Non-alcoholic fatty liver disease and thyroid dysfunction:A systematic review

Thyroid hormones are totally involved in the regulation of body weight, lipid metabolism, and insulin resistance. Therefore it is anticipated that thyroid hormones may have a role in the pathogenesis of non alcoholic fatty liver disease(NAFLD) and non alcoholic steatohepatitis(NASH). In this study, we reviewed the current literature on the association between thyroid dysfunction and NAFLD/NASH. A search for English language medical literature reporting an association between thyroid dysfunction and NAFLD/NASH in humans was conducted across PubMed, ISI Web of Science, and Scopus in August, 2013. Out of 140 studies initially identified through the search, 11 relevant articles were included in the final review. Thyroid dysfunctions in the form of overt or subclinical hypothyroidism are prevalent among patients with NAFLD/NASH. Hypothyroidism appears to be an independent risk factor for NAFLD/NASH in some studies; however, other newly published studies failed to find such anassociation. The results of the studies on the role of thyroid abnormalities in NAFLD/NASH are inconsistent, and further research is recommended to determine the relationship between hypothyroidism and NAFLD/NASH and the underlying mechanisms.

Non-alcoholic fatty liver disease: What the clinician needs to know

Non-alcoholic fatty liver disease(NAFLD) is the most frequent cause of liver disease in the Western world. Furthermore, it is increasing worldwide, paralleling the obesity pandemic. Though highly frequent, only about one fifth of affected subjects are at risk of developing the progressive form of the disease, non-alcoholic steatohepatitis with fibrosis. Even in the latter, liver disease is slowly progressive, though, since it is so prevalent, it is already the third cause of liver transplantation in the United States, and it is predicted to get to the top of the ranking in few years. Of relevance, fatty liver is also associated with increased overall mortality and particularly increased cardiovascular mortality. The literature and amount of published papers on NAFLD is increasing as fast as its prevalence, which makes it difficult to keep updated in this topic. This review aims to summarize the latest knowledge on NAFLD, in order to help clinicians understanding its pathogenesis and advances on diagnosis and treatment.

Risk of cardiovascular,cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)has emerged as a public health problem of epidemic proportions worldwide.Accumulating clinical and epidemiological evidence indicates that NAFLD is not only associated with liver-related morbidity and mortality but also with an increased risk of coronary heart disease(CHD),abnormalities of cardiac function and structure(e.g.,left ventricular dysfunction and hypertrophy,and heart failure),valvular heart disease(e.g.,aortic valve sclerosis)and arrhythmias(e.g.,atrial fibrillation).Experimental evidence suggests that NAFLD itself,especially in its more severe forms,exacerbates systemic/hepatic insulin resistance,causes atherogenic dyslipidemia,and releases a variety of pro-inflammatory,pro-coagulant and pro-fibrogenic mediators that may play important roles in the pathophysiology of cardiac and arrhythmic complications.Collectively,these findings suggest that patients with NAFLD may benefit from more intensive surveillance and early treatment interventions to decrease the risk for CHD and other cardiac/arrhythmic complications.The purpose of this clinical review is to summarize the rapidly expanding body of evidence that supports a strong association between NAFLD and cardiovascular,cardiac and arrhythmic complications,to briefly examine the putative biological mechanisms underlying this association,and to discuss some of the current treatment options that may influence both NAFLD and its related cardiac and arrhythmic complications.

Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions

Non-alcoholic fatty liver disease(NAFLD) in children is becoming a major health concern. A "multiple-hit" pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance(IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis(NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data(BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR(acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy(the "imperfect" gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention.Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle changes. When morbid obesity prevails, bariatric surgery should be considered.

Pediatric non-alcoholic fatty liver disease:New insights and future directions

One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease(NAFLD),which is the most common form of liver disease in children.NAFLD is defined by hepatic fat infiltration > 5% hepatocytes,as assessed by liver biopsy,in the absence of excessive alcohol intake,viral,autoimmune and drug-induced liver disease.It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis,which,in turn,can evolve into cirrhosis and end stage liver disease.Obesity and insulin resistance are the main risk factors for pediatric NAFLD.In fact,NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome,prediabetes and type 2 diabetes mellitus(T2D).In particular,it has been clearly shown in obese youth that the prevalence of metabolic syndrome,pre-diabetes and type 2 diabetes increaseswith NAFLD severity progression.Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition.Recently,a non-synonymous SNP(rs738409),characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene(PNPLA3),has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children.Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein.The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes,is aimed at acting upon specific targets involved in the pathogenesis.There are some therapeutic approaches that are being studied in children.This article reviews the current knowledge regarding the pediatric fatty liver disease,the new insights and the future directions.

Comparison between metabolic-associated fatty liver disease and nonalcoholic fatty liver disease:From nomenclature to clinical outcomes

As a result of the obesity epidemic,Nonalcoholic fatty liver disease(NAFLD)and its complications have increased among millions of people.Consequently,a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis;metabolic-associated fatty liver disease(MAFLD).This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD.This article discusses the rationale behind the nomenclature change,the main differences,and its clinical implications.

Non-alcoholic fatty liver disease in 2015

There is worldwide epidemic of non-alcoholic fatty liver disease(NAFLD). NAFLD is a clinical entity related to metabolic syndrome. Majority of the patients are obese but the disease can affect non-obese individuals as well. Metabolic factors and genetics play important roles in the pathogenesis of this disorder. The spectrum of disorders included in NAFLD are benign macrovesicular hepatic steatosis, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis of liver and hepatocellular carcinoma. Although the disease remains asymptomatic most of the time, it can slowly progress to end stage liver disease. It will be the most common indication of liver transplantation in the future. It is diagnosed by abnormal liver chemistry, imaging studies and liver biopsy. As there are risks of potential complications during liver biopsy, many patients do not opt for liver biopsy. There are some noninvasive scoring systems to find out whether patients have advanced hepatic fibrosis. At the present time, there are limited treatment options which include lifestyle modification to loose weight, vitamin E and thioglitazones. Different therapeutic agents are being investigated for optimal management of this entity. There are some studies done on incretin based therapies in patients with NAFLD. Other potential agents will be silent information regulator protein Sirtuin and antifibrotic monoclonal antibody Simtuzumab against lysyl oxidase like molecule 2. But they are still in the investigational phase.

Clinical approaches to non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)ranges from simple steatosis to nonalcoholic steatohepatitis(NASH),leading to fibrosis and potentially cirrhosis,and it is one of the most common causes of liver disease worldwide.NAFLD is associated with other medical conditions such as metabolic syndrome,obesity,cardiovascular disease and diabetes.NASH can only be diagnosed through liver biopsy,but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis,reducing the need for liver biopsy and risk to patients.Disease progression varies between individuals and is linked to a number of risk factors.Mechanisms involved in the pathogenesis are associated with diet and lifestyle,influx of free fatty acids to the liver from adipose tissue due to insulin resistance,hepatic oxidative stress,cytokines production,reduced very low-density lipoprotein secretion and intestinal microbiome.Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD.Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial.Omega 3 polyunsaturated fatty acids and statins may offer additional benefits.Bariatric surgery should be considered in morbidly obese patients.More research is needed to assess the impact of these treatments on a long-term basis.The objective of this article is to briefly review the diagnosis,management and treatment of this disease in order to aid clinicians in managing these patients.

Treatment options for alcoholic and non-alcoholic fatty liver disease: A review

Alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are serious health problems worldwide.These two diseases have similar pathological spectra,ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma.Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver(simple steatosis),a small percentage develops progressive liver disease.Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available.The treatment for ALD remains as it was 50 years ago:abstinence,nutritional support and corticosteroids(or pentoxifylline as an alternative if steroids are contraindicated).As for NAFLD,the treatment modality is mainly directed toward weight loss and co-morbidity management.Therefore,new pathophysiology directed therapies are urgently needed.However,the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy.Hence,a combination therapy towards multiple targets would eventually be required.In this review,we delineate the treatment options in ALD and NAFLD,including various new targeted therapies that are currently under investigation.We hope that soon we will be having an effective multi-therapeutic regimen for each disease.

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age?

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.

Current guidelines for the management of non-alcoholic fatty liver disease:A systematic review with comparative analysis

The current epidemic of non-alcoholic fatty liver disease(NAFLD) is reshaping the field of hepatology all around the world.The widespread diffusion of metabolic risk factors such as obesity,type2-diabetes mellitus,and dyslipidemia has led to a worldwide diffusion of NAFLD.In parallel to the increased availability of effective anti-viral agents,NAFLD is rapidly becoming the most common cause of chronic liver disease in Western Countries,and a similar trend is expected in Eastern Countries in the next years.This epidemic and its consequences have prompted experts from all over the word in identifying effective strategies for the diagnosis,management,and treatment of NAFLD.Different scientific societies from Europe,America,and Asia-Pacific regions have proposed guidelines based on the most recent evidence about NAFLD.These guidelines are consistent with the key elements in the management of NAFLD,but still,show significant difference about some critical points.We reviewed the current literature in English language to identify the most recent scientific guidelines about NAFLD with the aim to find and critically analyse the main differences.We distinguished guidelines from 5 different scientific societies whose reputation is worldwide recognised and who are representative of the clinical practice in different geographical regions.Differences were noted in: the definition of NAFLD,the opportunity of NAFLD screening in high-risk patients,the noninvasive test proposed for the diagnosis of NAFLD and the identification of NAFLD patients with advanced fibrosis,in the follow-up protocols and,finally,in the treatment strategy(especially in the proposed pharmacological management).These difference have been discussed in the light of the possible evolution of the scenario ofNAFLD in the next years.

Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: From “two hit theory” to “multiple hit model”

Nonalcoholic fatty liver disease(NAFLD) has become the dominant form of chronic liver disease in children and adolescents with the increasing prevalence of obesity worldwide. NAFLD represents a wide spectrum of conditions, ranging from fatty liver-which generally follows a benign, non-progressive clinical course-to non-alcoholic steatohepatitis, a subset of NAFLD that may progress to cirrhosis and end-stage liver disease or liver carcinoma. The underlying pathophysiological mechanism of "pediatric" NAFLD remains unclear, although it is strongly associated with obesity and insulin resistance. In this review we provide a general overview on the current understanding of NAFLD in children and adolescents, which underpins practice, enabling early diagnosis and appropriate therapeutic intervention for this life-threatening liver disease.

Prevalence of and risk factors for non-alcoholic fatty liver disease in a Chinese population: An 8-year follow-up study

AIM: To investigate the prevalence of and risk factors for non-alcoholic fatty liver disease(NAFLD) in a Chinese population.METHODS: A total of 1948 adults from China was followed for 8 years. A cross-sectional study was performed to investigate the prevalence of NAFLD at baseline, and then the participants were followed for 8 years to investigate risk factors for the development of NAFLD.RESULTS: A total of 1948 participants were enrolled at baseline, of whom 691 were diagnosed with NAFLD. During the 8-year follow-up, 337 baseline NAFLD-free participants developed NAFLD. They had a greaterincrease in body mass index(BMI), serum uric acid, fasting plasma glucose, very low-density lipoprotein cholesterol and a considerable decrease in high-density lipoprotein cholesterol. 123 participants who had NAFLD at baseline lost NAFLD during the 8-year follow-up period. They had a greater decrease in BMI, fasting plasma glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase.CONCLUSION: NAFLD is prevalent in Chinese population with a rapidly increasing tendency. It can be reversed when patients lose their weight, control their hyperlipidemia and hyperglycemia, and reduce the liver enzyme levels.

Lean-non-alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population

AIM: To study the prevalence and clinical biochemical, blood cell and metabolic features of lean-non-alcoholic fatty liver disease (lean-NAFLD) and its association with other diseases.

Vitamin D:A new player in non-alcoholic fatty liver disease?

Vitamin D through its active form 1a-25-dihydroxyvtamin D[1,25(OH)2D]is a secosteroid hormone that plays a key role in mineral metabolism.Recent years have witnessed a significant scientific interest on vitamin D and expanded its actions to include immune modulation,cell differentiation and proliferation and inflammation regulation.As our understanding of the many functions of vitamin D has grown,the presence of vitamin D deficiency has become one of the most prevalent micronutrient deficiencies worldwide.Concomitantly,non-alcoholic fatty liver disease(NAFLD)has become the most common form of chronic liver disease in western countries.NAFLD and vitamin D deficiency often coexist and epidemiologic evidence has shown that both of these conditions share several cardiometabolic risk factors.In this article we provide an overview of the epidemiology and pathophysiology linking NAFLD and vitamin D deficiency,as well as the available evidence on the clinical utility of vitamin D supplementation in NAFLD.

What is the role of adiponectin in obesity related non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries.Insulin resistance is a key factor in the pathogenesis of NAFLD,the latter being considered as the hepatic component of insulin resistance or obesity.Adiponectin is the most abundant adipose-specific adipokine.There is evidence that adiponectin decreases hepatic and systematic insulin resistance,and attenuates liver inflammation and fibrosis.Adiponectin generally predicts steatosis grade and the severity of NAFLD;however,to what extent this is a direct effect or related to the presence of more severe insulin resistance or obesity remains to be addressed.Although there is no proven pharmacotherapy for the treatment of NAFLD,recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications.In this adiponectin-focused review,the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are analyzed systematically.

Non-alcoholic fatty liver disease and diabetes: From physiopathological interplay to diagnosis and treatment

Non-alcoholic fatty liver disease(NAFLD)is highly prevalent in patients with diabetes mellitus and increasing evidence suggests that patients with type 2diabetes are at a particularly high risk for developing the progressive forms of NAFLD,non-alcoholic steatohepatitis and associated advanced liver fibrosis.Moreover,diabetes is an independent risk factor for NAFLD progression,and for hepatocellular carcinoma development and liver-related mortality in prospective studies.Notwithstanding,patients with NAFLD have an elevated prevalence of prediabetes.Recent studies have shown that NAFLD presence predicts the development of type2 diabetes.Diabetes and NAFLD have mutual pathogenetic mechanisms and it is possible that genetic and environmental factors interact with metabolic derangements to accelerate NAFLD progression in diabetic patients.The diagnosis of the more advanced stages of NAFLD in diabetic patients shares the same challenges as in non-diabetic patients and it includes imaging and serological methods,although histopathological evaluation is still considered the gold standard diagnostic method.An effective established treatment is not yet available for patients with steatohepatitis and fibrosis and randomized clinical trials including only diabetic patients are lacking.We sought to outline the published data including epidemiology,pathogenesis,diagnosis and treatment of NAFLD in diabetic patients,in order to better understand the interplay between these two prevalent diseases and identify the gaps that still need to be fulfilled in the management of NAFLD in patients with diabetes mellitus.

What about non-alcoholic fatty liver disease as a new criterion to define metabolic syndrome?

Non-alcoholic fatty liver disease (NAFLD) is currently not a component of the diagnostic criteria for metabolic syndrome (MetS); however, the development of NAFLD has some common mechanisms with the development of MetS, as they share the pathophysiologic basis of insulin resistance. It is also recognized that NAFLD is the hepatic manifestation of MetS. To define MetS, the presence of at least three of the proposed criteria is required, and sometimes it is sufficient to have only one laboratory value, modified by diet or drugs, for the classification of MetS. Ultrasonographically-detected NAFLD (US-NAFLD) is more stable, only changing during the middleto long-term. Although controversies over MetS continue, and considering that abdominal ultrasonography for diagnosing NAFLD has high specificity and guidelines to modify the natural course of NAFLD by diet composition or lifestyle have not yet been established, why should we not introduce US-NAFLD as a new criterion to define MetS?

Could metabolic syndrome lead to hepatocarcinoma via non-alcoholic fatty liver disease?

It was estimated that from 2002 to 2008 the risk of developing cancer increased a quarter-fold in men and two-fold in women due to excessive BMI. Obesity, metabolic syndrome and type 2 diabetes mellitus are strictly related and are key pathogenetic factors of non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease worldwide. The most important consequence of the “metabolic epidemics” is the probable rise in the incidence of hepatocarcinoma (HCC), and NAFLD is the major causative factor. Adipose tissue is not merely a storage organ where lipids are preserved as an energy source. It is an active organ with important endocrine, paracrine, and autocrine actions in addition to immune functions. Adipocytes produce a wide range of hormones, cytokines, and growth factors that can act locally in the adipose tissue microenvironment and systemically. In this article, the main roles of insulin growth factor (IGF)-1 and IGF-2 are discussed. The role of IGF-2 is not only confined to HCC, but it may also act in early hepato-carcinogenesis, as pre-neoplastic lesions express IGF-2 mRNA. IGF-1 and IGF-2 interact with specific receptors (IGF-1R and IGF-2R). IGF-1R is over-expressed in in vitro and in animal models of HCC and it was demonstrated that IGF ligands exerted their effects on HCC cells through IGF-1R and that it was involved in the degeneration of pre-neoplastic lesions via an increase in their mitotic activity. Both IGF-2R and TGF β, a growth inhibitor, levels are reduced in human HCC compared with adjacent normal liver tissues. Another key mechanism involves peroxisome proliferator-activated receptor (PPAR)γ. In in vitro studies, PPARγ inhibited various carcinomas including HCC, most probably by regulating apoptosis via the p21, p53 and p27 pathways. Finally, as a clinical consequence, to improve survival, efforts to achieve a “healthier diet” should be promoted by physicians and politicians.

Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease

MicroRNAs(miRNAs) are small non-coding RNAs that regulate multiple physiological and pathological functions through the modulation of gene expression at the post-transcriptional level. Accumulating evidence has established a role for miRNAs in the development and pathogenesis of liver disease. Specifically, a large number of studies have assessed the role of miRNAsin alcoholic liver disease(ALD) and non-alcoholic fatty liver disease(NAFLD), two diseases that share common underlying mechanisms and pathological characteristics. The purpose of the current review is to summarize and update the body of literature investigating the role of miRNAs in liver disease. In addition, the potential use of miRNAs as biomarkers and/or therapeutic targets is discussed. Among all miRNAs analyzed, miR-34 a, miR-122 and miR-155 are most involved in the pathogenesis of NAFLD. Of note, these three miRNAs have also been implicated in ALD, reinforcing a common disease mechanism between these two entities and the pleiotropic effects of specific miRNAs. Currently, no single miRNA or panel of miRNAs has been identified for the detection of, or staging of ALD or NAFLD. While promising results have been shown in murine models, no therapeutic based-miRNA agents have been developed for use in humans with liver disease.