Elsevier

Metabolism

Volume 65, Issue 8, August 2016, Pages 1017-1025
Metabolism

Nonalcoholic Fatty Liver Disease: From Pathogenesis to Emerging Treatment
Epidemiology and natural history of non-alcoholic fatty liver disease

https://doi.org/10.1016/j.metabol.2016.01.012Get rights and content

Abstract

Non-alcoholic steatohepatitis (NASH) is part of the spectrum of non-alcoholic fatty liver disease (NAFLD) that leads to progressive liver disease and presents a growing challenge to public health. Because of the increased prevalence of metabolic syndrome and obesity, NAFLD and NASH have expanded to a substantial extent. In NASH patients, advanced fibrosis is the major predictor of morbidity and liver-related mortality, and an accurate diagnosis of NASH is mandatory. Although there is currently no validated test of serum biomarkers available to diagnose NASH, and histologic evaluation with a liver biopsy remains the gold standard, screening for fibrosis is recommended in patients with suspicion of NASH. Clinical prediction models and serum biomarkers for advanced fibrosis have relatively good negative predictive value and can be useful for screening. Also, transient elastography is increasingly available to estimate fibrosis in NASH. Therefore, due to the lack of a reliable and accepted non-invasive diagnostic modality, screening for NASH in the general population is not currently recommended. Better understanding of the natural history of NASH is needed to evaluate the utility and cost-effectiveness of screening.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease worldwide. The US guidelines for NAFLD management define NAFLD as a) steatosis with ≥ 5% fat infiltration in imaging or histology and b) no alcohol, drug or viral induced steatosis [1]. Furthermore, diagnosis of NAFLD requires exclusion of other liver diseases, such as alcoholic liver disease, viral hepatitis, and Wilson's disease. Alcoholic hepatitis must be ruled out via a thorough history of alcohol consumption. Current guidelines also suggest a definition for significant alcohol consumption as ongoing or recent consumption of 21 or 14 average drinks per week or fewer for men and women, respectively. NAFLD patients may present with elevated liver enzymes [2].

The bulk of risk for progression to cirrhosis, hepatocellular carcinoma and liver transplant is in NAFLD patients with non-alcoholic steatohepatitis (NASH). NASH is a growing problem in developed countries, as the prevalence of obesity is rising. In patients with established NASH, 10-year survival is estimated to be around 60–70% [3], [4]. This review will provide the most current information about clinical presentation, epidemiology, natural history, and diagnostic modalities for NAFLD and NASH.

Section snippets

Clinical Presentation

Initial indicators for the presence of NAFLD include mild and asymptomatic elevation of liver enzymes. Some patients may present with mild malaise, fatigue, and right upper quadrant discomfort. Although liver enzymes may fluctuate overtime, NAFLD patients with advanced liver disease can present with completely normal liver enzymes. Nevertheless, it is important to note that NAFLD patients with type 2 diabetes, older age, and AST/ALT ratio > 1 are at higher risk for having NASH and fibrosis [2],

North America

The prevalence of NAFLD throughout North America is similar and is estimated to range from 27–34% within the general population [4], [6], [10]. However, in certain subpopulations the estimated prevalence of NAFLD is significantly higher. In fact, the prevalence of NAFLD in the morbidly obese ranges from 75% to 92% while the prevalence in patients with type 2 diabetes is estimated to be between 60% and 70% [10], [11], [12], [13], [14], [15], [16]. Furthermore, ethnic differences in the

Incidence

There is no precise data on the incidence rates for NAFLD. This is partly due to the fact that NAFLD is usually a silent disease which is discovered incidentally. Nevertheless, given that the prevalence of obesity in adults has almost doubled since the early 1960s (1962–48% vs 2010–75%), the incidence of obesity-related NAFLD has almost certainly increased [30], [31], [32].

In Asia, a few studies have reported an annual incidence of 3–5%; however, the exact incidence rates for NAFLD from

Natural History

NAFLD is closely associated with components of metabolic syndrome, especially visceral obesity. An estimated 40–45 million adults in the United States have NAFLD, associated with the high prevalence of obesity [6]. Although the exact prevalence of NASH in general population is unknown, it is estimated that about 3–5% of US adult population have NASH [1], [9]. It is almost certain that the prevalence is higher in certain subpopulations such as those with type 2 diabetes [7], [8], [9], [10], [11]

NASH Prognosis

Most long-term studies have suggested that the presence of histologic NASH predisposes patients to a potentially progressive type of liver disease. In fact, in a study with over 10 years of follow-up, the investigators determined that approximately 20% of NASH patients may develop cirrhosis and 8% may die of liver related causes [47]. Although the presence of fibrosis in NASH has been consistently associated with diabetes and age, only significant hepatic fibrosis (stage > 2) has been predictive

Diagnosis of NAFLD and NASH

Prior to discussing the diagnostic modalities for NASH, it is essential to briefly describe the pathogenesis of NAFLD and NASH in order to understand the strengths and limitations of each diagnostic test. There are several pathways that may lead to the accumulation of hepatic fat. These include increased hepatic lipogenesis, decreased expulsion of hepatic lipid stores, and/or diminished oxidation of free fatty acids in the liver [1], [39], [52], [53], [54], [55], [56], [57]. These processes

Non-invasive Diagnosis of NASH

Non-invasive diagnostic models for NASH have not been validated in long-term studies; however, a variety of non-invasive markers are available to assist clinicians in their decision-making and diagnosis process. Performance characteristics of these non-invasive tests are summarized in Table 1.

NASH Biomarkers

Several investigators are researching the use of biomarkers in distinguishing NASH by detecting serum markers of specific disease activity, including proteins associated with necrosis, fibrogenesis and the cytokines, adipokines, insulin resistance, and markers of apoptosis associated with the pathogenesis of NASH [77], [78], [79], [80], [81]. Thus far, however, none of the available biomarkers of NASH have been demonstrated to outperform clinical prediction models at detecting or ruling out

Fibrosis Assessment

A key element when assessing NAFLD patients is to determine the severity of fibrosis which has been found to be predictive of overall and disease specific mortality. Fibrosis scores can be estimated by non-invasive modalities, including clinical predictor models, biomarker panels, and elastography. A suggested screening algorithm for NASH-fibrosis in patients with suspected NAFLD is shown in Fig. 2.

Conclusion

Currently, the worldwide prevalence of NAFLD ranges from a low of 8% to a high of 45%. Given the epidemic of obesity, the incidence of NAFLD and its progressive form (NASH) is expected to grow. From the spectrum of NAFLD, NASH patients have a risk for progressive liver disease, including cirrhosis. Although the rate of progression may be 15–20%, the sheer number of patients with NASH has already made NASH, the second most common indication for liver transplantation, and the second most common

Authors Contributions

Yousef Fazel and Aaron B. Koenig: authors contributed equally to the study concept and design, acquisition of data and drafting of the manuscript; Mehmet Sayiner: drafting of the manuscript, critical revision of the manuscript for important intellectual content; Zachary D. Goodman: study design, critical revision of the manuscript for important intellectual content; Zobair M. Younossi: study design, acquisition of data, critical revision of the manuscript for important intellectual content.

Funding

This study was internally funded; no grant or external fund was accepted.

Conflict of Interest

The authors declare that they have no conflict of interest for this study.

Acknowledgements

The authors would like to thank Linda Henry and Dr. Pegah Golabi for their great support during the formation of this manuscript.

References (98)

  • A.H. Paredes et al.

    Nonalcoholic fatty liver disease

    Clin Liver Dis

    (2012)
  • T. Karlas et al.

    Gastrointestinal complications of obesity: non-alcoholic fatty liver disease (NAFLD) and its sequelae

    Best Pract Res Clin Endocrinol Metab

    (2013)
  • P. Mofrad et al.

    Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values

    Hepatology

    (2003)
  • P. Sorrentino et al.

    Silent non-alcoholic fatty liver disease-a clinical-histological study

    J Hepatol

    (2004)
  • L.B. Seeff et al.

    Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial

    Clin Gastroenterol Hepatol

    (2010)
  • K. Cusi et al.

    Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease

    J Hepatol

    (2014)
  • S. Gaia et al.

    Reliability of transient elastography for the detection of fibrosis in non-alcoholic fatty liver disease and chronic viral hepatitis

    J Hepatol

    (2011)
  • N. Chalasani et al.

    The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

    Hepatology

    (2012)
  • Z.M. Younossi

    Practical management of liver diseases

    (2008)
  • S. Caldwell et al.

    The natural history of non-alcoholic fatty liver disease

    Dig Dis

    (2010)
  • L.A. Adams et al.

    Nonalcoholic steatohepatitis: risk factors and diagnosis

    Expert Rev Gastroenterol Hepatol

    (2010)
  • M. Lazo et al.

    Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994

    Am J Epidemiol

    (2013)
  • G. Musso et al.

    Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis

    PLoS Medicine

    (2014)
  • G. Vernon et al.

    Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults

    Aliment Pharmacol Ther

    (2011)
  • I.R. Wanless et al.

    Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors

    Hepatology

    (1990)
  • J.F. Silverman et al.

    Liver pathology in morbidly obese patients with and without diabetes

    Am J Gastroenterol

    (1990)
  • P. Angulo et al.

    Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis

    Hepatology

    (1999)
  • Z.M. Younossi et al.

    Nonalcoholic fatty liver disease in lean individuals in the United States

    Medicine (Baltimore)

    (2012)
  • M. Lazo et al.

    The epidemiology of nonalcoholic fatty liver disease: a global perspective

    Semin Liver Dis

    (2008)
  • J.J. Pan et al.

    Gender and racial differences in nonalcoholic fatty liver disease

    World J Hepatol

    (2014)
  • J.D. Browning et al.

    Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity

    Hepatology

    (2004)
  • A.L. Schneider et al.

    Racial differences in nonalcoholic fatty liver disease in the U.S. population

    Obesity (Silver Spring)

    (2014)
  • M. Soresi et al.

    Nonalcoholic fatty liver and metabolic syndrome in Italy: results from a multicentric study of the Italian Arteriosclerosis Society

    Acta Diabetol

    (2013)
  • G. Bedogni et al.

    Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study

    Hepatology

    (2005)
  • G.C. Farrell et al.

    NAFLD in Asia—as common and important as in the West

    Nat Rev Gastroenterol Hepatol

    (2013)
  • D.N. Amarapurkar et al.

    How common is non-alcoholic fatty liver disease in the Asia-Pacific region and are there local differences?

    J Gastroenterol Hepatol

    (2007)
  • J.G. Fan et al.

    The importance of metabolic factors for the increasing prevalence of fatty liver in Shanghai factory workers

    J Gastroenterol Hepatol

    (2007)
  • Z. Wang et al.

    Prevalence and risk factors of fatty liver disease in the Shuiguohu district of Wuhan city, central China

    Postgrad Med J

    (2007)
  • A.S. Dassanayake et al.

    Prevalence and risk factors for non-alcoholic fatty liver disease among adults in an urban Sri Lankan population

    J Gastroenterol Hepatol

    (2009)
  • M.J. Pinidiyapathirage et al.

    Non-alcoholic fatty liver disease in a rural, physically active, low income population in Sri Lanka

    BMC Res Notes

    (2011)
  • G. Brunello et al.

    The rise in obesity across the Atlantic: an economic perspective

    (2008)
  • C.L. Ogden et al.

    Prevalence of obesity and trends in body mass index among US children and adolescents, 1999-2010

    JAMA

    (2012)
  • K.M. Flegal et al.

    Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010

    JAMA

    (2012)
  • A.H. Paredes et al.

    There is substantial phenotypic variability in lean versus obese subjects with NAFLD across the world: the Global NASH Study

    Hepatology

    (2014)
  • Z.M. Younossi et al.

    Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009

    Hepatology

    (2015)
  • B.Q. Starley et al.

    Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection

    Hepatology

    (2010)
  • M. Noureddin et al.

    Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients

    Hepatology

    (2013)
  • E.M. Brunt et al.

    Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings

    Hepatology

    (2011)
  • G. Bedogni et al.

    Incidence and natural course of fatty liver in the general population: the Dionysos study

    Hepatology

    (2007)

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