Non‐alcoholic fatty liver disease from pathogenesis to management: an update

Non‐alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the Western world, is tightly associated with obesity and metabolic syndrome. NAFLD entails an increased cardiometabolic and liver‐related risk, the latter regarding almost exclusively non‐alcoholic steatohepatitis (NASH), the progressive form of NAFLD. Pathogenetic models encompass altered hepatic lipid partitioning and adipokine action, increased oxidative stress, free fatty acid lipotoxicity. On this basis, lifestyle‐, drug‐ or surgically induced weight loss, insulin sensitizers, antioxidants, lipid‐lowering drugs have been evaluated in NAFLD/NASH. Most trials are small, of short duration, nonrandomized, without histological end points, thus limiting assessment of long‐term safety and efficacy of proposed treatments. All NAFLD patients should be evaluated for their metabolic, cardiovascular and liver‐related risk. Liver biopsy remains the gold standard for staging NAFLD, but non‐invasive methods are under intense development. Weight loss through lifestyle intervention is the initial approach, because of established efficacy on NAFLD‐associated cardiometabolic abnormalities, and to emerging benefits on necroinflammation and overall disease activity in NASH. Bariatric surgery warrants further evaluation before it can be routinely considered in morbidly obese NASH. Larger‐ and longer‐duration randomized trials assessing safety and benefits of drugs on patient‐oriented outcomes are needed before pharmacological treatment can be routinely recommended for NASH.     

Understanding the association between developing a fatty liver and subsequent cardio-metabolic complications

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries and is also predicted to become the most frequent indication for liver transplantation by 2030. In the last decade, it has become evident that the clinical burden of NAFLD is not restricted to liver-related morbidity or mortality, but there is now compelling evidence that NAFLD is a multisystem disease, affecting many extra-hepatic organs. In this article, we discuss the evidence linking NAFLD with important cardiometabolic complications (mainly Type 2 diabetes and cardiovascular disease) and the putative underlying mechanisms by which NAFLD may contribute to the development of these complications.     

Crosstalk between nonalcoholic fatty liver disease and cardiometabolic syndrome

Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by fat accumulation combined with low‐grade inflammation in the liver. A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue and de novo lipogenesis can lead to NAFLD and insulin resistance. Thus, individuals with obesity, insulin resistance, and dyslipidaemia are at the greatest risk of developing NAFLD. Conversely, NAFLD is a phenotype of cardiometabolic syndrome. Notably, researchers have discovered a close association between NAFLD and impaired glucose metabolism and focused on the role of NAFLD in the development of type 2 diabetes. Moreover, recent studies provide substantial evidence for an association between NAFLD and atherosclerosis and cardiometabolic disorders. Even if NAFLD can progress into severe liver disorders including nonalcoholic steatohepatitis (NASH) and cirrhosis, the majority of subjects with NAFLD die from cardiovascular disease eventually. In this review, we propose a potential pathological link between NAFLD/NASH and cardiometabolic syndrome. The potential factors that can play a pivotal role in this link, such as inflammation, insulin resistance, alteration in lipid metabolism, oxidative stress, genetic predisposition, and gut microbiota are discussed.     

Lipid-lowering agents in the management of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease in developed countries and is associated not only with increased risk for liver disease-related complications but also with higher cardiovascular morbidity. Accordingly, lipid-lowering agents are frequently considered in these patients to reduce cardiovascular risk. However, there have been concerns regarding the safety of these agents in patients with chronic liver diseases. In the present review, we discuss the safety of lipid-lowering agents in patients with NAFLD as well as their effects on both cardiovascular and liver disease in this population. Accumulating data suggest that statins are safe in patients with NAFLD and that they reduce the increased cardiovascular morbidity of this population. However, it is still unclear whether statins are also useful as a treatment for NAFLD per se, since there are very limited and conflicting data on their effects on liver histology. There is also very scarce evidence regarding the safety and efficacy of other lipid-lowering agents in patients with NAFLD. Randomized controlled studies are needed to evaluate the role of lipid-lowering agents and particularly statins for the prevention of both cardiovascular and liver disease-related complications in this high-risk population.     

Crosstalk between dietary patterns,obesity and nonalcoholic fatty liver disease

The prevalence of nonalcoholic fatty liver disease (NAFLD) is rising worldwide, paralleling the epidemic of obesity. The liver is a key organ for the metabolism of proteins, fats and carbohydrates. Various types of fats and carbohydrates in isocaloric diets differently influence fat accumulation in the liver parenchyma. Therefore, nutrition can manage hepatic and cardiometabolic complications of NAFLD. Even moderately reduced caloric intake, which leads to a weight loss of 5%-10% of initial body weight, is effective in improving liver steatosis and surrogate markers of liver disease status. Among dietary patterns, the Mediterranean diet mostly prevents the onset of NAFLD. Furthermore, this diet is also the most recommended for the treatment of NAFLD patients. However, clinical trials based on the dietary interventions in NAFLD patients are sparse. Since there are only a few studies examining dietary interventions in clinically advanced stages of NAFLD, such as active and fibrotic steatohepatitis, the optimal diet for patients in these stages of the disease must still be determined. In this narrative review, we aimed to critically summarize the associations between different dietary patterns, obesity and prevention/risk for NAFLD, to describe specific dietary interventions’ impacts on liver steatosis in adults with NAFLD and to provide an updated overview of dietary recommendations that clinicians potentially need to apply in their daily practice.     

Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?

Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population worldwide and may confer increased cardiometabolic risk with consequent adverse cardiovascular outcomes independent of traditional cardiovascular risk factors and the metabolic syndrome. It is characterized almost universally by insulin resistance and is strongly associated with type 2 diabetes and obesity. Non-alcoholic fatty liver disease is a marker of pathological ectopic fat accumulation combined with a low-grade chronic inflammatory state. This results in several deleterious pathophysiological processes including abnormal glucose, fatty acid and lipoprotein metabolism, increased oxidative stress, deranged adipokine profile, hypercoaguability, endothelial dysfunction, and accelerated progression of atherosclerosis. This ultimately leads to a dysfunctional cardiometabolic phenotype with cardiovascular mortality representing the main mode of premature death in NAFLD. This review is aimed at introducing NAFLD to the clinical cardiologist by discussing in-depth the evidence to date linking NAFLD with cardiovascular disease, reviewing the likely mechanisms underlying this association, as well as summarizing from a cardiologist's perspective, current and potential future treatment options for this increasingly prevalent disease.     

Nonalcoholic fatty liver disease and vascular disease:State-of-the-art

Nonalcoholic fatty liver disease(NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis(NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis(increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific lifestyle modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular disease improving overall prognosis and survival.     

Nonalcoholic fatty liver disease and cardiovascular risk

Nonalcoholic fatty liver disease (NAFLD) is a very common cause of chronic liver disease in the United States. A large proportion of patients with NAFLD have coexisting metabolic syndrome, a major risk factor for cardiovascular disease. A strong association between NAFLD and cardiovascular disease has been long suspected, and recent studies have confirmed that cardiovascular disease is the single most important cause of mortality in this patient population. NAFLD may pose cardiovascular risk beyond the risk conferred by traditional factors such as dyslipidemia, diabetes, and smoking. Health care providers managing patients with NAFLD should recognize this increased cardiovascular risk and should undertake early, aggressive risk factor modification.     

Impact of current treatments on liver disease,glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials

Aims/hypothesis  

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH): NAFLD causes an increased risk of cardiovascular disease, diabetes and liver-related complications (the latter confined to NASH). The effect of proposed treatments on liver disease, glucose metabolism and cardiovascular risk in NAFLD is unknown. We reviewed the evidence for the management of liver disease and cardio-metabolic risk in NAFLD.     

Non-alcoholic fatty liver disease - the heart of the matter

Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease in the Western world. There is a close association with the metabolic syndrome and NAFLD is considered to be the hepatic manifestation of the metabolic syndrome. The components of the metabolic syndrome include hypertension, obesity and insulin resistance which are well established cardiovascular risk factors. The mortality rate of NAFLD patients from myocardial infarction is higher than that in the general United States population and there is also an increased risk of non-fatal cardiovascular events. This article reviews the cardiovascular complications associated with NAFLD. In order to provide comprehensive care of NAFLD patients, physicians need to be aware of, and search for, the cardiac morbidity associated with NAFLD.     

Nonalcoholic steatohepatitis versus steatosis: Adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism

Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH). Though liver-related risk seems confined to NASH, it is currently unclear whether NASH has a higher risk of cardiovascular disease (CVD) and diabetes than SS as a result of the coexistence of obesity and other cardiometabolic confounders. Adipose tissue is an emerging modulator of liver disease in NAFLD and of cardiometabolic disease in the general population. We evaluated in SS and NASH (1) glucose homeostasis and cardiovascular risk profile and (2) the effect of adipose tissue dysfunction, assessed in fasting conditions and postprandially, on liver injury, glucose and lipoprotein metabolism, and markers of early atherosclerosis. Forty nonobese, nondiabetic, normolipidemic biopsy-proven NAFLD patients (20 with SS and 20 with NASH) and 40 healthy subjects, matched for overall/abdominal adiposity and metabolic syndrome, underwent an oral fat load test, with measurement of plasma triglyceride-rich lipoproteins, oxidized low-density lipoproteins, adipokines, and cytokeratin-18 fragments, and an oral glucose tolerance test with minimal model analysis to yield glucose homeostasis parameters. Circulating endothelial adhesion molecules were measured, and adipose tissue insulin resistance (adipose IR) index and visceral adiposity index were calculated. Despite similar fasting values, compared to SS, NASH showed a more atherogenic postprandial lipoprotein profile, an altered adipokine response (i.e., higher resistin increase and an adiponectin fall), and hepatocyte apoptosis activation after fat ingestion. Adipose IR index, endothelial adhesion molecules, and hepatic insulin resistance progressively increased across NAFLD stages. NASH, but not SS, showed an impaired pancreatic β-cell function. On multiple regression analysis, adipose IR index and postprandial adiponectin independently predicted liver histology and altered cardiometabolic parameters. Conclusion: Adipose tissue dysfunction, including a maladaptive adipokine response to fat ingestion, modulates liver injury and cardiometabolic risk in NAFLD. (HEPATOLOGY 2012;56:933-942).     

非酒精性脂肪性肝病与动脉粥样硬化之间关系的研究进展

非酒精性脂肪性肝病( NAFLD)常与肥胖、糖尿病、高血脂、高血压以及代谢综合征合并存在,认为是代谢综合征的肝脏表现。NAFLD的患病率约20％～30％,在2型糖尿病人群中NAFLD患病率更高。NAFLD与心血管疾病(CVD)关系密切,NAFLD患者的主要死亡原因是CVD。NAFLD和动脉粥样硬化(AS)关系密切,其机制可能涉及氧化应激、炎症反应、脂代谢紊乱、脂肪激素水平的变化和胰岛素抵抗等方面。本文就NAFLD和AS间的关系以及可能机制进行综述。     

Non-alcoholic Fatty Liver Disease and Cardiovascular Disease Risk

Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of liver disease in the United States and worldwide. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development and progression of cardiovascular disease (CVD). Recent prospective studies demonstrated that NAFLD, especially in its necroinflammatory form (NASH), is linked to an increased risk of CVD, independently of obesity and other shared cardiometabolic risk factors. This suggests that NAFLD/NASH is not merely a marker of CVD, but may also be actively involved in its pathogenesis, possibly through the systemic release of proinflammatory/proatherogenic factors from the inflamed/steatotic liver as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia. Health care providers managing NAFLD patients should recognize this increased CVD risk and undertake early, aggressive risk factor modification.     

The clinical aspects of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) has been increasingly recognized as the most common pathological conditions affecting the liver. In concert with the increase in Body Mass Index in developed countries that has occurred during the last decades, more and more individuals referred for evaluation of abnormal liver tests are found to have NAFLD. In most cases, the increase in fat within the liver is not associated with impaired liver structure or function in the long-term. However, liver steatosis should be considered to be a marker of the metabolic syndrome. A minority of patients with NAFLD develop liver cirrhosis but NAFLD is probably the most common underlying cause of cryptogenic cirrhosis. Patients with NAFLD have an increased cardiovascular mortality as well as increase in liver related complications compared with matched controls. The diagnostic evaluation of a patient with suspected NAFLD depends heavily on the setting. In whom and when a liver biopsy is indicated is controversial. An adequate history is of major importance and when alcohol is suspected to be a contributing factor to the liver steatosis, several biochemical and clinical parameters may differentiate alcoholic fatty liver and NAFLD. Unfortunately, no histological gold standard is available for non-alcoholic steatohepatitis (NASH) and there is still a significant diversity among pathologist concerning the minimal requirements for the term NASH. Management of patients with NAFLD should be aimed at fighting the metabolic risk factors such as visceral obesity, hyperglycemia, type II diabetes mellitus (DM) and hypertriglyceridemia. DM has been shown to be a predictor of worsening of fibrosis. Successful lifestyle modification with increased exercise and decreased food intake is able to remove the accumulation of liver fat and can reverse insulin resistance. Unfortunately, there are no well-controlled, randomized trials of weight control as therapy for NAFLD. Some pharmacological pilot trials have been undertaken in NAFLD, but no proved treatment for all patients with NAFLD and/or NASH is available at the current time.     

Nonalcoholic fatty liver disease as a sentinel marker for the development of diabetes mellitus in non-obese subjects

BackgroundNon alcoholic fatty liver disease (NAFLD) is associated with substantial cardiometabolic morbidity.AimsWe evaluated the long-term extrahepatic complications of NAFLD and sought to evaluate NAFLD in non-obese subjects.MethodsA total of 2920 participants were retrospectively selected from a health check-up center in 2000, and followed through to December 2010. NAFLD was diagnosed using ultrasonography. Subjects were stratified according to body mass index, NAFLD, and metabolic syndrome.ResultsThe prevalence of non-obese NAFLD subjects and metabolically unhealthy non-obese subjects was 14.4% and 8.7%, respectively. In the multivariate analysis, non-obese NAFLD subjects had a significantly higher risk for diabetes mellitus (DM; HR 2.69, 95% CI 1.72–4.20, P < 0.001); no increase was observed for hypertension or cardiovascular disease. Metabolically unhealthy non-obese subjects had a significantly higher risk for hypertension (HR 2.75, 95% CI 2.02–3.74, P < 0.001), DM (HR 5.72, 95% CI 3.68–8.89, P < 0.001), and cardiovascular disease (HR 2.93, 95% CI 1.53–5.63, P = 0.001). Subgroup analysis of non-obese subjects showed that NAFLD, without metabolic syndrome, conferred a higher risk for DM (HR 3.60, 95% CI 2.03–6.39, P < 0.001).ConclusionNon-obese subjects with NAFLD are at a higher risk for DM independent of metabolic syndrome.     

Nonalcoholic steatohepatitis and the cardiometabolic syndrome

Nonalcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the United States and involves a spectrum of progressive histopathologic changes. Common risk factors associated with NAFLD include obesity, diabetes, and hyperlipidemia. Although most patients with NAFLD have simple hepatic steatosis, a significant number develop nonalcoholic steatohepatitis, which may progress to fibrosis, cirrhosis, or end-stage liver disease. There is increasing evidence that NAFLD is a common feature in patients with the cardiometabolic syndrome, a onstellation of metabolic, cardiovascular, renal, and inflammatory abnormalities in which insulin resistance is thought to play a key role in end-organ pathogenesis. NAFLD is usually diagnosed after abnormal liver chemistry results are found during routine laboratory testing. No therapy has been proven effective for treating NAFLD/nonalcoholic steatohepatitis. Expert opinion emphasizes the importance of exercise, weight loss in obese and overweight individuals, treatment of hyperlipidemia, and glucose control.     

Non-alcoholic fatty liver disease and cardiovascular risk

Non-alcoholic fatty liver disease(NAFLD) is a chronic liver disease associated with insulin resistance and metabolic syndrome. The spectrum of disease ranges from simple steatosis to steatohepatitis and progression to cirrhosis. Compelling evidence over the past several years has substantiated a significant link between NAFLD and cardiovascular disease ranging from coronary artery disease to subclinical carotid atherosclerosis. Close follow up, treatment of risk factors for NAFLD, and cardiovascular risk stratification are necessary to predict morbidity and mortality in this subset of patients.     

Non-alcoholic fatty liver disease is associated with cardiovascular disease risk markers

Recognition of the link between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) has boosted research in this area. The main objective of this paper is to review the literature on NAFLD in the context of CVD, focussing on underlying mechanisms and treatment. Besides excessive fatty acid influx, etiologic factors may include components of the metabolic syndrome, cytokines and mitochondrial dysfunction. NAFLD is associated with both hepatic and systemic insulin resistance. In the case of NAFLD, the liver overproduces several atherogenic factors, notably inflammatory cytokines, glucose, lipoproteins and coagulation factors, and factors increasing blood pressure. Intervention studies on diet and laparoscopic surgery revealed improvements of hepatic fat content and CVD risk profile. Pharmacological approaches with potential benefit have been developed as well, but effects are often confounded by weight change. NAFLD is associated with an increased CVD risk profile (and hepatic risk). In order to improve CVD risk profile, prevention and treatment of NAFLD seem advisable. However, well-designed intervention studies, randomized clinical trials and long-term follow-up studies are scarce.     

Combination drug treatment in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) includes simple steatosis, a benign condition, and non-alcoholic steatohepatitis, a condition that beyond TG accumulation also includes necroinflammation and fibrosis. An association between NAFLD and cardiovascular disease (CVD) has been recently suggested. NAFLD patients usually have an increased CVD risk profile. NAFLD is also associated with metabolic syndrome (MetS) and is considered as the hepatic component of MetS by some authors. Currently, the only established treatment of NAFLD is gradual weight loss. However, multifactorial treatment of NAFLD risk factors may be needed to reduce the increased CVD risk of NALFD patients. Drug combinations that include antiobesity drugs (such as orlistat and sibutramine) and target CVD risk factors may be a good approach to NAFLD patients. Our group has investigated the orlistat-fenofibrate combination treatment in obese patients with MetS and the orlistat-ezetimibe and sibutramine-antihypertensive combination treatment in obese patients with hyperlipidaemia with promising results in CVD risk factor reduction and improvement of liver function tests. Small studies give promising results but double-blind, randomized trials examining the effects of such multifactorial treatment in hard CVD endpoints in NAFLD patients are missing.     

Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis

Non-alcoholic fatty liver disease (NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and more severe liver complications such as cirrhosis, hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidaemia, and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and, to a lesser extent, to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus, oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed, with conflicting results. In particular, vitamin E supplementation has been suggested for the treatment of non-diabetic, non-cirrhotic adults with active NASH, although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol, silybin, L-carnitine and pentoxiphylline. No trial so far, has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New, large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed.