DR. ZOBAIR M.

YOUNOSSI (Orcid ID : 0000-0001-9313-577X)

Article type : Review

Accepted Article
Corresponding author mail id:- zobair.younossi@inova.org

Global Perspectives on Non-alcoholic Fatty Liver Disease and Non-alcoholic

Steatohepatitis

Zobair Younossi, MD, MPH1,2, Frank Tacke MD PhD3, Marco Arrese MD4,5, Barjesh
Chander Sharma MD6, Ibrahim Mostafa MD7, Elisabetta Bugianesi MD8, Vincent Wai-Sun
Wong MD9, Yusuf Yilmaz MD10, Jacob George MD11, Jiangao Fan MD12, Miriam B. Vos
MD, MSPH13
1. Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, USA
2. Betty and Guy Beatty Center for Integrated Research, Inova Health System, USA
3. Department of Medicine III, University Hospital Aachen, Aachen, Germany
4. Departamento de Gastroenterolog´ıa, Escuela de Medicina, Pontificia Universidad
Catolica de Chile, Santiago, Chile
5. Centro de Envejecimiento y Regeneración, Facultad de Ciencias Biológicas, Pontificia
6. Department of Gastroenterology, GIPMER, New Delhi, India
7. Theodor Bilharz Research Institute, Cairo, Egypt
8. Division of Gastroenterology, University of Torino, Torino, Italy
9. Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
10. Department of Gastroenterology, Marmara University, School of Medicine, Istanbul,
Turkey
11. Department of Gastroenterology &Hepatology, Westmead Hospital, University of
Sidney, Australia
12. Center for Fatty Liver, Department of Gastroenterology, Xin Hua Hospital Affiliated
to Shanghai Jiao Tong university School of Medicine, Shanghai, China
13. Department of Pediatrics, School of Medicine and Nutrition Health Sciences, Emory
University, USA

Abstract

Over the past 2 decades, nonalcoholic fatty liver disease (NAFLD) has grown from a

relatively unknown disease to the most common cause of CLD in the world. In fact, 25% of

the world’s population is currently thought to have NAFLD. Non-alcoholic steatohepatitis

(NASH) is the subtype of NAFLD that can progress to cirrhosis, hepatocellular carcinoma,

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/hep.30251
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 and death. NAFLD and NASH are found in not only adults—there is a high prevalence in

children and adolescents. Due to NAFLD’s close association with type 2 diabetes (T2DM)
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and obesity, the latest models predict the prevalence of NAFLD and NASH will increase,

causing a tremendous clinical and economic burden and poor patient-reported outcomes.

Nonetheless, there is no accurate non-invasive method to detect NASH and treatment is

limited to life style modifications. To examine the state of NAFLD among different regions

and understand the global trajectory of this disease, an international group of experts came

together during 2017 AASLD Global NAFLD Forum. We provide a summary of this forum

and an assessment of the current state of NAFLD and NASH worldwide.

Introduction

Over the past three decades, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic

steatohepatitis (NASH) have gone from obscure liver diseases with histologic features similar

to alcoholic liver disease to the most prominent cause of CLD worldwide (1,2). In fact, after

its first description, there was initial skepticism that NASH was a real liver disease (3). In the

1990s, it became evident that NASH was part of the NAFLD spectrum, but with specific

histopathology and potential for progression (4).

Over the next decade, it became increasingly clear that NASH is the hepatic manifestation of

metabolic syndrome and is highly prevalent in obese and diabetic subjects (5). Additionally,

the increasing number of components of metabolic syndrome appear to increase the risk of

progression to NASH (6,7). In contrast to NAFLD from Western countries, data from Asia

indicate that a proportion of patients with NASH, especially from the rural regions, do not

meet the criteria for obesity and have “lean NAFLD” (8).

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 In 2018, it is estimated that about 25% of the world population has NAFLD (9) (Figure 1).

Several studies investigated progression of NAFLD and its subtypes (4, 10-19). Although
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most studies have concluded that NASH is the progressive form, recent data indicate that a

small subset of NAFLD without histologic features of NASH can develop progressive liver

disease (11). NASH is already considered among the top etiologies for hepatocellular

carcinoma (HCC) and indications for liver transplantation (LT) in the United States (U.S.)

(1,20-21).

Progression of NASH does not seem to be linear or simple—patients seem to have

spontaneous progression and regression of liver disease over a long period of time (11).

Although factors related to metabolic syndrome, especially presence of T2DM, seem to

promote progression (3, 6), factors independently associated with spontaneous regression of

NASH and NASH-related fibrosis are not fully described. However, the most current data

indicate a tight association between increasing prevalence of T2DM and progressive NASH.

In fact, given the increasing global epidemic of obesity and T2DM, a recent model has

estimated a 178% increase in liver deaths related to NASH by 2030 (13).

In addition to liver-related mortality and morbidity, NAFLD and NASH are associated with

several extrahepatic manifestations, adding to the burden of disease (Figure 2) (16). As our

clinical and epidemiologic understanding increases, clinical burden of NAFLD and NASH

related to its prevalence, incidence, and progressiveness must be coupled with its tremendous

economic burden, and its negative effects on patient-reported outcomes (PROs) (14).

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 Currently, there is no approved drug regimen to treat NASH (17). As a consequence of the

lack of treatment and the growing global epidemic of obesity, the prevalence of NAFLD is
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likely to increase, creating a serious health crisis in the next few decades. Given this global

burden, we summarize the data on NAFLD and NASH from different global regions.

Prevalence in the Americas

The prevalence of NAFLD in the general population of North America has been estimated to

be approximately 24% (9, 18). In contrast, the prevalence of NAFLD in South America is

32% (9). The prevalence of NAFLD varies among countries in Central and South America,

depending on the prevalence of obesity. The lowest prevalence of NAFLD in this region has

been reported from Peru (12.5%) with only 15% of the population being obese, while the

highest prevalence is reported from Belize at 29% with 35% being obese (9).

In addition to obesity, other factors may contribute to the prevalence and outcomes of

NAFLD such as genetic factors, including those associated with Native American and

Hispanic heritage. (1-8) A study that compared NAFLD in Hispanics of Mexican origin vs

those of Caribbean origin (Dominican Republic and Puerto Rican) reported that Hispanics of

Mexican origin had a higher prevalence of NAFLD (33%) than Hispanics of Dominican

origin (16%) or Puerto Rican origin (18%), (P<.01). After controlling for age, sex, body mass

index (BMI), waist circumference, hypertension, serum level of high-density lipoprotein,

levels of triglyceride and C-reactive protein, and insulin resistance, Hispanics of Mexicans

remained more likely to have NAFLD than those of Dominican or Puerto Rican origin (23).

A high prevalence of a polymorphism in the gene encoding patatin-like phospholipase

domain-containing 3 (PNPLA3; rs738409 C/G, M148I) in Hispanics has been proposed to

contribute to the high prevalence of NAFLD (1). Nonetheless, given the increasing trends of

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 obesity, T2DM, and the pediatric NAFLD in the Latin America, it is expected that the

NAFLD-associated liver disease burden will increase significantly.

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Because of histologic requirements, we do not have accurate data on the prevalence of

NASH. In the general US population, the prevalence of NASH is estimated between 1.5% to

6.45% (9). Although there are substantial efforts in the U.S. to understand NASH, its

biomarkers and drug treatment, a great number of challenges remains. Some of the efforts are

undertaken by AASLD, FDA, NIH, Liver Forum and chronic liver disease foundations to

address end points and biomarkers in NASH. Nevertheless, the most important challenge in

the U.S. is developing a national policy to address the epidemic of obesity, the main culprit

that fuels the growing burden of NAFLD.

Prevalence in Europe

The prevalence of NAFLD has been estimated at 20%–30% in the European Union, with

approximately 3% having NASH. (9) NAFLD prevalence rates varies from different

European countries. A population-based study from the North-Eastern rural part of Germany

determined the prevalence of fatty liver by ultrasound to be 29.9%. Only15.9% of these

patients had increased levels of serum alanine aminotransferase, supporting the concept that

prevalence of NAFLD can vary with diagnostic methods (22). Similar rates have been

described in the general population of Northern Italy with 25% having NAFLD by ultrasound

(23). Again, 5.9% to 54% of NAFLD had increased alanine aminotransferase (24). In

addition, similar rates have been reported from Spain (25.8%) (25) and UK (26.4%) (26).

In Eastern Europe, the prevalence of NAFLD by ultrasound was 22.6% in Hungary (27) and

20% in Romania (28). Similar to other regions, prevalence of NAFLD in Europe increases

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 with BMI, 25% (BMI<25kg/m2), 67% (BMI 25–30 kg/m2) and 91% (BMI ≥30 kg/m2). (29)

Similarly, risk factors for NAFLD (obesity or T2DM) are increasing in Europe, fueling its
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complications of cirrhosis and HCC (30-36).

In Europe, the most urgent challenge is to establish a set of biomarkers that, singly or in

combination, can enable the detection and monitoring of disease progression or regression in

NASH. The “Liver Investigation: Testing Marker Utility in Steatohepatitis” (LITMUS)

project has been funded and brings together clinicians and scientists from academic centers

across Europe and the European Federation of Pharmaceutical Industries and Associations

(EFPIA) to deal with this challenge. The common goal of this group is to develop validate

and qualify biomarkers for NAFLD, NASH and related fibrosis. In this context, LITMUS

will specifically seek biomarkers that (i) separate cases with non-NASH NAFLD from

NASH; (ii) track disease progression and/or monitor response to treatment; and (iii) predict

those at greatest risk of future progression to NASH, advanced liver fibrosis or liver-related

morbidity. It is expected that the LITMUS project can make important contribution the field

of NAFLD.

Prevalence in Asia

The NAFLD prevalence in Asia ranges from 15% to 40%, while NASH ranges from 2% to

3% (37,38). In this context, prevalence of NAFLD in India increased from 28% in 2015 to

31% in 2016 and is estimated to be 30.7% in the rural region of Haryana (39). The reported

prevalence of fatty liver has also increased in many regions of China (40) increased from 3.87%

in 1995 to 14.04% in 2002, 17.3% in 2005, and 43.65% in 2015 among Shanghai adults (41-

45). Additionally, about 5.0% of 7229 school children from the Yangtze River delta region in

China had NAFLD (7.5% in boys, 2.5% in girls, 5.6% in subjects with peripheral obesity,

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 12.9% in those with abdominal obesity and 44.8% in those with mixed obesity) (47).

Furthermore, prevalence of NAFLD from Korea and Taiwan ranges from 24% to 40% and 15%
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to 27%, respectively (9). In contrast, lower prevalence rates of 9% to 18% have been reported

from Japan (9).

Similar to the other regions of the world, accurate data on the prevalence of NASH from Asia

is lacking. Nevertheless, it is estimated that NASH affects 1.9% to 2.2% of general

population in Shanghai, China (46).

It is interesting that lean NAFLD seems to be more common in Asian countries than in

Western countries (Figure 3). There are differences in the profiles of Western vs Asian

NAFLD (48), and a gradient of lean to obese NAFLD is observed in Asian countries. It

appears that the rural areas in Asian countries have a lower prevalence of NAFLD while the

profile is more consistent with lean NAFLD, whereas in urban areas of Asia NAFLD

prevalence and risk profiles are similar to Western countries. (49) Although patients with lean

NAFLD from Asia seem to have lower rates of NASH, liver fibrosis, or metabolic

abnormalities, after adjustment for severity of visceral obesity, the clinical events and rates of

advanced fibrosis are similar between lean and obese patients with NAFLD (49).

Interestingly, PNPLA3rs738409 GG genotype is more common in Asian NAFLD patients

without metabolic syndrome [50]. Since Asians are more likely to harbor the GG genotype

than Caucasians, this may explain why the two populations have similar prevalence of

NAFLD even though Asians lower metabolic burden. Finally, similar to the West, the

extrahepatic manifestations of NAFLD in Asia include complications of the cardiovascular,

gastrointestinal, and renal systems (37).

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 Because Asia is a vast continent with much heterogeneity in genetic background, lifestyle and

economic status, it is important to study and compare the epidemiology and natural history of
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NAFLD across different Asian countries. To this end, The Gut and Obesity Asia (GO ASIA)

Workgroup has been established to serve as a platform for NAFLD researchers in Asia to

collaborate, expand the knowledge and understanding of NAFLD and NASH by collecting

real-world data from representative countries [51].

Prevalence in the Middle East and Turkey:

The prevalence of adult NAFLD in Middle Eastern countries has not been systematically

investigated. A recent meta-analysis suggested that the prevalence of NAFLD in the Middle

East is 31.79% (9). Additionally, data from Iran suggest that 33.9% of population have

NAFLD (52).

In addition to these meta-analyses, a cross-sectional population-based study from Israel

(N=352) suggest a prevalence of 30% for NAFLD detected by ultrasound and several

components of the metabolic syndrome were the main risk factors (53). Another cross-

sectional study from the central part of Iran (n=483) reported 39.3% prevalence of NAFLD

(54). These rates are significantly higher than the 15.3% reported from the rural Fars province

of Iran (55).

In addition to data from Israel and Iran, there is also growing evidence about the increase of

NAFLD prevalence in Turkey. Until recently, the prevalence of NAFLD in Turkey has been

reported from single-center, small-sized studies (56-58), reporting prevalence rates of 19.8%

(56), 23.2% (57), and 10.6% (58). These low rates may be explained by the fact that these

studies were conducted either in rural parts of the country (56) or in young individuals

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 (57,58). In a recent unpublished epidemiological survey conducted in 113,239 apparently

healthy subjects, the overall prevalence of NAFLD in Turkey was 48.3%. The prevalence
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was higher in those older than 50 (65.6%), males (64.0%), and in those with BMI>25 kg/m2

(63.5%). There are also geographical differences with the Central and Eastern Anatolia

regions showing the highest prevalence of NAFLD (57.1% and 55.7%). Importantly, the

prevalence of NAFLD in the region has increased by 22% from 43.5% (2007) to 53.1%

(2016) (YY 2018.) These findings indicate a rapidly increasing prevalence of NAFLD related

to the epidemic of obesity and T2DM in these regions. It is noteworthy that in a hospital-

based study, the prevalence of lean NAFLD in Turkey was 7.6% (59) while an autopsy-based

study of 330 children and adolescents suggested a prevalence of 6% with higher rates in

overweight than in normal-weight subjects (10.6% versus 4.9%) (59, 60)

Despite these emerging data from Israel, Turkey and Iran, there is a significant paucity of

data from the rest of the Middle East. Nonetheless, it is important to note that the rates of

obesity and T2DM in the region are rapidly increasing which could certainly fuel the burden

of NAFLD. Similar to the other reports from Asia, it is highly likely that the differences in

the prevalence rates for this region can be explained by differences between urban and rural

areas, as well as by the increasing burden of obesity over the years. Therefore, it can be

hypothesized that a westernized diet and a sedentary lifestyle have led to an increase in the

prevalence of obesity and NAFLD in the region.

The Middle East is expected to face major challenges with NAFLD, but there is no

systematic approach to deal with these challenges. Future large, multicenter, collaborative

epidemiological studies are needed to more thoroughly investigate the burden of NAFLD in

this region. A multi-prong approach leveraging social media to educate and spread awareness

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 about the burden of obesity, DM and its complications such as NAFLD are necessary to help

the region implement strategies to deal with the serious disease burden.
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Prevalence in Africa

The burden of NAFLD in Africa appears to vary widely, although finding accurate data is

difficult. In contrast to North America, Europe and Asia, there are very few studies on the

epidemiology of NAFLD from Africa. A meta-analysis estimated the prevalence of NAFLD

in Africa to be 13.48% (9). Given the paucity of data and the need to collect additional

information about NAFLD, a member of the Global Forum sent surveys to 37 medical

providers in 21 African and Middle Eastern countries. Based on the survey results, the

prevalence of NAFLD appears to range from 5% (in Ethiopia) to 30% (in Saudi Arabia).

Currently, there is no established program to provide a systematic approach to study NAFLD

in Africa. Nevertheless, the issue of NAFLD in Africa may be important not only for its own

risk of progressive liver disease but also because NAFLD could potentially worsen the course

of viral hepatitis which is quite prevalent in Africa. Future research programs to be better

understand NAFLD in different regions of Africa are needed.

Prevalence in Australia and Pacific Countries:

Consistent with data from other industrialized societies, a commissioned report noted that

NAFLD is the commonest liver disease in Australia, affecting a third of the population (5.5

million people; 40% of adults ≥ 50 years of age and 15% of school children) (61), and 13%

of the population of New Zealand (62). This is not surprising since Australia has one of the

highest burdens of overweight and obesity (63.4% of adults in 2014-15) (63).

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 A recent nationwide population-based survey of 9,447 individuals reported NAFLD is the

commonest cause of abnormal liver tests. Further, 47% of the population had elevated ALT
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attributable to truncal obesity (64). Over the last decades, there has been an increasing

appreciation of NAFLD in Australia and New Zealand by primary care physicians, with

diagnosis and referral prompted by obesity, features of the metabolic syndrome, the detection

of elevated liver enzymes, or a bright liver on ultrasound.

For much of the remainder of Oceania and the Pacific, including Micronesia, Melanesia and

Polynesia (roughly 22 nations and 10 million people), data on NAFLD/NASH prevalence are

lacking. However, if T2DM and obesity prevalence data are any indication, this region will

be a hotbed of NAFLD. For example, a global burden of disease study indicated that obesity

prevalence in men exceeded 50% in Tonga and in women from Kiribati, the Federated States

of Micronesia, Tonga, and Samoa (67). More worrisome, Pacific Island nations have the

highest global prevalence of diabetes, including 7 of the top 10 countries and all of the top six

[Tokelau (37.5%), Federated States of Micronesia, Marshall Islands, Kiribati, Cook Islands

and Vanuatu) where, in 2013, diabetes prevalence ranged from 37.5% in Tokelau to 24% in

Vanuatu (68).

While there are no coordinated plans to deal specifically with the challenge of NAFLD in

Australia and New Zealand, the parallel rises in obesity and T2DM prevalence is viewed as a

national health priority. Frequent campaigns have been undertaken by Federal and State

agencies promoting healthy food intake and physical activity, while obesity and T2DM

research is targeted for research funding. Such efforts have borne some fruit as Australian

national nutrition surveys between 1995 and 2011 reported for 12,000 participants’ positive

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 changes, including the consumption of more fruit, vegetables, peas, beans, nuts, seeds, pulses,

brown and wholegrain cereals, as well as reduced intake of sugars (65). Consistently, shorter-
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and longer-term declines in the availability and intake of added sugars and sugar-sweetened

beverages has been reported (66). Major efforts are now underway to reduced sedentary

behavior by encouraging physical activity. At an investigator-led level, consortiums are being

formed (often as part of international collaborations) to study NAFLD natural history,

pathophysiology, and to establish biobanks for biomarker development.

Global Incidence of NAFLD

There are few accurate data on NAFLD incidence in the general population. Some rates have

been estimated to range from 28.01 per 1000 person-years to 52.34 per 1000 person- (9). For

more details, please see supplementary material.

Clinical Outcomes

Complications of NAFLD/NASH have been reported worldwide. The rate of cirrhosis is

lower in Asia compared to Western countries. In Hong Kong, 3.7% of NAFLD patients had

fibrosis or cirrhosis. In biopsy-proven NAFLD from mainland China 1.97%-2.97% reported

cirrhosis. (71-72) In India, 2% of NAFLD patients had cirrhosis, while in Japan, 2.1% had

significant fibrosis (73).

In contrast, an estimated 10-15% of NAFLD patients from US and Europe have advanced

fibrosis (9). A study using NHANES (1999–2002 and 2009–2012 cycles) reported a 2.5-fold

increase in the prevalence of NASH-associated cirrhosis and 2-fold increase in the prevalence

of NAFLD-associated advanced fibrosis. The authors then predicted a 6% increase in

NAFLD and >100% increase in advanced liver diseases over the next 15 years. (74)

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 Liver-related mortality

Patients with NAFLD have an increased risk of liver-specific death—primarily those with
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histologically proven NASH. In a study of 289 NAFLD patients who were followed for 150

months, those with NASH had >6-fold higher risk of liver-related death than NAFLD without

NASH (75). Liver related mortality was increased 2-fold if T2DM and or histologic NASH

was present. (75) Other studies have independently associated insulin resistance and MS with

all-cause, liver-specific, and cardiovascular mortality (6-9). Although NASH is associated

with increased liver-related mortality, it is the stage of fibrosis that increases the risk of death

in NAFLD patients. (12, 76-79)

Although cardiovascular disease is the leading cause of death in NAFLD, a recent multicenter

study suggests that this is true for non-cirrhotic cases [80]. Among 458 patients with biopsy-

proven NAFLD from Europe, Asia, Australia and America, 37 died during a mean follow-up

of 5.5 years. Liver complications accounted for 50% of the deaths in patients with F3 fibrosis,

73% in those with early cirrhosis, and 100% in those with advanced cirrhosis. This suggests

that in NAFLD patients with advanced fibrosis, liver mortality will dominate.

Cardiovascular disease

The cause of death for most patients with NAFLD is related to cardiovascular diseases. (81)

When patients with NAFLD and liver fibrosis (stages 3 or 4) were followed for an average of

26 years, they had a 1.55-fold increase in risk for cardiovascular disease compared to

individuals without NAFLD (81-85). Similarly, 117 NAFLD patients and 507 controls from

South China were followed for 4 years showing higher rates of cardiovascular mortality in

NAFLD, especially if MS was present (0.19% and 0.17%, P=0.005). (86)

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 There has been intense research to understand the underlying mechanisms connecting

NAFLD to cardiovascular diseases (87). Prospective, long-term studies are needed to

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determine whether the presence of NAFLD, NASH, or advanced NASH (stage 3 and 4) is

independently associated with cardiovascular mortality and if treatment of these liver

diseases can modify the cardiovascular outcomes.

HCC

NAFLD is the third-most common cause of cancer-related death worldwide and seventh-most

common cause in the US (88). In a study of the Surveillance, Epidemiology, and End Results

database, investigators found that among the 4949 patients with HCC, 701 patients had

NAFLD, providing a prevalence of NAFLD-associated HCC of 14.1% (19).The cumulative

incidence of HCC among patients with NAFLD and cirrhosis has been reported to range from

2.4% to 12.8% over a median follow-up period of 3.2 to 7.2 years (89, 90). For more details

regarding HCC, please see supplementary material.

Liver Transplantation

NASH is the most rapidly growing indication for LT in the US (20,94-99). Despite the

resurgence of ALD, NASH is the second-leading indication for LT. For more detail about LT

and NASH, please see supplementary material.

Special Topics in Epidemiology of NAFLD

NAFLD in Diabetics

A recent systematic review of studies, comprising 88,978 persons with diabetes from 28

countries, found the overall global prevalence of NAFLD among persons with diabetes to be

57.80%. The highest rate was in Europe (66.19%) and the lowest was in Africa (13.20%)

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 (100). In this study, the overall prevalence of NASH among diabetic patients from whom

biopsies were available was 65.26%. In addition, the prevalence of advanced fibrosis (≥ F3)
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was 15.05% (100). In addition, prevalence of NAFLD diabetics can range from 42.6% in UK

patients (30) to 60-70% in Italy (31). In the absence of biopsy, the prevalence of NAFLD and

advanced fibrosis in diabetics (N=1918), as determined by vibration controlled transient

elastography, is estimated to be 72.8% and 17.7% [102]. Furthermore, a community-based

study from Netherlands estimated that significant fibrosis by elastography was present in

8.4% of NAFLD subjects which was associated with T2DM (32). These and other studies

have confirmed the high prevalence of NAFLD, NASH and advanced in patients with T2DM

(100-101).

Interactions between NAFLD and metabolic syndrome

In addition to T2DM, patients with NAFLD have a high prevalence of metabolic syndrome

(MS) and patients with MS have a high prevalence of NAFLD. This phenomenon has led

some to consider NAFLD as the hepatic manifestation of MS. Findings from many studies

worldwide corroborate this strong and reciprocal association.

A study conducted in Asia reported that the incidence of fatty liver increased by 14% in

patients with at least 3 components of MS compared to patients with fewer than 3 features

(37). Prevalence of MS among lean NAFLD was 36.1% in Shanghai, China, and fatty liver

appears to be a better predictor than overall obesity and abdominal obesity for the clustering

of risk factors for MS (43). In east China, 358 NAFLD patients and 788 matched controls

were followed for 6 years. Incidence of obesity (47.6% vs 19.5%), hypertension (69.6% vs

16.3%), hypertriglyceridemia (39.1% vs 16.3%), hypercholesterolemia (24.5% vs 17.3%),

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 T2DM (20.3% vs 5.2%) and MS (56.3% vs 16.3%) were significantly higher in NAFLD

group than controls. (42)

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These data were confirmed in a systematic review which reported a prevalence of 34% for

MS in patients with NAFLD (9). In fact, similar rates are reported worldwide. Of patients

with NAFLD in Asia, Europe, the Middle East, North America, and South America, 34%,

62%, 31%, 33%, and 37% have been reported to have MS (9).

In addition to high reciprocal prevalence rates, patients with NAFLD with multiple features

of MS are also at higher risk for advanced fibrosis and death than patients with NAFLD

without MS (100-106). A multivariate analysis of biopsies from 432 patients with NAFLD

independently associated increases in aspartate and alanine aminotransferases, presence of

diabetes, male sex, and Caucasian ethnicity with the presence of moderate to severe

histologic fibrosis (P<.0001). Additionally, an increase in the number of MS components

(T2DM, hypertension, and visceral obesity) increased the likelihood of advanced fibrosis in a

stepwise fashion- finding confirmed using NHANES III data. (101,106).

In addition to higher risk for advanced fibrosis in patients with NAFLD, the presence of MS

increases the risk for liver-related mortality and all-cause mortality (7). Other analysis of

NHANES III data determined MS independently increased liver-related mortality and overall

mortality (7, 75). These data indicate that not only the presence of metabolic derangement but

also its severity have negative effects on long-term outcomes of patients with NAFLD.

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 NAFLD in non-obese or lean individuals

Although NAFLD is closely linked to obesity and MS, approximately 5%–8% of patients
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with NAFLD in Western countries are considered lean (8,107). These NAFLD patients still

have abnormal glucose tolerance, and about one-third have a diagnosis of diabetes (64).

Interestingly, a higher proportion of lean individuals with NAFLD have the PNPLA3

rs738409 GG genotype and low serum concentrations of adiponectin, compared to controls

(107). These data indicate that lean patients with NAFLD have dysregulated glucose

metabolism and adipose tissue, as well as the PNPLA3 rs738409 GG genotype (107).

The similarities of lean NAFLD to obese or overweight NAFLD indicate a spectrum of

metabolic abnormalities in such a way that obese patients with NAFLD might have more

severe abnormalities whereas lean NAFLD patients have less severe metabolic defects. A

recent systematic review concluded that lean and obese patients with NAFLD have a

common altered metabolic profile but lean persons with NAFLD have excess abdominal

adipose tissue (108).

Lean NAFLD in Asia appears to differ from that of the West. Approximately 20% of the

Asian population has lean NAFLD (37). In China, patients with lean NAFLD had a lower

BMI and waist circumstance than obese NAFLD, but these were higher than individuals

without NAFLD (109). Furthermore, patients with lean NAFLD also had a significantly

higher visceral adiposity index and greater odds for having T2DM, hypertension, MS, and

central obesity than individuals without NAFLD (66). Similar findings have reported from

Korea, India, Iran, and Turkey. (110-112)

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 Despite the spectrum of metabolic abnormalities in patients with lean or obese NAFLD, it is

likely that other genetic and environmental factors affect risk. Studies are needed to
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investigate the role of gut microbiota and environmental factors, including exposures to

antibiotics, in development and progression of NAFLD.

Pediatric NAFLD

Based on analyses of surrogate makers, the prevalence of NAFLD in children has been

estimated to range from 2.6% to 17.3%. (113) In an autopsy series study of children,

investigators determined the overall prevalence of NAFLD to be 9.6%, but rates increased

with age. NAFLD was more common in boys, but the highest rate was in Hispanic children

(11.8%), while the lowest rate was in African-American children (1.5%). (114)

A longitudinal study of NHANES data estimated that the prevalence of NAFLD in

adolescents increased from 3.9% in 1988–1994 to 10.7% in 2007–2010 (P<.0001), affecting

all race/ethnic groups and both sexes. (115) Again, the prevalence of NAFLD increased with

age, BMI, Mexican-American ethnicity, and male sex. However, among obese adolescences,

the odds of NAFLD were higher with increased age, BMI, Mexican-American ethnicity, and

male sex. In 2007–2010, 48.1% of all obese male adolescents and 56.0% of obese Mexican-

American male adolescents were suspected to have NAFLD. (116)

Children seem to have a different presentation of advanced NAFLD than adults. In a cross-

sectional study of 813 children from the Nonalcoholic Steatohepatitis Clinical Research

Network with biopsy-proven NAFLD, researchers found that children with zone 1 steatosis

(18%) had significantly more advanced fibrosis and were younger than children without zone

1 steatosis. In children with steatosis in zone 3 (32%), a higher proportion had steatohepatitis

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 (30%) than children with steatosis in zone 1 (6%) (P<.001) (114). It is also important to note

that presence and progression of NASH in pediatric patients accelerates with T2DM (117-
Accepted Article
119).

Since there are few data from long-term studies (> 2 years) or studies with liver biopsy data,

the current pediatric data may not represent real-world pediatric patients. Additionally, non-

invasive fibrosis scoring systems designed for adults do not adequately predict which

children will develop liver fibrosis. Thus, pediatric markers are needed to determine risk of

fibrosis in children.

Patient Reported Outcomes in NAFLD

In addition to clinical outcomes, PROs are important to consider for NAFLD patients (120).

NAFLD has been found to cause a significant decrease in quality of life as measured by

various tools (16,120-122). In addition, some PRO impairment may be associated with

NAFLD comorbidities such as depression or the stage of fibrosis (123-125).

Although NASH itself can reduce HRQL scores, treatment of NASH can also affect HRQL.

Preliminary data from selonsertib in NASH suggested that reductions in hepatic fibrosis and

the amount of collagen were associated with improvements in HRQL (124). Although

generic HRQL instruments have been used to study NAFLD and NASH, a disease-specific

HRQL instrument (CLDQ NAFLD-NASH) was recently developed and validated (122, 126).

CLDQ-NAFLD-NASH was developed using an established rigorous methodology (patients’

interviews, focus groups, item reduction, factor analysis, and psychometric testing). As such,

the CLDQ-NAFLD-NASH is now being used in clinical trials of NASH to capture patients’

perspectives about their disease and treatment. (126).

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 Economic effects of NAFLD and NASH

NAFLD is also associated with a significant economic burden. For details regarding the
Accepted Article
Economic burden of NAFLD, please see the supplementary material.

Conclusions

The prevalence of NAFLD as well as the genetic and environmental factors that determine its

associated risk varies worldwide. The progressive form of NAFLD or NASH is associated

with liver-related mortality, reduced HRQL, and substantial economic burdens. In the context

of growing burden of NASH worldwide, there is a lack effective treatment regimen and

validated non-invasive diagnostic, prognostic and dynamic biomarkers. For details about

authors’ statement about future of NAFLD/NASH, please see supplementary material.

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 1. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J,
Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk
factors and prevention. Nat Rev Gastroenterol Hepatol. 2018 Jan;15(1):11-20. Doi
Accepted Article
10.1038/nrgastro.2017.109. Epub 2017 Sep 20. Review. PubMed PMID:
28930295.
2. Younossi ZM, Stepanova M, Rafiq N, Henry L, Loomba R, Makhlouf H,
Goodman Z. Nonalcoholic steatofibrosis independently predicts mortality in
nonalcoholic fatty liver disease. HepatolCommun. 2017 Jun 6;1(5):421-428.
3. Hossain N, Afendy A, Stepanova M, Nader F, Srishord M, Rafiq N, Goodman Z,
Younossi Z. Independent predictors of fibrosis in patients with nonalcoholic fatty
liver disease. Clin Gastroenterol Hepatol. 2009 Nov;7(11):1224-9, 1229.e1-2.
4. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ.
Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
Gastroenterology. 1999 Jun. 116(6):1413-9.
5. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison
SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty
liver disease: Practice guidance from the American Association for the Study of
Liver Diseases. Hepatology. 2018 Jan;67(1):328-357
6. Golabi P, Otgonsuren M, de Avila L, Sayiner M, Rafiq N, Younossi ZM.
Components of metabolic syndrome increase the risk of mortality in nonalcoholic
fatty liver disease (NAFLD). Medicine (Baltimore). 2018 Mar;97(13):e0214
7. Younossi ZM, Otgonsuren M, Venkatesan C, Mishra A. In patients with non-
alcoholic fatty liver disease, metabolically abnormal individuals are at a higher
risk for mortality while metabolically normal individuals are not. Metabolism.
2013 Mar;62(3):352-60.
8. Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, Lam B, Srishord M.
Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine
(Baltimore). 2012 Nov;91(6):319-27. doi: 10.1097/MD.0b013e3182779d49
9. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global
epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of
prevalence, incidence, and outcomes. Hepatology. 2016 Jul;64(1):73-84. doi:
10.1002/hep.28431. Epub 2016 Feb 22.
10. Younossi ZM, Reyes MJ, Mishra A, Mehta R, Henry L. Systematic review with
meta-analysis: non-alcoholic steatohepatitis - a case for personalised treatment
based on pathogenic targets. Aliment PharmacolTher. 2014 Jan;39(1):3-14.
11. Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R,
Goodman Z. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol
agreement and ability to predict liver-related mortality. Hepatology. 2011
Jun;53(6):1874-82
12. Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Increased risk of
mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review
and meta-analysis. Hepatology. 2017 May;65(5):1557-1565. doi:
10.1002/hep.29085. Epub 2017 Mar 31

This article is protected by copyright. All rights reserved.

 13. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of
nonalcoholic fatty liver disease demonstrates an exponential increase in burden of
disease. Hepatology. 2018 Jan;67(1):123-133. doi: 10.1002/hep.29466. Epub 2017
Accepted Article
Dec 1.
14. Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, Racila
A, Hunt S, Beckerman R. The economic and clinical burden of nonalcoholic fatty
liver disease in the United States and Europe. Hepatology. 2016 Nov;64(5):1577-
1586. doi: 10.1002/hep.28785. Epub 2016 Sep 26
15. Younossi ZM, Stepanova M, Henry L, Racila A, Lam B, Pham HT, Hunt S.A
disease-specific quality of life instrument for non-alcoholic fatty liver disease and
non-alcoholic steatohepatitis: CLDQ-NAFLD. Liver Int. 2017 Aug;37(8):1209-
1218.
16. Younossi ZM, Stepanova M, Lawitz E, Charlton M, Loomba R, Myers RP,
Subramanian M, McHutchison JG, Goodman Z. Improvement of hepatic fibrosis
and patient-reported outcomes in non-alcoholic steatohepatitis treated with
selonsertib. Liver Int. 2018 Jan 27.
17. Younossi ZM, Loomba R, Rinella ME, Bugianesi E, Marchesini G,
Neuschwander-Tetri BA, etal. Current and Future Therapeutic Regimens for Non-
alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis
(NASH).Hepatology. 2017 Dec 9
18. Younossi ZM, Stepanova M, Rafiq N, Henry L, Loomba R, Makhlouf H,
Goodman Z. Nonalcoholic steatofibrosis independently predicts mortality in
nonalcoholic fatty liver disease. HepatolCommun. 2017 Jun 6;1(5):421-428.
19. Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, Erario M, Hunt
S. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular
carcinoma (HCC) in the United States from 2004 to 2009.Hepatology. 2015
Dec;62(6):1723-30.
20. Younossi Z, Stepanova M, Ong JP, Jacobson IM, Bugianesi E, Duseja A, Eguchi
Y, Wong VW, Negro F, Yilmaz Y, Romero-Gomez M, George J, Ahmed A,
Wong R, Younossi I, Ziayee M, Afendy A; Global NASH Council. Non-alcoholic
Steatohepatitis is the Fastest Growing Cause of Hepatocellular Carcinoma in Liver
Transplant Candidates. Clin Gastroenterol Hepatol. 2018 Jun 13. pii: S1542-
3565(18)30611-6. doi:10.1016/j.cgh.2018.05.057. [Epub ahead of print] PubMed
PMID: 29908364.

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Accepted Article

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