Nonalcoholic fatty liver disease： An overview of current insights in pathogenesis, diagnosis and treatment

Estimates of people suffering from overweight （one billion） and obesity （300 million） are increasing. The accumulation of triglycerides in the liver, in the absence of excess alcohol intake, has been described in the early sixties. It was not until 1980, however, that Ludwig et al named this condition nonalcoholic steatohepatitis （NASH）. Subsequently, nonalcoholic fatty liver disease （NAFLD） has been used as a general name for conditions ranging from simple steatosis through steatohepatitis to end-stage liver disease （cirrhosis）. Many studies have demonstrated the significant correlation with obesity and insulin resistance. Other studies have revealed a signifi- cant correlation between hepatic steatosis, cardiovascu- lar disease and increased intima-media thickness. WHO estimated that at least two million patients will develop cirrhosis due to hepatic steatosis in the years to come. Longitudinal cohort studies have demonstrated that those patients with cirrhosis have a similar risk to devel- op hepatocellular carcinoma as those with other causes of cirrhosis. Taken all together, NAFLD has become the third most important indication for liver transplantation. There- fore, training programmes in internal medicine, gastroen- terology and hepatology should stress the importance of diagnosing this entity and treat properly those at risk for developing complications of portal hypertension and con- comittant cardiovascular disease. This review will focus on the clinical characteristics, pathophysiology, imaging tech- niques and the readily available therapeutic options.     

Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity

BACKGROUND/AIMS: Nonalcoholic steatohepatitis is an emerging clinical problem among the obese population. However, risk factors of progression to advanced forms of liver disease in this particular group of patients remain to be defined. METHODS: The demographics and clinical and histologic features of 46 obese patients were evaluated. The intrahepatic immunological phenotype was assessed in all liver biopsy samples by immunohistochemistry. RESULTS: Histologic findings of nonalcoholic steatohepatitis were observed in 69.5% of the obese population studied and significant fibrosis was evident in 41% of patients with nonalcoholic steatohepatitis. Age (p=0.003), degree of steatosis (p=0.000002), and grade of inflammation (p=0000) at liver biopsy were independent variables positively associated with fibrosis. Intrahepatic expression levels of several immunologic markers of inflammation as well as nitric oxide derivatives were significantly higher in the severe forms of nonalcoholic steatohepatitis than in the mildest forms. CONCLUSIONS: Obese persons with higher age, with greater degrees of hepatic steatosis, and specially those with increased grades of intrahepatic inflammation have the greatest risk for progression to fibrotic liver disease. An oxidative stress-triggered intrahepatic inflammatory response appears to be important in the pathogenesis of nonalcoholic steatohepatitis in obesity.     

Nonalcoholic fatty liver disease,metabolic risk factors,and hepatocellular carcinoma: An open question

Non-alcoholic liver disease(NAFLD) defines liver abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis with or without cirrhosis development, occurring in the absence of significant alcohol consumption, use of teratogenic medication, or hereditary disorders. The association between NAFLD and metabolic syndrome is well documented and widely recognized. Obesity, type 2 diabetes mellitus(T2DM), and dyslipidemia are the most common metabolic risk factors associated with NAFLD. Among the components of metabolic syndrome, current evidence strongly indicates obesity and diabetes as hepatocellular carcinoma(HCC) risk factors. There is also growing evidence that suggests an increased risk of HCC in NAFLD patients, even surpassing other etiologies in some high-income countries. Epidemiologic data demonstrate a parallel rise in prevalence of obesity, diabetes, NAFLD, and HCC. As obesity and its related diseases have steadily afflicted larger populations, HCC incidence is expected to increase in the future. Pathophysiologic mechanisms that underlie NAFLD development and subsequent progression to nonalcoholic steatohepatitis and cirrhosis(insulin resistance and hyperinsulinemia, oxidative stress, hepatic stellate cell activation, cytokine/adipocytokine signaling pathways, and genetic and environmental factors) appear to play a significant role in the development of NAFLD-related HCC. However, a comprehensive view of molecular mechanisms linking obesity, T2 DM, and NAFLD-related HCC, as well as the exact sequence of molecular events, is still not understood in its entirety. Good-quality data are still necessary, and efforts should continue towards better understanding the underlying carcinogenic mechanisms of NAFLD-related HCC. In this paper, we aimed to centralize the most important links supporting these relationships, focusing on obesity, T2 DM, and NAFLD-related HCC, as well as point out the major gaps in knowledge regarding the underlying molecular mechanisms behind them.     

NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications

While non-alcoholic fatty liver disease (NAFLD) is highly prevalent (15% to 45%) in modern societies, only 10% to 25% of cases develop hepatic fibrosis leading to cirrhosis, end-stage liver disease or hepatocellular carcinoma. Apart from pre-existing fibrosis, the strongest predictor of fibrotic progression in NAFLD is steatohepatitis or non-alcoholic steatohepatitis (NASH). The critical features other than steatosis are hepatocellular degeneration (ballooning, Mallory hyaline) and mixed inflammatory cell infiltration. While much is understood about the relationship of steatosis to metabolic factors (over-nutrition, insulin resistance, hyperglycemia, metabolic syndrome, hypoadiponectinemia), less is known about inflammatory recruitment, despite its importance for the perpetuation of liver injury and fibrogenesis. In this review, we present evidence that liver inflammation has prognostic significance in NAFLD. We then consider the origins and components of liver inflammation in NASH. Hepatocytes injured by toxic lipid molecules (lipotoxicity) play a central role in the recruitment of innate immunity involving Toll-like receptors (TLRs), Kupffer cells (KCs), lymphocytes and neutrophils and possibly inflammasome. The key pro-inflammatory signaling pathways in NASH are nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). The downstream effectors include adhesion molecules, chemokines, cytokines and the activation of cell death pathways leading to apoptosis. The upstream activators of NF-κB and JNK are more contentious and may depend on the experimental model used. TLRs are strong contenders. It remains possible that inflammation in NASH originates outside the liver and in the gut microbiota that prime KC/TLR responses, inflamed adipose tissue and circulating inflammatory cells. We briefly review these mechanistic considerations and project their implications for the effective treatment of NASH.     

Nonalcoholic fatty liver disease and hepatic cirrhosis: comparison with viral hepatitis-associated steatosis

Nonalcoholic fatty liver disease(NAFLD) including nonalcoholic steatohepatitis(NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus(HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity,type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review,the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed.     

非酒精性脂肪性肝病与肠道菌群失调新观点

非酒精性脂肪性肝病（NAFLD）在世界范围内患病率逐渐升高,“二次打击学说”发病机制已经被认可,但是具体的病理生理学发病机制还不完全清楚。近期,已有大量研究的新观点来解释肠道菌群在 NAFLD 发病机制中的作用,包括调节肠粘膜通透性、低水平炎症反应和免疫平衡,调节饮食胆碱代谢,调节胆汁酸代谢和增加细菌产生的内源性乙醇等。这些因素在分子水平上解释了肠道菌群如何促发 NAFLD 的发生,并进一步诱导其向非酒精性脂肪性肝炎（NASH）进展。     

Gut microbiota and nonalcoholic fatty liver disease

Recent evidence has linked obesity and the metabolic syndrome with gut dysbiota. The precise mechanisms underlying that association are not entirely understood; however, microbiota can enhance the extraction of energy from diet and regulate whole-body metabolism towards increased fatty acids uptake from adipose tissue and shift lipids metabolism from oxidation to de novo production. Obesity and high fat diet relate to a specific gut microbiota, which is enriched in Firmicutes and with less Bacterioidetes. Microbiota can also play a role in the development of hepatic steatosis, necroinflammation and fibrosis. In fact, some studies have shown an association between small intestinal bacterial overgrowth, increased intestinal permeability and nonalcoholic steatohepatitis (NASH). That association is, in part, due to increased endotoxinaemia and activation of the Toll-like receptor-4 signaling cascade. Preliminary data on probiotics suggest a potential role in NASH treatment, however randomized controlled clinical trials are still lacking.     

Obesity,fatty liver disease and intestinal microbiota

Nonalcoholic fatty liver disease(NAFLD) is a chronic liver disorder that is increasing in prevalence with the worldwide epidemic of obesity. NAFLD is the hepatic manifestation of the metabolic syndrome. The term NAFLD describes a spectrum of liver pathology ranges from simple steatosis to steatosis with inflammation nonalcoholic steatohepatitis and even cirrhosis. Metabolic syndrome and NAFLD also predict hepatocellular carcinoma. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms are not known. Intestinal ecosystem contains trillions of microorganisms including bacteria, Archaea, yeasts and viruses. Several studies support the relationship between the intestinal microbial changes and obesity and also its complications, including insulin resistance and NAFLD. Given that the gut and liver are connected by the portal venous system, it makes the liver more vulnerable to translocation of bacteria, bacterial products, endotoxins or secreted cytokines. Altered intestinal microbiota(dysbiosis) may stimulate hepatic fat deposition through several mechanisms: regulation of gut permeability, increasing low-grade inflammation, modulation of dietary choline metabolism, regulation of bile acid metabolism and producing endogenous ethanol. Regulation of intestinal microbial ecosystem by diet modifications or by using probiotics and prebiotics as a treatment for obesity and its complications might be the issue of further investigations.     

Noninvasive investigations for non alcoholic fatty liver disease and liver fibrosis

Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that have insulin resistance in common and are associated with metabolic conditions such as obesity, type 2 diabetes mellitus, and dyslipidemia. NAFLD ranges from simple liver steatosis, which follows a benign course, to nonalcoholic steatohepatitis (NASH), a more severe entity, with necroinflmmation and f ibrosis, which can progress to cryptogenic cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evalu...     

Nonalcoholic fatty liver disease: is all the fat bad?

Abstract
Nonalcoholic fatty liver disease is now a major cause of liver disease in developed countries, largely as a result of an epidemic of obesity, diabetes and sedentary lifestyles. This has resulted in raised clinical awareness and diagnostic refinement. The entity encompasses several histologic patterns from benign steatosis to nonalcoholic steatohepatitis, the latter having a significant risk of progressive fibrosis and the development of cirrhosis. Labor­atory tests and imaging are not able to distinguish steatosis from steatohepatitis, which requires liver biopsy. However following an assessment of several risk factors, patients can be stratified for the potential risk of fibrosis, allowing the rational use of liver biopsy. This review will describe the various patterns of nonalcoholic fatty liver disease and relate this to disease pathogenesis and progression. Strategies for management, including experimental interventions, will be discussed. (Intern Med J 2004; 34: 187−191)     

Advances in hepatocellular carcinoma: Nonalcoholic steatohepatitis-related hepatocellular carcinoma

An increase in the prevalence of obesity and diabetes mellitus has been associated with the rise in nonalcoholic fatty liver disease (NAFLD). Two-thirds of the obese and diabetic populations are estimated to develop NAFLD. Currently, NAFLD is the most common etiology for chronic liver disease globally. The clinical spectrum of NAFLD ranges from simple steatosis, an accumulation of fat greater than 5% of liver weight, to nonalcoholic steatohepatitis (NASH), a more aggressive form with necroinflammation and fibrosis. Among the patients who develop NASH, up to 20% may advance to cirrhosis and are at risk for complications of end-stage liver disease. One of the major complications observed in patients with NASH-related cirrhosis is hepatocellular carcinoma (HCC), which has emerged as the sixth most common cancer and second leading etiology of cancer-related deaths worldwide. The incidence of HCC in the United States alone has tripled over the last three decades. In addition, emerging data are suggesting that a small proportion of patients with NAFLD may be at higher risk for HCC in the absence of cirrhosis - implicating obesity and diabetes mellitus as potential risk factors for HCC.     

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.     

Lipidomics in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder in Western countries, comprises steatosis to nonalcoholic steatohepatitis (NASH), with the latter having the potential to progress to cirrhosis. The transition from isolated steatosis to NASH is still poorly understood, but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression. Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD. Changes in glycerophospholipid, sphingolipid, and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD, implicating that specific lipid species are involved in oxidative stress, inflammation, and cell death. In this article, we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.     

Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease

Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease (NAFLD). The change in gut microbiota may alter nutritional absorption and storage. In addition, gut microbiota are a source of Toll-like receptor (TLR) ligands, and their compositional change can also increase the amount of TLR ligands delivered to the liver. TLR ligands can stimulate liver cells to produce proinflammatory cytokines. Therefore, the gut-liver axis has attracted much interest, particularly regarding the pathogenesis of NAFLD. The abundance of the major gut microbiota, including Firmicutes and Bacteroidetes, has been considered a potential underlying mechanism of obesity and NAFLD, but the role of these microbiota in NAFLD remains unknown. Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD. For instance, a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability, which allows the leakage of bacterial components. Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD. In children, the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis (NASH) compared with those in obese control. Escherichia can produce ethanol, which promotes gut permeability. Thus, normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD. In addition, TLR signaling in the liver is activated, and its downstream molecules, such as proinflammatory cytokines, are increased in NAFLD. To data, TLR2, TLR4, TLR5, and TLR9 have been shown to be associated with the pathogenesis of NAFLD. Therefore, gut microbiota and TLRs are targets for NAFLD treatment.     

Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis

A growing body of evidence from multiple areas proposes that periodontal disease, accompanied by oral inflammation and pathological changes in the microbiome, induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A subgroup of NAFLD patients have a severely progressive form, namely nonalcoholic steatohepatitis (NASH), which is characterized by histological findings that include inflammatory cell infiltration and fibrosis. NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma. The oral microbiota may serve as an endogenous reservoir for gut microbiota, and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis. Gut dysbiosis increases the production of potential hepatotoxins, including lipopolysaccharide, ethanol, and other volatile organic compounds such as acetone, phenol and cyclopentane. Moreover, gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall, leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation. In particular, many animal studies support that oral administration of Porphyromonas gingivalis, a typical periodontopathic bacterium, induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis. NAFLD, also known as the hepatic phenotype of metabolic syndrome, is strongly associated with metabolic complications, such as obesity and diabetes. Periodontal disease also has a bidirectional relationship with metabolic syndrome, and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively. In this review, we will describe the link between periodontal disease and NAFLD with a focus on basic, epidemiological, and clinical studies, and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome. In conclusion, it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease, gut microbiota, and metabolic syndrome. Thus, the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics, prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.     

Nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease is a clinicopathologic syndrome that encompasses several clinical entities. The spectrum of conditions ranges from simple steatosis to steatohepatitis, fibrosis and end stage liver disease. The condition was originally described in obese, diabetic, middle-aged females without a history of significant alcohol use with liver histology consistent with alcoholic hepatitis. It is known that this entity occurs without any particular sex predilection, in lean individuals, as well as an increasing number of obese children. Other terms have been used to describe this clinical entity such as alcohol-like hepatitis, pseudo-alcoholic hepatitis, diabetic hepatitis and steatonecrosis. Ludwig and colleagues introduced the term nonalcoholic steatohepatitis (NASH) to describe patients fitting the picture of alcoholic hepatitis but without a history of significant alcohol abuse. The term nonalcoholic fatty liver disease (NAFLD) is used more frequently to include the spectrum of conditions that range from steatosis through steatohepatitis, fibrosis and cirrhosis. NASH is reserved for patients with steatohepatitis and fibrosis. NAFLD is now being recognized as the most common cause of elevated liver enzymes in the United States. Although the exact etiology of NAFLD is not known, it may be caused by insulin resistance coupled with increased oxidative stress to the hepatocytes. No specific therapy has been approved for this condition and the mainstay of management is weight loss.     

Mouse models for investigating the underlying mechanisms of nonalcoholic steatohepatitis-derived hepatocellular carcinoma

As the incidence of hepatocellular carcinoma(HCC) caused by infection with the hepatotropic viruses hepatitis B and hepatitis C decreases, greater attention has become focused on HCC caused by nonalcoholic steatohepatitis(NASH), an advanced form of nonalcoholic fatty liver disease which has shown increasing prevalence in correspondence with the overall increase in metabolic syndrome over the recent decades. Several clinical population studies have shown a positive relationship between NASH and HCC, while also providing initial insights into the underlying mechanisms of HCC development from NASH. Research into the pathological progression of NASH to HCC has advanced by use of several beneficial rodent models. In this review, we summarize the established mouse models for preclinical research of NASH-associated HCC and discuss the underlying hepatic mechanisms of NASH-related tumorigenesis identified to date that could lead to new targets for treatment and prevention.     

非酒精性脂肪性肝炎相关肝细胞癌111例临床荟萃分析

目的总结非酒精性脂肪性肝炎（NASH）基础上肝癌的临床特征。方法对以＂fatty liver、NASH、liver cancer、HCC＂等为关键词,在Pubmed、Medline、OVID数据库检索得到的1990至2010年发表的22篇文献中111例NASH基础上肝癌患者的临床资料进行汇总分析。结果 （1）发现肝功能异常的年龄为60岁,诊断NASH的年龄为63.9岁,诊断肝细胞癌（HCC）的年龄66.7岁;（2）男性占62%,男女之比1.64：1;（3）79%患者伴有肥胖,78%伴有糖尿病,33%伴有血脂异常,52%伴有高血压;（4）71%患者肿瘤为单发,肿瘤直径最小1.0 cm,最大13 cm（平均3.3 cm）;（5）大多数肿瘤发生在肝右叶;（6）67%HCC伴肝硬化,肿瘤组织以梁索型居多,分化程度多为良好～中分化;（7）多数患者无任何症状,常规体检时发现肿瘤;（8）65%病例AFP和/或PIVKAII升高;（9）大多数病例经手术切除治疗,术后平均随访24个月,21%患者死亡,15%复发。结论 NASH基础上HCC多见于男性,这类患者往往伴有代谢性疾病,尽管肿瘤分化程度较高,根治性切除率高,NASH无痛性进展使得大多患者发现肝癌已属晚期,导致预后相对较差。有必要对合并多元代谢紊乱的NASH患者,尤其是男性和年老患者进行定期HCC筛检。     

The importance of AST / ALT rate in nonalcoholic steatohepatitis diagnosis

BACKGROUND/AIMS: There is a histologic similarity between nonalcoholic steatohepatitis and alcoholic liver disease and in some cases differential diagnosis may be difficult, since some patients do not report abusive alcohol consumption. OBJECTIVE: Evaluating the usefulness of setting the rate AST/ALT for the differential diagnosis of nonalcoholic steatohepatitis and alcoholic liver disease. PATIENTS AND METHODS: Twenty nine obese patients with nonalcoholic steatohepatitis were compared with 28 patients with alcoholic liver disease. The diagnosis of nonalcoholic steatohepatitis was made after exclusion of other causes of liver disease and by histologic findings of, at least, macrovesicular steatosis and hepatocellular necrosis. RESULTS: In patients with nonalcoholic steatohepatitis the medium AST value was 52.3 +/- 21.2 U/L and ALT of 90.1 +/- 37.9 U/L, being the AST/ALT rate lower than 1 in all patients. In patients with alcoholic liver disease the medium AST value was 140 +/- 82.5 U/L and ALT was 50.6 +/- 40.3 U/L. The rate was higher than 1 in all cases and higher than 2 in 24 (85.7%), being statistically significant when compared with patients with nonalcoholic steatohepatitis. CONCLUSION: The AST/ALT rate seems to be useful in the differential diagnosis of liver diseases, while lower than 1 is highly suggestive of nonalcoholic steatohepatitis.