非酒精性脂肪性肝病与代谢综合征

非酒精性脂肪性肝病(NAFLD)事实上是一个肝脏脂肪性病变的疾病谱,包括单纯性脂肪肝、非酒精性脂肪性肝炎(NASH)、肝纤维化或肝硬化、肝衰竭,甚至部分患者发生肝细胞性肝癌。NAFLD与代谢综合征(MS)密切伴随,并认为是代谢综合征的肝脏表现。胰岛素抵抗可能是二者共同的发病基础。NAFLD已经成为MS、2型糖尿病(T2DM)和心血管疾病(CVD)的重要的独立预测因子,NAFLD成为T2DM和CVD高危人群,因此早期诊断和早期干预NAFLD对预防T2DM和CVD具有重要意义。     

Mechanisms,screening modalities and treatment options for individuals with non-alcoholic fatty liver disease and type 2 diabetes

Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum of disease ranging from excessive accumulation of fat within the liver (simple steatosis), inflammation (non-alcoholic steatohepatitis) through to fibrosis, cirrhosis and end-stage liver disease. There is also an increased risk of hepatocellular carcinoma. The principal risk factor for NAFLD is overweight or obesity, along with type 2 diabetes, and NAFLD itself is also a risk factor for incident type 2 diabetes. Overweight/obesity is synergistic with alcohol consumption in causing progressive and insidious liver damage. Recent consensus advocates a change in nomenclature from NAFLD to ‘metabolic associated fatty liver disease’ (MAFLD), reflective of the associated metabolic abnormalities (insulin resistance/type 2 diabetes and metabolic syndrome components). Additional extra-hepatic manifestations of NAFLD include cardiovascular disease, chronic kidney disease and certain cancers. Unlike other micro- and macrovascular complications of type 2 diabetes, systematic screening or surveillance protocols have not been widely adopted in routine diabetes care to assess for presence/severity of NAFLD. Various screening tools are available (non-invasive tests and biochemical indices) combined with imaging techniques (e.g. transient elastography) to detect steatosis and more importantly advanced fibrosis/cirrhosis to facilitate appropriate surveillance. Liver biopsy may be sometimes necessary. Treatment options for type 2 diabetes, including lifestyle interventions (dietary change and physical activity), glucose-lowering therapies and metabolic surgery, can modulate hepatic steatosis and to a lesser extent fibrosis. Awareness of the impact of liver disease on the choice of glucose-lowering medications in individuals with type 2 diabetes is also critical.     

Non-invasive evaluation of liver steatosis with imaging modalities: New techniques and applications

In the world, nonalcoholic fatty liver disease(NAFLD) accounts for majority of diffuse hepatic diseases. Notably, substantial liver fat accumulation can trigger and accelerate hepatic fibrosis, thus contributing to disease progression. Moreover, the presence of NAFLD not only puts adverse influences for liver but is also associated with an increased risk of type 2 diabetes and cardiovascular diseases. Therefore, early detection and quantified measurement of hepatic fat content are of great impor...     

From the metabolic syndrome to NAFLD or vice versa?

The metabolic syndrome encompasses metabolic and cardiovascular risk factors which predict diabetes and cardiovascular disease (CVD) better than any of its individual components. Nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome, with insulin resistance as the main pathogenetic mechanism. Recent data indicate that hyperinsulinemia is probably the consequence rather than cause of NAFLD and NAFLD can be considered an independent predictor of cardiovascular disease. Serum free fatty acids derived from lipolysis of visceral adipose tissue are the main source of hepatic triglycerides in NAFLD, although hepatic de novo lipogenesis and dietary fat supply contribute to the pathogenesis of NAFLD. Approximately 10–25% NAFLD patients develop NASH, the evolutive form of hepatic steatosis. Presumably in a genetically predisposed environment, this increased lipid overload overwhelms the oxidative capacity and reactive oxygen species are generated, leading to lipid peroxidation, cytokine induction, chemoattraction of inflammatory cells, hepatic stellate cell activation and finally fibrogenesis with extracellular matrix deposition. No currently available therapies for NAFLD and NASH exist. Recently nuclear receptors have emerged as key regulators of lipid and carbohydrate metabolism for which specific pharmacological ligands are available, making them attractive therapeutic targets for NAFLD and NASH.     

Nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and its association with cardiovascular disease

Introduction

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver disease that ranges from hepatic steatosis to non-alcoholic steatohepatitis. Obesity and diabetes mellitus are the prime risk factors for NAFLD. The aim of this study was to find out the prevalence of NAFLD among patients with type 2 diabetes mellitus and to detect the association of NAFLD with cardiovascular disease in them.

Epidemiology and risk factors of nonalcoholic fatty liver disease (NAFLD)

The nonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic steatosis, determined by either imaging or histology, in the absence of secondary causes of hepatic fat accumulation. Nonalcoholic fatty liver is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes or fibrosis. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. Although initial epidemiological studies have focused on its prevalence in the Western countries, it is becoming increasingly clear that NAFLD is highly prevalent in the Asia Pacific region, and there may be important distinctions in its phenotype between Asia Pacific and Western countries. Of particular interest are “lean NAFLD” and the “urban-rural divide,” which will be discussed in this review article. Obesity, dyslipidemia, type 2 diabetes and metabolic syndrome are established risk factors for developing NAFLD. Many other risk factors (e.g., hypothyroidism, polycystic ovary syndrome, obstructive sleep apnea, hypopituitarism and hypogonadism) for NAFLD have been described in the Western countries, but these associations are yet to be investigated adequately in the Asia Pacific region.     

Recent concepts in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is present in up to one-third of the general population and in the majority of patients with metabolic risk factors such as obesity and diabetes. Insulin resistance is a key pathogenic factor resulting in hepatic fat accumulation. Recent evidence demonstrates NAFLD in turn exacerbates hepatic insulin resistance and often precedes glucose intolerance. Once hepatic steatosis is established, other factors, including oxidative stress, mitochondrial dysfunction, gut-derived lipopolysaccharide and adipocytokines, may promote hepatocellular damage, inflammation and progressive liver disease. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies, however, staging the disease requires a liver biopsy. NAFLD is associated with an increased risk of all-cause death, probably because of complications of insulin resistance such as vascular disease, as well as cirrhosis and hepatocellular carcinoma, which occur in a minority of patients. NAFLD is also now recognized to account for a substantial proportion of patients previously diagnosed with 'cryptogenic cirrhosis'. Diabetes, obesity and the necroinflammatory form of NAFLD known as non-alcoholic steatohepatitis, are risk factors for progressive liver disease. Current treatment relies on weight loss and exercise, although various insulin-sensitizing medications appear promising. Further research is needed to identify which patients will achieve the most benefit from therapy.     

Which treatment for type 2 diabetes associated with non-alcoholic fatty liver disease?

Type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD) are highly prevalent in the community, and share common pathogenic mechanisms. There is also evidence that T2DM may be favored by hepatic fat accumulation; in turn the presence of T2DM is a risk factor for liver disease progression. The treatment of T2DM has considerably changed in the past few years; new drug classes, promoting glucose-lowering through mechanisms different from classical insulin-sensitizing or insulin-secreting action, have been added to continuing lifestyle intervention. Metformin and pioglitazone may be safely used in the presence of liver fat, whereas sulfonylureas and insulin itself have been associated with NAFLD progression and adverse outcome. Drugs acting on the incretin axis and on Na-glucose co-transport at renal tubular level offer new hopes for a tailored treatment able to reduce the burden of hepatic triglyceride accumulation and liver disease progression.     

Non-alcoholic fatty liver disease and hepatitis C infection

Non-alcoholic fatty liver disease (NAFLD) is now recognized as one of the most important causes of chronic liver disease in Western Countries, and is the hepatic manifestation of metabolic syndrome. The prevalence of NAFLD has increased with the global epidemic of obesity and type 2 diabetes mellitus. The pathophysiological hallmark of NAFLD is insulin resistance, associated with mediators of oxidative stress and inflammatory cytokines. Although simple steatosis by itself is generally benign, patients with histologically proven non-alcoholic steatohepatitis (NASH) can progress to cirrhosis. Hepatitis C (HCV) is another common cause of liver disease with some potential for progression to cirrhosis. Steatosis is present in almost 50% of patients infected by HCV. Hepatic steatosis in the setting of another liver disease (such as HCV) is associated liver disease progression. In particular, significant fibrosis is observed in patients with HCV whose liver biopsies show significant steatosis or superimposed NASH. This article reviews the host and viral factors potentially involved in the interaction between NAFLD and HCV. These factors include mediators of metabolic syndrome such as adipokines, inflammatory cytokines, factors associated with oxidative stress, lipid peroxidation products, as well as apoptosis and hepatic stellate cell activation with the resultant deposition of extracellular matrix. In addition to the mediators of metabolic syndrome (host factors), hepatic steatosis can be influenced by viral factors. The most important viral factor is HCV genotype 3, which has been independently associated with hepatic steatosis. Finally, superimposed NAFLD and visceral fat are associated with lower response rates to antiviral therapy in non-genotype 3 patients. Furthermore, viral clearance is associated with the resolution of hepatic steatosis in HCV genotype 3 but not other HCV genotypes. In these genotypes, hepatic steatosis and its impact on response to therapy are related to metabolic syndrome. Thus, the management of obesity and metabolic syndrome in patients with chronic hepatitis C may be important for reducing the risk of progression as well as improving the efficacy of antiviral therapy.     

Nonalcoholic fatty liver disease, adiponectin and insulin resistance in dipper and nondipper essential hypertensive patients

OBJECTIVE: The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is multifactorial, and the presence of insulin resistance is recognized as the pathophysiological hallmark of this condition. Arterial hypertension is referred as an insulin-resistant state, and insulin resistance may substantially contribute to the cardiovascular risk in this disorder. We examined the inter-relationship between insulin sensitivity, adiponectin levels, and NAFLD in hypertensive patients with different circadian blood pressure profiles. METHODS: Eighty never-treated patients with essential hypertension were selected for having a nocturnal decrement of blood pressure that was at least 10% (dippers, n=47) or less than 10% (nondippers, n=33) of daytime values. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for hepatic disease. The two groups were similar as to sex, age, and BMI. Abdominal fat distribution and NAFLD were assessed by ultrasonography. RESULTS: Hepatic steatosis was detected in 57.5% of all patients. Nondippers showed a higher prevalence of NAFLD than dippers (81.8 vs. 40.4%, P<0.005). Insulin and the homeostasis model of assessment index were higher (P<0.001) and adiponectin was lower (P<0.001) in nondippers than in dippers, whereas no difference was found in regional fat, liver enzymes, and other metabolic parameters. At multivariate analysis, factors independently associated with nondipping were insulin (P<0.05) and adiponectin (P<0.01) with the homeostasis model of assessment index being of borderline significance. CONCLUSION: In the absence of major risk factors for the development of NAFLD, a high prevalence of liver steatosis was associated with insulin resistance and low adiponectin levels in essential hypertensive patients with a nondipping profile.     

Risk factors associated with nonalcoholic fatty liver disease and its relationship with the hepatic histological changes

OBJECTIVE: The objective of this study is to determine the association between risk factors and nonalcoholic fatty liver disease (NAFLD), and to establish the relationship between risk factors and hepatic histological changes in obese women. METHODS: A case-control design study. Women with NAFLD (cases) were compared with a control group of obese women without NAFLD matched by age, body mass index, waist circumference, and body fat. Irrespective of serum aminotransferases levels, diagnosis of NAFLD was established by the presence of type II diabetes, hypertriglyceridemia, and ultrasonographic changes of hepatic steatosis. Diagnosis of nonalcoholic steatohepatitis was performed by a liver biopsy. Women with an aspartate aminotransferase/alanine aminotransferase (ALT) ratio of at least 1 underwent liver biopsy. Alcohol consumption, hepatitis, and drugs that promote cholestasis or liver injury were the exclusion criteria. Multiple regression analysis was used to compute the association between the risk factors and NAFLD, and Spearman's analysis was used to examine its relationship with histological hepatic changes. RESULTS: A total of 108 obese women were enrolled. The frequency of high blood pressure, hypertriglyceridemia, and diabetes was similar between the groups. ALT (54.4+/-33.3 and 39.8+/-29.8, P=0.03) but not aspartate aminotransferase (45.4+/-23.1 and 36.7+/-21.2, P=0.06) was significantly higher in the women with NAFLD. The multivariate regression analysis showed a significant association of ALT (odds ratio 2.7; 95% confidence interval, 1.3-10.4), but not other variables with NAFLD. Type II diabetes was strongly correlated with ballooning and inflammation, and ALT with inflammation and fibrosis. CONCLUSION: Obese women with similar metabolic alterations exhibit different hepatic outcomes. Elevation of ALT, but not other risk factors, was associated with NAFLD. Diabetes and ALT correlate with histological hepatic changes.     

Nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is present in up to one third of the general population and in the majority of patients with metabolic risk factors such as obesity and diabetes. Insulin resistance is a key pathogenic factor resulting in hepatic fat accumulation. Recent evidence demonstrates NAFLD in turn, exacerbates hepatic insulin resistance and often precedes glucose intolerance. Once hepatic steatosis is established, other factors including oxidative stress, mitochondrial dysfunction, gut-derived lipopolysaccharide and adipocytokines, may promote hepatocellular damage, inflammation and progressive liver disease. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies, however staging the disease requires a liver biopsy. NAFLD is associated with an increased risk of all-cause death, probably because of complications of insulin resistance such as vascular disease, as well as due to cirrhosis and hepatocellular carcinoma, which occurs in a minority of patients. NAFLD is also now recognized to account for a substantial proportion of patients previously diagnosed with 'cryptogenic cirrhosis'. Diabetes, obesity and the necroinflammatory form of NAFLD known as non-alcoholic steatohepatitis, are risk factors for progressive liver disease. Current treatment relies on weight loss and exercise, although various insulin-sensitizing medications appear promising. Further research is needed to identify which patients will achieve the most benefit from therapy.     

Hypertransaminasemia and severe hepatic steatosis without inflammation. A case report

Nonalcoholic fatty liver disease (NAFLD) is a medical condition that may progress to end-stage liver disease. The spectrum of NAFLD is wide and ranges from simple fat accumulation in hepatocytes (steatosis), to fat accumulation plus necroinflammatory activity with or without fibrosis (steatohepatitis). In addition, NAFLD is the most common cause of abnormal liver-test results among adults with a prevalence of 13%-23%. This case report is an example of a patient with asymptomatic hypertransaminasemia and severe hepatic steatosis without inflammation in which the diagnosis was made by liver biopsy.     

Hepatic steatosis and metabolic risk factors among patients with chronic hepatitis B: The multicentre,prospective CAP-Asia study

We aimed to compare the severity of liver disease, metabolic profile and cardiovascular disease (CVD) risk of chronic hepatitis B (CHB) patients with and without hepatic steatosis and patients with non-alcoholic fatty liver disease (NAFLD). Patients with NAFLD and CHB were prospectively enrolled from 10 Asian centres. Fibroscan was performed for all patients and hepatic steatosis was defined based on controlled attenuation parameter >248 dB/m. CVD risk was assessed using the Framingham risk score. The data for 1080 patients were analysed (67% NAFLD, 33% CHB). A high proportion (59%) of CHB patients had hepatic steatosis. There was a significant stepwise increase in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, controlled attenuation parameter and liver stiffness measurement, from CHB patients without hepatic steatosis to CHB patients with hepatic steatosis to NAFLD patients (p < 0.001 for all comparisons). There was a significant stepwise increase in the proportion of patients with metabolic syndrome and in CVD risk, with very high or extreme CVD risk seen in 20%, 48% and 61%, across the groups (p < 0.001 between CHB patients with and without hepatic steatosis and p < 0.05 between CHB patients with hepatic steatosis and NAFLD patients). In conclusion, there was a high proportion of CHB patients with hepatic steatosis, which should be diagnosed, as they may have more severe liver disease, so that this and their metabolic risk factors can be assessed and managed accordingly for a better long-term outcome     

Leber und Diabetes

Non-alcoholic fatty liver disease (NAFLD) affects about 30?% of the general population and 70?% of patients with type 2 diabetes. The disease manifests as steatosis of the liver on the basis of a genetic predisposition through environmental factors, such as obesity, nutrition and lack of physical activity. Although NAFLD has a relatively benign prognosis, the hepatic metabolic disturbance causes insulin resistance and is strongly associated with the development of diabetes and cardiovascular diseases. It is important to distinguish NAFLD from non-alcoholic steatohepatitis (NASH) which can lead to cirrhosis and hepatocellular carcinoma (HCC). The diagnosis can be made by exclusion of other hepatic diseases and by liver biopsy. Future efforts will focus on substituting the need for a biopsy by the use of non-invasive serum markers and measurement of liver stiffness. Therapeutic options for patients with NASH are currently limited to lifestyle intervention and administration of pioglitazone and vitamin E; however, it is probable that further therapeutic options will be available in the future, some of which are currently being tested in clinical trials.     

Nonalcoholic fatty liver disease and cardiovascular disease risk

Nonalcoholic fatty liver disease (NAFLD) is prevalent in people with the metabolic syndrome and type 2 diabetes. Evidence is now accumulating that NAFLD is associated with obesity and diabetes and may serve as a predictor of cardiovascular disease. Although at present, treatment of the individual risk factors pertinent to NAFLD is advocated, novel therapies are emerging that may target steatosis and/or inflammation, thus ameliorating the overall cardiovascular disease risk. Long-term outcome studies need to establish whether treatment of NAFLD (and in particular which therapy) will affect the long-term outcome.     

Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease

For a long time, hepatic steatosis was believed to be a benign condition. Only recently, liver steatosis, also termed non-alcoholic fatty liver disease (NAFLD), has gained much interest. In most cases of NAFLD, a condition regarded as the hepatic component of the metabolic syndrome, the enzyme alanine aminotransferase (ALT) is elevated and consequently has been used as a marker for NAFLD. More recently, several cross-sectional and prospective studies have demonstrated associations of this liver enzyme with features of the metabolic syndrome and type 2 diabetes mellitus. This review discusses the biochemical and metabolic properties of ALT, its applicability as a marker of NAFLD and describes its possible role in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus and subsequent cardiovascular disease. In addition, treatment strategies to ameliorate NAFLD and the associated risks are discussed.     

Association between non-alcoholic fatty liver disease and cardiovascular disease: a first message should pass

An association between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) has been recently suggested. Indeed, different studies have demonstrated that NAFLD patients present increased subclinical atherosclerosis compared to non-steatosic individuals, and are supported by the few follow-up studies revealing that CVD is the second most common cause of death in NAFLD patients. However, the nature of the relationship NAFLD/CVD is still under debate: is NAFLD a consequence of, or a contributor to, the dysmetabolic cascade leading to atherosclerosis? In this issue of the journal, McKimmie and coauthors analyzed a subset of 623 participants from the Diabetes Heart Study for hepatic steatosis, classic CVD risk factors, subcutaneous and visceral fat, coronary, aortic and carotid artery calcium, and carotid intima-media thickness. After adjusting for all the CVD risk factors plus visceral fat, they did not find independent associations between steatosis and the cardiovascular markers of interest, and conclude that NAFLD may be best described as an epiphenomenon in this context. The strength of this study resides in the numerosity of the sample, the broad cardiovascular examination, and the direct assessment by computed tomography of visceral fat, an undisputed major contributor to NAFLD, the metabolic syndrome and atherosclerosis. However, waiting for prospective and interventional studies in order to definitely determine the nature of the relationship NAFLD/CVD, sufficient evidence exists to derive a first message and transfer it into the clinical practice: an overall assessment of the CVD risk, and the aggressive management of the atherosclerotic risk factors, seem mandatory in all NAFLD patients.     

Bedside ultrasound in the diagnosis of nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)is the most common liver disease in the United States.While the American Association for the Study of Liver Diseases guidelines define NAFLD as hepatic steatosis detected either on histology or imaging without a secondary cause of abnormal hepatic fat accumulation,no imaging modality is recommended as standard of care for screening or diagnosis.Bedside ultrasound has been evaluated as a non-invasive method of diagnosing NAFLD with the presence of characteristic sonographic findings.Prior studies suggest characteristic sonographic findings for NAFLD include bright hepatic echoes,increased hepatorenal echogenicity,vascular blurring of portal or hepatic vein and subcutaneous tissue thickness.These sonographic characteristics have not been shown to aid bedside clinicians easily identify potential cases of NAFLD.While sonographic findings such as attenuation of image,diffuse echogenicity,uniform heterogeneous liver,thick subcutaneous depth,and enlarged liver filling of the entire field could be identifiedby clinicians from bedside ultrasound.The accessibility,ease of use,and low-side effect profile of ultrasound make bedside ultrasound an appealing imaging modality in the detection of hepatic steatosis.When used with appropriate clinical risk factors and steatosis involves greater than 33%of the liver,ultrasound can reliably diagnose NAFLD.Despite the ability of ultrasound in detecting moderate hepatic steatosis,it cannot replace liver biopsy in staging the degree of fibrosis.The purpose of this review is to examine the diagnostic accuracy,utility,and limitations of ultrasound in the diagnosis of NAFLD and its potential use by clinicians in routine practices.