The burden of NAFLD and NASH
Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of liver disorders of varying severity. These disorders are defined by the accumulation of fat in the liver and can range from the less severe nonalcoholic fatty liver (NAFL), to the more serious nonalcoholic steatohepatitis (NASH).1 The prevalence of NAFLD is steadily increasing in parallel with obesity and type 2 diabetes mellitus (T2DM), leading to a greater burden on healthcare systems.2,3
NAFLD and NASH
NAFLD is caused by a deposition of fat in the liver (steatosis), which is not related to excessive alcohol consumption or other liver disease aetiologies. There are two major subcategories of NAFLD: NAFL and NASH.1
NAFL is a more benign disease with minimal risk of progression to cirrhosis or liver failure. NASH is usually more severe, and defined by the additional presence of inflammation (hepatitis), ballooning of the liver, and steatosis.1
NASH can be a chronic, progressive disease, and has a higher risk of fibrosis, subsequent cirrhosis and liver failure.1 It can also lead to the most common form of primary liver cancer, hepatocellular carcinoma (HCC), although this is rare.4,5
Fibrosis: an independent predictor of liver-related morbidity and mortality
Liver fibrosis is an important and measurable biological marker of NAFLD severity, defined as the thickening and scarring of connective tissue due to hepatic injury. While patients with NAFL can develop fibrosis without developing NASH first, advanced fibrosis occurs more commonly in people with NASH.6
Severity of fibrosis is commonly defined using either the METAVIR, Scheuer or Batts-Ludwig grading systems, which each give a score of F1–F4.7–9 While these systems differ somewhat, they follow the same key progressions. Bridging fibrosis (F3) typically refers to fibrotic cross-linking that extends across the liver lobules, distorting the liver architecture. In cirrhosis (F4), fibrotic tissue forms septa, which dissect the liver tissue into nodules.10 The presence of NASH in combination with bridging fibrosis or cirrhosis can be referred to as ‘advanced fibrosis due to NASH’; this is the most serious form of NAFLD, due to the high risk of liver-specific morbidity and overall mortality.11 Advanced fibrosis is the most significant independent predictor of liver and cardiovascular-related mortality.12 More information on how fibrosis is identified and graded can be found on the Identifying people with NAFLD and Referral and diagnosis pages.
Figure 1. Grading fibrosis severity7-9
Epidemiology of NAFLD and NASH
In the general adult population, the global prevalence of NAFLD is estimated to be 25%, with similar figures cited in the United States (US) and Europe (both 24%).13 However, figures vary widely across population subtypes and geographical regions. In Romania, the prevalence is estimated to be 20%,14 while in Greece the prevalence may be as high as 40%.15
The prevalence of NASH in people with NAFLD is harder to estimate due to the invasive nature of liver biopsy, which is required for NASH diagnosis. Estimates for NASH prevalence in the general population have been shown to vary between 1.5% and 6.45%, which corresponds to approximately 6–26% of people with NAFLD.16
The prevalence of NAFLD has increased steadily over the past few decades. One study reported a doubling of prevalence in the US from 5.5% between 1988 and 1994 to 11% between 2005 and 2008. A similar increase was seen in NASH from 0.65% to 1.1% over the same period.2
Increases in NAFLD prevalence are likely due to corresponding increases in the prevalence of conditions observed over the same period.2 The global prevalence of T2DM in adults has risen from 4.7% in 1980 to 8.5% in 2014.17 Global obesity prevalence in 2016 was 13%, which is triple what it was in 1975.18
The percentage of people with NASH who developed cirrhosis, liver failure and HCC also increased in the US between 2006 and 2014.19
Comorbidities of NAFLD
NAFLD is strongly associated with each of the components of the metabolic syndrome (MetS).20 MetS consists of increased fasting plasma glucose/T2DM, hypertriglyceridaemia, low levels of high-density lipoprotein, increased waist circumference/obesity and hypertension.
These factors are all linked by their common association with poor diets and low levels of exercise. NAFLD may therefore represent the de facto hepatic component of MetS.21 The prevalence of MetS among people with NAFLD and NASH is 43% and 71%, respectively.13
Obesity and T2DM may be the two most clinically important comorbidities in NAFLD, due to their prediction of severe fibrosis.13,22,23 One study demonstrated that two thirds of people over the age of 45 with NAFLD, with both obesity and T2DM, had advanced fibrosis.22 Both of these comorbidities are more commonly found in people with NAFLD compared with the general population, and vice versa:13,23
- One large Italian study reported the prevalence of NAFLD in patients with T2DM to be 70%23
- Globally, 23% and 51% of people with NAFLD have T2DM or are obese, respectively, with higher estimates of approximately 44% and 82%, respectively, in people with NASH13
Other individual factors associated with a risk of developing NAFLD, or with disease progression, include the following:24
Older age (≥65 years old)25
≥28 kg/m2 body mass index26
High triglyceride levels (>2 mmol/L)26
Ratio of <1 for aspartate aminotransferase (AST):alanine transaminase (ALT)27
The progression of NAFLD does not always follow a clear, linear pathway. NAFLD can begin with less severe NAFL, subsequently progressing to NASH, advanced fibrosis, and eventually HCC and cirrhosis.28 However, some cases of NASH maintain a relatively constant level of activity, or even regress.6
Figure 2. Natural History of NAFLD and NASH13,28
Fibrosis is the most important diagnostic marker in people with NAFLD. Individuals with cirrhosis (F4) have worse survival rates and a higher chance of developing liver disease complications than those with bridging fibrosis (F3).29 Presence of fibrosis of all stages, hepatocyte ballooning, and portal inflammation all correlate with lower survival rates.30 People with NAFL can also develop fibrosis, albeit at a slower rate than those with NASH. For people with NAFL, without fibrosis at baseline (F0), the average progression was found to occur at a rate of one stage every 14.3 years. For people with NASH, progression occurs at twice the rate – one stage every 7.1 years.28 Despite this, both NAFL and NASH can be at least partially reversed with the right intervention.31
Although people with NASH are at a high risk of liver disease-related deaths, the leading cause of death in patients with NAFLD is cardiovascular disease (CVD).32 The risk of CVD persists even after accounting for underlying factors such as T2DM and obesity. However, the mechanisms by which NAFLD is linked to the development of CVD are still unclear.33
Individuals with advanced disease may eventually develop HCC; the yearly incidence of HCC from NASH-cirrhosis is approximately 2.6%.34 In a US-based population study of 4406 patients with HCC, 59% of cases were reported to have developed in people with NAFLD.35 It is not clear to what extent HCC arises due to NAFLD itself, or due to associated conditions such as T2DM and obesity.
NAFLD and NASH represent a large economic burden on healthcare systems.
The annual economic burden of both NAFLD and NASH across Germany, France, Italy and the United Kingdom (UK) is estimated to be €35 billion. In the UK alone, the economic impact is estimated to be £5.24 billion. In addition to the direct cost of treatment, it is estimated that societal costs due to loss of quality-adjusted life-years years may be as high as €188.08 billion in Europe, annually. Total costs are highest for patients aged 45–65 years, yet per-patient costs are highest in the 65+ group, which is thought to reflect the fact that a greater number of elderly patients have advanced disease.3
NASH is expected to become the leading cause of liver transplantation.
NASH is currently the second leading cause of liver disease among individuals awaiting liver transplantation in the US; new waitlist registrants with NASH have increased by 170% between 2004 and 2013. In comparison, new waitlist registrants with hepatitis C virus (HCV) and alcoholic liver disease (ALD) have increased by just 14% and 45%, respectively, during the same period.36 People with NASH are less likely to survive for 90 days on the waitlist compared with people with ALD. They are also less likely to receive a transplant after 90 days compared with people with ALD, HCV or both.36
Figure 3: Increase in waitlist numbers for liver transplant by indication in the US36
NAFLD and NASH have a noticeable impact on quality of life.
A number of studies have investigated the effect of NAFLD on patient quality of life (QoL). One study showed that more people with NAFLD reported having “fair” or “poor” health and were more likely to report physical health issues preventing them from their activities than healthy controls.37 Another study showed that individuals with NAFLD report higher levels of fatigue than healthy controls.38 When comparing different liver disease aetiologies, people with NAFLD were also found to report worse QoL outcomes than those with HCV or hepatitis B virus (HBV).39
Multiple studies have investigated physical health in people with NASH compared with those with NAFLD only.38,40
- In one study, physical health scores were even lower in patients with cirrhosis, compared with NASH and NAFLD-only groups41
- Another study demonstrated lower physical functioning, pain, and social functioning scores in people with both NASH and cirrhosis compared with those with bridging fibrosis (F3)40
- Further to these studies, higher enhanced liver fibrosis scores and NAFLD fibrosis scores are associated with significantly lower physical health scores in people with NASH42
NAFLD and NASH
The introductory page for the NASH and NAFLD section of Hepatic Health.
Identifying people with NAFLD
An overview of primary care testing and interpretation of results for people at risk of NAFLD.
Referral and diagnosis
Information relates to diagnostic testing including Fibroscan® and noninvasive tests.
Management of NAFLD and NASH
Information on lifestyle interventions, surgical interventions and multidisciplinary management for people with NAFLD and NASH.
Obesity and NASH
Exploring the prevalence of advanced fibrosis due to NASH in people with obesity.
Diabetes and NASH
Information on the prevalence of NAFLD in the context of type 2 diabetes mellitus, the burden of NAFLD and NASH in diabetes, assessment and diagnosis and referral and management.
- Sweet PH, et al. Nonalcoholic Fatty Liver Disease. Prim Care Clin Off Pract 2017;44:599–607.
- Younossi ZM, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011;9:524–30.e1; quiz e60.
- Younossi ZM, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 2016;64:1577–86.
- Hui J, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003;38:420–7.
- Adams LA, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113–21.
- McPherson S, et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015;62:1148–55.
- Bedossa P and Poynard T. An algorithm for the grading of activity in chronic hepatitis C. Hepatology 1996;24:289–93.
- Batts KP and Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995;19:1409–17.
- Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 1991;13:372–4.
- Lo RC and Kim H. Histopathological evaluation of liver fibrosis and cirrhosis regression. Clin Mol Hepatol 2017;23:302–7.
- Hagström H, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol 2017;67:1265–73.
- Ekstedt M, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015;61:1547–54.
- Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.
- Radu C, et al. Prevalence and associated risk factors of non-alcoholic fatty liver disease in hospitalized patients. J Gastrointestin Liver Dis 2008;17:255–60.
- Zois CD, et al. Steatosis and steatohepatitis in postmortem material from Northwestern Greece. World J Gastroenterol 2010;16:3944–9.
- Younossi ZM. The epidemiology of nonalcoholic steatohepatitis. Clin Liv Dis
- WHO. Diabetes: fact sheet. Available at https://www.who.int/news-room/fact-sheets/detail/diabetes. (last accessed January 2019)
- WHO. Obesity and overweight: fact sheet. Available at https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. (last accessed January 2019)
- Goldberg D, et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology 2017;152:1090–9.e1.
- Jinjuvadia R, et al. The Association Between Nonalcoholic Fatty Liver Disease and Metabolic Abnormalities in The United States Population. J Clin Gastroenterol 2017;51:160–6.
- Cortez-Pinto H, et al. Non-alcoholic fatty liver: another feature of the metabolic syndrome? Clin Nutr 1999;18:353–8.
- Angulo P, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356–62.
- Targher G, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007;30:1212–8.
- Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver Int 2017;37:81–4.
- Noureddin M, et al. Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients. Hepatology 2013;58:1644–54.
- Ha Y, et al. The association between Vitamin D insufficiency and nonalcoholic fatty liver disease: a population-based study. Nutrients 2017;9:806.
- Singh S, et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015;13:643–54.e1-9; quiz e39–40.
- Pais R, et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 2013;59:550–6.
- Axley P, et al. Patients with stage 3 compared to stage 4 liver fibrosis have lower frequency of and longer time to liver disease complications. PLoS One 2018;13:e0197117.
- Angulo P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015;149:389–97.e10.
- Vilar-Gomez E, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149:367–78.
- Söderberg C, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010;51:595–602.
- Oni ET, et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis 2013;230:258–67.
- Ascha MS, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51:1972–8.
- Sanyal A, et al. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin 2010;26:2183–91.
- Wong RJ, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015;148:547–55.
- Golabi P, et al. Non-alcoholic fatty liver disease (NAFLD) is associated with impairment of health related quality of life (HRQOL). Health Qual Life Outcomes 2016;14:18.
- Newton JL, et al. Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance. Gut 2008;57:807–13.
- Dan AA, et al. Health-related quality of life in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2007;26:815–20.
- Younossi ZM, et al. Severe impairment of patient-reported outcomes in patients with advanced fibrosis due to non-alcoholic steatohepatitis. The American Association for the Study of Liver Diseases, The Liver Meeting®, San Francisco, California. 9–13 November 2018: Abstract 1683.
- David K, et al. Quality of life in adults with nonalcoholic fatty liver disease: baseline data from the nonalcoholic steatohepatitis clinical research network. Hepatology 2009;49:1904–12.
- Younossi ZM, et al. Advanced fibrosis based on noninvasive tests in nonalcoholic steatohepatitis (NASH) is associated with impairment of patient-reported outcomes. The American Association for the Study of Liver Diseases, The Liver Meeting®, San Francisco, California. 9–13 November 2018: Abstract 1991.
LID/IHQ/18-12//1048d(1) Date of preparation August 2019