鼠非酒精性脂肪性肝炎疗效观察

目的观察二甲双胍对非酒精性脂肪性肝炎大鼠模型的干预作用。方法实验动物分3组,模型组和治疗组各12只雄性SD大鼠给予高脂肪高胆固醇饲料喂养,另设6只普通饲料喂养大鼠作为对照组。治疗组从高脂饮食第4周起在饮水中加用二甲双胍(每天250mgkg)。所有大鼠均于实验24周后处死,进行血清生化和肝脏组织学检测。结果与模型组相比,治疗组肝脏指数和腹腔脂肪含量显著减少(P均<0.001),且体重呈下降趋势;血清天冬氨酸转氨酶[(162.45±11.2)UL比(115.9±29.3)UL,P=0.01]、三酰甘油(1.10±0.24比0.75±0.30,P=0.01)水平显著下降;治疗组肝脏组织学炎症评分(1.20±1.14比4.83±1.05,P<0.01)和肝纤维化评分(0.70±0.48比1.42±0.45,P<0.05)显著下降,伴肝脂肪变程度减轻(P<0.05)。结论二甲双胍早期干预可显著改善高脂饮食大鼠脂肪性肝炎和纤维化程度,伴肝重、腹部脂肪含量及血清三酰甘油水平下降。     

NASH患者脂肪组织巨噬细胞计数的变化

目的：研究非酒精性脂肪性肝炎（NASH）患者网膜脂肪及皮下脂肪巨噬细胞数量的变化。方法选择NASH伴单纯性胆囊结石患者22例和单纯性胆囊结石患者28例。在腹腔镜手术中取肝组织、网膜脂肪组织和皮下脂肪组织。常规检测BMI、腹围、血糖、血酯、HOMA指数、胰岛素、游离脂肪酸;采用免疫组化法检测脂肪组织巨噬细胞。以抗CD68抗体标记巨噬细胞,抗CD11C标记M1亚群巨噬细胞,抗CD206抗体标记M2亚群巨噬细胞。结果 NASH患者血清AST （31.43±14.76）U/L对（23.68±9.64）U/L、TG （2.42±0.82）mmol/L对（1.65±0.47） mmol/L、胰岛素（83.18±44.34）mlu/L对（51.15±32.12）mlu/L和HOMA指数（21.00±14.75）对（12.43±10.66）显著高于胆囊结石患者（P＜0.05）;NASH患者网膜脂肪组织巨噬细胞数量为（34.41±15.35）,皮下脂肪组织巨噬细胞数量为（27.91±11.13）,而胆囊结石患者分别为（29.93±11.49）和（15.57±5.67）,（P＜0.01）;在22例NASH患者中,其NAS评分7分2例,6分6例,5分9例,4分5例。NASH患者皮下脂肪组织巨噬细胞、M1亚群巨噬细胞和M2亚群巨噬细胞数量与NAS评分呈正相关（P＜0.01）,但在网膜脂肪组织中三种细胞与NAS评分无显著性相关（P＆gt;0.05）。结论网膜脂肪及皮下脂肪中的巨噬细胞数量变化参与了NASH的发病过程。     

Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis

AIM:To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis(NASH) focusing on multicentric occurrence (MO) of HCC.METHODS:We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background.The clinical features were implicated with reference to the literature available.RESULTS:MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC(2 males and 2 females).One patient had synchronous MO;an advanced HCC,two well-differentiated HCCs and a dysplastic nodule,followed by the development of metachronous MO of HCC.The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule.Of these three patients,one had synchronous MO,one had metachronous MO and the other had both synchronous and metachronous MO.There were no obvious differences between the patients with or without MO in terms of liver function tests,tumor markers and anatomical extent of HCC.On the other hand,all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity,type 2 diabetes mellitus(T2DM),hypertension and cirrhosis.Although these conditions were not limited to MO of HCC,all the conditions were met in only one of eight patients without MO of HCC.Thus,concurrence of these conditions may be a predisposing situation to synchronous MO of HCC.In particular,old age,T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature.CONCLUSION:The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study.Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic improvement in NASH.