Nonalcoholic steatohepatitis and the metabolic syndrome

Relatively recently, the liver has been recognized as a major target of injury in patients with insulin resistance or the metabolic syndrome. Insulin resistance is associated with fat accumulation in the liver, a condition called nonalcoholic fatty liver disease (NAFLD). Excess fat in the liver is not a benign condition. Some patients with NAFLD develop necroinflammatory changes in the liver called nonalcoholic steatohepatitis (NASH) and a fraction of those will develop cirrhosis. About 20% all adults have NAFLD and 2% to 3% of adults have NASH. Approximately 20% of patients with NASH are at risk for developing cirrhosis and subsequently dying from end-stage liver disease. The diagnosis of NASH requires a high index of suspicion, especially in obese patients over the age of 45 years who have diabetes, because these are the patients at greatest risk for developing cirrhosis. Treatment focuses on addressing the underlying insulin resistance with increased exercise and weight reduction.     

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。     

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。     

The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease

OBJECTIVE: The ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is often greater than 2:1 in alcoholic hepatitis. The purpose of this study was to determine whether this ratio may be used to distinguish nonalcoholic steatohepatitis (NASH) from alcoholic liver disease. METHODS: Patients with NASH were matched with controls with alcoholic liver disease based on age, gender, and date of diagnosis. The diagnosis of alcoholic liver disease was based on exclusion of other causes and a significant history of alcohol consumption. The diagnosis of nonalcoholic steatohepatitis was based on exclusion of other causes of liver disease and a liver biopsy showing > 10% steatosis and inflammation. The two sided Student t test was used for statistical analysis. RESULTS: From 1990 to 1996, 70 patients with NASH were matched with 70 subjects with alcoholic liver disease. Patients with NASH had a mean AST to ALT ratio of 0.9 (range 0.3-2.8, median 0.7) and subjects with alcoholic liver disease a mean ratio of 2.6 (range 1.1-11.2, median 2.0). The mean AST levels were 66 U/L and 152 U/L, and the mean ALT levels 91 U/L and 70 U/L, in the nonalcoholic steatohepatitis and alcoholic liver disease groups, respectively. Although the absolute aminotransferase levels were significantly different in the two groups (p < 0.05), the greatest difference was observed in the AST to ALT ratio (p < 0.000001). Subset analysis of patients with NASH revealed mean AST to ALT ratios of 0.7, 0.9, and 1.4 for subjects with no fibrosis, mild fibrosis, or cirrhosis, respectively. The differences among these ratios were statistically significant (p < 0.05). CONCLUSIONS: The AST to ALT ratio appears to be a useful index for distinguishing nonalcoholic steatohepatitis from alcoholic liver disease. Although values < 1 suggest NASH, a ratio of > or = 2 is strongly suggestive of alcoholic liver disease.     

Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Cirrhosis Confirmed by Liver Histology after 14 Years

A 44-year-old patient progressed from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) cirrhosis. She was diagnosed with NAFL via a liver biopsy. At 56 years old, she was diagnosed with NASH stage 3 via a second liver biopsy. One year later, she was diagnosed with NASH cirrhosis via a third liver biopsy. This is the first study to report the gradual deterioration of liver histology shown via three liver biopsies and fibrosis markers in a patient who progressed from NAFL to NASH cirrhosis. Following menopause, it is necessary to be aware of the rapid development of liver fibrosis.     

Nonalcoholic steatohepatitis in children

Nonalcoholic steatohepatitis (NASH) is one entity in a spectrum of chronic liver disease related to obesity, hyperinsulinemia, insulin resistance, and liver cell injury from free fatty acid toxicity or other oxidant stress. The more inclusive term ‘nonalcoholic fatty liver disease’ (NAFLD) is increasingly being used to encompass the entire spectrum, which includes simple hepatic steatosis without inflammation (which may not lead to progressive liver injury), NASH itself, and the resulting cirrhosis (which may be devoid of steatosis). Children get NAFLD, and the incidence of this pediatric liver disease is rising as childhood obesity becomes increasingly prevalent. Although much remains to be learned about pediatric NAFLD, it is already evident that children with NASH risk progressive liver damage, including cirrhosis. Liver biopsy is required for definitive diagnosis, and other causes of fatty liver in childhood must be excluded. Gradual weight loss through increased regular exercise and a low-fat, low-refined carbohydrate diet appears to be effective. Drug treatments are being developed. Pediatric NASH is a serious complication of childhood obesity.     

Evaluation and management of obesity-related nonalcoholic fatty liver disease

The clinicopathologic spectrum of nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Simple steatosis has a relatively benign clinical course, but NASH can progress to cirrhosis and hepatocellular carcinoma. NAFLD occurs in the absence of significant alcohol use and is considered to be the hepatic manifestation of metabolic syndrome. NAFLD affects approximately 30% of the US population and the incidence seems to be rising as the obesity epidemic continues. At present, the most accurate modality for the diagnosis of NASH is liver biopsy; however, many patients do not have a liver biopsy, and in the absence of more-accurate imaging technologies and serum markers, the diagnosis is frequently one of exclusion. As yet there is no convincingly effective treatment for NAFLD--a multimodal treatment plan that targets obesity, insulin resistance, hyperlipidemia and hypertension might be the best option for these patients.     

Development from simple steatosis to liver cirrhosis and hepatocellular carcinoma: a 27-year follow-up case

Nonalcoholic fatty liver disease (NAFLD) is classified as nonalcoholic steatohepatitis (NASH) or simple steatosis (SS) according to histological findings. It is well recognized that NASH may develop into cirrhosis and hepatocellular carcinoma (HCC), both with unfavorable prognoses. Although the outlook of SS is reported to be better than that of NASH, the long-term prognosis of SS remains unclear. Here, we report the case of a patient who was diagnosed as having SS by a first liver biopsy, and later developed into cirrhosis and HCC over a period of 27 years. In 1980, a 42-year-old Japanese man was admitted because of abnormal liver function tests. He had no history of alcohol intake and was negative for hepatitis virus markers and autoantibodies. A liver biopsy specimen showed macrovesicular steatosis without ballooned hepatocytes, Mallory hyaline, lobular inflammation, or perisinusoidal/perivenular fibrosis, confirming the diagnosis of SS. The patient’s serum aminotransferase levels did not normalize despite repeated dietary instruction, and in 2001, liver histology demonstrated cirrhosis with mild steatosis and hepatocyte ballooning, leading to the diagnosis of NASH-related cirrhosis. HCC appeared in 2007. Overall, this patient progressed to cirrhosis and HCC in 20 and 27 years, respectively, following initial diagnosis. Platelet counts and degree of steatosis, as assessed by periodic ultrasonography, were seen to gradually reduce with progression of fibrosis. This case demonstrates that even a diagnosis of SS does not guarantee non-progression to cirrhosis and HCC, and careful follow-up is needed not only in patients with NASH, but also in those with SS.     

Natural history of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as one of the most common chronic liver diseases. The natural history of this liver disease remains unclear due to its indolent nature, the paucity of prospective studies, and the lack of consensus regarding the various forms of this disorder. Based on retrospective studies, it appears that the histologic features of NAFLD may be important determinants of the clinical course of this disease; patients with nonalcoholic steatohepatitis (NASH) appear to have a higher likelihood of progression to cirrhosis. There is an increased risk of hepatocellular carcinoma and end-stage liver disease among patients with NASH-related cirrhosis and those with cryptogenic cirrhosis, which likely represents a late stage of NAFLD. Recurrence of NASH has been described among patients who have undergone liver transplantation for NASH-related end-stage liver disease.     

非酒精性脂肪性肝病肝纤维化的诊断和治疗进展

非酒精性脂肪性肝病(NAFLD)正成为全球最常见的慢性肝病。从其疾病谱来看,非酒精性脂肪性肝炎(NASH)是疾病进展形式,可进展为肝纤维化,从而导致NAFLD相关肝硬化和肝癌。NASH肝纤维化与疾病预后密切相关,临床亟需有效措施诊断及干预疾病进展。重点介绍了目前非酒精性脂肪性肝纤维化的诊断和治疗进展。     

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.     

Features, diagnosis, and treatment of nonalcoholic fatty liver disease

As the global incidence of obesity has increased, nonalcoholic fatty liver disease (NAFLD) has become a worldwide health concern. NAFLD occurs in children and adults of all ethnicities and includes isolated fatty liver and nonalcoholic steatohepatitis (NASH). Patients with NASH are at risk for developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma and have increased all-cause mortality. NAFLD is associated with a variety of clinical conditions and is an independent risk factor for hepatocellular carcinoma. The pathogenesis of NAFLD and the specific steps that lead to NASH and advanced fibrosis are not fully understood, although researchers have found that a combination of environmental, genetic, and metabolic factors lead to advanced disease. There have been improvements in noninvasive radiographic methods to diagnose NAFLD, especially for advanced disease. However, liver biopsy is still the standard method of diagnosis for NASH. There are many challenges to treating patients with NASH, and no therapies have been approved by the U.S. Food and Drug Administration; multimodal approaches are being developed and becoming the standard of care. We review pathogenesis and treatment approaches for the West's largest liver-related public health concern.     

Mechanisms of disease progression in NASH: new paradigms

The incidence of nonalcoholic fatty liver disease is increasing at an astonishing rate in the US population. Although only a small proportion of these patients develop steatohepatitis (NASH), those who do have a greater likelihood of developing end-stage liver disease and complications. Research on liver fibrosis and NASH progression shows that hedgehog (Hh) is reactivated after liver injury to assist in liver repair and regeneration. When the process of tissue repair and regeneration is prolonged or when Hh ligand and related genes are aberrantly regulated and excessive, tissue repair goes awry and NASH progresses to cirrhosis and hepatocellular carcinoma.     

Evolving pathophysiologic concepts in nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is increasingly recognized as a relatively prevalent disorder (ie, occuring in 3% of adults) that may progress to cirrhosis in 15% to 40% of those who are afflicted. NASH is a subset of a broader diagnostic category, nonalcoholic fatty liver disease, a term applied to a condition involving the presence of excess fat in the liver with or without inflammation and cellular injury. A diagnosis of NASH is established by the presence of morphologic changes on liver biopsy similar to those seen in alcoholic hepatitis, including hepatocellular fat accumulation, evidence of lobular inflammation and cell injury, and in some cases, progressive fibrosis. Obesity and type 2 diabetes, two conditions associated with insulin resistance, are major risk factors for the development of NASH. Accumulating evidence suggests that the hyperinsulinemia associated with insulin resistance may be important in the pathogenesis of NASH. Clinical trials will now determine whether treatment of insulin resistance is an effective therapy for NASH.     

Nonalcoholic fatty liver disease

As the hepatic manifestation of the metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of asymptomatic liver enzyme elevations in Western nations. Although it is easy to diagnose NAFLD, a liver biopsy is currently required to diagnose nonalcoholic steatohepatitis (NASH). Patients with NASH are those at greatest risk of progression to cirrhosis and, thus, treatment efforts are targeted to these individuals. Although currently there are no FDA-approved treatments for NASH, a multidisciplinary approach that addresses comorbid conditions and promotes modest weight loss comprises the backbone of therapy.     

Non-invasive methods for the diagnosis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is the commonest chronic liver disease and includes simple steatosis and nonalcoholic steatohepatitis(NASH). Since NASH progresses to cirrhosis more frequently and increases liver-related and cardiovascular disease risk substantially more than simple steatosis, there is a great need to differentiate the two entities. Liver biopsy is the gold standard for the diagnosis of NAFLD but its disadvantages, including the risk of complications and sampling bias, stress the need for developing alternative diagnostic methods. Accordingly, several non-invasive markers have been evaluated for the diagnosis of simple steatosis and NASH, including both serological indices and imaging methods. The present review summarizes the current knowledge on the role of these markers in the diagnosis of NAFLD. Current data suggest that ultrasound and the fibrosis-4 score are probably the most appealing methods for detecting steatosis and for distinguishing NASH from simple steatosis, respectively, because of their low cost and relatively high accuracy. However, currently available methods, both serologic and imaging, cannot obviate the need for liver biopsy for diagnosing NASH due to their substantial false positive and false negative rates. Therefore, the current role of these methods is probably limited in patients who are unwilling or have contraindications for undergoing biopsy.     

Nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as a common liver disorder that represents the hepatic manifestation of the metabolic syndrome, a variably defined aggregate of disorders related to obesity, insulin resistance, type II diabetes, hypertension and hyperlipidemia. Nonalcoholic steatohepatitis (NASH) is the progressive form of liver injury that carries a risk for progressive fibrosis, cirrhosis, and end-stage liver disease. Hepatocellular carcinoma (HCC) is a documented complication in an as yet unknown percentage of cases of NASH cirrhosis. The diagnosis of nonalcoholic steatohepatitis requires histopathologic evaluation because the lesions of parenchymal injury and fibrosis cannot be detected by imaging studies or laboratory tests. This article will briefly discuss prevalence studies and the pathophysiology of NAFLD and focus on current discussions related to the specific lesions in the pathology of NASH, including the challenges of pediatric NASH and NASH-related cirrhosis.     

Effects of weight loss surgeries on liver disease

Obesity is the single most significant risk factor for the development of nonalcoholic fatty liver disease (NAFLD) in children and adults. NALFD is estimated to occur in 30 to 100% of obese adults, and in approximately 53% of obese children. The majority of obese patients have ultrasonographic evidence of fatty liver; 30% have histologically documented nonalcoholic steatohepatitis (NASH). Up to 25% of patients with NASH may progress to cirrhosis. In the United States, an estimated 65% of adults are overweight and 31% are obese. Between 2001 and 2002, the number of people with severe obesity, who are more than 100 pounds overweight, rose to nearly 11 million. Since 1970, levels of childhood and teen overweight have climbed to approximately 16% in those aged 6 to 19 years. Recent findings indicate that key features of NAFLD and NASH improve or resolve dramatically with weight loss. This article discusses weight loss surgeries and their effects on liver disease.     

Comparison of Hepatocellular Carcinoma Patients With Alcoholic Liver Disease and Nonalcoholic Steatohepatitis

Background: Alcoholic hepatitis and nonalcoholic steatohepatitis (NASH) show different clinical features with similar liver histology, but both disorders may progress to cirrhosis and hepatocellular carcinoma (HCC). HCC arising in alcoholic liver disease (ALD) or NASH, without hepatitis B or C virus infection, has been a rare observation, and there are no studies comparing the characteristics of ALD and NASH patients with HCC. Therefore, we compared the characteristics of ALD and NASH patients with HCC.
Methods: A total of 1202 patients received a diagnosis of HCC at Tokyo Women's Medical University from 1989 to 2003, and their clinical data were collected prospectively. A clinical diagnosis was made to diagnose ALD, and clinical and histological changes were required to diagnose NASH. Of these patients, 88 received a diagnosis of HCC arising from ALD. Among them, a biopsy specimen was obtained in 50 patients (ALD-HCC group). We compared the clinical and histological characteristics of 50 ALD and 8 NASH patients (NASH-HCC group) associated with HCC. They all were negative for hepatitis virus infection by serological methods.
Results: The most significant difference between these groups was sex. Women were significantly more common in the NASH-HCC group (6% vs. 63%; p < 0.0001). The median age was 65 years in the ALD-HCC group and 68 years in the NASH-HCC group. The risk factors for NASH all were high in the NASH-HCC group. However, liver function tests were similar in these groups. In the ALD-HCC group, 46 (92%) patients showed severe fibrosis; 2 had septal fibrosis and 44 had cirrhosis. All patients in the NASH-HCC group showed severe fibrosis, and seven had cirrhosis.
Conclusions: Severe fibrosis might be an important risk factor for HCC. Patients who have ALD or NASH with cirrhosis may develop HCC. This seems to occur in a sufficient number of cases to warrant regular screening for this complication.     

Noninvasive diagnostic criteria for nonalcoholic steatohepatitis based on gene expression levels in peripheral blood mononuclear cells

Journal of Gastroenterology - Nonalcoholic fatty liver disease (NAFLD) consists of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH); the latter progresses to liver cirrhosis...