Metabolic syndrome and nonalcoholic fatty liver diseases in children

The review of literature considers the problem of the metabolic syndrome and nonalcoholic fatty liver disease in children. It provides information about common pathogenesis of the metabolic syndrome and nonalcoholic fatty liver disease, the relationship of diagnosis and treatment.     

Metabolic aspects of adult patients with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome(MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance(IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD.     

Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults

BACKGROUND: Obesity and type 2 diabetes are well-known risk factors for the development of nonalcoholic fatty liver disease (NAFLD). However, NAFLD is not rare in nonobese, nondiabetic adults. The aim of this study was to evaluate the metabolic significance of NAFLD in nonobese, nondiabetic adults. METHODS: This study examined 768 nonobese (body mass index [BMI] [calculated as weight in kilograms divided by the square of height in meters], > or =18.5 and <30) (460 normal-weight and 308 overweight subjects), nondiabetic individuals older than 30 years who participated in a medical checkup. All the subjects had negative serologic findings for hepatitis B and C viruses and had an alcohol intake less than 140 g/wk. A standard interview, anthropometrics, a biochemical study, and abdominal ultrasonography were conducted. RESULTS: The prevalence of NAFLD in the enrolled subjects was 23.4%. In the normal-weight (BMI, > or =18.5 and <25) and overweight (BMI, > or =25 and <30) groups, NAFLD was a significant predictor of insulin resistance and other metabolic disorders, including hypertriglyceridemia and hyperuricemia. The odds ratio of the metabolic disorders in subjects with NAFLD compared with those without NAFLD in the normal-weight group was higher than that in the overweight group. Multiple logistic regression analysis showed that sex, waist circumference, triglyceride level, and insulin resistance were independently associated with NAFLD in the normal-weight group. CONCLUSIONS: Nonalcoholic fatty liver disease is closely associated with metabolic disorders, even in nonobese, nondiabetic subjects. Nonalcoholic fatty liver disease can be considered an early predictor of metabolic disorders, particularly in the normal-weight population.     

Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men

Type 2 diabetes mellitus (T2DM) is strongly associated with obesity in most, but not all, ethnic groups, suggesting important ethnic differences in disease susceptibility. Although it is clear that insulin resistance plays a major role in the pathogenesis of T2DM and that insulin resistance is strongly associated with increases in hepatic (HTG) and/or intramyocellular lipid content, little is known about the prevalence of insulin resistance and potential differences in intracellular lipid distribution among healthy, young, lean individuals of different ethnic groups. To examine this question, 482 young, lean, healthy, sedentary, nonsmoking Eastern Asians (n = 49), Asian-Indians (n = 59), Blacks (n = 48), Caucasians (n = 292), and Hispanics (n = 34) underwent an oral glucose tolerance test to assess whole-body insulin sensitivity by an insulin sensitivity index. In addition, intramyocellular lipid and HTG contents were measured by using proton magnetic resonance spectroscopy. The prevalence of insulin resistance, defined as the lower quartile of insulin sensitivity index, was approximately 2- to 3-fold higher in the Asian-Indians compared with all other ethnic groups, and this could entirely be attributed to a 3- to 4-fold increased prevalence of insulin resistance in Asian-Indian men. This increased prevalence of insulin resistance in the Asian-Indian men was associated with an approximately 2-fold increase in HTG content and plasma IL-6 concentrations compared with Caucasian men. These data demonstrate important ethnic and gender differences in the pathogenesis of insulin resistance in Asian-Indian men and have important therapeutic implications for treatment of T2DM and for the development of steatosis-related liver disease in this ethnic group.     

男性非酒精性脂肪性肝病患者血糖波动研究

选取48例糖耐量正常男性为研究对象,其中非酒精性脂肪性肝病23例为病例组,无脂肪肝25例为对照组,应用动态血糖监测系统评价血糖波动情况。结果显示,病例组平均血糖波动幅度[MAGE,（2.17±1.13对1.45±0.42）mmol/L]和血糖标准差[SDBG,（0.88±0.45对0.61±0.21）mmol/L]均高于对照组(P＜0.05)。MAGE和SDBG与体重指数、腰围和糖负荷后0.5h血糖升高值(AG30)呈正相关(均P＜0.05)。以MAGE为因变量,行多元线性回归分析显示,△G30、腰围和年龄被引入方程(P＜0.05或P＜0.01)。以SDBG为因变量,行多元线性回归分析显示,AG30和腰围被引入方程（P＜0.05或P＜0.01）。     

Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome are reaching epidemic levels worldwide, but data in Asia remain scarce. This cross-sectional study examined the metabolic and adipokine profiles of Chinese patients with biopsy-proven NAFLD and factors associated with severe disease. METHODS: Eighty ethnic Chinese with NAFLD and 41 healthy controls were recruited. Metabolic parameters and fasting adiponectin, tumor necrosis factor-alpha (TNF-alpha), leptin, and resistin levels were measured on the day of liver biopsy. Histology was scored according to Brunt's criteria. Metabolic syndrome was assessed by using both the International Diabetes Federation and Adult Treatment Panel III criteria. RESULTS: Twenty-eight patients had simple steatosis, and 52 patients had nonalcoholic steatohepatitis (NASH), defined as necroinflammatory grade >/=2 and/or fibrosis by Brunt's criteria. The ethnic-specific International Diabetes Federation criteria identified more cases of metabolic syndrome among NAFLD patients than the Adult Treatment Panel III criteria (70% vs 56%, P < .0001). On multivariate analysis, low adiponectin level, increased leptin level, and diabetes mellitus were associated with NAFLD. High TNF-alpha level and high body mass index were independent factors associated with NASH. TNF-alpha level had positive correlation with necroinflammatory grade (R = .35, P = .002) and fibrosis stage (R = .31, P = .005). CONCLUSIONS: Hypoadiponectinemia and elevated TNF-alpha levels are associated with the development of NAFLD and NASH, respectively, independent of other metabolic factors. Ethnic-specific definition of metabolic syndrome is more useful in the assessment of NAFLD patients.     

Metabolic inflammation as an instigator of fibrosis during nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is characterized by excessive storage of fatty acids in the form of triglycerides in hepatocytes. It is most prevalent in western countries and includes a wide range of clinical and histopathological findings, namely from simple steatosis to steatohepatitis and fibrosis, which may lead to cirrhosis and hepatocellular cancer. The key event for the transition from steatosis to fibrosis is the activation of quiescent hepatic stellate cells(qHSC) and their differentiation to myofibroblasts. Pattern recognition receptors(PRRs),expressed by a plethora of immune cells, serve as essential components of the innate immune system whose function is to stimulate phagocytosis and mediate inflammation upon binding to them of various molecules released from damaged, apoptotic and necrotic cells. The activation of PRRs on hepatocytes,Kupffer cells, the resident macrophages of the liver, and other immune cells results in the production of proinflammatory cytokines and chemokines, as well as profibrotic factors in the liver microenvironment leading to qHSC activation and subsequent fibrogenesis. Thus, elucidation of the inflammatory pathways associated with the pathogenesis and progression of NAFLD may lead to a better understanding of its pathophysiology and new therapeutic approaches.     

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.     

Review of nonalcoholic fatty liver disease in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. Women with PCOS frequently have metabolic complications including insulin resistance (IR), early diabetes, hypertension and dyslipidemia. Recent studies have demonstrated an association between PCOS and another metabolic complication: nonalcoholic fatty liver disease (NAFLD). NAFLD occurs as a result of abnormal lipid handling by the liver, which sensitizes the liver to injury and inflammation. It can progress to nonalcoholic steatohepatitis (NASH), which is characterized by hepatocyte injury and apoptosis. With time and further inflammation, NASH can progress to cirrhosis. Thus, given the young age at which NAFLD may occur in PCOS, these women may be at significant risk for progressive hepatic injury over the course of their lives. Many potential links between PCOS and NAFLD have been proposed, most notably IR and hyperandrogenemia. Further studies are needed to clarify the association between PCOS and NAFLD. In the interim, clinicians should be aware of this connection and consider screening for NAFLD in PCOS patients who have other metabolic risk factors. The optimal method of screening is unknown. However, measuring alanine aminotransferase and/or obtaining ultrasound on high-risk patients can be considered. First line treatment consists of lifestyle interventions and weight loss, with possible pharmacologic interventions in some cases.     

Epidemiology of nonalcoholic fatty liver

Nonalcoholic fatty liver (NAFL) is increasingly recognized as an important and common public health problem that can lead to cirrhosis and hepatic failure. Because it is often asymptomatic,many people may not know that they have it. NAFL is closely linked to obesity, which in the United States and other developed countries is becoming more common. Consequently, the proportion of the population affected by NAFL will likely increase. Despite the growing importance of this condition, knowledge of the epidemiology of NAFL is limited by the lack of an accurate,noninvasive measure for use in screening of the general population.This article reviews information available from studies with relatively unselected samples with regard to prevalence, demographics,and risk factors for NAFL.     

Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease （NAFLD） is an increasingly recognized cause of liver-related morbidity and mortality. It can develop secondary to numerous causes but a great majority of NAFLD cases occur in patients who are obese or present with other components of metabolic syndrome （hypertension, dyslipidemia, diabetes）. This is called primary NAFLD and insulin resistance plays a key role in its pathogenesis. Obesity is characterized by expanded adipose tissue, which is under a state of chronic inflammation. This disturbs the normal storage and endocrine functions of adipose tissue. In obesity, the secretome （adipokines, oytokines, free fatty acids and other lipid moieties） of fatty tissue is amplified, which through its autocrine, paracrine actions in fat tissue and systemic effects especially in the liver leads to an altered metabolic state with insulin resistance （IR）. IR leads to hyperglycemia and reactive hyperinsulinemia, which stimulates lipid-accumulating processes and impairs hepatic lipid metabolism. IR enhances free fatty acid delivery to liver from the adipose tissue storage due to uninhibited lipolysis. These changes result in hepatic abnormal fat accumulation, which may initiate the hepatic IR and further aggravate the altered metabolic state of whole body. Hepatic steatosis can also be explained by the fact that there is enhanced dietary fat delivery and physical inactivity. IR and NAFLD are also seen in various lipodystrophic states in contrary to popular belief that these problems only occur due to excessive adiposity in obesity. Hence, altered physiology of adipose tissue is central to development of IR, metabolic syndrome and NAFLD.     

Genes and nonalcoholic fatty liver disease

Whereas most individuals with nonalcoholic fatty liver disease (NAFLD) will have steatosis, only a minority will ever develop progressive disease. Family studies and interethnic variations in susceptibility suggest that genetic factors may be important in determining disease risk. Although no genetic associations with advanced NAFLD have been replicated in large studies, preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, tumor necrosis factor-α, transforming growth factor-β, and angiotensinogen may be associated with steatohepatitis and/or fibrosis. With the advent of high-throughput gene analyses and the reduced cost of whole genomewide scans, it seems likely that genes contributing to inherited susceptibility to this common disease will be identified in the near future.     

蛋白质组学技术在非酒精性脂肪肝研究中的应用

非酒精性脂肪肝（nonalcoholic fatty liver，NAFL），又称非酒精性脂肪性肝病（nonalcoholic fatty liver disease，NAFLD），是一组以肝细胞脂肪变性、坏死、炎性细胞浸润等为主要特征的临床病理综合征，其肝脏组织学病变与酒精性肝病相类似，但无过量饮酒史。根据病理学改变及临床表现，可将NAFLD分为单纯性NAFLD和非酒精性脂肪性肝炎（nonalcoholic steatohepatitis，NASH）。NASH却可逐渐进展为肝硬化、肝癌等终末期肝病，已成为目前仅次于慢性病毒性肝炎和酒精性肝病的重要肝硬化前期病变。     

丙型肝炎与非酒精性脂肪肝

丙型肝炎病毒(HCV)感染中非酒精性脂肪性肝病(NAFLD)多见。目前认为,基因1型HCV感染伴有NAFLD常提示有代谢综合征,基因3型HCV感染与肝脂肪变有独立相关性,HCV伴NAFLD可增加严重肝纤维化和抗病毒治疗失败的危险性、。本文对此作简要介绍。     

Biomarkers in nonalcoholic fatty liver disease

BACKGROUND:

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition characterized by insulin resistance, type 2 diabetes and fat accumulation in the liver that may cause hepatic inflammation and progressive scarring leading to nonalcoholic steatohepatitis (NASH) and irreversible liver damage (cirrhosis). As a result, there has been increased recognition of the need to assess and closely monitor individuals for risk factors of components of NAFLD and NASH, as well as the severity of these conditions using biomarkers.

AIM:

To review the biomarkers used to diagnose and define the severity of NAFLD and NASH.

METHODS:

A comprehensive PubMed and Google Scholar literature search was performed using the terms “non-alcoholic fatty liver disease”, “non-alcoholic steatohepatitis”, as well as the name of each biomarker known to be used. Articles indexed between 2004 and 2014 were used. Each author read the publications separately and the results were discussed.

RESULTS:

Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression or both. Serum biomarkers, including total cholesterol, triglycerides, insulin resistance and C-peptide, have been used for many years. Emerging biomarkers, such as apolipoprotein A1, apolipoprotein B, leptin, adiponectin, free fatty acids, ghrelin and tumour necrosis factor-alpha, have been proposed as tools that could provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of cell death and mitochondrial dysfunction (cytokeratins) represent powerful predictors of risk. For biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in sex and ethnic origin are a necessity.

CONCLUSIONS:

The present review attempts to provide a comprehensive analysis of the emerging risk biomarkers of NAFLD and NASH, and to use the clinical significance and analytical considerations of each biomarker pointing out sentinel features of disease progression.     

非酒精性脂肪性肝病患者血清脂肪细胞因子研究进展

作为代谢综合征的肝脏表现,非酒精性脂肪性肝病（NAFLD）的主要特征为胰岛素抵抗（IR）和肝脂肪沉积。脂肪细胞因子作为脂肪细胞分泌的多肽,在 NAFLD 和 IR 的发病中发挥着重要的作用。本文综述了瘦素、脂联素、视黄醇结合蛋白4、成纤维细胞生长因子21和趋化素等新发现的细胞因子与 NAFLD 发病之间的关系。