NAFLD Lancet

Seminar
Non-alcoholic fatty liver disease

Elizabeth E Powell, Vincent Wai-Sun Wong, Mary Rinella
Lancet 2021; 397: 2212–24 Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% and is a leading cause of cirrhosis and
Published Online hepatocellular carcinoma. NAFLD encompasses a disease continuum from steatosis with or without mild
April 21, 2021 inflammation (non-alcoholic fatty liver), to non-alcoholic steatohepatitis (NASH), which is characterised by
https://doi.org/10.1016/
necroinflammation and faster fibrosis progression than non-alcoholic fatty liver. NAFLD has a bidirectional
S0140-6736(20)32511-3
association with components of the metabolic syndrome, and type 2 diabetes increases the risk of cirrhosis and
Centre for Liver Disease
Research, Faculty of Medicine, related complications. Although the leading causes of death in people with NAFLD are cardiovascular disease and
University of Queensland, extrahepatic malignancy, advanced liver fibrosis is a key prognostic marker for liver-related outcomes and overall
Translational Research mortality, and can be assessed with combinations of non-invasive tests. Patients with cirrhosis should be screened for
Institute, Brisbane, QLD,
hepatocellular carcinoma and oesophageal varices. There is currently no approved therapy for NAFLD, although
Australia (Prof E E Powell MD);
Department of several drugs are in advanced stages of development. Because of the complex pathophysiology and substantial
Gastroenterology and heterogeneity of disease phenotypes, combination treatment is likely to be required for many patients with NAFLD.
Hepatology, Princess Alexandra Healthy lifestyle and weight reduction remain crucial to the prevention and treatment of NAFLD.
Hospital, Brisbane, QLD,
Australia (Prof E E Powell);
Department of Medicine and Introduction highlight progress in non-invasive tests to assess liver
Therapeutics, Chinese Over the past four decades, non-alcoholic fatty liver disease severity and the importance of a collaborative
University of Hong Kong, disease (NAFLD) has become the most common chronic approach to diagnosis, risk stratification, and management
Hong Kong Special
liver disorder (with a global prevalence of around 25% of to improve health outcomes for people with NAFLD.
Administrative Region, China
(Prof V W-S Wong MD); State the adult population)1 and is recognised to have a close,
Key Laboratory of Digestive bidirectional association with components of metabolic Definition
Disease, Chinese University of syndrome.2 Although less than 10% of people with NAFLD is the liver component of a cluster of conditions
Hong Kong, Hong Kong Special
Administrative Region, China
NAFLD develop liver-related complications, a key that are associated with metabolic dysfunction. Although
(Prof V W-S Wong); challenge is to identify those who are at the highest fatty liver hepatitis resulting in cirrhosis was described
Northwestern University, risk among the many people affected by NAFLD. Due to nearly 20 years beforehand,8 the term non-alcoholic
Feinberg School of Medicine, its high prevalence, NAFLD is now the most rapidly steatohepatitis (NASH) was first coined by Ludwig and
Chicago, IL, USA
(Prof M Rinella MD)
increasing cause of liver-related mortality worldwide3 colleagues in 1980.9 NAFLD is defined by the presence of
and is emerging as an important cause of end-stage liver steatosis in more than 5% of hepatocytes in association
Correspondence to:
Prof Elizabeth E Powell, disease,4 primary liver cancer,5 and liver transplantation with metabolic risk factors (particularly, obesity and type 2
Department of Gastroenterology with a substantial health economic burden. Despite the diabetes) and in the absence of excessive alcohol consump
and Hepatology, Princess growing concern, NAFLD is underappreciated as an tion (≥30 g per day for men and ≥20 g per day for women)
Alexandra Hospital, Brisbane,
QLD 4102, Australia
important chronic disease6 and there are few national or other chronic liver diseases.10 Current nomenclature
[email protected] strategies or policies for NAFLD.7 suggests that NAFLD is more of a diagnosis of exclusion
This Seminar describes the epidemiology, natural than of inclusion, and there is an ongoing debate about
history, and risk factors for progression of NAFLD. We the limitations of the present terminology and diagnostic
criteria.11,12 In 2020, an international panel of experts
proposed the concept of metabolic dysfunction-associated
Search strategy and selection criteria fatty liver disease (MAFLD) to highlight the contribution
We searched PubMed and MEDLINE to identify studies and of cardiometabolic risk factors to the development and
reviews published between Jan 1, 1980, and Dec 31, 2020, progression of liver disease (even among patients with
relevant to the scope of this Seminar with the terms other liver diseases);11 however, MAFLD is not the currently
“non-alcoholic fatty liver disease”, “non-alcoholic accepted nomenclature by the American Association for
steatohepatitis”, “NAFLD”, “NASH”, “fatty liver”, the Study of Liver Diseases or the European Association
“epidemiology”, “prevalence”, “incidence”, “disease burden”, for the Study of Liver Diseases.
“non-invasive tests”, “liver fibrosis”, “blood tests”, “liver NAFLD is an umbrella term for a broad range of cli
stiffness measurement”, “natural history”, “pathogenesis”, nicopathological findings. Histologically, NAFLD encom
“treatment”, “pharmacotherapy”, and “risk stratification”. passes a disease continuum (figure 1 A–C) that includes
Articles were considered regardless of language. We selected steatosis with or without mild inflammation (non-alcoholic
references that provided current, evidence-based insight into fatty liver, NAFL) and a necroinflammatory subtype
non-alcoholic fatty liver disease. Most of the articles (NASH), which is additionally characterised by the
selected were published within the past 5 years, although we presence of hepatocellular injury (hepatocyte ballooning).
also included highly referenced, older publications that The predominant drivers of disease can vary substantially
contributed to new knowledge or understanding of among patients with NAFLD. Furthermore, disease
non-alcoholic fatty liver disease. progression and response to treatment are heterogeneous.
Information about disease activity and, in particular, the
2212 www.thelancet.com Vol 397 June 5, 2021

Seminar
A B C
D E F
Figure 1: Histological and radiological assessment of non-alcoholic fatty liver disease

(A) Non-alcoholic fatty liver is characterised by macrovesicular steatosis (large round non-staining areas represent lipid droplets in hepatocytes [grey arrow];
haematoxylin and eosin stain; magnification ×40) with no or little necroinflammation. (B) Apart from fat accumulation, non-alcoholic steatohepatitis (NASH) is
characterised by the presence of lobular inflammation and hepatocyte ballooning. At the centre of the image is a ballooned hepatocyte surrounded by inflammatory
cells (red arrow; haematoxylin and eosin stain; magnification ×40). (C) As disease progresses, accumulating liver fibrosis will eventually result in cirrhosis. On the right
of this image is a cirrhotic nodule surrounded by thick fibrous tissue. In some cases, steatosis and necroinflammation might reduce or disappear as the disease
progresses to cirrhosis, a condition referred to as burned-out NASH (sirius red; magnification ×10). (D) Ultrasonography, the most common method to diagnose fatty
liver, characterised by bright liver echotexture (yellow bracket) and blurring of deeper structures (red arrow). (E) Vibration-controlled transient elastography, a point-
of-care measurement of liver stiffness for the estimation of fibrosis that can also estimate hepatic steatosis using the controlled attenuation parameter. The machine
is equipped with an M-mode ultrasound for the localisation of liver parenchyma (green triangle). The elastogram (red arrow) represents the measurement of liver
stiffness. A steeper slope indicates that the shear-wave velocity is higher, and the liver is stiffer. (F) Magnetic resonance elastography of a patient with NASH cirrhosis,
currently one of the most accurate non-invasive tests of liver fibrosis, with the colour scheme reflecting stiffness in different parts of the liver. Red colour shows areas
with greater stiffness (yellow circle).
extent of liver fibrosis is necessary to assess the severity of disease prevalence. In people with other conditions (eg,
liver disease and provide prognostic information. Growing alcohol-related liver disease, and viral or autoimmune
insights from metabolomics, genomics, and other areas hepatitis), fatty liver frequently coexists and might have
will enable disease phenotyping and facilitate potential a synergistic role in liver injury.19 Importantly, the
disease stratification in the future. disease and economic burden of NAFLD will probably
increase during the coming decades.20,21 Health-care
Epidemiology and disease burden utilisation and expenditure are particularly high among
NAFLD is now the most common cause of chronic liver patients with NAFLD and advanced fibrosis or type 2
disease worldwide, with a prevalence that varies from diabetes and those requiring hospital admis sion.22,23
13·5% in Africa to 31·8% in the Middle East,1 which is Little information is available regarding the effect of
likely driven by differences in overall caloric intake, NAFLD on patients’ daily lives,24 which will be important
physical activity, body fat distribution, socioeconomic data to collect in future intervention or treatment
status, and genetic composition. Because of its close studies.
association with the metabolic syndrome, NAFLD is seen The number of cases of childhood obesity, an important
in 47·3–63·7% of people with type 2 diabetes and up to risk factor for NAFLD, is still increasing; in the USA, the
80% of people with obesity.13,14 However, some people prevalence of obesity among children aged 2–5 years
with a healthy body-mass index (eg, <25 kg/m² in White increased from 8·4% in 2011–12 to 13·9% in 2015–16.25
people and <23 kg/m² in Asian people) can still develop Although the increase appears to have slowed in many
NAFLD, often described as non-obese or lean NAFLD.15 high-income countries, the rise in body-mass index
These patients usually have central obesity or other among children and adolescents has accelerated in east
metabolic risk factors.16 and south Asia.26 Among children, the pooled mean
Although less than 10%17,18 of patients with NAFLD prevalence of NAFLD is 7·6% in the general population
develop cirrhotic complications and hepatocellular and 34·2% in clinics for paediatric obesity.27 Individuals
carcinoma during the 10–20 years after diagnosis, the with disease onset in childhood have a higher risk of
absolute numbers are substantial given the high developing liver-related events and other comorbidities
www.thelancet.com Vol 397 June 5, 2021 2213

Seminar
NAFLD spectrum
NAFL.36 The histological scoring system for staging
fibrosis ranges from stage 0 (no fibrosis) to stage 4
NAFL NASH Compensated Decompensated (cirrhosis). The natural course of NAFLD is inconstant
cirrhosis cirrhosis
and is characterised by bidirectional and concordant
*
changes in both disease activity and fibrosis stage.39
Fibrosis Nevertheless, the presence of fibrosis, in particular
progression advanced fibrosis (stage 3 and 4), is a key prognostic
marker for liver-related outcomes and overall
mortality.17,18,40 In a meta-analysis of 13 studies comprising
4428 patients with NAFLD, patients with stage 4 fibrosis
Hepatocellular
carcinoma (cirrhosis) had higher all-cause mortality (relative risk
[RR] 3·42, 95% CI 2·63–4·46) and liver-related mortality
Factors associated with NAFLD and NASH progression
(RR 11·13, 4·15–29·84) than those without fibrosis.40
Comorbid illness Genetic factors Environmental factors Although there is substantial collinearity between the
• Type 2 diabetes • PNPLA3 • Fructose
• Insulin resistance • TM6SF2 • Cholesterol presence of NASH and clinically significant fibrosis, this
• Dyslipidaemia • GCKR • Alcohol collinearity diminishes at the cirrhotic stage as features
• Obesity • MBOAT7 • Exercise
• Hypertension • HSD17B13 • Coffee
such as steatosis or those specific to NASH might no
• Hypopituitarism longer be visible.41 Hence, most people with cryptogenic
cirrhosis (cirrhosis of unknown cause) with metabolic
Figure 2: Spectrum of NAFLD comorbidities and no other known cause of liver disease
Factors in black have an established association with NAFLD and NASH are likely to have burned-out NASH.42 It is not uncommon
progression (broadly classified into comorbid illness, genetic factors, and for individuals with NAFLD to be undiagnosed for decades,
environmental factors).34 Green indicates a protective factor. NAFL=non-alcoholic
fatty liver. NAFLD=non-alcoholic fatty liver disease. NASH=non-alcoholic
even well after cirrhosis has developed. NAFLD is often
steatohepatitis. *Fibrosis regression. not recognised until patients have evidence of portal
hypertension (eg, splenomegaly, and thrombocytopenia)
associated with metabolic syndrome during their lifetime or develop liver related complications. Progression
than those with disease onset in adulthood.28 from compensated cirrhosis to decompensated disease
(eg, ascites, hepatic encephalopathy, or bleeding gastro
Natural history oesophageal varices) with complications of portal
The relationship between NAFLD and all-cause mortality hypertension or liver failure occurs at a rate of approxi
is unresolved, with some studies detecting a modest mately 3–4% per year.43 Cirrhosis is also the strongest risk
increase in risk of all-cause mortality compared with factor for the development of hepatocellular carcinoma;
the general population,29–31 and others reporting no the annual incidence of hepatocellular carcinoma is
association between NAFLD and mortality.32,33 NAFLD is 10·6 per 1000 person-years in patients with NASH
a heterogeneous condition with varying rates of disease cirrhosis.44 Although approximately 20% of NAFLD-
progression and clinical outcomes, which might be related hepatocellular carcinoma occurs in patients with
driven by the varying predominant mechanisms for the non-cirrhotic livers, the overall risk of hepatocellular
development of the disease (figure 2).35 In the majority of carcinoma in the absence of cirrhosis is very low (annual
patients, liver disease is stable or slowly progressive and incidence of 0·08 per 1000 person-years).44 Driven by its
will not result in cirrhosis or liver-related death. However, high prevalence in the general population, NAFLD is now
a small proportion of affected individuals develop the second leading cause of end-stage liver disease45 and
advanced fibrosis and are at risk of developing compli the second most common cause of primary liver cancer
cations of end-stage liver disease and hepatocellular among adults waiting for liver transplantation in the USA.5
carcinoma. Recognising the diversity in disease progres Similarly in Europe, NAFLD now accounts for 8·4% of
sion and the factors that influence it is instrumental to annual transplantations, and among all people receiving a
developing guidance for patient care. liver transplant, hepatocellular carcinoma was found in a
Studies assessing paired liver biopsy samples although greater proportion of indivi duals with NAFLD (39·1%)
prone to ascertainment and selection bias,36 contribute than without NAFLD (28·9%, p<0·001).46 Although the
important data on the rate of disease progression. increase in liver transplantation for NASH cirrhosis might
Although fibrosis can develop in livers affected by NAFL partly reflect a higher awareness of NAFLD as a cause of
or NASH, fibrosis progression occurs at a more rapid end-stage liver disease, natural history and modelling
rate in people with NASH, which is likely driven studies suggest that not only the total, but also the relative
by necroinflammation.37,38 A meta-analysis of NAFLD proportion of those with advanced liver disease and liver-
studies assessing paired liver biopsy samples found that related outcomes (including hepatocellular carcinoma)
fibrosis worsened by one stage (from baseline stage 0 due to NAFLD, are increasing.20,47
fibrosis) on average during 7·1 years for patients with Despite the risk of progressive liver disease, the leading
NASH and by one stage over 14·3 years for patients with cause of death in patients with NAFLD is cardiovascular

Seminar
disease, followed by extrahepatic malignancy (eg, colo

rectal cancer or breast cancer). These causes of death are
likely to be due to cardiometabolic risk factors that are
shared in NAFLD and cardiovascular disease, although it ↑Adipose tissue
Ectopic fat
is unclear to what extent NAFLD has a direct causative
Altered organ crosstalk
role in the development of cardiovascular disease.48 The Environmental ↑ Fatty acids
bidirectional relationship between NAFLD and some risk factors
metabolic syndrome features (particularly type 2 diabetes Insulin resistance
and hypertension), in addition to its characteristic Genetic Metabolic dysregulation
predisposition Innate immune activation ↑De-novo lipogenesis
proatherogenic lipid profile,49 is one mechanism by which
NAFLD might augment cardiovascular risk. Patients with Altered gut microbiome
NAFLD have a 1·9-times higher risk of incident cancers ↑Lipopolysaccharides ↑Lipotoxic lipids
than the general population, particularly cancers involving Altered gut permeability concentration
the liver, gastrointestinal tract, and uterus.50 The biological
Inflammation
mechanisms might be driven by the association of NAFLD Tissue regeneration
Cellular stress
with visceral adiposity and chronic low-grade inflam Fibrogenesis
mation, but this mechanism has not yet been determined.51
Patients with NAFLD, particularly those with clinically
significant fibrosis, have a higher risk of severe COVID-19
Figure 3: Multiple pathways and interactions between different organs, affect the pathogenesis of
than patients without NAFLD.52 The risk of severe illness non-alcoholic fatty liver disease
from SARS-CoV-2 infection might be independent of In the setting of environmental risk factors and heritable factors, crosstalk between the liver, adipose tissue, and
metabolic comorbidities,52 although diabetes and obesity gastrointestinal tract leads to systemic inflammation and insulin resistance, resulting in increased hepatic delivery
of fatty acids and de-novo lipogenesis. This metabolic milieu leads to the formation of lipotoxic lipids that
are also established risk factors.
contribute to cellular stress with subsequent stimulation of inflammation, tissue regeneration, and fibrogenesis.
Pathogenesis
The primary driver of NAFLD is overnutrition, which genetic risk variants show a synergistic interaction with
causes expansion of adipose depots as well as accumulation obesity.58,59
of ectopic fat (figure 3). In this setting, macrophage Interdependence and crosstalk between the liver and
infiltration of the visceral adipose tissue compartment other organs (particularly, adipose tissue and the gut)
creates a proinflammatory state that promotes insulin might also contribute to metabolic dysregulation and
resistance. Inappropriate lipolysis in the setting of insulin inflammation in NAFLD.60–62 Alterations in gut microbiota
resistance results in unabated delivery of fatty acids to the composition are seen in patients with NAFLD and
liver, which, along with increased de-novo lipogenesis, some data suggest that there is a faecal-microbiome
overwhelms its metabolic capacity. The imbalance in lipid signature associated with advanced fibrosis.63,64 However,
metabolism leads to the formation of lipotoxic lipids confirmation of these bacterial signatures in different
that contribute to cellular stress (ie, oxidative stress and patient cohorts and geographical regions controlling for
endoplasmic reticulum stress), inflammasome activation environmental factors is required to determine the
and apoptotic cell death, and subsequent stimulation of signature’s clinical significance and use for future
inflammation, tissue regeneration, and fibrogenesis.53,54 diagnostic purposes. Factors produced by bacteria (eg,
Inflammatory and profibrogenic macrophages are impli lipopolysaccharide or short-chain fatty acids) or derived
cated in the progression of liver fibrosis and might also from bile acid metabolism could influence liver inflam
have a role in chronic inflammatory processes in other mation and disease progression in NAFLD, although as
tissues.55 yet, clear causal effects have not been established.
These pathogenic pathways of NAFLD are influenced
by multiple metabolic, genetic, and microbiome-related Risk stratification and assessment of disease
factors that are not completely understood. NAFLD severity
has a heritable component, with genetic differences NAFLD is most often diagnosed by imaging, although it
between individuals influencing disease risk estimates can be inferred from clinical risk scores (eg, fatty liver
by 20–70%.56 A single-nucleotide polymorphism in the index) or identified histologically. In routine practice, the
PNPLA3 gene is the best characterised genetic variant most commonly used test is abdominal ultrasonography
associated with susceptibility to NAFLD.57 However, (figure 1D). On abdominal ultrasonography, hepatic
known genetic variants account for a small proportion steatosis is characterised by a bright liver echotexture and
(10–20%) of overall heritability,56 although this proportion blurring of the hepatic vasculature.65 Abdominal ultra
varies across populations. These genes or genetic sonography has two important limitations: advanced
variants might influence multiple traits—sometimes fibrosis can coarsen hepatic echotexture and blur vascular
with divergent effects on NAFLD and comorbid con pattern; and its sensitivity is low when steatosis is
ditions such as coronary artery disease—and several mild (<30%). MRI-based measurements of hepatic

Seminar
liver diseases. However, liver enzyme concentrations can

Panel: Non-invasive fibrosis scores* be normal in more than half of patients with NAFLD,
Non-alcoholic fatty liver disease fibrosis score and correlate poorly with the histological severity.73
–1·675 + 0·037 × age (years) + 0·094 × body mass index (kg/m²) + 1·13 × impaired Traditionally, liver biopsy was used to characterise and
fasting glycaemia or diabetes (yes=1, no=0) + 0·99 × aspartate aminotransferase to quantify histological features of steatosis, inflammation,
alanine aminotransferase ratio – 0·013 × platelet count (×10⁹/L) – 0·66 × albumin hepatocyte ballooning, and fibrosis. However, this
concentration (g/dL) invasive procedure is not suitable for widespread use to
• Patients at low risk of advanced fibrosis have a score of less than –1·455 (age assess disease stage or determine progression or
<65 years) or less than 0·12 (age ≥65 years); a score greater than 0·675 is suggestive of response to therapy. In addition to its risk and cost, liver
advanced fibrosis biopsy is prone to sampling bias.74 Intraobserver and
• Interpret with caution in patients who are younger than 35 years; the score is less interobserver variability in histological assessment is
accurate in patients who are younger than 35 years also well documented in liver biopsy.75,76 Therefore,
• There is a high rate of intermediate scores researchers have developed and validated several
non-invasive tests for NAFLD.
Fibrosis-4 index for liver fibrosis Among the histological features of NAFLD, the severity
Age (years) × aspartate aminotransferase concentration (IU/L) of liver fibrosis has the strongest correlation with
liver-related morbidity and mortality.40,47 Simple fibrosis
platelet count (×109/L) × √(alanine aminotransferase concentration [IU/L]) scores, such as the NAFLD fibrosis score, Fibrosis-4
(FIB-4) index, and aspartate aminotransferase-to-platelet
• Patients at low risk of advanced fibrosis have an index of less than 1·3 (age <65 years) ratio index comprise demographic, clinical, and routine
or less than 2·0 (age ≥65 years); a score greater than 3·25 is suggestive of advanced laboratory parameters and are inexpensive to use
fibrosis (panel).66 Aspartate aminotransferase is an important
• Interpret with caution in patients who are younger than 35 years; the score is less component in these scores and tends to increase in
accurate in patients who are younger than 35 years concentration (relative to alanine aminotransferase) in
*Low platelet count suggestive of advanced fibrosis; concentration of alanine aminotransferase falls and aspartate advanced fibrosis. Although the overall accuracy of these
aminotransferase is stable or rises with increasing fibrosis. scores is moderate, they have high negative predictive
values to exclude advanced liver fibrosis, especially in
community and primary care settings.77 Patients with
For more on non-alcoholic fatty steatosis (eg, MRI proton density fat fraction) can detect low fibrosis scores are also at a low risk of developing
liver disease fibrosis score see as little as 5% fat and are sensitive to dynamic change, liver-related complications.78
https://www.mdcalc.com/nafld-
non-alcoholic-fatty-liver-
but are more often used in the research setting and in Among blood biomarkers, the Enhanced Liver Fibrosis
disease-fibrosis-score clinical trials to evaluate the efficacy of NASH treatments, (ELF) score (combining hyaluronic acid, tissue inhi
For more on the fibrosis-4 index rather than in routine practice.66,67 bitor of metalloproteinase 1, and amino-terminal
for liver fibrosis see https:// propeptide of type III procollagen [PIIINP]) has been
www.mdcalc.com/fibrosis-4-fib- Risk factors for progressive disease tested in various cross-sectional studies and clinical
4-index-liver-fibrosis
Type 2 diabetes is associated with a more than two-times trials.79,80 The UK National Institute for Health and Care
increased risk of advanced fibrosis, cirrhosis-related Excellence suggests that the ELF score be used for
complications, and liver disease mortality (figure 2).68 patients with NAFLD and suggests referring patients
Obesity (ie, body-mass index >30 kg/m²), lipid abnor with a score of 10·51 or higher to hepatologists for
malities (ie, low concentrations of HDL cholesterol and evaluation.81 Although available in many parts of the
high concentrations of triglycerides), and hypertension world, ELF is not yet approved by the US Food and
are also associated with an increased risk of severe liver Drug Administration (FDA). Furthermore, performance
disease, although the effect sizes are smaller than for characteristics of ELF in NAFLD are incompletely
type 2 diabetes.68 Patients with NAFLD who are older than delineated as they were mostly determined from cohorts
60 years have a higher prevalence of advanced fibrosis with a high prevalence of advanced fibrosis.82 Pro-C3 is
than younger patients,69 reflecting a longer duration of another biomarker that is used to measure the propeptide
metabolic dysfunction and liver disease. A variant of the cleaved from the intact collagen molecule and indicates
PNPLA3 gene is associated with NAFLD histological fibrogenesis. Pro-C3 has been used in early phase clinical
severity and development of hepatocellular carcinoma as trials to infer the potential effect of new drugs on the
well as liver-related and all-cause mortality.56,70,71 However, prevention of fibrosis progression.83
the clinical role of genotyping of variants has not been Another method to estimate liver fibrosis in patients
established.72 with NAFLD is to measure liver stiffness by ultrasound-
based elastography (eg, vibration-controlled transient
Non-invasive tests of disease severity elastography, point-shear wave elastography, and two-
Clinicians usually use liver enzyme concentrations dimensional shear wave elastography) and magnetic
(eg, serum alanine aminotransferase and aspartate resonance elastography (figures 1E, F).66,84,85 Among
aminotransferase) to assess and monitor patients with these methods, transient elastography has been most

Seminar
extensively evaluated, is widely available, and can be paucity of available effective therapeutic interventions.99
used as a point-of-care test.86 It is also possible to There are also concerns about the possible consequences
estimate hepatic steatosis by controlled attenuation of overdiagnosis of NAFLD, particularly regarding the
parameter measurement at the same time. A liver potential physical harms of investigation and treatment,
stiffness cutoff of 6·5–7·9 kPa has approximately 90% and psychosocial harms of labelling people with the
sensitivity in excluding stage 3 and 4 fibrosis, whereas disease.100 Additional studies are needed to evaluate
patients with cirrhosis typically have liver stiffness whether screening would improve clinical outcomes and
more than 12–15 kPa.66,84,85,87 The liver stiffness measure whether it is cost-effective. Nevertheless, once NAFLD is
ment also correlates with future risk of hepatocellular diagnosed, we recommend risk stratification by assessing
carcinoma and cirrhotic complications.88,89 The for the presence of advanced fibrosis or cirrhosis, and
Baveno VI criteria combine liver stiffness measurement the evaluation of cardiovascular risk and comorbid
(≥20 kPa) by transient elastography with platelet count illnesses.
(<150 × 10⁹ platelets per L) to identify patients at risk of Some local health districts and specialty networks are
having varices that need treatment, and have been investigating integrated management plans and referral
validated in patients with NAFLD.90,91 pathways for patients with NAFLD.101–105 All pathways
Because many clinical trials are of patients with NASH recommend testing for advanced fibrosis (bridging
(NAFLD activity score of ≥4 with at least one point each fibrosis [stage 3] and cirrhosis [stage 4]) in patients with a
in steatosis, lobular inflammation, and hepatocyte diagnosis of NAFLD, although the specific testing
ballooning) and fibrosis stage 2 or higher, several groups algorithms vary. Overall, expert opinion favours a
have proposed composite scores to identify these pragmatic, staged approach with inexpensive simple
patients. One example of these composite scores is the fibrosis scores (eg, NAFLD fibrosis score or FIB-4) as a
FibroScan-aspartate aminotransferase (FAST) score, first step to identify individuals at low risk of advanced
which comprises aspartate aminotransferase concentra fibrosis, who can be managed in primary care. Individuals
tion, liver stiffness, and controlled attenuation parameter with indeterminate or high-risk simple scores require
measurements by FibroScan.92 In different settings, the additional assessment with locally available second-line
FAST score has a C-statistic of 0·74–0·95 in identifying fibrosis tests (eg, ultrasound-based elastography or
fibrotic NASH. Similarly, the NIS4 algorithm comprises serum ELF test), and might require referral to secondary
four biomarkers (miR-34a-5p, alpha-2 macroglobulin, care for investigation of liver disease or management of
CHI3L1, and glycated haemoglobin) and has a C-statistic advanced fibrosis. Patients without advanced fibrosis
of 0·76–0·83.93 Depending on regulatory approval, at initial assessment require ongoing monitoring in
these scores might be used to select patients for primary care to identify progressive liver disease, and
pharmacological treatment. retesting 3–5 years after initial assessment has been
proposed (figure 4).106
Prevention, evaluation, and management of NAFLD in People with type 2 diabetes have a high prevalence
primary care and diabetes clinics of NAFLD (40–70%), and are more likely to develop
Since primary care is the initial point of contact for most advanced fibrosis, cirrhosis, and hepatocellular carci
people with health concerns (including metabolic risk noma than people without diabetes.107 In addition,
factors), primary care clinicians have a key role in the multimorbidity and polypharmacy are common in
prevention, diagnosis, risk stratification, and management patients with type 2 diabetes and NAFLD, highlighting a
of NAFLD. Few studies have examined primary prevention need for multidisciplinary management to address their
of NAFLD; nevertheless data suggest that improved diet complex health-care needs.108 In secondary care diabetes
quality94 and sustained or increased physical activity95–97 clinics, the prevalence of advanced fibrosis among
reduces the risk of developing NAFLD, even among patients with NAFLD is 10–20%, 109–112 which is
individuals with high genetic risk.94 Primary-care clinicians two to four times higher than in primary care. There is
have a pivotal role in promoting and coordinating lifestyle increasing recognition that an assessment of NAFLD
interventions with dietary modification and exercise, and and liver fibrosis needs to be incorporated into the
in management of metabolic comorbidities. routine care of patients with type 2 diabetes.109 As a result,
As we now have various non-invasive tests to diagnose the American Diabetes Association now recommends
fatty liver and liver fibrosis, one relevant concern is that “Patients with type 2 diabetes and elevated liver
whether screening for NAFLD is worthwhile, particularly enzymes (alanine aminotransferase) or fatty liver on
when patients participate in secondary prevention ultrasound should be evaluated for the presence of
programmes for diabetes or metabolic syndrome. Recom non-alcoholic steatohepatitis and liver fibrosis.”113
mendations from hepatology associations regarding However, alanine aminotransferase measurements are
screening patients for NAFLD are inconsis tent; some notoriously inaccurate and are within the normal range
guidelines10,98 advocate screening in high-risk populations in most people with type 2 diabetes and NAFLD; thus
(eg, people with obesity, type 2 diabetes, or metabolic with this strategy, many patients with clinically significant
syndrome) whereas others do not, partly reflecting the liver disease will not be diagnosed.

Seminar
commitment in addition to clear recommendations and

Patients with suspected fatty liver support from the treatment team. Barriers to weight
loss (eg, financial constraints, medical comorbidities,
Imaging or hepatic steatosis scores Incidental finding during investigations for other education, and little access to healthy food) should be
conditions considered when developing a treatment plan. Although
not considered first-line therapy due to the surgical risk,
bariatric surgery in patients with severe obesity can lead to
substantial (15–25%) durable weight reduction and
Fatty liver detected; exclude excess alcohol consumption, viral hepatitis, secondary causes of fatty liver
(eg, use of systemic steroids, tamoxifen and methotrexate), and other liver diseases as appropriate improvement in liver histological features of NASH and
fibrosis.115 Weight loss improves NAFLD and all of its
associated cardiometabolic comorbidities, which then
Diagnosis of non-alcoholic fatty liver disease established
favourably affects cardiovascular and malignancy related
risk. There is an independent contribution of NASH to
Perform simple fibrosis score (eg, FIB-4 and NFS) cardiovascular and cancer risk but we do not yet know if
liver targeted treatment interventions will reduce them.
Optimising management with existing therapeutics

FIB-4 <1·3 (age <65 years) and FIB-4 1·3–3·25 (age <65 years) FIB-4 >3·25; NFS >0·675
<2·0 (age ≥65 years); NFS less and 2·0–3·25 (age ≥65 years);
There is currently no FDA or European Medicines
than –1·455 (age <65 years) NFS –1·455 to 0·675 (age Agency (EMA) approved therapy for NASH. However,
and <0·12 (age ≥65 years) <65 years) and 0·12–0·675 (age several drugs that are currently available for other
≥65 years)
indications have been stu died in phase 2b trials for
NAFLD (table). Ursodeoxycholic acid, omega-3 fatty
Advanced fibrosis unlikely; Indeterminate results Possible advanced fibrosis acids, and metformin have not shown histological
manage metabolic factors and benefit, whereas other therapies, such as vitamin E
retest in 3 years
and pioglitazone, have53 and are endorsed by current
guidelines as possible treatment in selected patients with
NASH.99 The benefits of vitamin E (RRR-α-tocopherol
Use specific fibrosis biomarkers (eg, ELF and elastography) [also known as d-α-tocopherol]) for NASH have been
or refer for specialist care shown in several randomised controlled trials, including
a phase 2b trial in which 84 participants were given
Figure 4: Proposed diagnostic and referral pathway for non-alcoholic fatty liver disease in primary care vitamin E to reduce steatosis and improve histological
To establish the diagnosis of non-alcoholic fatty liver disease, it is necessary to exclude concomitant liver diseases
and secondary causes of hepatic steatosis. This process usually includes careful documentation of alcohol
NASH in patients without diabetes or cirrhosis.116 In a
consumption and medication intake (eg, systemic steroids, tamoxifen, and methotrexate), and excluding viral randomised controlled trial of patients with type 2
hepatitis by checking HBsAg and anti-hepatitis C virus antibody. Additional assessment for less common causes of diabetes and NASH assigned to 18 months of vitamin E
liver disease would depend on the clinical picture and local epidemiology. ELF=Enhanced Liver Fibrosis score. alone (n=36), combination therapy of vitamin E with
FIB-4=Fibrosis-4 index. NFS=non-alcoholic fatty liver disease fibrosis score.
pioglitazone (n=37), or a placebo (n=32), only those
assigned to combination therapy achieved the histological
Management of NASH endpoint (ie, an improvement of NASH by >2 points
Although the liver related burden of NASH is substantial without worsening of fibrosis).120 Vitamin E use should
and increasing, cardiovascular disease and malignancy be considered in the context of its potential adverse
are the leading causes of death in people with effects, which include an increased risk of bleeding, and
NAFLD.4,17,18,20 Therefore, management of NASH deserves its association between higher doses and adverse cardio
a holistic approach that strives to minimise cardiovascular vascular outcomes.99 Although statins have no discernible
risk and to reduce drivers of steatosis and systemic histological benefit on NASH itself, they are safe and
inflammation. should be used as appropriate for cardiovascular risk
The balance between nutrients and energy is pivotal in reduction.
the development of NAFLD and NASH. Central obesity is Most individuals with NASH are insulin resistant;121
an important driver of disease through the promotion however, ameliorating insulin resistance (although
of insulin resistance and proinflammatory signalling. important) is an insufficient therapeutic strategy if
Although the macronutrient content of the diet is used alone. For example, metformin (a weak insulin
important, weight loss of more than 5–7% reduces hepatic sensitiser compared with thiazolidinediones) reduces
fat content and steatohepatitis, and, for weight loss in the progression to type 2 diabetes and is an important
excess of 10%, even fibrosis is reduced in a large proportion diabetic treatment, but it has no effect on NASH disease
of people, irrespective of method of weight loss.114 activity. Conversely, some drugs that improve NASH
Sustained weight loss is challenging because it requires a histology have no effect on insulin resistance (eg,
transformation of ingrained behaviour patterns. Even in vitamin E, obeticholic acid, and many other drugs in
the short term, success requires substantial personal development).116,122,123

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Effects on the liver Quality of evidence Other benefits Key adverse events Contraindications and
cautions
Pioglitazone Improves hepatic Several small* to Improves insulin Weight gain, fluid Contraindicated in patients
steatosis and moderate† phase 2 sensitivity and diabetic retention, bone loss, and with NYHA class III or IV
necroinflammation, and randomised controlled control might increase bladder heart failure; maximum
can improve fibrosis trials116 cancer dose 15 mg if used in
combination with
gemfibrozil or other strong
CYP2C8 inhibitors
Vitamin E Improves hepatic steatosis Several small* to Neutral metabolic A meta-analysis suggests Caution in patients with
and necroinflammation; moderate† randomised effects a small increase in overall high cardiovascular risk
might prevent liver controlled trials; data on mortality at high doses; and those at high risk of
decompensation and clinical outcomes based might increase risk of bleeding
mortality in patients with on a retrospective cohort bleeding, prostate cancer,
advanced liver fibrosis study with propensity heart failure, and
score matching116,117 haemorrhagic stroke
GLP-1 agonists‡ Improves hepatic Several small* to Improves diabetic Nausea, vomiting, Discontinue GLP-1 agonists
steatosis and moderate† randomised control, reduces major dyspepsia, diarrhoea, and immediately in case of
necroinflammation controlled trials118 adverse cardiovascular constipation acute pancreatitis; might
events and weight cause acute kidney injury
rarely; semaglutide might
increase diabetic
retinopathy complications
SGLT2 inhibitors§ Improves hepatic Several small* Improves diabetic Genitourinary infection, Contraindicated if
steatosis, randomised controlled control; modest weight acute kidney injury, and estimated glomerular
necroinflammation, and trials with non-invasive reduction; might have euglycaemic diabetic filtration rate is less than
liver enzymes tests; two small* renoprotective benefits; ketoacidosis; might 45 mL/min per 1·73 m²
uncontrolled paired liver canagliflozin and increase the risk of
biopsy studies119 empagliflozin reduce fractures and limb
major adverse amputations
cardiovascular events
NYHA=New York Heart Association. *Small was defined as less than 50 participants in the active group. †Moderate was defined as 50–100 participants in the active group.
‡For example, liraglutide and semaglutide. §For example, canagliflozin, dapagliflozin, and empagliflozin.
Table: Potential use of off-label therapy for non-alcoholic steatohepatitis
Thiazolidinediones, such as pioglitazone, might endpoints (NASH resolution without worsening of

prevent the development of type 2 diabetes.124 Multiple fibrosis; or an improvement in fibrosis of one stage or
trials in patients with and without diabetes have shown more without worsening of NASH). These agents
that pioglitazone improves NASH activity125 with a have the additional benefit of inducing weight loss.
numerical, but not statically significant, improvement Semaglutide 0·4 mg/day given subcutaneously was
in fibrosis in phase 2b trials, including a US National more effective than liraglutide and resulted in an
Institutes of Health sponsored trial by the NASH 18% weight loss during a 52-week period with similar
Clinical Research Network that had 80 participants in tolerability.130 Semaglutide 2·4 mg a week given sub
the active group.116,126 Although pioglitazone-associated cutaneously is currently being explored in several
average weight gain (2·4–4·8 kg) is a side-effect, it is contexts to manage obesity.131 All of these classes of
less than the average weight gain associated with drugs are being evaluated for the treatment of NASH.
insulin (3–10 kg). Another factor limiting widespread In a phase 2 randomised controlled trial, subcutaneous
use of pioglitazone in NASH is the risk of bone loss semaglutide 0·4 mg daily reached the primary endpoint
related to the negative effects of PPAR-γ activation on of NASH resolution with no worsening of fibrosis in
bone remodelling. It appears unlikely at this time that 59% of patients, compared with 17% in the placebo
either vitamin E or pioglitazone will be studied in group (p<0·001).132 It is difficult to discern if these
phase 3 studies; however, other drugs that modulate effects are independent of weight loss; however, the
PPAR-γ and complementary mechanisms are being results represent the highest rate of NASH resolution
developed. ever reported in NASH therapeutic trials.
For individuals with concomitant type 2 diabetes,
there is a growing list of antidiabetic medications that Emerging therapeutics of NASH
are cardioprotective and renoprotective.127–129 Several of Numerous drugs with different mechanisms of action,
these medications, including several GLP-1 recep tor targeting lipid metabolism, inflammatory, or fibrotic
agonists and SGLT2 inhibitors, are currently being pathways, are in development as treatment for NASH.53,133
studied in phase 2 and phase 3 trials to assess their To achieve full FDA approval, a therapeutic intervention is
efficacy on one of the two FDA-approved histological required to show a clinically meaningful benefit, defined

Seminar
as an improvement in how a patient feels, functions, or Several drugs are in advanced stages of development for
survives. Since most patients with NASH have few liver- NASH; however, there have already been multiple failures
specific symptoms, full approval of these drugs will related to disease heterogeneity, variable placebo response,
require the drug to reduce the development of liver-related low efficacy, and, in some cases, overinterpretation of
events or mortality. Given the course of the disease in phase 2 results.137 Several phase 2b trials that showed
NASH—it often takes decades to produce liver-related favourable efficacy with respect to fat reduction and
events or death, even in the context of advanced fibrosis— histological endpoints have already been continued in
ongoing trials are mainly focused on surrogate endpoints, phase 3 trials, which will provide more definitive data.138,139
such as histology, that are reasonably likely to translate Several advanced phase trials that focused on NASH
into clinically meaningful benefit. The FDA is considering cirrhosis have not met their endpoints; however, other
two histological endpoints for conditional approval trials using promising therapies from non-cirrhotic
of NASH therapeutic agents. These endpoints are: NASH trials are ongoing.137 Future treatment will require
NASH resolution without worsening of fibrosis; or an combination therapy in most patients, consisting of a
improvement in fibrosis of one stage or more without so-called backbone therapy and an additional agent,
worsening of NASH. In comparison, EMA requires tailored to the individual. Currently, the independent
statistically significant improvement in both histological benefit of drugs in development need to be shown before
endpoints. Alternatively, if a therapeutic agent is combination therapy is approved. Several combination
primarily evaluated for its antifibrotic effects, it should trials are now underway. For example, the ATLAS trial
show an efficacy in improving fibrosis by two or more showed a trend towards greater fibrosis improvement
stages. Previously, efficacy of NASH therapeutic agents with cilofexor (a farnesoid X receptor agonist) and
has been moderate with statistical significance hedging firsocostat (an acetyl-CoA carboxylase [ACC1] inhibitor)
on a somewhat unpredictable placebo response rate and than either alone (21% vs 12% improvement) in patients
variability in histological interpretation, which is beyond with NASH and F3–4 fibrosis.140 Patients receiving this
the scope of this Seminar.134 combination treatment were also more likely to have a
REGENERATE, a trial that compared two doses of 2-point or better improvement in the NAFLD activity
obeticholic acid (a potent farnesoid X receptor agonist) score than those receiving monotherapy. However, given
with placebo, was the first phase 3 trial to meet the the modest difference, more effective combinations will
primary endpoint of an improvement in fibrosis of one be needed.
stage or more without worsening of NASH, recapitulating
the findings of the FLINT phase 2b trial.122,123 Although Challenges and prospects
statistically significant, the magnitude of response was Although valuable progress has been made during the
modest, which supports the notion that combination past 40 years in learning about the natural history
therapy will be required to adequately treat the majority and underlying biology of NAFLD, there are still many
of patients. Although obeticholic acid failed to achieve challenges. NAFLD is largely under-recognised by
the NASH resolution endpoint, it did improve each of health-care professionals and the wider community.
the individual histological features of NASH (eg, Implementation of strategies to identify, and appro
steatosis, inflammation, and hepatocyte ballooning). The priately manage, at-risk patients with advanced fibrosis
REGENERATE trial was the first NASH treatment to will require action by clinicians in primary care, diabetes
meet its endpoint; however, two side-effects of the drug clinics, and other specialists who treat patients with
reduced enthusiasm for conditional approval. In the trial, metabolic risk factors, although substantial hurdles,
pruritus occurred in 51% of patients given 25 mg of such as cost and access to second-line tests, will need to
obeticholic acid, in 28% of those given 10 mg of be addressed. There is an increasing awareness of
obeticholic acid, and 19% of patients given placebo. The the need for a multipronged public health response
extent to which pruritus can be mitigated with other to address NAFLD risk factors and the underlying
medications or dose reduction while retaining some obesogenic environment.7,141
degree of efficacy is unknown. Increase in LDL concentra There are several barriers to the development of highly
tion is directly related to the drug’s inhibition of the effective therapeutic interventions. One of the most
enzyme CYP7A1 and can be mitigated with the use of important challenges in the field is a continued reliance
statins.135 The cardiovascular effect of an increase in LDL on liver biopsy for diagnosis. A reliable biomarker that
concentration, or its reduction with a statin, when treated can accurately diagnose and stage NAFLD across the
with obeticholic acid, or more broadly during CYP7A1 entire disease spectrum does not yet exist.66,142,143 A
inhibition, is not yet known. The 2020 decision by the diagnostic biomarker, in conjunction with a prognostic
FDA to delay conditional approval of obeticholic acid biomarker (of which some currently hold promise),
until more efficacy and safety data are available might would allow the identification of high-risk individuals on
reflect some of these concerns. The FDA has requested whom resources should be concentrated. A second
the REGENERATE trial con tinues so that clinical challenge is the substantial heterogeneity of NAFLD and
outcome data can be reviewed in the future.136 the current limited understanding of disease phenotypes.

Seminar
The ability to phenotype patients would permit more 10 European Association for the Study of the Liver, European
accurate prognostication, selection of appropriate Association for the Study of Diabetes, European Association for the
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literature search, writing, revision, and approval of the final version. 16 Wei JL, Leung JC, Loong TC, et al. Prevalence and severity of
Declaration of interests nonalcoholic fatty liver disease in non-obese patients: a population
VW-SW served as a consultant or advisory board member for 3V-BIO, study using proton-magnetic resonance spectroscopy.
Am J Gastroenterol 2015; 110: 1306–14.
AbbVie, Allergan, Boehringer Ingelheim, US Center for Outcomes
Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi 17 Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no
other histologic features, is associated with long-term outcomes of
Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum
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Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET-NASH, 149: 389–97.e10.
and Terns; and served as a speaker for AbbVie, Bristol-Myers Squibb,
18 Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest
Echosens, and Gilead Sciences. VW-SW has also received an unrestricted predictor for disease-specific mortality in NAFLD after up to
grant from Gilead Sciences for fatty liver research. MR is a scientific 33 years of follow-up. Hepatology 2015; 61: 1547–54.
consultant or advisory board member for Centara, Madrigal, Gilead 19 Powell EE, Jonsson JR, Clouston AD. Steatosis: co-factor in other
Sciences, Genfit, Galecto, Amgen, Alnylam, Thetis, Lipocine, Coherus, liver diseases. Hepatology 2005; 42: 5–13.
NGM Biopharmaceuticals, Enanta, Immuron, Fractyl, ProSciento, Gelesis, 20 Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD
Merck, Metacrine, Viking Therapeutics, Allergan, Cymabay, Boehringer disease burden in China, France, Germany, Italy, Japan, Spain,
Ingelheim, Genentech, Sagimet Bio, Terns, Siemens, Novartis, Bristol- United Kingdom, and United States for the period 2016–2030.
Myers Squibb, and Intercept Pharmaceuticals. MR has received J Hepatol 2018; 69: 896–904.
independent research funding from Novartis, and owns no stocks and 21 Estes C, Chan HLY, Chien RN, et al. Modelling NAFLD disease
does not participate on speakers bureaus. EEP served as a consultant or burden in four Asian regions-2019-2030. Aliment Pharmacol Ther
advisory board member for CSL Behring and has received an unrestricted 2020; 51: 801–11.
grant from Siemens Healthineers. EEP owns no stocks and does not 22 Allen AM, Van Houten HK, Sangaralingham LR, Talwalkar JA,
participate on speakers bureaus. McCoy RG. Healthcare cost and utilization in nonalcoholic fatty
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Seminar

Non-alcoholic fatty liver disease

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Figure 1: Histological and radiological assessment of non-alcoholic fatty liver disease

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disease, followed by extrahepatic malignancy (eg, colo­

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liver diseases. However, liver enzyme concentrations can

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commitment in addition to clear recommendations and

Optimising management with existing therapeutics

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Table: Potential use of off-label therapy for non-alcoholic steatohepatitis

Thiazolidinediones, such as pioglitazone, might endpoints (NASH resolution without worsening of

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disease, followed by extrahepatic malignancy (eg, colo