Natural History Of Nonalcoholic Fatty Liver Disease Research Articles

Recompensation in cirrhosis: unravelling the evolving natural history of nonalcoholic fatty liver disease.

Recompensation has gained increasing attention in the field of cirrhosis, particularly in chronic liver disease with a definite aetiology. The current global prevalence of obesity and nonalcoholic fatty liver disease (NAFLD) is increasing, but there is currently a lack of a clear definition for recompensation in NAFLD-related cirrhosis. Here, we provide an up-to-date perspective on the natural history of NAFLD, emphasizing the reversible nature of the disease, summarizing possible mechanisms underlying recompensation in NAFLD, discussing challenges that need to be addressed and outlining future research directions in the field. Recompensation is a promising goal in patients with NAFLD-related cirrhosis, and further studies are needed to explore its underlying mechanisms and uncover its clinical features.

Long-term major adverse liver outcomes in 1,260 patients with non-cirrhotic NAFLD

Long-term studies of the prognosis of NAFLD are scarce. Here, we investigated the risk of major adverse liver outcomes (MALO) in a large cohort of patients with NAFLD. We conducted a cohort study with data from Swedish university hospitals. Patients (n= 1,260) with NAFLD without cirrhosis were diagnosed through biopsy or radiology, and had fibrosis estimated through vibration-controlled transient elastography, biopsy, or FIB-4 score between 1974 and 2020 and followed up through 2020. Each patient was matched on age, sex, and municipality with up to 10 reference individuals from the general population (n= 12,529). MALO were ascertained from Swedish national registers. The rate of events was estimated by Cox regression. MALO occurred in 111 (8.8%, incidence rate= 5.9/1,000 person-years) patients with NAFLD and 197 (1.6%, incidence rate= 1.0/1,000 person-years) reference individuals during a median follow up of 13 years. The rate of MALO was higher in patients with NAFLD (hazard ratio= 6.6; 95% CI= 5.2-8.5). The risk of MALO was highly associated with the stage of fibrosis at diagnosis. In the biopsy subcohort (72% of total sample), there was no difference in risk between patients with and without non-alcoholic steatohepatitis. The 20-year cumulative incidences of MALO were 2% for the reference population, 3% for patients with F0, and 35% for F3. Prognostic information from biopsy was comparable to FIB-4 (C-indices around 0.73 vs. 0.72at 10 years). This study provides updated information on the natural history of NAFLD, showing a high rate of progression to cirrhosis in F3 and a similar prognostic capacity of non-invasive tests to liver biopsy. Several implications for clinical care and future research may be noted based on these results. First, the risk estimates for cirrhosis development are important when communicating risk to patients and deciding on clinical monitoring and treatment. Estimates can also be used in updated health-economic evaluations, and for regulatory agencies. Second, our results again highlight the low predictive information obtained from ascertaining NASHstatus by histology and call for more objective means by which to define NASH. Such methods may include artificial intelligence-supported digital pathology. We highlight that NASH is most likely the causal factor for fibrosis progression in NAFLD, but the subjective definition makes the prognostic value of a histological NASH diagnosis of limited value. Third, the finding that prognostic information from biopsy and the very simple Fibrosis-4 score were comparable is important as it may lead to fewer biopsies and further move the field towards non-invasive means by which to define fibrosis and, importantly, use non-invasive tests as outcomes in clinical trials. However, all modalities had modest discriminatory capacity and new risk stratification systems are needed in NAFLD. Repeated measures of non-invasive scores may be a potential solution.

Looking ahead to potential incretin combination therapies for nonalcoholic steatohepatitis in patients with diabetes

ABSTRACT Introduction There are no drugs approved by regulatory agencies for the treatment of nonalcoholic fatty liver disease (NAFLD); incretin combination therapies are being developed for treatment of type 2 diabetes and research has moved to test their usefulness in NAFLD. Areas covered We reviewed the literature on the effectiveness of dual and triple peptides combining receptor agonists of the glucagon-like peptide 1, the glucose-dependent insulinotropic peptide, and glucagon to treat NAFLD and its associated metabolic diseases, and/or the cardiovascular risk intimately connected with the cluster of the metabolic syndrome. Other combination peptides involved the glucagon-like peptide 2 receptor, the fibroblast growth factor 21, the cholecystokinin receptor 2, and the amylin receptor. Expert opinion Both dual and triple agonists are promising, based on animal, pharmacokinetic and proof-of concept studies, showing effectiveness both in the presence and the absence of diabetes on a few validated surrogate NAFLD biomarkers, but the majority of studies are still in progress. Considering the long natural history of NAFLD, final proof of their efficacy on primary clinical liver outcomes might be also derived from the analysis of large databases of National Healthcare Systems or Insurance companies, when used in diabetes for improving glycemic control, after careful propensity-score matching.

Editors' Note: Association of Nonalcoholic Fatty Liver Disease and Fibrosis With Incident Dementia and Cognition: The Rotterdam Study.

Dr. Xiao et al. investigated the association of nonalcoholic fatty liver disease (NAFLD) and fibrosis with incident dementia and cognition among participants in the Rotterdam Study, a prospective cohort study that included 3,975 patients with available fatty liver index (FLI), 4,577 patients with abdominal ultrasound, and 3,300 patients with liver stiffness assessments. NAFLD was defined as FLI ≥60 or steatosis on ultrasound and fibrosis as liver stiffness ≥8.0 kPa. Over 5 or more years of follow-up, NAFLD and liver fibrosis were not associated with an increased risk of incident dementia, and NAFLD was not associated with impaired cognitive function. Of interesting, NAFLD diagnosis was associated with a significantly decreased risk of incident dementia in the first 5 years of follow-up after FLI assessment. In response, Dr. Gupta notes the current lack of a biological model for linking NAFLD to protection from dementia, seeks evidence for weight loss–induced NAFLD regression, and wonders what phenomena might be occurring in these patients before vs after 5 years of follow-up to explain the study observations. Responding to these comments, the authors note that weight loss is the hallmark of NAFLD regressions, citing studies where regressions occurred even with slight weight reductions. They also note the interesting observation in several dementia cohorts (including theirs) of weight loss occurring in the years before dementia onset. By excluding the initial years of follow-up to address confounding by these intertwined mechanisms of weight loss and dementia, they note that the apparent beneficial effect of NAFLD disappeared. They posit that the presence of NAFLD may simply reflect the absence of weight loss rather than any true protective effect against dementia, but note the need for further studies to clarify these questions. This correspondence highlights the challenges of disentangling the complex interplay between weight loss and the natural history of NAFLD and dementia. Dr. Xiao et al. investigated the association of nonalcoholic fatty liver disease (NAFLD) and fibrosis with incident dementia and cognition among participants in the Rotterdam Study, a prospective cohort study that included 3,975 patients with available fatty liver index (FLI), 4,577 patients with abdominal ultrasound, and 3,300 patients with liver stiffness assessments. NAFLD was defined as FLI ≥60 or steatosis on ultrasound and fibrosis as liver stiffness ≥8.0 kPa. Over 5 or more years of follow-up, NAFLD and liver fibrosis were not associated with an increased risk of incident dementia, and NAFLD was not associated with impaired cognitive function. Of interesting, NAFLD diagnosis was associated with a significantly decreased risk of incident dementia in the first 5 years of follow-up after FLI assessment. In response, Dr. Gupta notes the current lack of a biological model for linking NAFLD to protection from dementia, seeks evidence for weight loss–induced NAFLD regression, and wonders what phenomena might be occurring in these patients before vs after 5 years of follow-up to explain the study observations. Responding to these comments, the authors note that weight loss is the hallmark of NAFLD regressions, citing studies where regressions occurred even with slight weight reductions. They also note the interesting observation in several dementia cohorts (including theirs) of weight loss occurring in the years before dementia onset. By excluding the initial years of follow-up to address confounding by these intertwined mechanisms of weight loss and dementia, they note that the apparent beneficial effect of NAFLD disappeared. They posit that the presence of NAFLD may simply reflect the absence of weight loss rather than any true protective effect against dementia, but note the need for further studies to clarify these questions. This correspondence highlights the challenges of disentangling the complex interplay between weight loss and the natural history of NAFLD and dementia.

Natural History of NAFLD.

The epidemiology and the current burden of chronic liver disease are changing globally, with non-alcoholic fatty liver disease (NAFLD) becoming the most frequent cause of liver disease in close relationship with the global epidemics of obesity, type 2 diabetes and metabolic syndrome. The clinical phenotypes of NAFLD are very heterogeneous in relationship with multiple pathways involved in the disease progression. In the absence of a specific treatment for non-alcoholic steatohepatitis (NASH), it is important to understand the natural history of the disease, to identify and to optimize the control of factors that are involved in disease progression. In this paper we propose a critical analysis of factors that are involved in the progression of the liver damage and the occurrence of extra-hepatic complications (cardiovascular diseases, extra hepatic cancer) in patients with NAFLD. We also briefly discuss the impact of the heterogeneity of the clinical phenotype of NAFLD on the clinical practice globally and at the individual level.

Treatments for NAFLD: State of Art.

Non-alcoholic fatty liver disease (NAFLD) is to date the most common chronic liver disease in clinical practice and, consequently, a major health problem worldwide. It affects approximately 30% of adults in the general population and up to 70% of patients with type 2 diabetes (T2DM). Despite the current knowledge of the epidemiology, pathogenesis, and natural history of NAFLD, no specific pharmacological therapies are until now approved for this disease and, consequently, general strategies have been proposed to manage it. They include: (a) lifestyle change in order to promote weight loss by diet and physical activity, (b) control of the main cardiometabolic risk factors, (c) correction of all modifiable risk factors leading the development and progression of advanced forms of NAFLD, and (d) prevention of hepatic and extra-hepatic complications. In the last decade, several potential agents have been widely investigated for the treatment of NAFLD and its advanced forms—shedding some light but casting a few shadows. They include some glucose-lowering drugs (such as pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose co-transporter-2 (SGLT-2) inhibitors), antioxidants (such as vitamin E), statins or other lipid lowering agents, bile and non-bile acid farnesoid X activated receptor (FXR) agonists, and others. This narrative review discusses in detail the different available approaches with the potential to prevent and treat NAFLD and its advanced forms.

Metabolic Imaging in Non-Alcoholic Fatty Liver Disease: Applications of Magnetic Resonance Spectroscopy.

Non-alcoholic fatty liver disease (NAFLD) is poised to dominate the landscape of clinical hepatology in the 21st century. Its complex, interdependent aetiologies, non-linear disease progression and uncertain natural history have presented great challenges to the development of effective therapies. Progress will require an integrated approach to uncover molecular mediators, key pathogenic milestones and response to intervention at the metabolic level. The advent of precision imaging has yielded unprecedented insights into these processes. Quantitative imaging biomarkers such as magnetic resonance imaging (MRI), spectroscopy (MRS) and elastography (MRE) present robust, powerful tools with which to probe NAFLD metabolism and fibrogenesis non-invasively, in real time. Specific advantages of MRS include the ability to quantify static metabolite concentrations as well as dynamic substrate flux in vivo. Thus, a vast range of key metabolic events in the natural history of NAFLD can be explored using MRS. Here, we provide an overview of MRS for the clinician, as well as key pathways exploitable by MRS in vivo. Development, optimisation and validation of multinuclear MRS, in combination with other quantitative imaging techniques, may ultimately provide a robust, non-invasive alternative to liver biopsy for observational and longitudinal studies. Through enabling deeper insight into inflammatory and fibrogenic cascades, MRS may facilitate identification of novel therapeutic targets and clinically meaningful endpoints in NAFLD. Its widespread use in future could conceivably accelerate study design, data acquisition and availability of disease-modifying therapies at a population level.

The Natural History of NAFLD, a Community-Based Study at a Large Health Care Delivery System in the United States.

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. However, the natural history of NAFLD is incomplete. This is a retrospective cohort study of patients identified with NAFLD by diagnosis codes in a large, community-based health care delivery system. The objectives were (1) to follow patients from initial NAFLD presentation through progression to cirrhosis and/or decompensated cirrhosis to liver cancer, liver transplant, and death for up to 10 years; and (2) to conduct disease progression analysis restricted to patients with NAFLD identified as having diabetes at baseline. A total of98,164 patients with full NAFLD and 26,488 with diabetes were divided into three baseline prevalent states: (1) no cirrhosis, (2) compensated cirrhosis, and (3) decompensated cirrhosis. In baseline patients without cirrhosis, annual rates of compensated cirrhosis, decompensated cirrhosis, and death were 0.28%, 0.31%, and 0.63% per year, respectively. With baseline compensated cirrhosis, the annual rates of decompensation and death were 2.4% and 6.7% per year. Finally, in those with decompensated cirrhosis at baseline, the death rate was 8.0% per year. In those without cirrhosis and with cirrhosis at baseline, the rates of liver cancer and death were increased approximately 2-fold in the diabetic subpopulation compared with the full NAFLD cohort. Age and comorbidities increased with increasing disease severity. Cox proportional hazards regression analysis showed that cirrhosis was strongly associated with death and liver cancer, and that diabetes was associated with a significant increase in the hazard of both liver cancer and death (2.56 [2.04-3.20] and 1.43 [1.35-1.52]), respectively. Conclusion: The findings of this community-based study further our understanding of the natural history of NAFLD and demonstrate that diabetes is a major factor in the progression of this disease.

Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by lipid accumulation in hepatocytes in the absence of excessive alcohol consumption. The global prevalence of NAFLD is constantly increasing. NAFLD is a disease spectrum comprising distinct stages with different prognoses. Non-alcoholic steatohepatitis (NASH) is a progressive condition, characterized by liver inflammation and hepatocyte ballooning, with or without fibrosis. The natural history of NAFLD is negatively influenced by NASH onset and by the progression towards advanced fibrosis. Pathogenetic mechanisms and cellular interactions leading to NASH and fibrosis involve hepatocytes, liver macrophages, myofibroblast cell subpopulations, and the resident progenitor cell niche. These cells are implied in the regenerative trajectories following liver injury, and impairment or perturbation of these mechanisms could lead to NASH and fibrosis. Recent evidence underlines the contribution of extra-hepatic organs/tissues (e.g., gut, adipose tissue) in influencing NASH development by interacting with hepatic cells through various molecular pathways. The present review aims to summarize the role of hepatic parenchymal and non-parenchymal cells, their mutual influence, and the possible interactions with extra-hepatic tissues and organs in the pathogenesis of NAFLD.

Non-alcoholic fatty liver disease: A growing public health problem in Turkey.

Non-alcoholic fatty liver disease (NAFLD) is histologically classified as either non-alcoholic fatty liver or non-alcoholic steatohepatitis (NASH). NASH is the progressive subtype of NAFLD. Individuals with NASH are at significant risk of developing hepatic fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related and all-cause mortality. NAFLD is closely associated with obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome, and cardiovascular events. Its prevalence is estimated to be above 30% in Turkey; and recent studies confirm this estimate. According to these studies, the prevalence of NAFLD in Turkey is between 48.3% and 60.1%. Currently, Turkey can be considered a risky region in terms of NAFLD burden as it is the most obese country in Europe with an obesity prevalence of 32.1% according to the 2016 World Health Organization data. Moreover, along with the increasing prevalence of obesity and T2DM in Turkey, the burden of NAFLD is estimated to increase in the upcoming decade. Despite the growing burden, we lack well-designed systemic studies that investigate NAFLD and its marked histological severity. In this review, we present studies on the burden of NAFLD and NASH, the natural history of NAFLD, and its association with other systemic diseases conducted with Turkish populations.

Too much medicine: overdiagnosis and overtreatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of liver disease. This remarkable rise in prevalence over the past 20 years is largely through the recognition of fatty liver in the absence of excessive alcohol consumption as a disease. The natural history of NAFLD is incompletely understood, and although a small proportion of individuals with NAFLD will develop complications of liver disease, most will not. This raises the prospect of widespread overdiagnosis of NAFLD. Clinical practice guidelines from the European specialist societies representing hepatology, endocrinology, and obesity endorse screening for NAFLD in at-risk groups, and this further increases the likelihood of overdiagnosis and consequent overtreatment through false-positive testing. Predictable outcomes of overdiagnosis include physical harms through investigation and treatment, and psychosocial harms through disease labelling. Prospective studies are required to better understand both the benefits and risks associated with an early diagnosis of NAFLD.

Screening for non-alcoholic fatty liver disease in children: do guidelines provide enough guidance?

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the industrialized world in children. Its high prevalence and important health risks make NAFLD highly suitable for screening. In practice, screening is widely, albeit not consistently, performed. To review the recommendations on screening for NAFLD in children. Recommendations on screening were reviewed from major paediatric obesity guidelines and NAFLD guidelines. A literature overview is provided on open questions and controversies. Screening for NAFLD is advocated in all obesity and most NAFLD guidelines. Guidelines are not uniform in whom to screen, and most guidelines do not specify how screening should be performed in practice. Screening for NAFLD remains controversial, due to lack of a highly accurate screening tool, limited knowledge to predict the natural course of NAFLD and limited data on its cost effectiveness. Guidelines provide little guidance on how screening should be performed. Screening for NAFLD remains controversial because not all conditions for screening are fully met. Consensus is needed on the optimal use of currently available screening tools. Research should focus on new accurate screening tool, the natural history of NAFLD and the cost effectiveness of different screening strategies in children.

AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions

This review summarizes our current understanding of nonalcoholic fatty liver disease (NAFLD), a multi-factorial systemic disease resulting from a complex interaction between a specific genetic background and multiple environmental/metabolic “hits”.The role of gut microbiota, lipotoxicity, inflammation and their molecular pathways is reviewed in-depth. We also discuss the epidemiology and natural history of NAFLD by pinpointing the remarkably high prevalence of NAFLD worldwide and its inherent systemic complications: hepatic (steatohepatitis, advanced fibrosis and cirrhosis), cardio-metabolic (cardiovascular disease, cardiomyopathy, arrhythmias and type 2 diabetes) and neoplastic (primary liver cancers and extra-hepatic cancers).Moreover, we critically report on the diagnostic role of non-invasive biomarkers, imaging techniques and liver biopsy, which remains the reference standard for diagnosing the disease, but cannot be proposed to all patients with suspected NAFLD.Finally, the management of NAFLD is also reviewed, by highlighting the lifestyle changes and the pharmacological options, with a focus on the innovative drugs.We conclude that the results of ongoing studies are eagerly expected to lead to introduce into the clinical arena new diagnostic and prognostic biomarkers, prevention and surveillance strategies as well as to new drugs for a tailored approach to the management of NAFLD in the individual patient.

Modern diagnostics of nonalcoholic fatty liver disease: noninvasive research methods

Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as the most common cause of chronic liver disease worldwide. NAFLD represents a wide spectrum of conditions, ranging from simple benign steatosis to nonalcoholic steatohepatitis, which sometimes progresses to cirrhosis and hepatocellular carcinoma. The pivotal issue in the management of patients with NAFLD is the diagnosis of steatohepatitis and fibrosis at an early stage. In this review we present recent data on nonalcoholic fatty liver disease evaluation. Although liver biopsy is regarded as the gold standard for assessment of hepatic steatosis and steatohepatitis, its use has several limitations, including the potential risk of sampling errors, intra- and interobserver variability, invasiveness and the stress it causes to patients, the high cost and the potential for complications. In this review a simple and reliable non-invasive alternative with indicated sensitivity and specificity is described. Non-invasive markers should aim ; in primary care settings, to identify the risk of developing NAFLD among individuals with increased metabolic risk; in secondary and tertiary care settings, to identify those with a worse prognosis, e.g. severe steatohepatitis; monitor disease progression; predict response to therapeutic interventions. Achieving these objectives could reduce the need for liver biopsy. Thus, according to the natural history of NAFLD, all patients with a low risk of developing advanced disease, eventually diagnosed by one of above non-invasive parameters, could be referred to primary care, whereas subjects at high risk of developing advanced disease should be sent to specialists for the evaluation of the degree of fibrosis and the choice of specific management. According to the Clinical Practice Guidelines for the management of NAFLD, ultrasound is the preferred first-line diagnostic procedure for imaging of NAFLD, as it provides additional diagnostic information. Whenever imaging tools are not available or feasible (e.g. large epidemiological studies), serum biomarkers and scores are an acceptable alternative for the diagnosis of steatosis. The combination of biomarkers/scores and transient elastography might confer additional diagnostic accuracy. At the same time, the identification of advanced fibrosis or cirrhosis by serum biomarkers/scores and/or elastography is less accurate and needs to be confirmed by liver biopsy, according to the clinical context. Аlthough there are a range of controversial issues regarding the use of non-invasive methods for the assessment of NAFLD, these methods are being actively developed, researched and introduced into clinical practice as an equivalent and substitute for liver biopsy.

PTH-112 Association between Helicobacter Pylori Infection and Nonalcoholic Fatty Liver Disease in The United States

Introduction Helicobacter pylori infection has been implicated in the pathogenesis of various gastrointestinal, hematologic, and systemic diseases. Association between Helicobacter pylori infection and nonalcoholic fatty liver disease (NAFLD) is poorly characterised. The aim of this study was to investigate the association between H. pylori positivity with cagA status and NAFLD in the large general population. Methods The Third National Health and Nutrition Examination Survey (NHANES) from 1988 to 1994 was utilised in this study. NAFLD was defined by ultrasonographic detection of hepatic steatosis without other known liver diseases. Antibodies to H. pylori and cagA of participants 20 years and older were measured in using ELISA. Results Among total of 5,404 participants who had results of both ultrasonography and H. pylori serology, the prevalence of NAFLD was 31.9%. The prevalence of NAFLD was higher in H. pylori positive subjects (33.5±1.79%) than in negative subjects (26.1±1.65%, p cagA positive group, participants with negative cagA had higher prevalence of NAFLD (31.1±2.30% vs. 36.4±2.37%, p H. pylori positivity in multivariable analysis (Odds ratio [OR]: 1.17; 95% confidence interval [CI]: 0.95–1.43) with marginal significance. With regard to presence of cagA protein, H. pylori and cagA positivity was not associated with NAFLD (OR: 1.05; 95% CI: 0.81–1.37) but, cagA negative H. pylori positivity was significantly associated with NAFLD in multivariable analysis (OR: 1.30; 95% CI: 1.01–1.67). Conclusion The prevalence of NAFLD was higher in H. pylori positive subjects than in negative subjects. Especially, cagA negative H. pylori positivity was significantly associated with NAFLD, independent of other known factors in the general population. References 1 Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 2007; 11 :1–16, vii. 2 Kim D, Kim WR, Kim HJ, Therneau TM. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2013; 57 :1357–65. 3 Chung GE, Kim D, Kim W, et al . Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. J Hepatol 2012; 57 :150–6. Disclosure of Interest None Declared

Global Epidemiology of Nonalcoholic Fatty Liver Disease and Perspectives on US Minority Populations.

Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome predicted to be the next global epidemic affecting millions of people worldwide. The natural course of this disease including its subtype, non-alcoholic steatohepatitis (NASH), is not clearly defined especially in the African-American segment of the US population. To conduct a review of the global epidemiology of NAFLD with emphasis on US minority populations. A thorough search of evidence-based literature was conducted using the Pubmed database and commercial web sources such as Medscape and Google Scholar. NAFLD and its subtype NASH are becoming the principal cause of chronic liver disease across the world. In the US, Hispanics are the most disproportionately affected ethnic group with hepatic steatosis, and elevated aminotransferase levels, whereas African-Americans are the least affected. Genetic disparities involved in lipid metabolism seem to be the leading explanation for the lowest incidence and prevalence of both NAFLD and NASH in African-Americans. The unprecedented rise in the prevalence of NAFLD globally requires an initiation of population cohort studies with long-term follow-up to determine the incidence and natural history of NAFLD and its underrepresentation in African-Americans. Future studies should also focus on the delineation of the interplay between genetic and environmental factors that trigger the development of NAFLD and NASH.

Treatment of Nonalcoholic Fatty Liver Disease: The Role of Medical, Surgical, and Endoscopic Weight Loss.

Nonalcoholic fatty liver disease (NAFLD) represents a rapidly growing cause of chronic liver disease in the United States and is associated with significant morbidity and mortality, including progression to liver cirrhosis and hepatocellular carcinoma. NAFLD comprises a spectrum of liver conditions, ranging from simple steatosis to steatosis with inflammation (steatohepatitis) and progressive fibrosis. Weight loss represents a first line therapeutic modality for the management of NAFLD. Herein, we review the evidence base for medical, surgical, and endoscopic approaches to weight loss and their potential impact on the natural history of NAFLD.

Epidemiology and Natural History of NAFLD.

SummaryParalleling the growing prevalence of obesity and metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) is emerging as the most frequent hepatopathy in adults and children. The true prevalence of pediatric NAFLD is still unknown, because of the heterogeneity of diagnostic methods used for diagnosis in the available studies and the different characteristics of the populations evaluated. Pediatric NAFLD is typically of primary origin and it is strongly associated with several features of the metabolic syndrome. Age, gender and race/ethnicity are significant determinants of risk, and sex hormones, insulin sensitivity and adipocytokines are implicated in the pathogenesis of pediatric NAFLD. The natural history of NAFLD in children is still poorly understood, because of its complex nature and the scarcity of prospective studies, especially in pediatric populations. Both genetic and environmental factors seem to be implicated in the development and progression of the disease via multiple mechanisms that involve liver crosstalk with other organs and tissues, especially gut and adipose tissue. To evaluate and effectively treat pediatric NAFLD, the pathophysiology and natural history of the disease should be clarified and noninvasive methods for screening, diagnosis, and longitudinal assessment developed.

Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolism

Genetic factors that predispose individuals to nonalcoholic fatty liver disease (NAFLD) and associated diabetes and cardiovascular disease are unclear. The transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) modulates lipogenesis and insulin sensitivity and was experimentally connected to NAFLD. We assessed the impact of a common SREBF-1c polymorphism on the incidence and severity of NAFLD and on associated glucose and lipoprotein dysmetabolism. We followed up 212 randomly selected, nonobese, nondiabetic, insulin-sensitive participants in a population-based study without NAFLD or metabolic syndrome at baseline who were characterized for the common SREBF-1c gene rs11868035 A/G polymorphism, dietary habits, physical activity, adipokine profile, C-reactive protein (CRP), and circulating markers of endothelial dysfunction. A comparable cohort of NAFLD patients underwent a liver biopsy, an oral-glucose-tolerance test with minimal model analysis of glucose homeostasis variables, and an oral-fat-tolerance test with measurement of plasma lipoproteins, adipokines, and cytokeratin-18 fragments. SREBF-1c predicted the 7-y incidence of NAFLD (OR: 1.71; 95% CI: 1.15, 2.53) and diabetes and the 7-y elevation in CRP and endothelial dysfunction markers. In biopsy-proven NAFLD patients, the SREBF-1c A allele conferred increased risk of severe steatosis and nonalcoholic steatohepatitis; more-severe hepatic, muscle, and adipose tissue insulin resistance; and pancreatic β cell dysfunction. SREBF-1c A allele carriers also had an impaired oral fat tolerance with a postprandial accumulation of large triglyceride-rich lipoproteins and oxidized LDLs, lower HDL cholesterol and adiponectin concentrations, and cytokeratin-18 fragment elevation. SREBF-1c polymorphism is associated with increased risk of developing NAFLD with more severe liver histology and derangement in glucose and lipoprotein metabolism, which contribute to the presentation and natural history of NAFLD.

Epidemiology and Natural History of Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease burden across the world. By definition, although the histopathologic features of NAFLD are identical to that of alcoholic liver disease, its diagnosis requires absence of significant alcohol use and absence of other causes of chronic liver disease. We now know that NAFLD is not simply a disease of the Western world. It is manifested across the world, in varying rates, across gender, across varying ethnicities, and in its association with other host factors. In this review article, the definition of NAFLD, its spectrum, ranging from mild steatosis to hepatocellular injury and inflammation defined as non-alcoholic steatohepatitis (NASH) is discussed. Mild steatosis is generally a stable disease whereas NASH can be progressive. Based on current published literature, current incidence and prevalence of NAFLD and NASH are discussed. It is also accepted that these processes will continue to increase in prevalence with the rise of obesity, type II diabetes, and associated metabolic syndrome. Some of the risk factors have been well-established and are discussed. In addition, this review also presents emerging associations with other risk factors for NAFLD. Natural history of NAFLD is variable depending upon the histologic subtypes and other underlying comorbidities and is discussed in this review as well.