We searched PubMed and MEDLINE to identify studies and reviews published between Jan 1, 1980, and Dec 31, 2020, relevant to the scope of this Seminar with the terms “non-alcoholic fatty liver disease”, “non-alcoholic steatohepatitis”, “NAFLD”, “NASH”, “fatty liver”, “epidemiology”, “prevalence”, “incidence”, “disease burden”, “non-invasive tests”, “liver fibrosis”, “blood tests”, “liver stiffness measurement”, “natural history”, “pathogenesis”, “treatment”, “pharmacotherapy”, and “risk
SeminarNon-alcoholic fatty liver disease
Introduction
Over the past four decades, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder (with a global prevalence of around 25% of the adult population)1 and is recognised to have a close, bidirectional association with components of metabolic syndrome.2 Although less than 10% of people with NAFLD develop liver-related complications, a key challenge is to identify those who are at the highest risk among the many people affected by NAFLD. Due to its high prevalence, NAFLD is now the most rapidly increasing cause of liver-related mortality worldwide3 and is emerging as an important cause of end-stage liver disease,4 primary liver cancer,5 and liver transplantation with a substantial health economic burden. Despite the growing concern, NAFLD is underappreciated as an important chronic disease6 and there are few national strategies or policies for NAFLD.7
This Seminar describes the epidemiology, natural history, and risk factors for progression of NAFLD. We highlight progress in non-invasive tests to assess liver disease severity and the importance of a collaborative approach to diagnosis, risk stratification, and management to improve health outcomes for people with NAFLD.
Section snippets
Definition
NAFLD is the liver component of a cluster of conditions that are associated with metabolic dysfunction. Although fatty liver hepatitis resulting in cirrhosis was described nearly 20 years beforehand,8 the term non-alcoholic steatohepatitis (NASH) was first coined by Ludwig and colleagues in 1980.9 NAFLD is defined by the presence of steatosis in more than 5% of hepatocytes in association with metabolic risk factors (particularly, obesity and type 2 diabetes) and in the absence of excessive
Epidemiology and disease burden
NAFLD is now the most common cause of chronic liver disease worldwide, with a prevalence that varies from 13·5% in Africa to 31·8% in the Middle East,1 which is likely driven by differences in overall caloric intake, physical activity, body fat distribution, socioeconomic status, and genetic composition. Because of its close association with the metabolic syndrome, NAFLD is seen in 47·3–63·7% of people with type 2 diabetes and up to 80% of people with obesity.13, 14 However, some people with a
Natural history
The relationship between NAFLD and all-cause mortality is unresolved, with some studies detecting a modest increase in risk of all-cause mortality compared with the general population,29, 30, 31 and others reporting no association between NAFLD and mortality.32, 33 NAFLD is a heterogeneous condition with varying rates of disease progression and clinical outcomes, which might be driven by the varying predominant mechanisms for the development of the disease (figure 2).35 In the majority of
Pathogenesis
The primary driver of NAFLD is overnutrition, which causes expansion of adipose depots as well as accumulation of ectopic fat (figure 3). In this setting, macrophage infiltration of the visceral adipose tissue compartment creates a proinflammatory state that promotes insulin resistance. Inappropriate lipolysis in the setting of insulin resistance results in unabated delivery of fatty acids to the liver, which, along with increased de-novo lipogenesis, overwhelms its metabolic capacity. The
Risk stratification and assessment of disease severity
NAFLD is most often diagnosed by imaging, although it can be inferred from clinical risk scores (eg, fatty liver index) or identified histologically. In routine practice, the most commonly used test is abdominal ultrasonography (figure 1D). On abdominal ultrasonography, hepatic steatosis is characterised by a bright liver echotexture and blurring of the hepatic vasculature.65 Abdominal ultrasonography has two important limitations: advanced fibrosis can coarsen hepatic echotexture and blur
Management of NASH
Although the liver related burden of NASH is substantial and increasing, cardiovascular disease and malignancy are the leading causes of death in people with NAFLD.4, 17, 18, 20 Therefore, management of NASH deserves a holistic approach that strives to minimise cardiovascular risk and to reduce drivers of steatosis and systemic inflammation.
The balance between nutrients and energy is pivotal in the development of NAFLD and NASH. Central obesity is an important driver of disease through the
Challenges and prospects
Although valuable progress has been made during the past 40 years in learning about the natural history and underlying biology of NAFLD, there are still many challenges. NAFLD is largely under-recognised by health-care professionals and the wider community. Implementation of strategies to identify, and appropriately manage, at-risk patients with advanced fibrosis will require action by clinicians in primary care, diabetes clinics, and other specialists who treat patients with metabolic risk
Search strategy and selection criteria
Declaration of interests
VW-SW served as a consultant or advisory board member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, US Center for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET-NASH, and Terns; and served as a speaker for AbbVie, Bristol-Myers Squibb, Echosens, and Gilead Sciences. VW-SW has also received an unrestricted grant from Gilead Sciences for
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