Elsevier

The Lancet

Volume 397, Issue 10290, 5–11 June 2021, Pages 2212-2224
The Lancet

Seminar
Non-alcoholic fatty liver disease

https://doi.org/10.1016/S0140-6736(20)32511-3Get rights and content

Summary

Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD encompasses a disease continuum from steatosis with or without mild inflammation (non-alcoholic fatty liver), to non-alcoholic steatohepatitis (NASH), which is characterised by necroinflammation and faster fibrosis progression than non-alcoholic fatty liver. NAFLD has a bidirectional association with components of the metabolic syndrome, and type 2 diabetes increases the risk of cirrhosis and related complications. Although the leading causes of death in people with NAFLD are cardiovascular disease and extrahepatic malignancy, advanced liver fibrosis is a key prognostic marker for liver-related outcomes and overall mortality, and can be assessed with combinations of non-invasive tests. Patients with cirrhosis should be screened for hepatocellular carcinoma and oesophageal varices. There is currently no approved therapy for NAFLD, although several drugs are in advanced stages of development. Because of the complex pathophysiology and substantial heterogeneity of disease phenotypes, combination treatment is likely to be required for many patients with NAFLD. Healthy lifestyle and weight reduction remain crucial to the prevention and treatment of NAFLD.

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

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

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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