Clinical and histological features of nonalcoholic steatohepatitis in Iranian patients

Background  

Although several studies have been performed on risk factors and natural course of NASH, it seems that NASH tends to be more than a disease confined to strict boundaries. The objective of this study was to assess the clinical and paraclinical features and risk factors for non-alcoholic steatohepatitis (NASH) patients in an Iranian population     

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”。     

Clinical,anthropometric, biochemical,and histological characteristics of nonobese nonalcoholic fatty liver disease patients of Bangladesh

Background

Nonalcoholic fatty liver disease (NAFLD) is considered to be a disease of obese individuals, yet lean patients are increasingly susceptible to have NAFLD. The aim of this study was to evaluate the profile of nonobese patients by comparing with obese NAFLD patients.

Methods

We have included 465 patients of NAFLD after exclusion of other diseases, and 220 with elevated alanine aminotransferase (ALT) were biopsied. Patients were biochemically and clinically evaluated: blood pressure, body mass index (BMI), and waist circumference (WC) were recorded for every patient. A BMI ?≥?25 kg/m² was defined as obese, and those with a BMI of <25 kg/m² were labeled as nonobese. Histological activity was expressed with NAFLD activity score (NAS).

Results

Of 465 cases, 119 (25.6 %) were nonobese. Diabetes was noted in 122 (26.2 %) and hypertension in 122 (26.2 %). Metabolic syndrome was present in 253 (59.7 %), low HDL cholesterol in 228 (64.8 %), hypertriglyceridemia in 297 (73.2 %), and WC above normal in 308 (70.2 %). Males were predominating in the nonobese compared to females in the obese (p?=?0.001). Hypertriglyceridemia and low high-density lipoprotein was similar in the obese and nonobese (76.2 % vs. 72.3 %, p?=?0.5 and 65.2 % vs. 64.6 %, p?=?1.0, respectively). The grades of steatosis, lobular inflammation, ballooning, NAS, and the stage of fibrosis did not also significantly differ between obese and nonobese patients. Nonalcoholic steatohepatitis (NASH) was 53.1 % in nonobese.

Conclusion

Nonobese was 25.6 % among NAFLD patients of Bangladesh, and 53.1 % of nonobese NAFLD cases were NASH. Though they were nonobese by BMI grade, they were metabolically similar to obese. Males were predominant in the nonobese, whereas females in the obese. NASH and fibrosis were similar in the obese and nonobese.     

Pathology of nonalcoholic steatohepatitis.

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.     

Current biochemical studies of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis suggest a new therapeutic approach

The study population in this report by Lin et al. was ob/ob mice that have an inherited genetic deficiency of the appetite-suppressing hormone leptin. These mice develop hyperinsulinemia, insulin resistance, and fatty livers. Compared with their lean littermates and wild-type C57BL-6 mice, ob/ob mice have hepatomegaly. In this study, the authors compared three different groups of adult mice (aged 8-10 wk), including male ob/ob C57BL-6 mice, their lean littermates, and wild-type C57BL-6 mice of the same age and sex.The primary purpose of this study was to test the efficacy of metformin for treatment of fatty liver disease in obese, ob/ob mice that develop hyperinsulinemia or insulin resistance and fatty livers. Metformin therapy was found to eliminate fatty liver disease in this model. The potential mechanisms of the action of metformin were the inhibition of hepatic tumor necrosis factor (TNF)alpha and several TNF-inducible responses, which are likely to promote hepatic steatosis and necrosis.In these experiments, ob/ob mice were divided into three treatment groups. Group 1 consisted of eight mice that were treated with metformin and permitted to consume a nutritiously replete liquid mouse diet ad libitum. Mice in group 2 (n = 8) did not receive metformin but were pair-fed the same volume of liquid diet that the mice in the metformin-treated group had consumed on the previous day. Obese ob/ob mice in group 3 (n = 4) and lean mice received no metformin, as with the mice in group 2, but were permitted to consume the liquid diet ad libitum. Liquid diet was given to facilitate accurate daily comparison of food intake among the various treatment groups. All mice were weighed at the beginning of the study and weekly thereafter until killed and then sera, fat, and liver tissues were collected. Tissues were either fixed in buffered formalin and processed from the deceased mice for histology or snap frozen in liquid nitrogen and stored until RNA and proteins were isolated.The feeding protocol was repeated with a second group of 18 ob/ob mice. After 4 wk, hepatocytes were obtained by in situ liver perfusion with collagenase and assayed for cellular adenosine triphosphate (ATP) content. In each experiment, hepatocytes isolated from 3 mice from each treatment group were suspended in a medium and pooled for subsequent analysis to evaluate cell viability, determine the number of obtained cells, and to assay cellular ATP content. These experiments were repeated using another 3 mice from each treatment group, so that analysis of hepatocytes took place from six ob/ob mice in each feeding group.Hepatic steatosis was decreased significantly only in the metformin-treated group. The authors found that metformin's beneficial effect on the fatty liver disease of mice was not due to its ability to constrain hyperphagia, nor due to decreased caloric ingestion, because the daily caloric intakes of the metformin-treated mice and the pair-fed control mice were virtually identical. These caloric intakes were consistently approximately 20% less than that of another obese control group that was permitted to consume diet ad libitum. The authors also observed no significant effect of metformin on serum glucose concentration from fed, ob/ob mice. Metformin is known to reduce hyperinsulinemia by about 40% in both of these obese hyperinsulinemic and insulin-resistant rodent strains. In conclusion, Lin et al. documented that metformin improves fatty liver disease and reverses hepatomegaly, steatosis, and aminotransferase abnormalities in mice. In addition, the authors suggest that metformin might inhibit dieting-induced redistribution of lipid from the liver to adipose tissue depots. In summary, this study identifies a potential treatment for fatty liver disease in humans.     

20例非酒精性脂肪性肝硬化的临床特征分析

目的探讨非酒精性脂肪性肝硬化的临床特征。方法回顾性分析20例非酒精性脂肪性肝硬化初治住院患者的临床资料,以30例乙型肝炎肝硬化初治住院患者作为对照,记录患者性别、年龄、血糖、血脂、白细胞、血小板、凝血酶原活动度、凝血酶原国际标准化比率、总胆红素、白蛋白、胆碱脂酶、尿素氮、肌酐、电解质（血钾、钠、氯）、腹部超声及胃镜等临床数据,计算MELD评分,比较两组间的差异。结果非酒精性脂肪性肝硬化组平均年龄为（69.15±13.84）岁,明显高于对照组[（48.67±15.09）岁,P=0.021];男性占35%（7/20）,女性占65%（13/20）,对照组男性占80%（24/30）,女性占20%（6/30）;高血压、糖尿病及血脂紊乱的发病率分别为60%（12/20）、75%（15/20）和55%（11/20）,明显高于对照组（分别为16.7%、46.7%和10%,P=0.008、0.015、0.041）;凝血酶原活动度为（75.26±8.57）%,明显高于对照组[（52.37±10.86）%,P=0.038],凝血酶原国际标准化比率为1.03±0.25,显著低于对照组（1.44±0.31,P=0.042）;电解质紊乱占5%（1/20）,明显低于对照组63.3%（19/30,P=0.023）;MELD评分为7.69±3.46,显著低于对照组（16.54±9.50,P=0.002）。结论非酒精性脂肪性肝硬化的临床特征为年龄大、女性多见、高血压、糖尿病、血脂紊乱等合并症发病率高,肝功能储备及肾脏功能较好、电解质紊乱少见,预后相对良好,脾功能亢进、食管静脉曲张、腹水等门脉高压表现与乙型肝炎肝硬化相似。     

环氧合酶与非酒精性脂肪性肝炎

环氧合酶(COX)是体内催化花生四烯酸分解为前列腺素(PG)的关键酶,它在多种组织和细胞的炎症过程和增殖中发挥重要作用.     

Alcoholic and nonalcoholic steatohepatitis

The constellation of histopathologic lesions that characterize alcoholic and nonalcoholic steatohepatitis has been well described and has served as the basis for clinical diagnosis, natural history studies, and experimental models for analyses of etiopathogenesis. The lesions common to both entities include, to varying degrees, steatosis, liver cell ballooning, lobular inflammation with a notable component of polymorphonuclear leukocytes, and a characteristic form of fibrosis that is initially located in the perisinusoidal regions of acinar zone 3. Cirrhosis with or without steatosis or steatohepatitis may occur in both entities. Mallory's hyaline is common but not necessary; megamitochondria and varying amounts of iron may be observed in either process. Hepatocellular carcinoma is a recognized complication of both processes, albeit with greater frequency in the former. Alcoholic hepatitis may present with more severe clinical and histologic manifestations than the nonalcoholic counterpart, including significant morbidity and mortality. The perivenular lesions collectively referred to as sclerosing hyaline necrosis are markers of severity, and are not common in nonalcoholics. In many instances, however, the microscopic lesions of these two processes are similar, likely as a reflection of common pathogenetic pathways, and the distinction between the two is ultimately clinically derived.     

Pathophysiology of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) affects approximately 30% of adults and 20% of children in the United States. Nonalcoholic steatohepatitis (NASH) is its most severe histologic form and progresses to cirrhosis in 20% of these patients. Once developed, 30% to 40% of patients with NASH cirrhosis will experience a liver-related death. Consequently, it has become extremely important to understand the pathophysiology of NASH to develop sound therapeutic interventions. It is now recognized that nonhepatic mechanisms are largely responsible for the development of insulin resistance, which causes hepatic steatosis. Once developed, oxidative stress and diminished antioxidants within the liver initiate the progression from steatosis alone to NASH and ultimately to cirrhosis. However, not all patients progress to cirrhosis. As is the case for other common complex metabolic diseases, it is the interaction between the environment and genetics that will determine the phenotypic expression of NAFLD and NASH in each individual patient. Which of the pathophysiologic factors (which are discussed in this review), either alone or in combination, will eventually provide the basis for the most effective therapy has yet to be determined.     

水飞蓟宾治疗非酒精性脂肪性肝炎临床疗效观察

目的评价水飞蓟宾胶囊治疗非酒精性脂肪性肝炎（NASH）的临床疗效。方法非酒精性脂肪性肝炎患者72例,随机分为两组。治疗组40例给予水飞蓟宾治疗,对照组32例服用护肝片治疗,疗程均为12周。测定治疗前后两组患者血清酶学、血脂及腹部超声变化,并记录患者临床症状。结果治疗后两组临床症状、血清酶学、血脂及脂肪肝程度差异均有统计学意义,未发现明显不良反应。结论水飞蓟宾胶囊治疗NASH可改善患者临床症状,降低血清转氨酶及血脂,减轻肝内脂肪沉积,具有显著疗效且用药安全。     

Clinical indicators for progression of nonalcoholic steatohepatitis to cirrhosis

Non-alcoholic fatty liver disease (NAFLD), is a disease spectrum characterized by fat accumulation in hepatocytes presenting as hepatic steatosis to advance disease with active hepatic inflammation, known as nonalcoholic steatohepatitis. Chronic steatohepatitis will lead to progressive hepatic fibrosis causing cirrhosis and increased risk for developing hepatocellular carcinoma (HCC). Fatty liver disease prevalence has increased at alarming rates alongside obesity, diabetes and metabolic syndrome to become the second most common cause of cirrhosis after alcohol related liver disease worldwide. Given this rise in prevalence, it is becoming increasingly more important to find non-invasive methods to diagnose disease early and stage hepatic fibrosis. Providing clinicians with the tools to diagnose and treat the full spectrum of NAFLD will help prevent known complications such as cirrhosis and HCC and improve quality of life for the patients suffering from this disease. This article discusses the utility of current non-invasive liver function testing in the clinical progression of fatty liver disease along with the imaging modalities that are available. Additionally, we summarize available treatment options including targeted medical therapy through four different pathways, surgical or endoscopic intervention.     

环氧合酶-2与非酒精性脂肪性肝炎关系的研究进展

非酒精性脂肪性肝炎( NASH)呈慢性肝脏脂毒性炎症表现,是非酒精性脂肪性肝病(NAFLD)的重要转折点,存在肝病重症化趋势.环氧合酶-2(COX -2)作为启动炎症反应的关键酶同样涉及到NASH的形成及进展.本文就COX -2及其抑制剂与NASH关系的研究予以综述.     

Non-invasive diagnosis of nonalcoholic fatty liver and nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the USA and many other parts of the world. Its prevalence continues to rise; currently affecting about one in four adults and 10% of children in the USA. NAFLD represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign, no-progressive clinical course, to nonalcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Currently, the diagnosis of NASH requires an invasive liver biopsy with drawbacks of sampling and interpretation error. Clinical risk factors for NASH include diabetes and the metabolic syndrome; however, these are not sufficiently predictive of the condition by themselves. Routine liver enzyme levels are not reliable; however, novel plasma hepatocyte cell death markers either alone or in combination with clinical risk factors are potential non-invasive diagnostic tools for the future. This review provides a concise overview of the role non-invasive diagnostic tools for the differentiation of fatty liver from NASH as well as for the determination of presence and extent of fibrosis.     

Steatosis and nonalcoholic steatohepatitis. A comparative analysis

Liver biopsies with a main histological diagnosis of steatosis were selected from 3,422 liver biopsies carried out in our department between January 1995 and December 1998. Patients with known risk factors for steatosis, such as excessive alcohol consumption, hepatitis C infection, treatment with amiodarone, perhexiline maleate, tamoxifen, antiviral drugs (didanosine, zidovudine) methotrexate, sodium valproate or total parenteral nutrition, Wilson's disease and organ transplant were subsequently excluded. Of the 43 liver biopsies finally included in the study, 23 showed simple steatosis and 20 steatohepatitis. Eighty-one per cent of the patients were male (mean age of 44 years) and the majority were asymptomatic. The most frequent indication for liver biopsy was hypertransaminasemia. No differences were observed between the two groups in terms of frequency and severity of classical risk factors for steatosis (diabetes mellitus, dyslipemia and obesity). Thirty-five percent of patients with steatohepatitis and 26% of those with simple steatosis had none of these risk factors. Patients with steatohepatitis were older than those with simple steatosis. They presented more severe symptomatology, the degree of steatosis was more intense and laboratory investigations showed greater alterations. These results suggest that simple steatosis and nonalcoholic steatohepatitis are two different phases of the same disease. The difficulty in clinical differentiation justifies carrying out liver biopsy, especially in patients with more severe symptomatology whose laboratory results show greater alterations, since these patients present more marked histological lesions, are at risk of developing liver cirrhosis and require therapy.     

Changes in histological criteria lead to different prevalences of nonalcoholic steatohepatitis in severe obesity

The worldwide obesity epidemic contributes to the increasing incidence of a number of diseases, as nonalcoholic fatty-liver disease (NAFLD) and its most severe form, the nonalcoholic steatohepatitis (NASH). Data on the prevalence of NASH has varied from 18.5%(5) to 69%(43 )in obesity, an unacceptable wide range. The aim of our study was to evaluate how prevalence of NASH is influenced by the different diagnostic histological criteria. Consecutive assessment of 325 obese patients referred for bariatric surgery (BMI >or = 35 kg/m(2)), 146 of whose were submitted to histological analysis of the liver allowed the evaluation of the prevalence of NAFLD. Steatohepatitis was diagnosed histologically using 3 types of criteria: a) broad criteria, where steatosis was associated with at least 2 of the following parameters: any degree of lobular inflammatory infiltrate, hepatocellular ballooning and perisinusoidal/ perivenular fibrosis; b) restricted criteria, where the hepatocellular ballooning was of moderate or severe intensity; c) ultrarestricted criteria, which required perisinusoidal and/or perivenular fibrosis. NAFLD was present in 111 (76%) of the patients, and the prevalence of NASH was 25.3% when ultrarestricted criteria were used, 41.1% with restricted criteria and 55.5% with broad criteria. In conclusion, more accurate definition of the criteria for histological diagnosis of NASH should be required, so that further clinicopathological studies may define the long-term progression of the disease and evaluate therapeutic strategies.     

Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) encompasses both simple steatosis and nonalcoholic steatohepatitis (NASH). Differentiation of these two entities requires histopathologic evaluation. The aim of this study was to establish a reliable diagnostic model for differentiating steatosis from steatohepatitis utilizing both clinical characteristics and a panel of biochemical markers of lipid peroxidation and fibrosis. Eighty subjects with biopsy proven NAFLD were enrolled, 39 with simple steatosis and 41 with histopathologic evidence of NASH. Demographic and laboratory data to include serologic testing for 8-epi-PGF(2alpha), transforming growth factor-beta (TGF-beta), adiponectin, and hyaluronic acid (HA) were obtained and compared between the two groups. There were significant differences between the two groups with respect to age (P=0.004), female gender (P=0.024), aspartate aminotransferase (AST) (P=0.028), body mass index (BMI) (P=0.003), fasting insulin (0.018), AST/alanine aminotransferase (ALT) ratio (AAR) (P=0.017), quantitative insulin sensitivity check index (QUICKI) (P=0.002), and HA (P=0.029). A composite index for distinguishing steatosis from NASH was calculated by summing the risk factors of age >or=50 years, female gender, AST>or=45 IU/l, BMI >or=30 mg/kg2, AAR>or=0.80, and HA>or=55 microg/l, and its accuracy was determined by receiver operating characteristic (ROC) analysis to be 0.763 (95% CI: 0.650-0.876). The presence of three or more risk factors had a sensitivity, specificity, PPV, and NPV of 73.7%, 65.7%, 68.2%, and 71.4%, respectively. In addition, HA at a cutoff of 45.3 microg/l was a good predictor of advanced fibrosis. In conclusion, we propose a noninvasive screening model for distinguishing simple steatosis from NASH. Identifying patients at risk for NASH will allow clinicians to more accurately determine who may benefit from liver biopsy.