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Received: 28 October 2016    Accepted: 31 October 2016

DOI: 10.1111/liv.13299

REVIEW ARTICLE

The epidemiology of non-alcoholic fatty liver disease

Stefano Bellentani

Gastroenterology and Hepatology

Service, Clinica Santa Chiara, Locarno,
Switzerland
Correspondence
Dr. Med Stefano Bellentani, Gastroenterology
and Hepatology Service - Clinica Santa Chiara,
Via Franscini 4, 6601 Locarno, Switzerland.
Email: bellentanistefano@gmail.com or
s.bellentani@clinicasantachiara.ch
Funding information
None.
Handling Editor: Zobair Younossi
Abstract
The increase in Non-alcoholic Fatty Liver Disease (NAFLD) and the imminent disap-
pearance of chronic viral hepatitis thanks to new and effective therapies is motivating
hepatologists to change their clinical approach to chronic liver disease. NAFLD-­cirrhosis
or NAFLD-­Hepatocellular Carcinoma (HCC) are now the second cause of liver trans-
plantation in the USA. This short-­review is focused to the epidemiology of NAFLD/
Non-alchoholic Steatohepatitis (NASH), including the definition of this disease which
should be revised as well discussing the prevalence, risk factors for progression, natural
history and mortality. NAFLD is considered to be the hepatic manifestation of the met-
abolic syndrome (MS). It affects 25-­30% of the general population and the risk factors
are almost identical to those of MS. The natural history involves either the develop-
ment of cardiovascular diseases or cirrhosis and HCC. HCC can also develop in NASH
in the absence of cirrhosis (45% of cases). We conclude that an international consensus
conference on the definition, natural history, policies of surveillance and new pharma-
cological treatments of NAFLD and NASH is urgently needed.

KEYWORDS
cirrhosis, epidemiology, hepatocellular carcinoma, non-alcoholic fatty liver disease, non-alcoholic
steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is a negative definition of a
very common disease that refers to the presence of hepatic steatosis
when no other causes for secondary hepatic fat accumulation (e.g, heavy
alcohol consumption, hypothyroidism, drugs, etc.) are present. NAFLD
may progress to cirrhosis or directly to Hepatocellular Carcinoma (HCC)
and is probably an important cause of cryptogenic cirrhosis.1-6
Non-alcoholic fatty liver disease is subdivided into non-alcoholic
fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). In NAFL, he-
patic steatosis is present without evidence of inflammation, whereas in
NASH, hepatic steatosis is associated with hepatic inflammation that is
histologically undistinguishable from alcoholic steatohepatitis.6, 7 Other
terms that have been used to describe NASH include pseudo-­alcoholic
hepatitis, alcohol-­like hepatitis, fatty liver hepatitis, steatonecrosis
and diabetic hepatitis. Recently, other acronyms such as: BASH (Both
Alcoholic and Non-alcoholic Liver Disease), DASH (Drug Associated
SteatoHepatitis), CASH (Chemotherapy Associated SteatoHepatitis),
PASH (PNPLA3-­Associated SteatoHepatitis) have been used.
This short review is presented to help the reader better understand
the epidemiology of NAFLD, which will become in the near future, the
most frequent liver disease and the first cause of liver transplantation.
1 | EPIDEMIOLOGY
1.1 | Prevalence
NAFLD is the most common liver disorder in Western industrialized
countries, and NAFLD has a reported prevalence of 6-­35% (median
20%) worldwide.8 In Europe, the median prevalence is 25-­26%9 with
wide variations in different populations (see Table 1).

Abbreviations: BASH, both alcoholic and non-alcoholic liver disease; CASH, chemotherapy
1.2 | Risk factors
associated steatohepatitis; DASH, drug associated steatohepatitis; DCH, dis-metabolic
chronic hepatitis; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MASH, metabol-
The major risk factors for NAFLD are the same as the components
ic-associated steatohepatitis; NAFLD, non-alcoholic fatty liver disease; NAFL, non-alcoholic
fatty liver; NASH, non-alcoholic steatohepatitis; PASH PNPLA3-associated steatohepatitis. of the metabolic syndrome: central obesity, type 2 diabetes mellitus,

Liver International 2017; 37 (Suppl. 1): 81–84 wileyonlinelibrary.com/journal/liv © 2017 John Wiley & Sons A/S.  |  81
Published by John Wiley & Sons Ltd
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82       BELLENTANI

dyslipidaemia and insulin resistance. Today, NAFLD is considered “de

facto” to be the hepatic component of the metabolic syndrome.8, 10
One of the most important risk factors is histological evidence of he-
patic inflammation.11 Others factors that have been associated with
disease progression or advanced fibrosis include:
• Older age12, 13
• Diabetes mellitus14
• Elevated serum aminotransferases (≥2 times the upper limit of nor-
mal in one study)14-16
• Presence of ballooning degeneration plus Mallory hyaline or fibrosis
on biopsy17-19
• Body mass index (BMI) ≥28 kg/m215
• A higher visceral adiposity index, which takes into account waist cir-
cumference, BMI, triglycerides and high-density lipoprotein level20
• Heavy alcohol consumption21, 22
●
Light or moderate alcohol consumption may have beneficial effects
on the liver22, 23
•
Coffee consumption has been associated with a lower risk of
progression24
1.3 | Natural History and Mortality
The natural history of NAFLD/NASH mirrors the natural history of
the metabolic syndrome, and is the hepatic expression of NAFLD.
Cardiovascular and not hepatic disease is the most common cause
of death among patients with NAFLD/NASH, although patients
with NASH are at increased risk of liver-­related deaths compared
to patients without. 21, 25 Patients with NAFLD/NASH may even-
tually develop cirrhosis, but only if they do not die of cardiovas-
25
cular diseases first. The association with cardiovascular disease
suggests that the threshold to develop policies of monitoring for
cardiovascular disease should be reduced in patients with NAFLD
26
or NASH. Progression to cirrhosis or hepatocellular carcinoma
(HCC) only occurs in 2.5% of patients with NASH, and it is usu-
ally slower than with other chronic liver diseases. The progression
Key Point Boxes
• The estimated prevalence of NAFLD is 6-35% worldwide
(median 20%)
• Central obesity, type 2 diabetes mellitus, dyslipidaemia
and insulin resistance are the main risk factors.
•
Older age, diabetes, elevated aminotransferases,
BMI > 28 kg/m2, heavy alcohol consumption are risk fac-
tors for progression to fibrosis and cirrhosis
• Cardiovascular disease is the first cause of mortality
• Screening for HCC should be encouraged in the patients
with cirrhosis or extensive fibrosis
of NAFLD or NASH to cirrhosis has been estimated to be 57
and 28 years,27 respectively, compared to 20-­30 years for HCV
infection.28
Up to 70% of patients with cryptogenic cirrhosis have risk fac-
tors for NAFLD. While the risk of disease progression in patients with
NAFLD has been evaluated in numerous studies, the results have dif-
fered, and the risk of developing advanced fibrosis in patients with
NAFLD is unclear. A meta-­analysis that included 11 studies looked
at the progression of fibrosis in 366 patients with NAFLD.26 Overall,
fibrosis progressed in 132 (36%), remained stable in 158 (46%), and
improved in 76 (21%). It appears that patients with simple steatosis
on biopsy are at a low risk of developing significant fibrosis, whereas
those with non-alcoholic steatohepatitis are at higher risk.29 In ad-
dition, disease has been shown to regress in some patients with
fibrosis.13-15
Finally, it is not clear if patients with NAFLD have increased overall
mortality rates compared to the general population. The largest study
from the United States suggests that the overall mortality rate is not
increased, while smaller studies and studies in other populations sug-
gest a slight increase in mortality. Recurrence of NAFLD has been also
reported following liver transplantation.30-32

T A B L E   1   Prevalence of NAFLD in different population in Europe

Case Identification Prevalence NAFLD Reference Number

14 EU Countries FLI 33% (adults) 34

Germany US and LE 2% (36% in obese children) 35
Germany US 30% (adults) 36
Greece Histology 31% (adults) 37
Italy US 26% (adults) 38
Italy US 12.5% (adolescents) 39
Italy US 44% (obese children) 40
Italy US 69.5% (diabetic pts) 41
Romania US 20% (adults) 42
Spain US 25.8% (adults) 43
UK US 46.2% (diabetic pts) 44

FLI, fatty liver index; US, ultrasound; LE, liver enzymes.

BELLENTANI
1.4 | Hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is associated with cirrhosis because of
NAFLD or NASH (HCC-­NASH). In a recently published systematic re-
view of 61 studies and case series of patients with NAFLD or NASH, the
risk of HCC in those with cirrhosis ranged from 2.4 percent over 7 years
to 12.8% over 3 years,33 the risk of mortality from HCC in patients with-
out cirrhosis was 0-­3% after follow-­up periods of up to 20 years.
Our group recently showed that the clinical, biological features
and survival of HCC-­NASH are similar to those of the most common
HCV-­related HCC.5 However, HCC-­NASH is diagnosed later com-
pared HCV-­HCC, and, most importantly, HCC-­NASH may also de-
velop in the absence of cirrhosis.5 We conclude that HCC surveillance
should be recommended not only in patients with NASH-­related cir-
rhosis, but also in those at risk of developing HCC with high grade of
fibrosis, and in selected high risk populations (diabetic, obese, etc.).
2 | CONCLUSIONS
In conclusion, I would like to provoke the international community
of hepatologists and suggest that a consensus conference is needed
to change the name of non-alcoholic fatty liver disease (NAFLD), like
the new term PBC (now changed by an International consensus from
Primary Biliary Cirrhosis to Primary Biliary Cholangitis) to metabolic-­
associated fatty liver disease (MAFLD), and non-alcoholic steatohepa-
titis (NASH) to metabolic-­associated steatohepatitis (MASH) or simply
dis-­metabolic chronic hepatitis (DCH), as well as to develop new pro-
tocols for the diagnosis and treatment of NASH and new policies for
the surveillance of patients with NAFLD.
CO NFLI CTS OF I NTE RE ST
None.
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