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<!doctype html> <html lang="en" xmlns:mml="http://www.w3.org/1998/Math/MathML"> <head> <title>Recent Epidemiology of Nonalcoholic Fatty Liver Disease</title>  <script async src="https://www.googletagmanager.com/gtag/js?id=G-5QF0037K49"></script> <script> window.dataLayer = window.dataLayer || []; function gtag(){dataLayer.push(arguments);} gtag('js', new Date()); gtag('config', 'UA-3438586-31'); gtag('config', 'G-5QF0037K49'); </script> <meta charset="utf-8"> <meta name="viewport" content="user-scalable=no, initial-scale=1.0, maximum-scale=1.0, minimum-scale=1.0, width=device-width" /> <meta name="HandheldFriendly" content="true"> <meta name="format-detection" content="telephone=no"> <meta http-equiv="X-UA-Compatible" content="IE=Edge"> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_doi" content="10.5009/gnl20127" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_abstract_html_url" content="https://www.gutnliver.org/journal/view.html?doi=10.5009/gnl20127" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_pdf_url" content="https://www.gutnliver.org/journal/download_pdf.php?doi=10.5009/gnl20127" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_volume" content="15" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_issue" content="2" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_firstpage" content="206" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_lastpage" content="216" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_journal_title" content="Gut and Liver" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_journal_title_abbrev" content="Gut and Liver" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_publisher" content="Editorial Office of Gut and Liver" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_keywords" content="Fatty liver; Nonalcoholic steatohepatitis; Prevalence; Mortality; Natural history" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_author" content="Soumya Murag"> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_author_institution" content="Department of Medicine, Santa Clara Valley Medical Center, Santa Clara, CA, USA"> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_author" content="Aijaz Ahmed"> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_author_institution" content="Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA"> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_author" content="Donghee Kim"> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_author_institution" content="Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA"> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_title" content="Recent Epidemiology of Nonalcoholic Fatty Liver Disease" /> <meta xmlns="https://www.w3.org/1999/xhtml" name="citation_online_date" content="2020/09/15" /> <meta name="dc.title" content="Recent Epidemiology of Nonalcoholic Fatty Liver Disease" /> <meta name="dc.type" content="text" /> <meta name="dc.publisher" content="Editorial Office of Gut and Liver" /> <meta name="dc.contributors" content="Soumya Murag, Aijaz Ahmed, and Donghee Kim" /> <meta name="dc.date" content="2021/03/15" /> <meta name="dc.identifier" content="doi:10.5009/gnl20127" /> <meta name="dc.language" content="en" /> <meta property="og:title" content="Recent Epidemiology of Nonalcoholic Fatty Liver Disease"> <meta property="og:url" content="https://www.gutnliver.org/journal/view.html?doi=10.5009/gnl20127"> <meta property="og:image" content="https://www.gutnliver.org/asset/images/og-img.jpg"> <meta property="og:type" content="article"> <meta property="og:site_name" content="Gut and Liver"> <meta property="og:description" content="Soumya Murag, Aijaz Ahmed, and Donghee Kim. 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Aims and Scope <i class="xi-plus"></i></a> <div class="help-sub-list"> <p> Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. <a href="/content/about/aims_and_scope.html" class="more">+MORE</a> </p> </div> </li> <li> <a href="#n">2. 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2012-05-10 페이지내 section 링크 function ViewNamePositionFun(ID) { location.href = "/journal/view.html?doi=10.5009/gnl20127" + ID; return false; } // Blue !!! 2012-05-10 참고문헌 연결시 배경색을 넣음. var tmpID = ""; function ViewReferencePositionFun(ID) { if (tmpID) document.getElementById(tmpID.substring(1)).style.backgroundColor = "#FFFFFF"; location.href = "/journal/view.html?doi=10.5009/gnl20127" + ID; document.getElementById(ID.substring(1)).style.backgroundColor = "#F2F2FF"; tmpID = ID; } //]]> </script> <a href="#n" class="btn-split"><img src="/asset/images/sub/ic-split.png" alt=""> Split Viewer</a> <div class="section01"> <h2></h2> </div> <div id="origin_a"> <div class="inner_content">  <script src="https://crossmark-cdn.crossref.org/widget/v2.0/widget.js"></script> <a data-target="crossmark"><img src="//crossmark-cdn.crossref.org/widget/v2.0/logos/CROSSMARK_Color_horizontal.svg" width="150" /></a> <div class="origin_section02"><h2>Recent Epidemiology of Nonalcoholic Fatty Liver Disease</h2><p>Soumya Murag<sup>1</sup> <a href='https://orcid.org/0000-0002-7548-2281' target='_blank' title="Soumya Murag"><img src='/journal/img/orcid.png' ></a>, Aijaz Ahmed<sup>2</sup> <a href='https://orcid.org/0000-0002-3609-8586' target='_blank' title="Aijaz Ahmed"><img src='/journal/img/orcid.png' ></a>, Donghee Kim<sup>2</sup> <a href='https://orcid.org/0000-0003-1919-6800' target='_blank' title="Donghee Kim"><img src='/journal/img/orcid.png' ></a></p><div class="text-right"><a href="#n" class="author-info-btn btn">Author Info <sup>+</sup></a></div><p class="author-info"><sup>1</sup>Department of Medicine, Santa Clara Valley Medical Center, Santa Clara, CA, and <sup>2</sup>Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA</p><p><strong>Correspondence to: </strong>Donghee Kim<br>ORCID <a href="https://orcid.org/0000-0003-1919-6800"><span class="link">https://orcid.org/0000-0003-1919-6800</span></a><br>E-mail <a href="mailto:dhkimmd@stanford.edu">dhkimmd@stanford.edu</a></p><div class="origin_date"><strong >Received</strong>: April 13, 2020; <strong >Revised</strong>: May 26, 2020; <strong >Accepted</strong>: May 26, 2020</div><p class="origin_txt">This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<a href="http://creativecommons.org/licenses/by-nc/4.0" onclick="window.open(this.href);return false;" class="link">http://creativecommons.org/licenses/by-nc/4.0</a>) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></div> <div class="origin_section01"><p>Gut Liver 2021;15(2):206-216. <span class="link"><a href='https://doi.org/10.5009/gnl20127' target='_blank'>https://doi.org/10.5009/gnl20127</a></span></p><p><strong>Published online</strong> September 15, 2020, <strong>Published date</strong> March 15, 2021 </p><p>Copyright © Gut and Liver.</p> </div> <div class="origin_section03" id="body00"> <div class="section03_tit clear"> <h3>Abstract</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><p>The ongoing obesity epidemic and the increasing recognition of metabolic syndrome have contributed to the growing prevalence of nonalcoholic fatty liver disease (NAFLD), the most common form of liver disease worldwide. It is imperative to understand the incidence and prevalence of NAFLD as it is associated with a profound economic burden of hospitalizations, including the shifting trends in liver transplantation. The long-term cumulative healthcare cost of NAFLD patients has been shown to be 80% higher than that of non-NAFLD patients. We explore diagnostic challenges in identifying those with NAFLD who have a higher predilection to progress to end-stage liver disease. We aim to assess all-cause and cause-specific mortality as it relates to NAFLD.</p><p><strong>Keywords</strong>: Fatty liver, Nonalcoholic steatohepatitis, Prevalence, Mortality, Natural history</p></div></div> <div class="origin_section03" id="body01"> <div class="section03_tit clear"> <h3>INTRODUCTION</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div><p>Fatty infiltration of the liver was only sporadically recognized in early literature and generally felt to be a benign condition. Until the 1990s, most studies recognized nonalcoholic fatty liver disease (NAFLD) as an “innocent bystander” rather than the “guilty party” in patients with cryptogenic cirrhosis,<sup><span class="xref"><a href="#B1">1</a></span></sup> which was commonly used for end-stage liver disease in which the underlying etiology remains unidentified. The landmark comment by Ludwig <italic>et al.</italic><sup><span class="xref"><a href="#B2">2</a></span></sup> in 1980 first described the term “nonalcoholic steatohepatitis (NASH)” after identifying 20 nonalcoholic patients with liver biopsies showing changes similar to alcoholic hepatitis. Caldwell <italic>et al.</italic><sup><span class="xref"><a href="#B3">3</a></span></sup> recognized that the risk factors for cryptogenic cirrhosis paralleled those for NASH and NAFLD. Subsequent studies found that cirrhosis tends to occur at an older age in obese patients, further suggesting cryptogenic cirrhosis as a downstream effect of NASH and NAFLD.<sup><span class="xref"><a href="#B4">4</a></span></sup></p> <p>A major limitation in understanding the epidemiology of NAFLD has been the lack of a distinct classification of the disease. For example, under the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9 CM), NAFLD has been grouped under cryptogenic cirrhosis or “other chronic nonalcoholic liver diseases” or “unspecified chronic liver disease without alcohol,” underestimating at least 42.1% of individuals with NAFLD that were otherwise diagnosed by chart review.<sup><span class="xref"><a href="#B5">5</a></span></sup> The misclassification of nomenclature has been an inherent problem in understanding pathophysiology and the prevalence of NAFLD, and its impact on downstream health outcomes. This review on NAFLD will further explore the current trends in epidemiology, recognize the importance of establishing the diagnosis of NAFLD in the context of chronic liver disease, and explore the diagnostic nuances in tracking the progression of NAFLD over time.</p></div></div></div> <div class="origin_section03" id="body02"> <div class="section03_tit clear"> <h3>DEFINITIONS</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div><p>The diagnosis of NAFLD requires more than or equal to 5% of hepatic fat accumulation and exclusion of other etiologies of liver disease such as viral hepatitis, autoimmune liver disease, hemochromatosis, Wilson’s disease, drug-induced liver disease as well as significant alcohol consumption.<sup><span class="xref"><a href="#B6">6</a></span></sup> The American Association for the Study of Liver Diseases Practice Guideline for NAFLD defines significant alcohol consumption as current or recent alcohol consumption of >21 standard drinks per week in men and >14 drinks per week in women over 2 year period.<sup><span class="xref"><a href="#B6">6</a></span></sup> Diagnosis of NAFLD needs to be ruled out secondary causes of fatty infiltration, including lipodystrophy, starvation, Cushing’s disease, and steatogenic medications (corticosteroids, amiodarone, methotrexate, tamoxifen, and anti-retroviral therapy).<sup><span class="xref"><a href="#B6">6</a></span></sup> As seen in <span class="xref"><a href="#T1">Table 1</a></span>, NAFLD refers to a broad array of histological variety from nonalcoholic fatty liver (NAFL) to NASH, which may or may not present with fibrosis that can progress to end-stage liver diseases such as cirrhosis or hepatocellular carcinoma (HCC).<sup><span class="xref"><a href="#B7">7</a></span></sup> NASH is defined as the presence of over 5% of hepatic fat accumulation and lobular inflammation with hepatocyte ballooning degeneration, with or without any fibrosis.<sup><span class="xref"><a href="#B6">6</a></span></sup> NASH cirrhosis is defined as the presence of cirrhosis with current or previous histological evidence of NAFL or NASH.<sup><span class="xref"><a href="#B6">6</a></span></sup></p></div></div></div> <div class="origin_section03" id="body03"> <div class="section03_tit clear"> <h3>EPIDEMIOLOGY</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div><h3>1. Incidence of NAFLD</h3> <p>There are scattered and limited data regarding the incidence of NAFLD in the general population. With the recent transition to ICD-10-CM with a specific diagnostic code for NAFLD, a study in England showed the incidence rate of NAFLD of 29 per 100,000 person-years with significant underestimated rates due to ICD-10 code.<sup><span class="xref"><a href="#B8">8</a></span></sup> A meta-analysis published in 2016 showed that the pooled regional incidence rate estimates for Israel and Asia were 28.0 per 1,000 person-years (95% confidence interval [CI], 19.3 to 40.6) and 52.3 per 1,000 person-years (95% CI, 28.3 to 96.8) and respectively.<sup><span class="xref"><a href="#B9">9</a></span></sup> A recent meta-analysis in Asia during 1999 to 2019, described the overall pooled incidence rate was 50.9 per 1,000 person-years (95% CI, 44.8 to 57.4).<sup><span class="xref"><a href="#B10">10</a></span></sup> Regarding trends in incidence of NAFLD, a community cohort study in Olmsted County, Minnesota, reported that NAFLD incidence increased 5-fold, from 62 per 100,000 person-years in 1997 to 329 per 100,000 person-years in 2014.<sup><span class="xref"><a href="#B11">11</a></span></sup> The increase was highest (7-fold) in young adults aged 18–39 years from 20 to 140 per 100,000 person-years.<sup><span class="xref"><a href="#B11">11</a></span></sup> While NAFLD was identified based on the ICD-9-CM code-based algorithm and underestimated in this study, this study suggests a substantial increase in incidence, with a shift in the burden of disease toward a younger population.<sup><span class="xref"><a href="#B11">11</a></span></sup></p> <h3>2. Prevalence of NAFLD</h3> <p>The true prevalence of NAFLD is hard to measure accurately due to the lack of consistent diagnostic criteria. NAFLD can be diagnosed using a radiologic assessment, while the degree of fibrosis and diagnosis of NASH requires a liver biopsy. The prevalence of NAFLD could be defined by histology, imaging, and blood tests, which are a much less reliable method of diagnosing NAFLD.</p> <p>A systemic review and meta-analysis on the global epidemiology of NAFLD estimated prevalence of NAFLD by imaging to be 25.2% (95% CI, 22.1 to 28.7)<sup><span class="xref"><a href="#B9">9</a></span></sup> with an estimated prevalence of NASH to be lower ranging from 3 to 5%.<sup><span class="xref"><a href="#B12">12</a></span></sup> It is noted that the Middle East and South America have the highest prevalence of 32% (95% CI, 13.5 to 58.2) and 30.5% (95% CI, 22.7 to 39.4), respectively, and the lowest prevalence in Africa at 13.5% (95% CI, 5.9 to 28.7).<sup><span class="xref"><a href="#B9">9</a></span>,<span class="xref"><a href="#B13">13</a></span></sup> <span class="xref"><a href="#T2">Table 2</a></span> summarizes the recent prevalence of NAFLD from across the world.<sup><span class="xref"><a href="#B14">14</a></span></sup> Based on the United States (US) Third National Health and Nutrition Examination Survey (NHANES III), an extensive representative survey of the US civilian population, the prevalence of NAFLD by ultrasonography is estimated to be 34.0% in the US.<sup><span class="xref"><a href="#B15">15</a></span></sup> In the population-based cohort study from the United Kingdom, among 3,768 young adults (mean age, 24.0 years; interquartile range, 23.0 to 25.0) with available controlled attenuation parameter scores by transient elastography, 20.7% (95% CI, 19.4 to 22.0) subjects had suspected steatosis, with 10.0% presenting having severe steatosis.<sup><span class="xref"><a href="#B16">16</a></span></sup> Interestingly, 2.7% (95% CI, 2.2 to 3.2) had suspected fibrosis (F2–F4) by transient elastography.<sup><span class="xref"><a href="#B16">16</a></span></sup></p> <h3>3. Current trends and future projections in NAFLD</h3> <p>Based on the serial NHANES dataset, the prevalence of NAFLD using noninvasive panels by US Fatty Liver Index, increased from 20.0% (1988–1994) to 28.3% (1999–2004) to 33.2% (2009–2012) and 31.9% (2013–2016) over 30 years.<sup><span class="xref"><a href="#B17">17</a></span></sup> According to numerous studies which combined liver biopsy, noninvasive radiologic modalities as well as liver enzymes, 3% to 5% of NAFLD can progress to NASH with advanced fibrosis or cirrhosis, which is 1.25% of all population,<sup><span class="xref"><a href="#B12">12</a></span>,<span class="xref"><a href="#B18">18</a></span></sup> as described in <span class='xref'><a href="#F1" title="">Fig. 1</a></span>. The prevalence of NAFLD-related advanced fibrosis increased from 2.6% (2005–2008) and 4.4% (2009–2012) to 5.0% (2013–2016) among subjects with NAFLD defined as the hepatic steatosis index; and from 3.3% (2005–2008) and 6.4% (2009–2012), to 6.8% (2013–2016) among those with NAFLD defined as US Fatty Liver Index (p<0.01).<sup><span class="xref"><a href="#B19">19</a></span></sup> In this study, advanced fibrosis was defined as having at least one of the high probabilities for advanced fibrosis using three noninvasive fibrosis markers.<sup><span class="xref"><a href="#B19">19</a></span></sup> Among type 2 diabetics from 1989 to 2018, the global prevalence was 55.5% for NAFLD, 37.3% for NASH and 17.0% for advanced fibrosis.<sup><span class="xref"><a href="#B20">20</a></span></sup> A recent study using the Markov prediction model reported that NAFLD is projected to increase by 21% from 83 million in 2015 to 101 million in 2030.<sup><span class="xref"><a href="#B18">18</a></span></sup> NASH is forecasted to grow 63% from 17 million in 2015 to 27 million in 2030.<sup><span class="xref"><a href="#B18">18</a></span></sup> Incidence of decompensated cirrhosis is predicted to increase 168% by 2030, while the incidence of HCC is projected to increase by 137%.<sup><span class="xref"><a href="#B18">18</a></span></sup> Using Markov modelling of the burden of NAFLD-related disease in eight countries including China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States, prevalence of NASH will increase 15% to 56%, while liver-related mortality and advanced liver disease will more than double due to an aging population and the projected rising prevalence of diabetes.<sup><span class="xref"><a href="#B21">21</a></span></sup></p> <h3>4. Hospitalizations and economic burdens in NAFLD</h3> <p>The National Inpatient Sample is the largest publicly available, all-payer database of national hospital discharges in the US. It contains a 20% stratified and weighted sample of the US community and academic hospital. Hospitalization rates for decompensated cirrhosis and HCC increased approximately 1.5-fold from 2005–2006 to 2013–2014 in the US.<sup><span class="xref"><a href="#B22">22</a></span></sup> Hospitalization rates with NAFLD-related decompensated cirrhosis increased from 13.4 per 100,000 hospitalizations to 32.1 per 100,000 hospitalizations with an annual increase of 10.6%, a magnitude 2-fold higher than chronic hepatitis C virus infection or alcoholic liver disease.<sup><span class="xref"><a href="#B22">22</a></span></sup> The proportion of NAFLD among hospitalizations with decompensated cirrhosis steadily increased from 12.7% to 20.1% while the percentage of chronic hepatitis C infection (39.3% to 27.6%) and alcoholic liver disease decreased (39.0% to 37.4%) from 2005 to 2014.<sup><span class="xref"><a href="#B22">22</a></span></sup> Hospitalizations for NAFLD-related HCC also increased with an annual rate of 8%.<sup><span class="xref"><a href="#B22">22</a></span></sup> Other studies have also exhibited similar trends indicating NASH cirrhosis is the fastest-growing etiology of liver cirrhosis to contribute to hospitalizations.<sup><span class="xref"><a href="#B23">23</a></span></sup> This trend echoes the idea that there is a subset of NAFLD patients who may be “rapid progressors” and need closer monitoring.</p> <p>The burden of NAFLD on healthcare costs and resource utilization remains significant nowadays. A study based on real-world data from a US medical claims determined that the long-term cumulative healthcare cost of NAFLD is 80% higher than that of a non-NAFLD of similar age and metabolic comorbidities,<sup><span class="xref"><a href="#B24">24</a></span></sup> although this study only considered private insurance and Medicare Advantage health plans. Patients limiting with healthcare access are less likely to have private insurance or Medicare Advantage plans and may be diagnosed with NAFLD at a later stage; there may be a considerable difference in healthcare costs for the management for these populations.<sup><span class="xref"><a href="#B25">25</a></span></sup> This hypothesis raises the concern that NAFLD will impact minorities and patients who experience health disparities.<sup><span class="xref"><a href="#B25">25</a></span></sup> A recent study in Sweden showed that healthcare costs were approximately twice as high in biopsy-confirmed NAFLD patients than in matched controls, which were primarily attributed to higher rates of hospitalizations and outpatient visits.<sup><span class="xref"><a href="#B26">26</a></span></sup></p> <h3>5. Risk factors and the extrahepatic manifestation of NAFLD</h3> <p>Although NAFLD has been considered as the hepatic manifestation of the metabolic syndrome, a growing body of evidence suggests that NAFLD may be a key driver in metabolic syndrome.<sup><span class="xref"><a href="#B27">27</a></span></sup> The hepatic manifestations of NAFLD are merely one component of a multi-organ systemic disease, which impacts on the cardiovascular, endocrine, renal system, and extrahepatic malignancies.<sup><span class="xref"><a href="#B27">27</a></span></sup> Type 2 diabetes or insulin resistance, dyslipidemia, and obesity are associated with the risk of NAFLD.<sup><span class="xref"><a href="#B27">27</a></span></sup> Conditions with emerging associations are hypothyroidism, polycystic ovarian syndrome, obstructive sleep apnea, etc.<sup><span class="xref"><a href="#B27">27</a></span></sup> Of these, obesity is the best documented as a risk factor for NAFLD. World Health Organization (WHO) Global Health Observatory data from 2014 estimates 15% of women and 11% of men aged over 18 are obese, with many studies indicating a strong correlation between future prevalence of NAFLD and the increasing obesity epidemic.<sup><span class="xref"><a href="#B28">28</a></span></sup> Compared with normal-weight counterparts, patients with compensated cirrhosis had worse outcomes if they were obese.<sup><span class="xref"><a href="#B29">29</a></span></sup> While NAFLD is strongly associated with obesity, 3% to 30% of nonobese subjects had NAFLD, especially reported in Asian populations.<sup><span class="xref"><a href="#B30">30</a></span></sup> In the US study based on the NHANES III, the prevalence of ultrasonography-detected hepatic steatosis to be 21% (mild-severe hepatic steatosis) in the lean population (body mass index <25 kg/m<sup>2</sup>)<sup><span class="xref"><a href="#B31">31</a></span></sup> and 27% in nonobese population (body mass index <30 kg/m<sup>2</sup>).<sup><span class="xref"><a href="#B30">30</a></span></sup> Potential risk factors for nonobese NAFLD include visceral obesity, high fructose intake, weight gain even within normal-weight limits, genetic risk factors.<sup><span class="xref"><a href="#B30">30</a></span></sup> A recent study using the biopsy-proven NAFLD cohort determined that a strong association of NASH and significant fibrosis with the metabolically unhealthy phenotype irrespective of obesity status.<sup><span class="xref"><a href="#B32">32</a></span></sup> The presence of NASH and significant fibrosis did not differ significantly between metabolic unhealthy nonobese and metabolic healthy obese groups.<sup><span class="xref"><a href="#B32">32</a></span></sup> This has been thought to be due to metabolic milieu beyond obesity may play a pathogenic role.</p> <p>Type 2 diabetes mellitus and insulin resistance promote lipolysis of the adipose tissue leading to deposition of the accumulation of free fatty acids into the liver. Individuals with diabetes had a 3-fold higher risk of death from NAFLD or NASH.<sup><span class="xref"><a href="#B33">33</a></span></sup> While the age-standardized mortality decreased in viral hepatitis, mortality increased rapidly in NAFLD at an annual rate of 11.6% (95% CI, 9.5 to 13.8) among individuals with diabetes in the US from 2007 to 2017.<sup><span class="xref"><a href="#B34">34</a></span></sup> In fact, the association between diabetes and NAFLD is so strong, it is now questioned whether NAFLD is a pathogenic component to the development of type 2 diabetes.<sup><span class="xref"><a href="#B35">35</a></span></sup> While the bidirectional relationship between NAFLD and type 2 diabetes is still being studied, it is well known that the presence of NAFLD in patients with type 2 DM seems to be a risk factor for all-cause mortality, as discussed below.<sup><span class="xref"><a href="#B36">36</a></span></sup></p> <p>Significant differences in the prevalence of NAFLD were observed between different race/ethnicity groups. Regardless of men and women, Hispanics had substantially higher NAFLD prevalence when compared to non-Hispanic whites and non-Hispanic blacks based on the third NHANES.<sup><span class="xref"><a href="#B37">37</a></span></sup> A study using the recent 2011 to 2016 NHANES showed that prevalence was highest among Hispanic Americans (42.4%), followed by non-Hispanic whites (28.4%), Asian Americans (18.3%) and non-Hispanic blacks (17.4%).<sup><span class="xref"><a href="#B38">38</a></span></sup> Regarding advanced fibrosis, the NAFLD-related advanced fibrosis increased steadily in non-Hispanic whites. However, it leveled off during 2013 to 2016 in non-Hispanic blacks.<sup><span class="xref"><a href="#B19">19</a></span></sup> Underlying genetic components are likely to play a role in the differences in the prevalence of NAFLD among race/ethnic groups. Genetic factors are further discussed below.</p></div></div></div> <div class="origin_section03" id="body04"> <div class="section03_tit clear"> <h3>MORTALITY IN NAFLD</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div><h3>1. All-cause mortality</h3> <p>The first community-based study regarding the survival of patients (n=435) diagnosed with NAFLD using imaging or histology was conducted in Olmsted County, Minnesota, from 1980 to 2000. The study reported a significant decrease in survival for patients with NAFLD compared to the general Minnesota population of the same age and sex at 7.6 years of follow-up (standardized mortality ratio, 1.34; 95% CI, 1.003 to 1.76).<sup><span class="xref"><a href="#B39">39</a></span></sup> Some of studies show similar findings with increased all-cause mortality with ranges of standardized mortality ratio of 1.34 to 2.6 and hazard ratio (HR) of 1.004 to 1.038.<sup><span class="xref"><a href="#B40">40</a></span></sup> However, several other studies showed no difference in all-cause survival between subjects with or without NAFLD.<sup><span class="xref"><a href="#B40">40</a></span></sup> A study using the third NHANES data with linked mortality data reported no significant difference in the all-cause mortality of US-diagnosed NAFLD compared with the non-NAFLD.<sup><span class="xref"><a href="#B15">15</a></span></sup> The most important reasons for this inconsistency among studies might be due to diversity in the NAFLD spectrum according to the study population and consideration for metabolic abnormalities as confounders. A recent study using 27 years follow-up data of the third NHANES, NAFLD was associated with the increased risk for all-cause mortality (HR, 1.20; 95% CI, 1.08 to 1.34), while this study did not consider any metabolic variables as confounders. In this study, the population attributable fraction of NAFLD for all-cause mortality is 7.5% (95% CI, 3.0 to 12.0), while those of diabetes was 38.0% (95% CI, 13.1 to 63.0).<sup><span class="xref"><a href="#B41">41</a></span></sup> This discrepancy sheds light on the importance of identifying high-risk populations within NAFLD that correlates with decreased survival. Compared to subjects without advanced fibrosis, those with a high probability of advanced fibrosis had a 69% increase in mortality after adjustment for other known predictors of mortality.<sup><span class="xref"><a href="#B15">15</a></span></sup> These increases in mortality were almost entirely from cardiovascular causes.<sup><span class="xref"><a href="#B15">15</a></span></sup> An international longitudinal study based on the liver biopsy determined that the fibrosis stage was independently associated with all-cause and liver-related mortality regardless of the presence or severity of other histologic features.<sup><span class="xref"><a href="#B42">42</a></span></sup> In this study, the NAFLD scoring system did not provide any long-term prognostic information.<sup><span class="xref"><a href="#B42">42</a></span></sup> Therefore, defining the presence of advanced fibrosis and the rate of fibrosis progression correlates with survival guides the development of diagnostic pathways that aim to stratify low-risk NAFLD patients from those that will progress to fibrosis or cirrhosis. While liver biopsy remains the gold standard, noninvasive fibrosis markers have been developed (<span class="xref"><a href="#T3">Table 3</a></span>), including fibrosis-4 (FIB-4), NAFLD fibrosis score as well as aspartate aminotransferase (AST) to platelet ratio index (APRI). A retrospective analysis using the NASH Clinical Research Network database validated the diagnostic performance of FIB-4 score (C-statistics: 0.80) and NAFLD fibrosis score (0.78) for advanced fibrosis.<sup><span class="xref"><a href="#B43">43</a></span></sup> While stratification by fibrosis using NAFLD fibrosis score, FIB-4, and APRI at baseline proved to be a significant predictor of all-cause mortality, discussed previously,<sup><span class="xref"><a href="#B15">15</a></span></sup> this study demonstrated that changes in FIB-4, APRI or NAFLD fibrosis score were significantly associated with disease progression including progression to advanced fibrosis.<sup><span class="xref"><a href="#B43">43</a></span></sup> Further study is needed to confirm the longitudinal association between dynamic changes in noninvasive fibrosis panels and all-cause mortality in NAFLD. Similarly, vibration-controlled transient elastography and magnetic resonance elastography could identify advanced fibrosis with superior accuracy,<sup><span class="xref"><a href="#B44">44</a></span>,<span class="xref"><a href="#B45">45</a></span></sup> however, limitation remains for clinical use for primary physician or epidemiologic study.</p> <p>In addition to the fibrosis stage, several other factors should be considered in predicting outcomes of patients with NAFLD. First, the inclusion of age in the scoring systems may increase predictive power but create biases, especially in the setting of rising rates of childhood obesity. Secondly, race/ethnicity and genetic factors may play a pivotal role in all-cause mortality. A single variant of phospholipase domain-containing 3 or <italic>PNPLA3</italic> (rs738409) gene was strongly associated with NAFLD, NASH, and decompensated cirrhosis.<sup><span class="xref"><a href="#B52">52</a></span>,<span class="xref"><a href="#B53">53</a></span></sup> The highest frequency of this allele was in Hispanics, followed by non-Hispanic whites and least in non-Hispanic blacks.<sup><span class="xref"><a href="#B53">53</a></span></sup> While we may be able to obtain static measurements of the presence or absence of fibrosis, the level of disease activity is difficult to ascertain. Genetic variants may have underpinnings of understanding NAFLD disease activity. <italic>PNPLA3</italic> and another common genetic variation called transmembrane 6 superfamily member 2 (<italic>TM6SF2</italic>) combined with lipoprotein insulin resistance index and age, were able to predict advanced fibrosis with a receiver operative characteristic curve of 0.82.<sup><span class="xref"><a href="#B54">54</a></span></sup> A recent population-based study showed that the homozygous <italic>PNPLA3</italic> <italic>I148M</italic> (rs738409) GG genotype was longitudinally associated with the increased risk for all-cause mortality in the general population and NAFLD.<sup><span class="xref"><a href="#B55">55</a></span></sup> Thirdly, not enough data exists to determine the frequency and duration of monitoring for NAFLD. A meta-analysis of patients with NASH with no fibrosis on biopsy indicates the mean rate of progression was 0.13 stage (95% CI, 0.07 to 0.18 stage) per year.<sup><span class="xref"><a href="#B51">51</a></span></sup> However, in subgroup analysis, 21.2% of patients progressed four stages of fibrosis over a mean 5.9 (±3.7) years.<sup><span class="xref"><a href="#B51">51</a></span></sup> The heterogeneity in “rapid progressors” indicates a need for further investigation for factors that may determine fibrosis or all-cause mortality. <span class='xref'><a href="#F2" title="">Fig. 2</a></span> identifies risk factors such as fibrosis stage, biochemical markers, as well as imaging findings that predict the risk of progression to fibrosis and/or cirrhosis in recent literature. Overall, noninvasive fibrosis algorithms, platelet count, and AST have been consistently identified as predictors of fibrosis progression. The risk for progression of fibrosis in NAFLD consists of an interplay between genetic factors, biochemical markers, as well as intrinsic microbial factors.<sup><span class="xref"><a href="#B56">56</a></span></sup></p> <p>In terms of mortality trends in chronic liver disease in the US, age-standardized hepatitis C virus infection-related mortality increased from 2007 to 2013, followed by a marked decrease after the introduction of direct-acting antiviral agents (from 2014 to 2016).<sup><span class="xref"><a href="#B57">57</a></span></sup> The annual percentage changes (APC) in hepatitis C virus infection-related mortality increased 2.0% per year (2007–2014) but decreased 6.4% per year (2014–2016).<sup><span class="xref"><a href="#B57">57</a></span></sup> In contrast, age-standardized mortality increased for NAFLD (APC 6.1% [2007–2013] and APC 11.3% [2013–2016]).<sup><span class="xref"><a href="#B57">57</a></span></sup> Mortality for cirrhosis (APC, 15.4%; 95% CI, 14.1 to 16.7) from NAFLD also increased over the previous decade.<sup><span class="xref"><a href="#B58">58</a></span></sup> <span class='xref'><a href="#F3" title="">Fig. 3</a></span> shows an increase in the risk of all-cause mortality, with increasing stage of fibrosis among subjects with NAFLD irrespective of the presence of NASH.<sup><span class="xref"><a href="#B59">59</a></span></sup> The magnitude of increasing relative risk appeared identical between subjects with NAFLD with/without NASH, with overlapping 95% CI of relative risk estimates.<sup><span class="xref"><a href="#B59">59</a></span></sup></p> <h3>2. Cause-specific mortality and complications</h3> <p>Cardiovascular disease is the leading cause of mortality in patients with NAFLD. Compared with other chronic liver diseases, the cause of death in NAFLD was more likely to be cardiovascular disease (approximately 20%).<sup><span class="xref"><a href="#B60">60</a></span></sup> In addition, cardiovascular mortality is highest in NAFLD patients with metabolic syndromes.<sup><span class="xref"><a href="#B61">61</a></span></sup> Traditional cardiovascular risk factors such as dyslipidemia, smoking, insulin resistance, hypertension, and abdominal obesity, share a substantial overlap with risk factors for NAFLD.<sup><span class="xref"><a href="#B62">62</a></span></sup> Association between cardiovascular diseases and NAFLD cannot be attributable to shared risk factors between two diseases.<sup><span class="xref"><a href="#B63">63</a></span></sup> Among patients with NAFLD, advanced fibrosis by noninvasive panels was a statistically significant predictor of cardiovascular mortality (HR, 3.46; 95% CI, 1.91 to 6.25 for NAFLD fibrosis score; HR, 2.53; 95% CI, 1.33 to 4.83 for APRI; HR, 2.68; 95% CI, 1.44 to 4.99 for FIB-4).<sup><span class="xref"><a href="#B15">15</a></span></sup> An international study with biopsy-proven NAFLD with bridging fibrosis or cirrhosis determined that NAFLD with bridging fibrosis had non-hepatic malignancies and cardiovascular events predominantly, while NASH cirrhosis had mostly liver-related events.<sup><span class="xref"><a href="#B64">64</a></span></sup> A meta-analysis including 34,043 adults showed that subjects with NAFLD more likely to develop non-fatal and/or fatal cardiovascular disease events than those without NAFLD (odds ratio, 1.64; 95% CI, 1.26 to 2.13) over a median 7 years.<sup><span class="xref"><a href="#B65">65</a></span></sup> In addition, subjects with more severe NAFLD, including advanced fibrosis were had a higher risk of non-fatal and/or fatal cardiovascular events (odds ratio, 2.58; 95% CI, 1.78 to 3.75).<sup><span class="xref"><a href="#B65">65</a></span></sup></p> <p>The second most common cause of death is malignancy. Historical Korean cohort study including 25,947 subjects (NAFLD: 33.6%) during the median 7.5 years follow-up reported that the cancer incidence rate of NAFLD was higher than that of non-NAFLD (782.9 vs 592.8 per 100,000 person-years: HR, 1.32; 95% CI, 1.17 to 1.49).<sup><span class="xref"><a href="#B66">66</a></span></sup> NAFLD was associated with the incidence of colorectal cancer in males (HR, 2.01; 95% CI, 1.10 to 3.68) and breast cancer in females (HR, 1.92; 95% CI, 1.15 to 3.20).<sup><span class="xref"><a href="#B66">66</a></span></sup> Another cohort study from Olmsted County, Minnesota, demonstrated that NAFLD was associated with a nearly 2-fold increase in the overall risk of incident cancers during a median 8 years (incidence rate ratio, 1.9; 95% CI, 1.3 to 2.7).<sup><span class="xref"><a href="#B67">67</a></span></sup> The highest risk increase was noted in uterine, followed by stomach, pancreas, and colon cancer.<sup><span class="xref"><a href="#B67">67</a></span></sup></p> <p>Liver disease is also an essential contributor to death among patients with NAFLD, being the third most common cause and accounting for 13% of all deaths in a study by Adams <italic>et al.</italic><sup><span class="xref"><a href="#B39">39</a></span></sup> In contrast, “chronic liver disease and cirrhosis” is the 13th leading cause of death among the Minnesota general population, accounting for <1% of all deaths. This implies that the increased overall mortality rate among NAFLD patients compared with the general population is at least partly due to complications of NAFLD.<sup><span class="xref"><a href="#B39">39</a></span></sup> Due to second-generation direct-acting antiviral agents approved late 2013, there has been a significant reduction in the waitlist burden related to chronic hepatitis C virus infection; however, the number of total registrants awaiting liver transplantation continues to rise. In 2016, for the first time, both alcoholic liver disease and NASH had surpassed chronic hepatitis C virus infection as the leading indications of liver transplantation in the US.<sup><span class="xref"><a href="#B68">68</a></span></sup> HCC is the third leading cause of cancer-related deaths in the world. There is an increase in the rate of HCC reported by Surveillance, Epidemiology, and End Results-Medicare linked database from 2004 to 2009, which is not explained by the increase of incidence in NAFLD. Data suggest a poorer prognosis with HCC from NAFLD-cirrhosis as 62% of patients with NAFLD-related HCC died within 1 year than those with HCC related to viral hepatitis and a majority (84.3%) of patients with NAFLD-related HCC died of their primary liver cancer.<sup><span class="xref"><a href="#B69">69</a></span></sup> A study using the US national mortality data showed that there was a linear increase in the age-standardized HCC-related mortality rates for NAFLD (19.1%; 95% CI, 14.0 to 24.5).<sup><span class="xref"><a href="#B58">58</a></span></sup> Among patients with NAFLD, cardiovascular disease increased at a gradual pace (APC, 2.0%; 95% CI, 0.6 to 3.4), whereas liver-related mortality increased rapidly (APC, 12.6%; 95% CI, 11.7 to 13.5) based on the US national mortality data from 2007 to 2017.<sup><span class="xref"><a href="#B60">60</a></span></sup></p></div></div></div> <div class="origin_section03" id="body05"> <div class="section03_tit clear"> <h3>CURRENT HEALTH POLICY</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div><p>Even though the prevalence of NAFLD is already 30% and projected to increase substantially, there is no clear consensus currently on the most cost-effective to identify the approximately 100 million NAFLD patients in the US general population that will progress to the 1.5% who experience fibrosis and cirrhosis. In fact, no clear national policies exist regarding identifying high-risk populations and monitoring for progression to cirrhosis. In 2018 and 2019, a comprehensive survey of the national policy in 29 European countries showed an absence of written national strategies or action plans for NAFLD and a small portion of countries had national clinical guidelines (34%) and recommended screening for NAFLD (38%) in all patients with either diabetes, obesity, and/or metabolic syndrome.<sup><span class="xref"><a href="#B70">70</a></span></sup> This could indicate the lack of appreciation for the high prevalence and the lack of clear guidelines in identifying and following high-risk patients using current diagnostic methods and classification scores.</p></div></div></div> <div class="origin_section03" id="body06"> <div class="section03_tit clear"> <h3>CONCLUSIONS</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div><p>This review summarizes the worldwide incidence and prevalence of NAFLD, discusses diagnostic nuances in determining subjects with NAFLD who progress to cirrhosis, and quantifies downstream impacts on the healthcare economy in the context of all-cause and cause-specific mortality. Currently, the estimated prevalence of NAFLD by imaging was 25.2%, with an estimated prevalence of NASH to be lower, ranging from 3% to 5%. NAFLD can progress to NASH with advanced fibrosis or cirrhosis in about 3% to 5% of NAFLD. The fibrosis stage is independently associated with all-cause and liver-related mortality regardless of the presence or severity of other histologic features. Further study is needed to confirm the longitudinal association between dynamic changes in noninvasive fibrosis panels and all-cause mortality. Age, race/ethnicity, sex, metabolic comorbidities, and genetics were associated with outcomes of NAFLD. Cardiovascular disease, extrahepatic malignancy, and end-stage liver disease are the leading cause of mortality in patients with NAFLD. This review identifies that screening guidelines for NAFLD to identify high-risk populations and monitoring for progression to cirrhosis remains a significant unmet need in the field.</p></div></div></div> <div class="origin_section03" id="body07"> <div class="section03_tit clear"> <h3>CONFLICTS OF INTEREST</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div><br /> <p>No potential conflict of interest relevant to this article was reported.</p> </div></div></div> <div class="origin_section03" id="body08"> <div class="section03_tit clear"> <h3>Figures</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div> <dd id='F1'> <img src='https://pdf.medrang.co.kr/GNL/2021/015/gnl-15-2-206-f1.jpg' width='200' align='left' class='view_img pointer btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f1.jpg&md=fig&idx=1' data-target="#file-modal" /> <a href='#' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f1.jpg&md=fig&idx=1' data-target="#file-modal" target="_blank" class='j_text_size full_blink btn-file' ><strong>Fig. 1.</strong></a></strong>Estimated number of individuals in the US population affected by nonalcoholic fatty liver disease (NAFLD). All numbers are estimated by the current prevalence of NAFLD, nonalcoholic steatohepatitis (NASH), NASH cirrhosis.<sup><span class="xref"><a href="#B9">9</a></span></sup>,<span class="xref"><a href="#B12">12</a></span>,<span class="xref"><a href="#B18">18</a></span></sup> <br clear='all' /> </dd> <dd id='F2'> <img src='https://pdf.medrang.co.kr/GNL/2021/015/gnl-15-2-206-f2.jpg' width='200' align='left' class='view_img pointer btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f2.jpg&md=fig&idx=2' data-target="#file-modal" /> <a href='#' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f2.jpg&md=fig&idx=2' data-target="#file-modal" target="_blank" class='j_text_size full_blink btn-file' ><strong>Fig. 2.</strong></a></strong>Recent literature summarizing risk factors for nonalcoholic fatty liver disease (NAFLD) progression.<sup><span class="xref"><a href="#B46">46</a></span>-<span class="xref"><a href="#B51">51</a></span></sup><br/>NASH, nonalcoholic steatohepatitis; NAS, NAFLD activity score; INR, international normalized ratio; AST, aspartate aminotransferase; ALT, alanine transferase; FIB-4, fibrosis-4; NFS, NAFLD fibrosis score; APRI, AST to platelet ratio index; OR, odds ratio; CI, confidence interval. <br clear='all' /> </dd> <dd id='F3'> <img src='https://pdf.medrang.co.kr/GNL/2021/015/gnl-15-2-206-f3.jpg' width='200' align='left' class='view_img pointer btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f3.jpg&md=fig&idx=3' data-target="#file-modal" /> <a href='#' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f3.jpg&md=fig&idx=3' data-target="#file-modal" target="_blank" class='j_text_size full_blink btn-file' ><strong>Fig. 3.</strong></a></strong>All-cause mortality of NAFLD patients with and without NASH by fibrosis stage.<sup><span class="xref"><a href="#B59">59</a></span></sup><br/>NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; RR, relative risk; CI, confidence interval. <br clear='all' /> </dd> </dl></div> <div class="origin_section03" id="body09"> <div class="section03_tit clear"> <h3>Tables</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div> <div id='T1' class='table-responsive'><label><a href='#' class='j_text_size full_blink btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f1.jpg&md=tbl&idx=1 ' data-target="#file-modal""><strong>Table 1</strong></a></label> <p>Definition of Nonalcoholic Fatty Liver Disease</p> <table frame="hsides" rules="groups"> <tbody> <tr> <td rowspan="2" valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Nonalcoholic fatty liver disease</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">-Greater than 5% of hepatic fat accumulation</td> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">-Exclusion of other etiologies of liver diseases (i.e., infection, alcohol)</td> </tr> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Nonalcoholic fatty liver</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">-Hepatic steatosis without any histological manifestation of ballooning degeneration or fibrosis</td> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Nonalcoholic steatohepatitis (NASH)</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">-Hepatic steatosis with histological manifestation of ballooning degeneration, lobular inflammation with or without fibrosis</td> </tr> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">NASH cirrhosis</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">-NASH with the presence of cirrhosis</td> </tr> </tbody> </table> <br /></div> <div id='T2' class='table-responsive'><label><a href='#' class='j_text_size full_blink btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f2.jpg&md=tbl&idx=2 ' data-target="#file-modal""><strong>Table 2</strong></a></label> <p>Global Incidence and Prevalence of NAFLD</p> <table frame="hsides" rules="groups"> <thead> <tr> <th valign="middle" align="center" style="background-color:#e9e7f1;">Author (year)</th> <th valign="middle" align="center" style="background-color:#e9e7f1;">Country</th> <th valign="middle" align="center" style="background-color:#e9e7f1;">Description of study</th> <th valign="middle" align="center" style="background-color:#e9e7f1;">Diagnostic method</th> <th valign="middle" align="center" style="background-color:#e9e7f1;">Incidence or prevalence of NAFLD (%)</th> </tr> </thead> <tbody> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Incidence</td> <td valign="top" align="center"/> <td valign="top" align="center"/> <td valign="top" align="center"/> <td valign="top" align="center"/> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Younossi <br/><italic>et al</italic>. (2016)<sup><span class="xref"><a href="#B9">9</a></span></sup></td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Asia and Israel</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">5 Studies</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance spectroscopy OR blood testing</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">For Asia, 52.3 per 1,000 <br/>(95% CI, 28.31–96.77);<br/>Israel, 28.01 per 1,000 person-years (95% CI, 19.34–40.57)</td> </tr> <tr> <td valign="top" align="left" style="padding-left:20px; text-indent:-10px;">Li <italic>et al</italic>. (2019)<sup><span class="xref"><a href="#B10">10</a></span></sup></td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Asia</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">18 Studies</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance imaging/spectroscopy OR liver biopsy OR blood testing/predictive indices (fatty liver index or hepatic steatosis index) or ICD-9-CM codes</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">50.9 per 1,000 person-years <br/>(95% CI, 44.8–57.4)</td> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Allen <italic>et al</italic>. (2018)<sup><span class="xref"><a href="#B11">11</a></span></sup></td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">USA</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Community cohort study <br/>(n=3,869 subjects)</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">ICD-9-CM codes</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">329 per 100,000 person–years in 2014</td> </tr> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Prevalence</td> <td valign="top" align="center"/> <td valign="top" align="center"/> <td valign="top" align="center"/> <td valign="top" align="center"/> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Younossi <br/><italic>et al</italic>. (2016)<sup><span class="xref"><a href="#B9">9</a></span></sup></td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Africa, Asia, Europe, Middle East, North America, South America</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">86 Studies included in meta-analysis from 22 countries, 1989-2015 (n=8,515,431)</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance imaging/spectroscopy</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">25.2% (95% CI, 22.1–27.9)</td> </tr> <tr> <td valign="top" align="left" style="padding-left:20px; text-indent:-10px;">Li <italic>et al</italic>. (2019)<sup><span class="xref"><a href="#B10">10</a></span></sup></td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Asia</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">237 Observational studies included in meta-analysis 1999-2019 (n=13,044,518)</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance imaging/spectroscopy, serum based indicies, OR liver biopsy</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">30.5% (95% CI, 29.3–30.9)</td> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Kim <italic>et al</italic>. (2013)<sup><span class="xref"><a href="#B15">15</a></span></sup></td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">USA</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">US national representative samples (n=11,154)</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Ultrasonography</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">34.0%<br/>3.2% (advanced fibrosis)</td> </tr> <tr> <td valign="top" align="left" style="padding-left:20px; text-indent:-10px;">Abeysekera <br/><italic>et al</italic>. (2020)<sup><span class="xref"><a href="#B16">16</a></span></sup></td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">UK</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">UK Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n=4,021)</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Transient elastography with controlled attenuation parameter (CAP) score</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">20.7% (95% CI, 19.4–22.0) for steatosis<br/>2.7% (95% CI, 2.2–3.2) for suspected fibrosis (F2-F4)</td> </tr> </tbody> </table> <table-wrap-foot> <fn id="t2fn1"><p>NAFLD, nonalcoholic fatty liver disease; CI, confidence interval; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.</p></fn> </table-wrap-foot> <br /></div> <div id='T3' class='table-responsive'><label><a href='#' class='j_text_size full_blink btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f3.jpg&md=tbl&idx=3 ' data-target="#file-modal""><strong>Table 3</strong></a></label> <p>Formulas of Noninvasive Fibrosis Marker Panels</p> <table frame="hsides" rules="groups"> <thead> <tr> <th valign="middle" align="center" style="background-color:#e9e7f1;">Formula</th> <th valign="middle" align="center" style="background-color:#e9e7f1;">Equation</th> </tr> </thead> <tbody> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Fibrosis-4</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">(Age [years]×AST [U/L])/(platelet [10<sup>9</sup>/L]×(ALT [U/L])<sup>1/2</sup>)</td> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">NAFLD fibrosis score</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">–1.675+(0.037×age [years])+(0.094×BMI [kg/m<sup>2</sup>])+(1.13×IFG or diabetes [yes=1, no=0])<br/>+(0.99×AST/ALT)–(0.013×platelet count [10<sup>9</sup>/L])–(0.66×albumin [g/dL])</td> </tr> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">APRI</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">([AST/upper limit of normal]/platelet count [10<sup>9</sup>/L])×100</td> </tr> </tbody> </table> <table-wrap-foot> <fn id="t3fn1"><p>AST, aspartate aminotransferase; ALT, alanine transferase; NAFLD, nonalcoholic fatty liver disease; BMI, body mass index; IFG, impaired fasting glucose; APRI, AST to platelet ratio index.</p></fn> </table-wrap-foot> <br /></div></div> <div class="origin_section03" id="body10"> <div class="section03_tit clear"> <h3>References</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">DEFINITIONS</a></li><li><a class="list_name" href="#body03">EPIDEMIOLOGY</a></li><li><a class="list_name" href="#body04">MORTALITY IN NAFLD</a></li><li><a class="list_name" href="#body05">CURRENT HEALTH POLICY</a></li><li><a class="list_name" href="#body06">CONCLUSIONS</a></li><li><a class="list_name" href="#body07">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body08">Figure</a></li><li><a class="list_name" href="#body09">Table</a></li><li><a class="list_name" href="#body10">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"> <ol> <li id='B1'><div class='j_text_size' style='text-align:justify;word-break:break-all;'>Day CP, James OF. Hepatic steatosis: innocent bystander or guilty party? Hepatology 1998;27:1463-1466.</div> <div> <a href='https://pubmed.ncbi.nlm.nih.gov/9620314' target='_new'><img src='./img/pubmed_link.gif' alt='Pubmed' /></a> <a href='https://doi.org/10.1002/hep.510270601' target='_new'><img src='./img/crossref_link.gif' alt='CrossRef' /></a> </div></li> <li id='B2'><div class='j_text_size' style='text-align:justify;word-break:break-all;'>Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55:434-438.</div> <div> <a href='https://pubmed.ncbi.nlm.nih.gov/7382552' target='_new'><img src='./img/pubmed_link.gif' alt='Pubmed' /></a> </div></li> <li id='B3'><div class='j_text_size' style='text-align:justify;word-break:break-all;'>Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. 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}); }); </script> <div id="split-wrap"> <div class="split-header-wrap"> <div class="split-header cf">  <div class="left-con"> <div class="menu"> <ul class="cf"> <li><a href="https://www.gutnliver.org/journal/download_pdf.php?doi=10.5009/gnl20127" target="_blank"><img src="/asset/images/sub/ic-split-pdf.png" alt=""> PDF</a></li> <li><a href="#n" class="btn-standard"><img src="/asset/images/sub/ic-split-standard.png" alt=""> Standard view</a></li> <li><a href="#n" data-toggle="modal" class="btn-citation" data-remote="/journal/citation.html?uid=1764" data-target="#citation-modal" data-uid="1764"><img src="/asset/images/sub/ic-split-export.png" alt=""> Export citation</a></li> <li> <a href="#n" class="btn-split-share"><img src="/asset/images/sub/ic-split-share.png" alt=""> Share <i class="xi-caret-down-min"></i></a> <ul class="split-sns-list">  <li><a href="https://twitter.com/intent/tweet?text=Recent+Epidemiology+of+Nonalcoholic+Fatty+Liver+Disease+%3A%3A+Gut+and+Liver&url=https%3A%2F%2Fwww.gutnliver.org%2Fjournal%2Fview.html%3Fspage%3D206%26volume%3D15%26number%3D2" onclick="popen(this.getAttribute('href'), 'ShareContents', 750, 500, 1, 'bcenter');return false;" id="TwitterTopView" alt="Add to Twitter" title="Twitter">Twitter</a></li> <li><a href="https://www.linkedin.com/shareArticle?mini=true&url=https%3A%2F%2Fwww.gutnliver.org%2Fjournal%2Fview.html%3Fuid%3D1764&title=Recent+Epidemiology+of+Nonalcoholic+Fatty+Liver+Disease" onclick="popen(this.getAttribute('href'), 'ShareContents', 750, 500, 1, 'bcenter');return false;" id="LinkedinTopView" alt="Add to Linkedin" title="Linkedin">Linkedin</a></li>   <li><a href="https://social-plugins.line.me/lineit/share?url=https://www.gutnliver.org/journal/view.html?volume=15&number=2&spage=206" onclick="popen(this.getAttribute('href'), 'ShareContents', 500, 500, 1, 'bcenter');return false;" id="LineTopView" alt="Add to Line" title="Line">Line</a></li> </ul> </li> </ul> </div> </div>   <div class="right-con"> <div class="menu"> <ul class="split-tab cf"> <li class="on"><a href="#n">Contents</a></li> <li><a href="#n">Figure</a></li> <li><a href="#n">Table</a></li> <li><a href="#n">References</a></li> </ul> </div> </div>  <a href="#n" class="btn-split-close"><i class="xi-close"></i></a> </div> </div>  <div class="split-container cf">  <div class="left-con"> <div class="split-left-con"> <div class="title-wrap"> <h3>Article</h3> </div> <div class="left-contents"> <h4>Review Article</h4> <div class="inner-contents">  <script src="https://crossmark-cdn.crossref.org/widget/v2.0/widget.js"></script> <a data-target="crossmark"><img src="//crossmark-cdn.crossref.org/widget/v2.0/logos/CROSSMARK_Color_horizontal.svg" width="150" /></a> <div class="origin_section01"><p>Gut and Liver 2021; 15(2): 206-216</p><p style="word-break: break-all;"><strong>Published online</strong> March 15, 2021 <a href='https://doi.org/10.5009/gnl20127' target='_blank'>https://doi.org/10.5009/gnl20127</a></p><p>Copyright © Gut and Liver.</p> </div> <div class="origin_section02"><h2>Recent Epidemiology of Nonalcoholic Fatty Liver Disease</h2><p>Soumya Murag<sup>1</sup> <a href='https://orcid.org/0000-0002-7548-2281' target='_blank' title="Soumya Murag"><img src='/journal/img/orcid.png' ></a>, Aijaz Ahmed<sup>2</sup> <a href='https://orcid.org/0000-0002-3609-8586' target='_blank' title="Aijaz Ahmed"><img src='/journal/img/orcid.png' ></a>, Donghee Kim<sup>2</sup> <a href='https://orcid.org/0000-0003-1919-6800' target='_blank' title="Donghee Kim"><img src='/journal/img/orcid.png' ></a></p><p><sup>1</sup>Department of Medicine, Santa Clara Valley Medical Center, Santa Clara, CA, and <sup>2</sup>Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA</p><p><strong>Correspondence to:</strong>Donghee Kim<br>ORCID <a href="https://orcid.org/0000-0003-1919-6800">https://orcid.org/0000-0003-1919-6800</a><br>E-mail <a href="mailto:dhkimmd@stanford.edu">dhkimmd@stanford.edu</a></p><div class="origin_date"><strong >Received</strong>: April 13, 2020; <strong >Revised</strong>: May 26, 2020; <strong >Accepted</strong>: May 26, 2020</div><p class="origin_txt">This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<a href="http://creativecommons.org/licenses/by-nc/4.0" onclick="window.open(this.href);return false;">http://creativecommons.org/licenses/by-nc/4.0</a>) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></div> <div class="body-section" id="body-section00"> <div class="section03_tit clear"> <h3>Abstract</h3> </div><div class="go_section" id="fulltext_Area"><p>The ongoing obesity epidemic and the increasing recognition of metabolic syndrome have contributed to the growing prevalence of nonalcoholic fatty liver disease (NAFLD), the most common form of liver disease worldwide. It is imperative to understand the incidence and prevalence of NAFLD as it is associated with a profound economic burden of hospitalizations, including the shifting trends in liver transplantation. The long-term cumulative healthcare cost of NAFLD patients has been shown to be 80% higher than that of non-NAFLD patients. We explore diagnostic challenges in identifying those with NAFLD who have a higher predilection to progress to end-stage liver disease. We aim to assess all-cause and cause-specific mortality as it relates to NAFLD.</p><p><strong>Keywords</strong>: Fatty liver, Nonalcoholic steatohepatitis, Prevalence, Mortality, Natural history</p></div></div> <div class="body-section" id="body-section01"> <div class="section03_tit clear"> <h3>INTRODUCTION</h3> </div><div class="go_section" id="fulltext_Area"><div><p>Fatty infiltration of the liver was only sporadically recognized in early literature and generally felt to be a benign condition. Until the 1990s, most studies recognized nonalcoholic fatty liver disease (NAFLD) as an “innocent bystander” rather than the “guilty party” in patients with cryptogenic cirrhosis,<sup><span class='xref'><a href="#B1" class="tooltip-img" title="">1</a></span></sup> which was commonly used for end-stage liver disease in which the underlying etiology remains unidentified. The landmark comment by Ludwig <italic>et al.</italic><sup><span class='xref'><a href="#B2" class="tooltip-img" title="">2</a></span></sup> in 1980 first described the term “nonalcoholic steatohepatitis (NASH)” after identifying 20 nonalcoholic patients with liver biopsies showing changes similar to alcoholic hepatitis. Caldwell <italic>et al.</italic><sup><span class='xref'><a href="#B3" class="tooltip-img" title="">3</a></span></sup> recognized that the risk factors for cryptogenic cirrhosis paralleled those for NASH and NAFLD. Subsequent studies found that cirrhosis tends to occur at an older age in obese patients, further suggesting cryptogenic cirrhosis as a downstream effect of NASH and NAFLD.<sup><span class='xref'><a href="#B4" class="tooltip-img" title="">4</a></span></sup></p> <p>A major limitation in understanding the epidemiology of NAFLD has been the lack of a distinct classification of the disease. For example, under the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9 CM), NAFLD has been grouped under cryptogenic cirrhosis or “other chronic nonalcoholic liver diseases” or “unspecified chronic liver disease without alcohol,” underestimating at least 42.1% of individuals with NAFLD that were otherwise diagnosed by chart review.<sup><span class='xref'><a href="#B5" class="tooltip-img" title="">5</a></span></sup> The misclassification of nomenclature has been an inherent problem in understanding pathophysiology and the prevalence of NAFLD, and its impact on downstream health outcomes. This review on NAFLD will further explore the current trends in epidemiology, recognize the importance of establishing the diagnosis of NAFLD in the context of chronic liver disease, and explore the diagnostic nuances in tracking the progression of NAFLD over time.</p></div></div></div> <div class="body-section" id="body-section02"> <div class="section03_tit clear"> <h3>DEFINITIONS</h3> </div><div class="go_section" id="fulltext_Area"><div><p>The diagnosis of NAFLD requires more than or equal to 5% of hepatic fat accumulation and exclusion of other etiologies of liver disease such as viral hepatitis, autoimmune liver disease, hemochromatosis, Wilson’s disease, drug-induced liver disease as well as significant alcohol consumption.<sup><span class='xref'><a href="#B6" class="tooltip-img" title="">6</a></span></sup> The American Association for the Study of Liver Diseases Practice Guideline for NAFLD defines significant alcohol consumption as current or recent alcohol consumption of >21 standard drinks per week in men and >14 drinks per week in women over 2 year period.<sup><span class='xref'><a href="#B6" class="tooltip-img" title="">6</a></span></sup> Diagnosis of NAFLD needs to be ruled out secondary causes of fatty infiltration, including lipodystrophy, starvation, Cushing’s disease, and steatogenic medications (corticosteroids, amiodarone, methotrexate, tamoxifen, and anti-retroviral therapy).<sup><span class='xref'><a href="#B6" class="tooltip-img" title="">6</a></span></sup> As seen in <span class="xref"><a href="#T1">Table 1</a></span>, NAFLD refers to a broad array of histological variety from nonalcoholic fatty liver (NAFL) to NASH, which may or may not present with fibrosis that can progress to end-stage liver diseases such as cirrhosis or hepatocellular carcinoma (HCC).<sup><span class='xref'><a href="#B7" class="tooltip-img" title="">7</a></span></sup> NASH is defined as the presence of over 5% of hepatic fat accumulation and lobular inflammation with hepatocyte ballooning degeneration, with or without any fibrosis.<sup><span class='xref'><a href="#B6" class="tooltip-img" title="">6</a></span></sup> NASH cirrhosis is defined as the presence of cirrhosis with current or previous histological evidence of NAFL or NASH.<sup><span class='xref'><a href="#B6" class="tooltip-img" title="">6</a></span></sup></p></div></div></div> <div class="body-section" id="body-section03"> <div class="section03_tit clear"> <h3>EPIDEMIOLOGY</h3> </div><div class="go_section" id="fulltext_Area"><div><h3>1. Incidence of NAFLD</h3> <p>There are scattered and limited data regarding the incidence of NAFLD in the general population. With the recent transition to ICD-10-CM with a specific diagnostic code for NAFLD, a study in England showed the incidence rate of NAFLD of 29 per 100,000 person-years with significant underestimated rates due to ICD-10 code.<sup><span class='xref'><a href="#B8" class="tooltip-img" title="">8</a></span></sup> A meta-analysis published in 2016 showed that the pooled regional incidence rate estimates for Israel and Asia were 28.0 per 1,000 person-years (95% confidence interval [CI], 19.3 to 40.6) and 52.3 per 1,000 person-years (95% CI, 28.3 to 96.8) and respectively.<sup><span class='xref'><a href="#B9" class="tooltip-img" title="">9</a></span></sup> A recent meta-analysis in Asia during 1999 to 2019, described the overall pooled incidence rate was 50.9 per 1,000 person-years (95% CI, 44.8 to 57.4).<sup><span class='xref'><a href="#B10" class="tooltip-img" title="">10</a></span></sup> Regarding trends in incidence of NAFLD, a community cohort study in Olmsted County, Minnesota, reported that NAFLD incidence increased 5-fold, from 62 per 100,000 person-years in 1997 to 329 per 100,000 person-years in 2014.<sup><span class='xref'><a href="#B11" class="tooltip-img" title="">11</a></span></sup> The increase was highest (7-fold) in young adults aged 18–39 years from 20 to 140 per 100,000 person-years.<sup><span class='xref'><a href="#B11" class="tooltip-img" title="">11</a></span></sup> While NAFLD was identified based on the ICD-9-CM code-based algorithm and underestimated in this study, this study suggests a substantial increase in incidence, with a shift in the burden of disease toward a younger population.<sup><span class='xref'><a href="#B11" class="tooltip-img" title="">11</a></span></sup></p> <h3>2. Prevalence of NAFLD</h3> <p>The true prevalence of NAFLD is hard to measure accurately due to the lack of consistent diagnostic criteria. NAFLD can be diagnosed using a radiologic assessment, while the degree of fibrosis and diagnosis of NASH requires a liver biopsy. The prevalence of NAFLD could be defined by histology, imaging, and blood tests, which are a much less reliable method of diagnosing NAFLD.</p> <p>A systemic review and meta-analysis on the global epidemiology of NAFLD estimated prevalence of NAFLD by imaging to be 25.2% (95% CI, 22.1 to 28.7)<sup><span class='xref'><a href="#B9" class="tooltip-img" title="">9</a></span></sup> with an estimated prevalence of NASH to be lower ranging from 3 to 5%.<sup><span class='xref'><a href="#B12" class="tooltip-img" title="">12</a></span></sup> It is noted that the Middle East and South America have the highest prevalence of 32% (95% CI, 13.5 to 58.2) and 30.5% (95% CI, 22.7 to 39.4), respectively, and the lowest prevalence in Africa at 13.5% (95% CI, 5.9 to 28.7).<sup><span class='xref'><a href="#B9" class="tooltip-img" title="">9</a></span>,<span class='xref'><a href="#B13" class="tooltip-img" title="">13</a></span></sup> <span class="xref"><a href="#T2">Table 2</a></span> summarizes the recent prevalence of NAFLD from across the world.<sup><span class='xref'><a href="#B14" class="tooltip-img" title="">14</a></span></sup> Based on the United States (US) Third National Health and Nutrition Examination Survey (NHANES III), an extensive representative survey of the US civilian population, the prevalence of NAFLD by ultrasonography is estimated to be 34.0% in the US.<sup><span class='xref'><a href="#B15" class="tooltip-img" title="">15</a></span></sup> In the population-based cohort study from the United Kingdom, among 3,768 young adults (mean age, 24.0 years; interquartile range, 23.0 to 25.0) with available controlled attenuation parameter scores by transient elastography, 20.7% (95% CI, 19.4 to 22.0) subjects had suspected steatosis, with 10.0% presenting having severe steatosis.<sup><span class='xref'><a href="#B16" class="tooltip-img" title="">16</a></span></sup> Interestingly, 2.7% (95% CI, 2.2 to 3.2) had suspected fibrosis (F2–F4) by transient elastography.<sup><span class='xref'><a href="#B16" class="tooltip-img" title="">16</a></span></sup></p> <h3>3. Current trends and future projections in NAFLD</h3> <p>Based on the serial NHANES dataset, the prevalence of NAFLD using noninvasive panels by US Fatty Liver Index, increased from 20.0% (1988–1994) to 28.3% (1999–2004) to 33.2% (2009–2012) and 31.9% (2013–2016) over 30 years.<sup><span class='xref'><a href="#B17" class="tooltip-img" title="">17</a></span></sup> According to numerous studies which combined liver biopsy, noninvasive radiologic modalities as well as liver enzymes, 3% to 5% of NAFLD can progress to NASH with advanced fibrosis or cirrhosis, which is 1.25% of all population,<sup><span class='xref'><a href="#B12" class="tooltip-img" title="">12</a></span>,<span class='xref'><a href="#B18" class="tooltip-img" title="">18</a></span></sup> as described in <span class='xref'><a href="#F1" title="">Fig. 1</a></span>. The prevalence of NAFLD-related advanced fibrosis increased from 2.6% (2005–2008) and 4.4% (2009–2012) to 5.0% (2013–2016) among subjects with NAFLD defined as the hepatic steatosis index; and from 3.3% (2005–2008) and 6.4% (2009–2012), to 6.8% (2013–2016) among those with NAFLD defined as US Fatty Liver Index (p<0.01).<sup><span class='xref'><a href="#B19" class="tooltip-img" title="">19</a></span></sup> In this study, advanced fibrosis was defined as having at least one of the high probabilities for advanced fibrosis using three noninvasive fibrosis markers.<sup><span class='xref'><a href="#B19" class="tooltip-img" title="">19</a></span></sup> Among type 2 diabetics from 1989 to 2018, the global prevalence was 55.5% for NAFLD, 37.3% for NASH and 17.0% for advanced fibrosis.<sup><span class='xref'><a href="#B20" class="tooltip-img" title="">20</a></span></sup> A recent study using the Markov prediction model reported that NAFLD is projected to increase by 21% from 83 million in 2015 to 101 million in 2030.<sup><span class='xref'><a href="#B18" class="tooltip-img" title="">18</a></span></sup> NASH is forecasted to grow 63% from 17 million in 2015 to 27 million in 2030.<sup><span class='xref'><a href="#B18" class="tooltip-img" title="">18</a></span></sup> Incidence of decompensated cirrhosis is predicted to increase 168% by 2030, while the incidence of HCC is projected to increase by 137%.<sup><span class='xref'><a href="#B18" class="tooltip-img" title="">18</a></span></sup> Using Markov modelling of the burden of NAFLD-related disease in eight countries including China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States, prevalence of NASH will increase 15% to 56%, while liver-related mortality and advanced liver disease will more than double due to an aging population and the projected rising prevalence of diabetes.<sup><span class='xref'><a href="#B21" class="tooltip-img" title="">21</a></span></sup></p> <h3>4. Hospitalizations and economic burdens in NAFLD</h3> <p>The National Inpatient Sample is the largest publicly available, all-payer database of national hospital discharges in the US. It contains a 20% stratified and weighted sample of the US community and academic hospital. Hospitalization rates for decompensated cirrhosis and HCC increased approximately 1.5-fold from 2005–2006 to 2013–2014 in the US.<sup><span class='xref'><a href="#B22" class="tooltip-img" title="">22</a></span></sup> Hospitalization rates with NAFLD-related decompensated cirrhosis increased from 13.4 per 100,000 hospitalizations to 32.1 per 100,000 hospitalizations with an annual increase of 10.6%, a magnitude 2-fold higher than chronic hepatitis C virus infection or alcoholic liver disease.<sup><span class='xref'><a href="#B22" class="tooltip-img" title="">22</a></span></sup> The proportion of NAFLD among hospitalizations with decompensated cirrhosis steadily increased from 12.7% to 20.1% while the percentage of chronic hepatitis C infection (39.3% to 27.6%) and alcoholic liver disease decreased (39.0% to 37.4%) from 2005 to 2014.<sup><span class='xref'><a href="#B22" class="tooltip-img" title="">22</a></span></sup> Hospitalizations for NAFLD-related HCC also increased with an annual rate of 8%.<sup><span class='xref'><a href="#B22" class="tooltip-img" title="">22</a></span></sup> Other studies have also exhibited similar trends indicating NASH cirrhosis is the fastest-growing etiology of liver cirrhosis to contribute to hospitalizations.<sup><span class='xref'><a href="#B23" class="tooltip-img" title="">23</a></span></sup> This trend echoes the idea that there is a subset of NAFLD patients who may be “rapid progressors” and need closer monitoring.</p> <p>The burden of NAFLD on healthcare costs and resource utilization remains significant nowadays. A study based on real-world data from a US medical claims determined that the long-term cumulative healthcare cost of NAFLD is 80% higher than that of a non-NAFLD of similar age and metabolic comorbidities,<sup><span class='xref'><a href="#B24" class="tooltip-img" title="">24</a></span></sup> although this study only considered private insurance and Medicare Advantage health plans. Patients limiting with healthcare access are less likely to have private insurance or Medicare Advantage plans and may be diagnosed with NAFLD at a later stage; there may be a considerable difference in healthcare costs for the management for these populations.<sup><span class='xref'><a href="#B25" class="tooltip-img" title="">25</a></span></sup> This hypothesis raises the concern that NAFLD will impact minorities and patients who experience health disparities.<sup><span class='xref'><a href="#B25" class="tooltip-img" title="">25</a></span></sup> A recent study in Sweden showed that healthcare costs were approximately twice as high in biopsy-confirmed NAFLD patients than in matched controls, which were primarily attributed to higher rates of hospitalizations and outpatient visits.<sup><span class='xref'><a href="#B26" class="tooltip-img" title="">26</a></span></sup></p> <h3>5. Risk factors and the extrahepatic manifestation of NAFLD</h3> <p>Although NAFLD has been considered as the hepatic manifestation of the metabolic syndrome, a growing body of evidence suggests that NAFLD may be a key driver in metabolic syndrome.<sup><span class='xref'><a href="#B27" class="tooltip-img" title="">27</a></span></sup> The hepatic manifestations of NAFLD are merely one component of a multi-organ systemic disease, which impacts on the cardiovascular, endocrine, renal system, and extrahepatic malignancies.<sup><span class='xref'><a href="#B27" class="tooltip-img" title="">27</a></span></sup> Type 2 diabetes or insulin resistance, dyslipidemia, and obesity are associated with the risk of NAFLD.<sup><span class='xref'><a href="#B27" class="tooltip-img" title="">27</a></span></sup> Conditions with emerging associations are hypothyroidism, polycystic ovarian syndrome, obstructive sleep apnea, etc.<sup><span class='xref'><a href="#B27" class="tooltip-img" title="">27</a></span></sup> Of these, obesity is the best documented as a risk factor for NAFLD. World Health Organization (WHO) Global Health Observatory data from 2014 estimates 15% of women and 11% of men aged over 18 are obese, with many studies indicating a strong correlation between future prevalence of NAFLD and the increasing obesity epidemic.<sup><span class='xref'><a href="#B28" class="tooltip-img" title="">28</a></span></sup> Compared with normal-weight counterparts, patients with compensated cirrhosis had worse outcomes if they were obese.<sup><span class='xref'><a href="#B29" class="tooltip-img" title="">29</a></span></sup> While NAFLD is strongly associated with obesity, 3% to 30% of nonobese subjects had NAFLD, especially reported in Asian populations.<sup><span class='xref'><a href="#B30" class="tooltip-img" title="">30</a></span></sup> In the US study based on the NHANES III, the prevalence of ultrasonography-detected hepatic steatosis to be 21% (mild-severe hepatic steatosis) in the lean population (body mass index <25 kg/m<sup>2</sup>)<sup><span class='xref'><a href="#B31" class="tooltip-img" title="">31</a></span></sup> and 27% in nonobese population (body mass index <30 kg/m<sup>2</sup>).<sup><span class='xref'><a href="#B30" class="tooltip-img" title="">30</a></span></sup> Potential risk factors for nonobese NAFLD include visceral obesity, high fructose intake, weight gain even within normal-weight limits, genetic risk factors.<sup><span class='xref'><a href="#B30" class="tooltip-img" title="">30</a></span></sup> A recent study using the biopsy-proven NAFLD cohort determined that a strong association of NASH and significant fibrosis with the metabolically unhealthy phenotype irrespective of obesity status.<sup><span class='xref'><a href="#B32" class="tooltip-img" title="">32</a></span></sup> The presence of NASH and significant fibrosis did not differ significantly between metabolic unhealthy nonobese and metabolic healthy obese groups.<sup><span class='xref'><a href="#B32" class="tooltip-img" title="">32</a></span></sup> This has been thought to be due to metabolic milieu beyond obesity may play a pathogenic role.</p> <p>Type 2 diabetes mellitus and insulin resistance promote lipolysis of the adipose tissue leading to deposition of the accumulation of free fatty acids into the liver. Individuals with diabetes had a 3-fold higher risk of death from NAFLD or NASH.<sup><span class='xref'><a href="#B33" class="tooltip-img" title="">33</a></span></sup> While the age-standardized mortality decreased in viral hepatitis, mortality increased rapidly in NAFLD at an annual rate of 11.6% (95% CI, 9.5 to 13.8) among individuals with diabetes in the US from 2007 to 2017.<sup><span class='xref'><a href="#B34" class="tooltip-img" title="">34</a></span></sup> In fact, the association between diabetes and NAFLD is so strong, it is now questioned whether NAFLD is a pathogenic component to the development of type 2 diabetes.<sup><span class='xref'><a href="#B35" class="tooltip-img" title="">35</a></span></sup> While the bidirectional relationship between NAFLD and type 2 diabetes is still being studied, it is well known that the presence of NAFLD in patients with type 2 DM seems to be a risk factor for all-cause mortality, as discussed below.<sup><span class='xref'><a href="#B36" class="tooltip-img" title="">36</a></span></sup></p> <p>Significant differences in the prevalence of NAFLD were observed between different race/ethnicity groups. Regardless of men and women, Hispanics had substantially higher NAFLD prevalence when compared to non-Hispanic whites and non-Hispanic blacks based on the third NHANES.<sup><span class='xref'><a href="#B37" class="tooltip-img" title="">37</a></span></sup> A study using the recent 2011 to 2016 NHANES showed that prevalence was highest among Hispanic Americans (42.4%), followed by non-Hispanic whites (28.4%), Asian Americans (18.3%) and non-Hispanic blacks (17.4%).<sup><span class='xref'><a href="#B38" class="tooltip-img" title="">38</a></span></sup> Regarding advanced fibrosis, the NAFLD-related advanced fibrosis increased steadily in non-Hispanic whites. However, it leveled off during 2013 to 2016 in non-Hispanic blacks.<sup><span class='xref'><a href="#B19" class="tooltip-img" title="">19</a></span></sup> Underlying genetic components are likely to play a role in the differences in the prevalence of NAFLD among race/ethnic groups. Genetic factors are further discussed below.</p></div></div></div> <div class="body-section" id="body-section04"> <div class="section03_tit clear"> <h3>MORTALITY IN NAFLD</h3> </div><div class="go_section" id="fulltext_Area"><div><h3>1. All-cause mortality</h3> <p>The first community-based study regarding the survival of patients (n=435) diagnosed with NAFLD using imaging or histology was conducted in Olmsted County, Minnesota, from 1980 to 2000. The study reported a significant decrease in survival for patients with NAFLD compared to the general Minnesota population of the same age and sex at 7.6 years of follow-up (standardized mortality ratio, 1.34; 95% CI, 1.003 to 1.76).<sup><span class='xref'><a href="#B39" class="tooltip-img" title="">39</a></span></sup> Some of studies show similar findings with increased all-cause mortality with ranges of standardized mortality ratio of 1.34 to 2.6 and hazard ratio (HR) of 1.004 to 1.038.<sup><span class='xref'><a href="#B40" class="tooltip-img" title="">40</a></span></sup> However, several other studies showed no difference in all-cause survival between subjects with or without NAFLD.<sup><span class='xref'><a href="#B40" class="tooltip-img" title="">40</a></span></sup> A study using the third NHANES data with linked mortality data reported no significant difference in the all-cause mortality of US-diagnosed NAFLD compared with the non-NAFLD.<sup><span class='xref'><a href="#B15" class="tooltip-img" title="">15</a></span></sup> The most important reasons for this inconsistency among studies might be due to diversity in the NAFLD spectrum according to the study population and consideration for metabolic abnormalities as confounders. A recent study using 27 years follow-up data of the third NHANES, NAFLD was associated with the increased risk for all-cause mortality (HR, 1.20; 95% CI, 1.08 to 1.34), while this study did not consider any metabolic variables as confounders. In this study, the population attributable fraction of NAFLD for all-cause mortality is 7.5% (95% CI, 3.0 to 12.0), while those of diabetes was 38.0% (95% CI, 13.1 to 63.0).<sup><span class='xref'><a href="#B41" class="tooltip-img" title="">41</a></span></sup> This discrepancy sheds light on the importance of identifying high-risk populations within NAFLD that correlates with decreased survival. Compared to subjects without advanced fibrosis, those with a high probability of advanced fibrosis had a 69% increase in mortality after adjustment for other known predictors of mortality.<sup><span class='xref'><a href="#B15" class="tooltip-img" title="">15</a></span></sup> These increases in mortality were almost entirely from cardiovascular causes.<sup><span class='xref'><a href="#B15" class="tooltip-img" title="">15</a></span></sup> An international longitudinal study based on the liver biopsy determined that the fibrosis stage was independently associated with all-cause and liver-related mortality regardless of the presence or severity of other histologic features.<sup><span class='xref'><a href="#B42" class="tooltip-img" title="">42</a></span></sup> In this study, the NAFLD scoring system did not provide any long-term prognostic information.<sup><span class='xref'><a href="#B42" class="tooltip-img" title="">42</a></span></sup> Therefore, defining the presence of advanced fibrosis and the rate of fibrosis progression correlates with survival guides the development of diagnostic pathways that aim to stratify low-risk NAFLD patients from those that will progress to fibrosis or cirrhosis. While liver biopsy remains the gold standard, noninvasive fibrosis markers have been developed (<span class="xref"><a href="#T3">Table 3</a></span>), including fibrosis-4 (FIB-4), NAFLD fibrosis score as well as aspartate aminotransferase (AST) to platelet ratio index (APRI). A retrospective analysis using the NASH Clinical Research Network database validated the diagnostic performance of FIB-4 score (C-statistics: 0.80) and NAFLD fibrosis score (0.78) for advanced fibrosis.<sup><span class='xref'><a href="#B43" class="tooltip-img" title="">43</a></span></sup> While stratification by fibrosis using NAFLD fibrosis score, FIB-4, and APRI at baseline proved to be a significant predictor of all-cause mortality, discussed previously,<sup><span class='xref'><a href="#B15" class="tooltip-img" title="">15</a></span></sup> this study demonstrated that changes in FIB-4, APRI or NAFLD fibrosis score were significantly associated with disease progression including progression to advanced fibrosis.<sup><span class='xref'><a href="#B43" class="tooltip-img" title="">43</a></span></sup> Further study is needed to confirm the longitudinal association between dynamic changes in noninvasive fibrosis panels and all-cause mortality in NAFLD. Similarly, vibration-controlled transient elastography and magnetic resonance elastography could identify advanced fibrosis with superior accuracy,<sup><span class='xref'><a href="#B44" class="tooltip-img" title="">44</a></span>,<span class='xref'><a href="#B45" class="tooltip-img" title="">45</a></span></sup> however, limitation remains for clinical use for primary physician or epidemiologic study.</p> <p>In addition to the fibrosis stage, several other factors should be considered in predicting outcomes of patients with NAFLD. First, the inclusion of age in the scoring systems may increase predictive power but create biases, especially in the setting of rising rates of childhood obesity. Secondly, race/ethnicity and genetic factors may play a pivotal role in all-cause mortality. A single variant of phospholipase domain-containing 3 or <italic>PNPLA3</italic> (rs738409) gene was strongly associated with NAFLD, NASH, and decompensated cirrhosis.<sup><span class='xref'><a href="#B52" class="tooltip-img" title="">52</a></span>,<span class='xref'><a href="#B53" class="tooltip-img" title="">53</a></span></sup> The highest frequency of this allele was in Hispanics, followed by non-Hispanic whites and least in non-Hispanic blacks.<sup><span class='xref'><a href="#B53" class="tooltip-img" title="">53</a></span></sup> While we may be able to obtain static measurements of the presence or absence of fibrosis, the level of disease activity is difficult to ascertain. Genetic variants may have underpinnings of understanding NAFLD disease activity. <italic>PNPLA3</italic> and another common genetic variation called transmembrane 6 superfamily member 2 (<italic>TM6SF2</italic>) combined with lipoprotein insulin resistance index and age, were able to predict advanced fibrosis with a receiver operative characteristic curve of 0.82.<sup><span class='xref'><a href="#B54" class="tooltip-img" title="">54</a></span></sup> A recent population-based study showed that the homozygous <italic>PNPLA3</italic> <italic>I148M</italic> (rs738409) GG genotype was longitudinally associated with the increased risk for all-cause mortality in the general population and NAFLD.<sup><span class='xref'><a href="#B55" class="tooltip-img" title="">55</a></span></sup> Thirdly, not enough data exists to determine the frequency and duration of monitoring for NAFLD. A meta-analysis of patients with NASH with no fibrosis on biopsy indicates the mean rate of progression was 0.13 stage (95% CI, 0.07 to 0.18 stage) per year.<sup><span class='xref'><a href="#B51" class="tooltip-img" title="">51</a></span></sup> However, in subgroup analysis, 21.2% of patients progressed four stages of fibrosis over a mean 5.9 (±3.7) years.<sup><span class='xref'><a href="#B51" class="tooltip-img" title="">51</a></span></sup> The heterogeneity in “rapid progressors” indicates a need for further investigation for factors that may determine fibrosis or all-cause mortality. <span class='xref'><a href="#F2" title="">Fig. 2</a></span> identifies risk factors such as fibrosis stage, biochemical markers, as well as imaging findings that predict the risk of progression to fibrosis and/or cirrhosis in recent literature. Overall, noninvasive fibrosis algorithms, platelet count, and AST have been consistently identified as predictors of fibrosis progression. The risk for progression of fibrosis in NAFLD consists of an interplay between genetic factors, biochemical markers, as well as intrinsic microbial factors.<sup><span class='xref'><a href="#B56" class="tooltip-img" title="">56</a></span></sup></p> <p>In terms of mortality trends in chronic liver disease in the US, age-standardized hepatitis C virus infection-related mortality increased from 2007 to 2013, followed by a marked decrease after the introduction of direct-acting antiviral agents (from 2014 to 2016).<sup><span class='xref'><a href="#B57" class="tooltip-img" title="">57</a></span></sup> The annual percentage changes (APC) in hepatitis C virus infection-related mortality increased 2.0% per year (2007–2014) but decreased 6.4% per year (2014–2016).<sup><span class='xref'><a href="#B57" class="tooltip-img" title="">57</a></span></sup> In contrast, age-standardized mortality increased for NAFLD (APC 6.1% [2007–2013] and APC 11.3% [2013–2016]).<sup><span class='xref'><a href="#B57" class="tooltip-img" title="">57</a></span></sup> Mortality for cirrhosis (APC, 15.4%; 95% CI, 14.1 to 16.7) from NAFLD also increased over the previous decade.<sup><span class='xref'><a href="#B58" class="tooltip-img" title="">58</a></span></sup> <span class='xref'><a href="#F3" title="">Fig. 3</a></span> shows an increase in the risk of all-cause mortality, with increasing stage of fibrosis among subjects with NAFLD irrespective of the presence of NASH.<sup><span class='xref'><a href="#B59" class="tooltip-img" title="">59</a></span></sup> The magnitude of increasing relative risk appeared identical between subjects with NAFLD with/without NASH, with overlapping 95% CI of relative risk estimates.<sup><span class='xref'><a href="#B59" class="tooltip-img" title="">59</a></span></sup></p> <h3>2. Cause-specific mortality and complications</h3> <p>Cardiovascular disease is the leading cause of mortality in patients with NAFLD. Compared with other chronic liver diseases, the cause of death in NAFLD was more likely to be cardiovascular disease (approximately 20%).<sup><span class='xref'><a href="#B60" class="tooltip-img" title="">60</a></span></sup> In addition, cardiovascular mortality is highest in NAFLD patients with metabolic syndromes.<sup><span class='xref'><a href="#B61" class="tooltip-img" title="">61</a></span></sup> Traditional cardiovascular risk factors such as dyslipidemia, smoking, insulin resistance, hypertension, and abdominal obesity, share a substantial overlap with risk factors for NAFLD.<sup><span class='xref'><a href="#B62" class="tooltip-img" title="">62</a></span></sup> Association between cardiovascular diseases and NAFLD cannot be attributable to shared risk factors between two diseases.<sup><span class='xref'><a href="#B63" class="tooltip-img" title="">63</a></span></sup> Among patients with NAFLD, advanced fibrosis by noninvasive panels was a statistically significant predictor of cardiovascular mortality (HR, 3.46; 95% CI, 1.91 to 6.25 for NAFLD fibrosis score; HR, 2.53; 95% CI, 1.33 to 4.83 for APRI; HR, 2.68; 95% CI, 1.44 to 4.99 for FIB-4).<sup><span class='xref'><a href="#B15" class="tooltip-img" title="">15</a></span></sup> An international study with biopsy-proven NAFLD with bridging fibrosis or cirrhosis determined that NAFLD with bridging fibrosis had non-hepatic malignancies and cardiovascular events predominantly, while NASH cirrhosis had mostly liver-related events.<sup><span class='xref'><a href="#B64" class="tooltip-img" title="">64</a></span></sup> A meta-analysis including 34,043 adults showed that subjects with NAFLD more likely to develop non-fatal and/or fatal cardiovascular disease events than those without NAFLD (odds ratio, 1.64; 95% CI, 1.26 to 2.13) over a median 7 years.<sup><span class='xref'><a href="#B65" class="tooltip-img" title="">65</a></span></sup> In addition, subjects with more severe NAFLD, including advanced fibrosis were had a higher risk of non-fatal and/or fatal cardiovascular events (odds ratio, 2.58; 95% CI, 1.78 to 3.75).<sup><span class='xref'><a href="#B65" class="tooltip-img" title="">65</a></span></sup></p> <p>The second most common cause of death is malignancy. Historical Korean cohort study including 25,947 subjects (NAFLD: 33.6%) during the median 7.5 years follow-up reported that the cancer incidence rate of NAFLD was higher than that of non-NAFLD (782.9 vs 592.8 per 100,000 person-years: HR, 1.32; 95% CI, 1.17 to 1.49).<sup><span class='xref'><a href="#B66" class="tooltip-img" title="">66</a></span></sup> NAFLD was associated with the incidence of colorectal cancer in males (HR, 2.01; 95% CI, 1.10 to 3.68) and breast cancer in females (HR, 1.92; 95% CI, 1.15 to 3.20).<sup><span class='xref'><a href="#B66" class="tooltip-img" title="">66</a></span></sup> Another cohort study from Olmsted County, Minnesota, demonstrated that NAFLD was associated with a nearly 2-fold increase in the overall risk of incident cancers during a median 8 years (incidence rate ratio, 1.9; 95% CI, 1.3 to 2.7).<sup><span class='xref'><a href="#B67" class="tooltip-img" title="">67</a></span></sup> The highest risk increase was noted in uterine, followed by stomach, pancreas, and colon cancer.<sup><span class='xref'><a href="#B67" class="tooltip-img" title="">67</a></span></sup></p> <p>Liver disease is also an essential contributor to death among patients with NAFLD, being the third most common cause and accounting for 13% of all deaths in a study by Adams <italic>et al.</italic><sup><span class='xref'><a href="#B39" class="tooltip-img" title="">39</a></span></sup> In contrast, “chronic liver disease and cirrhosis” is the 13th leading cause of death among the Minnesota general population, accounting for <1% of all deaths. This implies that the increased overall mortality rate among NAFLD patients compared with the general population is at least partly due to complications of NAFLD.<sup><span class='xref'><a href="#B39" class="tooltip-img" title="">39</a></span></sup> Due to second-generation direct-acting antiviral agents approved late 2013, there has been a significant reduction in the waitlist burden related to chronic hepatitis C virus infection; however, the number of total registrants awaiting liver transplantation continues to rise. In 2016, for the first time, both alcoholic liver disease and NASH had surpassed chronic hepatitis C virus infection as the leading indications of liver transplantation in the US.<sup><span class='xref'><a href="#B68" class="tooltip-img" title="">68</a></span></sup> HCC is the third leading cause of cancer-related deaths in the world. There is an increase in the rate of HCC reported by Surveillance, Epidemiology, and End Results-Medicare linked database from 2004 to 2009, which is not explained by the increase of incidence in NAFLD. Data suggest a poorer prognosis with HCC from NAFLD-cirrhosis as 62% of patients with NAFLD-related HCC died within 1 year than those with HCC related to viral hepatitis and a majority (84.3%) of patients with NAFLD-related HCC died of their primary liver cancer.<sup><span class='xref'><a href="#B69" class="tooltip-img" title="">69</a></span></sup> A study using the US national mortality data showed that there was a linear increase in the age-standardized HCC-related mortality rates for NAFLD (19.1%; 95% CI, 14.0 to 24.5).<sup><span class='xref'><a href="#B58" class="tooltip-img" title="">58</a></span></sup> Among patients with NAFLD, cardiovascular disease increased at a gradual pace (APC, 2.0%; 95% CI, 0.6 to 3.4), whereas liver-related mortality increased rapidly (APC, 12.6%; 95% CI, 11.7 to 13.5) based on the US national mortality data from 2007 to 2017.<sup><span class='xref'><a href="#B60" class="tooltip-img" title="">60</a></span></sup></p></div></div></div> <div class="body-section" id="body-section05"> <div class="section03_tit clear"> <h3>CURRENT HEALTH POLICY</h3> </div><div class="go_section" id="fulltext_Area"><div><p>Even though the prevalence of NAFLD is already 30% and projected to increase substantially, there is no clear consensus currently on the most cost-effective to identify the approximately 100 million NAFLD patients in the US general population that will progress to the 1.5% who experience fibrosis and cirrhosis. In fact, no clear national policies exist regarding identifying high-risk populations and monitoring for progression to cirrhosis. In 2018 and 2019, a comprehensive survey of the national policy in 29 European countries showed an absence of written national strategies or action plans for NAFLD and a small portion of countries had national clinical guidelines (34%) and recommended screening for NAFLD (38%) in all patients with either diabetes, obesity, and/or metabolic syndrome.<sup><span class='xref'><a href="#B70" class="tooltip-img" title="">70</a></span></sup> This could indicate the lack of appreciation for the high prevalence and the lack of clear guidelines in identifying and following high-risk patients using current diagnostic methods and classification scores.</p></div></div></div> <div class="body-section" id="body-section06"> <div class="section03_tit clear"> <h3>CONCLUSIONS</h3> </div><div class="go_section" id="fulltext_Area"><div><p>This review summarizes the worldwide incidence and prevalence of NAFLD, discusses diagnostic nuances in determining subjects with NAFLD who progress to cirrhosis, and quantifies downstream impacts on the healthcare economy in the context of all-cause and cause-specific mortality. Currently, the estimated prevalence of NAFLD by imaging was 25.2%, with an estimated prevalence of NASH to be lower, ranging from 3% to 5%. NAFLD can progress to NASH with advanced fibrosis or cirrhosis in about 3% to 5% of NAFLD. The fibrosis stage is independently associated with all-cause and liver-related mortality regardless of the presence or severity of other histologic features. Further study is needed to confirm the longitudinal association between dynamic changes in noninvasive fibrosis panels and all-cause mortality. Age, race/ethnicity, sex, metabolic comorbidities, and genetics were associated with outcomes of NAFLD. Cardiovascular disease, extrahepatic malignancy, and end-stage liver disease are the leading cause of mortality in patients with NAFLD. This review identifies that screening guidelines for NAFLD to identify high-risk populations and monitoring for progression to cirrhosis remains a significant unmet need in the field.</p></div></div></div> <div class="body-section" id="body-section07"> <div class="section03_tit clear"> <h3>CONFLICTS OF INTEREST</h3> </div><div class="go_section" id="fulltext_Area"><div><br /> <p>No potential conflict of interest relevant to this article was reported.</p> </div></div></div> <div class="body-section" id="body-section08"> <div class="section03_tit clear"> <h3>Tables</h3> </div> <div id='T1' class='table-responsive'><label>Table 1</label> <p>Definition of Nonalcoholic Fatty Liver Disease</p> <table frame="hsides" rules="groups"> <tbody> <tr> <td rowspan="2" valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Nonalcoholic fatty liver disease</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">-Greater than 5% of hepatic fat accumulation</td> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">-Exclusion of other etiologies of liver diseases (i.e., infection, alcohol)</td> </tr> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Nonalcoholic fatty liver</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">-Hepatic steatosis without any histological manifestation of ballooning degeneration or fibrosis</td> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Nonalcoholic steatohepatitis (NASH)</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">-Hepatic steatosis with histological manifestation of ballooning degeneration, lobular inflammation with or without fibrosis</td> </tr> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">NASH cirrhosis</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">-NASH with the presence of cirrhosis</td> </tr> </tbody> </table> </div> <div id='T2' class='table-responsive'><label>Table 2</label> <p>Global Incidence and Prevalence of NAFLD</p> <table frame="hsides" rules="groups"> <thead> <tr> <th valign="middle" align="center" style="background-color:#e9e7f1;">Author (year)</th> <th valign="middle" align="center" style="background-color:#e9e7f1;">Country</th> <th valign="middle" align="center" style="background-color:#e9e7f1;">Description of study</th> <th valign="middle" align="center" style="background-color:#e9e7f1;">Diagnostic method</th> <th valign="middle" align="center" style="background-color:#e9e7f1;">Incidence or prevalence of NAFLD (%)</th> </tr> </thead> <tbody> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Incidence</td> <td valign="top" align="center"/> <td valign="top" align="center"/> <td valign="top" align="center"/> <td valign="top" align="center"/> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Younossi <br/><italic>et al</italic>. (2016)<sup><span class="xref"><a href="#B9">9</a></span></sup></td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Asia and Israel</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">5 Studies</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance spectroscopy OR blood testing</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">For Asia, 52.3 per 1,000 <br/>(95% CI, 28.31–96.77);<br/>Israel, 28.01 per 1,000 person-years (95% CI, 19.34–40.57)</td> </tr> <tr> <td valign="top" align="left" style="padding-left:20px; text-indent:-10px;">Li <italic>et al</italic>. (2019)<sup><span class="xref"><a href="#B10">10</a></span></sup></td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Asia</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">18 Studies</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance imaging/spectroscopy OR liver biopsy OR blood testing/predictive indices (fatty liver index or hepatic steatosis index) or ICD-9-CM codes</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">50.9 per 1,000 person-years <br/>(95% CI, 44.8–57.4)</td> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Allen <italic>et al</italic>. (2018)<sup><span class="xref"><a href="#B11">11</a></span></sup></td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">USA</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Community cohort study <br/>(n=3,869 subjects)</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">ICD-9-CM codes</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">329 per 100,000 person–years in 2014</td> </tr> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Prevalence</td> <td valign="top" align="center"/> <td valign="top" align="center"/> <td valign="top" align="center"/> <td valign="top" align="center"/> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Younossi <br/><italic>et al</italic>. (2016)<sup><span class="xref"><a href="#B9">9</a></span></sup></td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Africa, Asia, Europe, Middle East, North America, South America</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">86 Studies included in meta-analysis from 22 countries, 1989-2015 (n=8,515,431)</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance imaging/spectroscopy</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">25.2% (95% CI, 22.1–27.9)</td> </tr> <tr> <td valign="top" align="left" style="padding-left:20px; text-indent:-10px;">Li <italic>et al</italic>. (2019)<sup><span class="xref"><a href="#B10">10</a></span></sup></td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Asia</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">237 Observational studies included in meta-analysis 1999-2019 (n=13,044,518)</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance imaging/spectroscopy, serum based indicies, OR liver biopsy</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">30.5% (95% CI, 29.3–30.9)</td> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Kim <italic>et al</italic>. (2013)<sup><span class="xref"><a href="#B15">15</a></span></sup></td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">USA</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">US national representative samples (n=11,154)</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Ultrasonography</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">34.0%<br/>3.2% (advanced fibrosis)</td> </tr> <tr> <td valign="top" align="left" style="padding-left:20px; text-indent:-10px;">Abeysekera <br/><italic>et al</italic>. (2020)<sup><span class="xref"><a href="#B16">16</a></span></sup></td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">UK</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">UK Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n=4,021)</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Transient elastography with controlled attenuation parameter (CAP) score</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">20.7% (95% CI, 19.4–22.0) for steatosis<br/>2.7% (95% CI, 2.2–3.2) for suspected fibrosis (F2-F4)</td> </tr> </tbody> </table> <table-wrap-foot> <fn id="t2fn1"><p>NAFLD, nonalcoholic fatty liver disease; CI, confidence interval; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.</p></fn> </table-wrap-foot> </div> <div id='T3' class='table-responsive'><label>Table 3</label> <p>Formulas of Noninvasive Fibrosis Marker Panels</p> <table frame="hsides" rules="groups"> <thead> <tr> <th valign="middle" align="center" style="background-color:#e9e7f1;">Formula</th> <th valign="middle" align="center" style="background-color:#e9e7f1;">Equation</th> </tr> </thead> <tbody> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Fibrosis-4</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">(Age [years]×AST [U/L])/(platelet [10<sup>9</sup>/L]×(ALT [U/L])<sup>1/2</sup>)</td> </tr> <tr> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">NAFLD fibrosis score</td> <td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">–1.675+(0.037×age [years])+(0.094×BMI [kg/m<sup>2</sup>])+(1.13×IFG or diabetes [yes=1, no=0])<br/>+(0.99×AST/ALT)–(0.013×platelet count [10<sup>9</sup>/L])–(0.66×albumin [g/dL])</td> </tr> <tr> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">APRI</td> <td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">([AST/upper limit of normal]/platelet count [10<sup>9</sup>/L])×100</td> </tr> </tbody> </table> <table-wrap-foot> <fn id="t3fn1"><p>AST, aspartate aminotransferase; ALT, alanine transferase; NAFLD, nonalcoholic fatty liver disease; BMI, body mass index; IFG, impaired fasting glucose; APRI, AST to platelet ratio index.</p></fn> </table-wrap-foot> </div></div> </div> </div> </div> </div>   <div class="right-con"> <div class="tabcon-wrap">  <div class="split-tabcon">  <ul class="split-contents-list"><li><a href="#body-section00">Abstract</a></li><li><a href="#body-section01">INTRODUCTION</a></li><li><a href="#body-section02">DEFINITIONS</a></li><li><a href="#body-section03">EPIDEMIOLOGY</a></li><li><a href="#body-section04">MORTALITY IN NAFLD</a></li><li><a href="#body-section05">CURRENT HEALTH POLICY</a></li><li><a href="#body-section06">CONCLUSIONS</a></li><li><a href="#body-section07">CONFLICTS OF INTEREST</a></li><li><a href="#body-section08">Figure</a></li><li><a href="#body-section09">Table</a></li></ul> </div>   <div class="split-tabcon"> <div class="figure-wrap" id="F1"> <div class="figure-title-wrap"> <h3>Fig 1.</h3> <div class="tools"> <a href="https://pdf.medrang.co.kr/download.php?file_dir=GNL/2021/015/&f_name=gnl-15-2-206-f1.jpg" download><img src="/asset/images/sub/ic-download.png" alt=""> Download</a> </div> </div> <div class="figure-con"> <img src='https://pdf.medrang.co.kr/GNL/2021/015/gnl-15-2-206-f1.jpg' width='200' align='left' class='view_img pointer btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f1.jpg&md=fig&idx=1' data-target="#file-modal" target="_blank" /> </div> <div class="figure-con"> <a href='#' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f1.jpg&md=fig&idx=1' data-target="#file-modal" target="_blank" class='j_text_size full_blink btn-file' ><strong>Figure 1.</strong></a>Estimated number of individuals in the US population affected by nonalcoholic fatty liver disease (NAFLD). All numbers are estimated by the current prevalence of NAFLD, nonalcoholic steatohepatitis (NASH), NASH cirrhosis.<sup><span class="xref"><a href="#B9">9</a></span></sup>,<span class="xref"><a href="#B12">12</a></span>,<span class="xref"><a href="#B18">18</a></span></sup> </div> <div class="figure-con"> Gut and Liver 2021; 15: 206-216<a href='https://doi.org/10.5009/gnl20127' target='_blank'>https://doi.org/10.5009/gnl20127</a>  </div> </div> <div class="figure-wrap" id="F2"> <div class="figure-title-wrap"> <h3>Fig 2.</h3> <div class="tools"> <a href="https://pdf.medrang.co.kr/download.php?file_dir=GNL/2021/015/&f_name=gnl-15-2-206-f2.jpg" download><img src="/asset/images/sub/ic-download.png" alt=""> Download</a> </div> </div> <div class="figure-con"> <img src='https://pdf.medrang.co.kr/GNL/2021/015/gnl-15-2-206-f2.jpg' width='200' align='left' class='view_img pointer btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f2.jpg&md=fig&idx=2' data-target="#file-modal" target="_blank" /> </div> <div class="figure-con"> <a href='#' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f2.jpg&md=fig&idx=2' data-target="#file-modal" target="_blank" class='j_text_size full_blink btn-file' ><strong>Figure 2.</strong></a>Recent literature summarizing risk factors for nonalcoholic fatty liver disease (NAFLD) progression.<sup><span class="xref"><a href="#B46">46</a></span>-<span class="xref"><a href="#B51">51</a></span></sup><br/>NASH, nonalcoholic steatohepatitis; NAS, NAFLD activity score; INR, international normalized ratio; AST, aspartate aminotransferase; ALT, alanine transferase; FIB-4, fibrosis-4; NFS, NAFLD fibrosis score; APRI, AST to platelet ratio index; OR, odds ratio; CI, confidence interval. </div> <div class="figure-con"> Gut and Liver 2021; 15: 206-216<a href='https://doi.org/10.5009/gnl20127' target='_blank'>https://doi.org/10.5009/gnl20127</a>  </div> </div> <div class="figure-wrap" id="F3"> <div class="figure-title-wrap"> <h3>Fig 3.</h3> <div class="tools"> <a href="https://pdf.medrang.co.kr/download.php?file_dir=GNL/2021/015/&f_name=gnl-15-2-206-f3.jpg" download><img src="/asset/images/sub/ic-download.png" alt=""> Download</a> </div> </div> <div class="figure-con"> <img src='https://pdf.medrang.co.kr/GNL/2021/015/gnl-15-2-206-f3.jpg' width='200' align='left' class='view_img pointer btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f3.jpg&md=fig&idx=3' data-target="#file-modal" target="_blank" /> </div> <div class="figure-con"> <a href='#' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f3.jpg&md=fig&idx=3' data-target="#file-modal" target="_blank" class='j_text_size full_blink btn-file' ><strong>Figure 3.</strong></a>All-cause mortality of NAFLD patients with and without NASH by fibrosis stage.<sup><span class="xref"><a href="#B59">59</a></span></sup><br/>NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; RR, relative risk; CI, confidence interval. </div> <div class="figure-con"> Gut and Liver 2021; 15: 206-216<a href='https://doi.org/10.5009/gnl20127' target='_blank'>https://doi.org/10.5009/gnl20127</a>  </div> </div> </div> <div class="split-tabcon"> <div class="inner-contents"> <dl> <dd id='T1' style='padding: 10px 0;width:100%;overflow-x:auto;overflow-y:hidden;'> <p style='text-indent: 0pt; margin-bottom: 0px;'><span style='color:#1567b7; font-weight:bold; font-size:14px;'><a href='#' class='j_text_size full_blink btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f1.jpg&md=tbl&idx=1' data-target="#file-modal""><strong>Table 1</strong></a></span> Definition of Nonalcoholic Fatty Liver Disease</p><table frame="hsides" rules="groups"><tbody><tr><td rowspan="2" valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Nonalcoholic fatty liver disease</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">-Greater than 5% of hepatic fat accumulation</td></tr><tr><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">-Exclusion of other etiologies of liver diseases (i.e., infection, alcohol)</td></tr><tr><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Nonalcoholic fatty liver</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">-Hepatic steatosis without any histological manifestation of ballooning degeneration or fibrosis</td></tr><tr><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Nonalcoholic steatohepatitis (NASH)</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">-Hepatic steatosis with histological manifestation of ballooning degeneration, lobular inflammation with or without fibrosis</td></tr><tr><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">NASH cirrhosis</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">-NASH with the presence of cirrhosis</td></tr></tbody></table> <br clear='all' /> </dd> </dl></div> <div class="inner-contents"> <dl> <dd id='T2' style='padding: 10px 0;width:100%;overflow-x:auto;overflow-y:hidden;'> <p style='text-indent: 0pt; margin-bottom: 0px;'><span style='color:#1567b7; font-weight:bold; font-size:14px;'><a href='#' class='j_text_size full_blink btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f2.jpg&md=tbl&idx=2' data-target="#file-modal""><strong>Table 2</strong></a></span> Global Incidence and Prevalence of NAFLD</p><table frame="hsides" rules="groups"><thead><tr><th valign="middle" align="center" style="background-color:#e9e7f1;">Author (year)</th><th valign="middle" align="center" style="background-color:#e9e7f1;">Country</th><th valign="middle" align="center" style="background-color:#e9e7f1;">Description of study</th><th valign="middle" align="center" style="background-color:#e9e7f1;">Diagnostic method</th><th valign="middle" align="center" style="background-color:#e9e7f1;">Incidence or prevalence of NAFLD (%)</th></tr></thead><tbody><tr><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Incidence</td><td valign="top" align="center"/><td valign="top" align="center"/><td valign="top" align="center"/><td valign="top" align="center"/></tr><tr><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Younossi <break/><italic>et al</italic>. (2016)<sup><span class="xref"><a href="#B9">9</a></span></sup></td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Asia and Israel</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">5 Studies</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance spectroscopy OR blood testing</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">For Asia, 52.3 per 1,000 <break/>(95% CI, 28.31–96.77);<break/>Israel, 28.01 per 1,000 person-years (95% CI, 19.34–40.57)</td></tr><tr><td valign="top" align="left" style="padding-left:20px; text-indent:-10px;">Li <italic>et al</italic>. (2019)<sup><span class="xref"><a href="#B10">10</a></span></sup></td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Asia</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">18 Studies</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance imaging/spectroscopy OR liver biopsy OR blood testing/predictive indices (fatty liver index or hepatic steatosis index) or ICD-9-CM codes</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">50.9 per 1,000 person-years <break/>(95% CI, 44.8–57.4)</td></tr><tr><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Allen <italic>et al</italic>. (2018)<sup><span class="xref"><a href="#B11">11</a></span></sup></td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">USA</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Community cohort study <break/>(n=3,869 subjects)</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">ICD-9-CM codes</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">329 per 100,000 person–years in 2014</td></tr><tr><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Prevalence</td><td valign="top" align="center"/><td valign="top" align="center"/><td valign="top" align="center"/><td valign="top" align="center"/></tr><tr><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Younossi <break/><italic>et al</italic>. (2016)<sup><span class="xref"><a href="#B9">9</a></span></sup></td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Africa, Asia, Europe, Middle East, North America, South America</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">86 Studies included in meta-analysis from 22 countries, 1989-2015 (n=8,515,431)</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance imaging/spectroscopy</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">25.2% (95% CI, 22.1–27.9)</td></tr><tr><td valign="top" align="left" style="padding-left:20px; text-indent:-10px;">Li <italic>et al</italic>. (2019)<sup><span class="xref"><a href="#B10">10</a></span></sup></td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Asia</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">237 Observational studies included in meta-analysis 1999-2019 (n=13,044,518)</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Ultrasonography, computed tomography scan OR magnetic resonance imaging/spectroscopy, serum based indicies, OR liver biopsy</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">30.5% (95% CI, 29.3–30.9)</td></tr><tr><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:20px; text-indent:-10px;">Kim <italic>et al</italic>. (2013)<sup><span class="xref"><a href="#B15">15</a></span></sup></td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">USA</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">US national representative samples (n=11,154)</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">Ultrasonography</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">34.0%<break/>3.2% (advanced fibrosis)</td></tr><tr><td valign="top" align="left" style="padding-left:20px; text-indent:-10px;">Abeysekera <break/><italic>et al</italic>. (2020)<sup><span class="xref"><a href="#B16">16</a></span></sup></td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">UK</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">UK Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n=4,021)</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Transient elastography with controlled attenuation parameter (CAP) score</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">20.7% (95% CI, 19.4–22.0) for steatosis<break/>2.7% (95% CI, 2.2–3.2) for suspected fibrosis (F2-F4)</td></tr></tbody></table><table-wrap-foot><fn id="t2fn1"><p style='text-indent: 0pt; margin-bottom: 0px;'>NAFLD, nonalcoholic fatty liver disease; CI, confidence interval; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.</p></fn></table-wrap-foot> <br clear='all' /> </dd> </dl></div> <div class="inner-contents"> <dl> <dd id='T3' style='padding: 10px 0;width:100%;overflow-x:auto;overflow-y:hidden;'> <p style='text-indent: 0pt; margin-bottom: 0px;'><span style='color:#1567b7; font-weight:bold; font-size:14px;'><a href='#' class='j_text_size full_blink btn-file' data-toggle="modal" data-remote='./popup_file.html?uid=1764&file=gnl-15-2-206-f3.jpg&md=tbl&idx=3' data-target="#file-modal""><strong>Table 3</strong></a></span> Formulas of Noninvasive Fibrosis Marker Panels</p><table frame="hsides" rules="groups"><thead><tr><th valign="middle" align="center" style="background-color:#e9e7f1;">Formula</th><th valign="middle" align="center" style="background-color:#e9e7f1;">Equation</th></tr></thead><tbody><tr><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">Fibrosis-4</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">(Age [years]×AST [U/L])/(platelet [10<sup>9</sup>/L]×(ALT [U/L])<sup>1/2</sup>)</td></tr><tr><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">NAFLD fibrosis score</td><td valign="top" align="left" style="background-color:#f6f7f7; padding-left:10px; text-indent:-10px;">–1.675+(0.037×age [years])+(0.094×BMI [kg/m<sup>2</sup>])+(1.13×IFG or diabetes [yes=1, no=0])<break/>+(0.99×AST/ALT)–(0.013×platelet count [10<sup>9</sup>/L])–(0.66×albumin [g/dL])</td></tr><tr><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">APRI</td><td valign="top" align="left" style="padding-left:10px; text-indent:-10px;">([AST/upper limit of normal]/platelet count [10<sup>9</sup>/L])×100</td></tr></tbody></table><table-wrap-foot><fn id="t3fn1"><p style='text-indent: 0pt; margin-bottom: 0px;'>AST, aspartate aminotransferase; ALT, alanine transferase; NAFLD, nonalcoholic fatty liver disease; BMI, body mass index; IFG, impaired fasting glucose; APRI, AST to platelet ratio index.</p></fn></table-wrap-foot> <br clear='all' /> </dd> </dl></div> </div> </div>  <div class="split-tabcon"> <div class="inner-contents"> <div class="body-section"> <div class="section03_tit clear"> <h3>References</h3> </div><div id="fulltext_Area"> <ol> <li id='B1'><div class='j_text_size'>Day CP, James OF. 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All numbers are estimated by the current prevalence of NAFLD, nonalcoholic steatohepatitis (NASH), NASH cirrhosis.<sup><span class="xref"><a href="#B9">9</a></span></sup>,<span class="xref"><a href="#B12">12</a></span>,<span class="xref"><a href="#B18">18</a></span></sup>|@|~(^,^)~|@|Recent literature summarizing risk factors for nonalcoholic fatty liver disease (NAFLD) progression.<sup><span class="xref"><a href="#B46">46</a></span>-<span class="xref"><a href="#B51">51</a></span></sup><br/>NASH, nonalcoholic steatohepatitis; NAS, NAFLD activity score; INR, international normalized ratio; AST, aspartate aminotransferase; ALT, alanine transferase; FIB-4, fibrosis-4; NFS, NAFLD fibrosis score; APRI, AST to platelet ratio index; OR, odds ratio; CI, confidence interval.|@|~(^,^)~|@|All-cause mortality of NAFLD patients with and without NASH by fibrosis stage.<sup><span class="xref"><a href="#B59">59</a></span></sup><br/>NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; RR, relative risk; CI, confidence interval. </div> <div class="file-con"> Gut and Liver 2021;15:206~216 <a href='https://doi.org/10.5009/gnl20127' target='_blank'>https://doi.org/10.5009/gnl20127</a> </div> <div class="copy">© Gut and Liver</div> </div> <div class="modal-footer text-center"> © 2023. <span style="color: #0156C2; font-weight: bold;">Gut and Liver</span>. / Powered by <a href="https://www.inforang.com" onclick="window.open(this.getAttribute('href'));return false;">INFOrang Co., Ltd</a> </div> </div> </div> </div>   <div class="modal fade article-modal" id="help-modal" role="dialog"> <div class="modal-dialog">  <div class="modal-content"> <a href="#n" class="close" data-dismiss="modal"><i class="xi-close-thin"></i></a> <div class="modal-header"> <img src="/asset/images/h1-logo.png" alt="GNL Gut and Liver"> </div> <div class="modal-body"> <div class="help-pop-wrap"> <ul class="help-list"> <li> <a href="#n">1. 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The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication. </p> </div> </li> </ul> </div> </div> </div> </div> </div>   <div class="modal fade article-modal" id="share-modal" role="dialog"> <input type="hidden" value="" id="sns_val"> <div class="modal-dialog">  <div class="modal-content"> <div class="modal-header"> <img src="/asset/images/h1-logo.png" alt="Gut and Liver"> </div> <div class="modal-body cf"> <h4>Share by SNS</h4> <ul class="cf">  <li><a href="#n" class="btn-facebook" id="FacebookTopView" alt="Add to Facebook" title="Facebook" target="_blank"><img src="/asset/images/sub/ic-sns01.png" alt="Facebook" ></a></li> <li><a href="#n" class="btn-twitter" id="TwitterTopView" alt="Add to Twitter" title="Twitter" target="_blank"><img src="/asset/images/sub/ic-sns02.png" alt="twitter"></a></li>  <li><a href="#n" class="btn-line" id="LineTopView" alt="Add to Line" title="Line" target="_blank"><img src="/asset/images/sub/ic-sns04.png" alt="line"></a></li> <li><a href="#n" class="btn-inLink" id="LinkedinTopView" alt="Add to Linkedin" title="Linkedin" target="_blank"><img src="/asset/images/sub/ic-sns06.png" alt="linkedin"></a></li>  </ul> <div class="btn-wrap text-right"> <a href="#n" class="close btn-close" data-dismiss="modal">Close</a> </div> </div> </div> </div> </div>  <script> $(document).ready(function(e){ // 2020-08-25 15:46:28 !!! 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KJJ !!! 스크립트 변경 $('.btn-file').on('click',function(e){ var button = $(e.relatedTarget); var data_remote = $(this).data("remote"); $('#file-modal').find(('.modal-dialog')).load(data_remote); }); }); </script>   <div id="split_m" class="modal fade article-modal view-modal" role="dialog"> <div class="modal-dialog">  <div class="modal-content"> <div class="modal-header"> <h4>Contents</h4> <a href="#n" class="close btn-close" data-dismiss="modal"><i class="xi-close"></i></a> </div> <div id="section-list" class="modal-body cf split-wrap-m"> <div class="section-container cf"> <div class="section-con"> <ul class="sectionM-contents-list"><li><a href="#body00" data-dismiss="modal">Abstract <i class="xi-angle-right"></i></a></li><li><a href="#body01" data-dismiss="modal">INTRODUCTION <i class="xi-angle-right"></i></a></li><li><a href="#body02" data-dismiss="modal">DEFINITIONS <i class="xi-angle-right"></i></a></li><li><a href="#body03" data-dismiss="modal">EPIDEMIOLOGY <i class="xi-angle-right"></i></a></li><li><a href="#body04" data-dismiss="modal">MORTALITY IN NAFLD <i class="xi-angle-right"></i></a></li><li><a href="#body05" data-dismiss="modal">CURRENT HEALTH POLICY <i class="xi-angle-right"></i></a></li><li><a href="#body06" data-dismiss="modal">CONCLUSIONS <i class="xi-angle-right"></i></a></li><li><a href="#body07" data-dismiss="modal">CONFLICTS OF INTEREST <i class="xi-angle-right"></i></a></li><li><a href="#body08" data-dismiss="modal">Figure <i class="xi-angle-right"></i></a></li><li><a href="#body09" data-dismiss="modal">Table <i class="xi-angle-right"></i></a></li></ul>  </div> </div> </div> </div> </div> </div>  <script defer src='//js.trendmd.com/trendmd.min.js' data-trendmdconfig='{"journal_id":"58940","element":"#trendmd-suggestions"}'></script> </body> </html>