Clinical Nutrition 40 (2021) 2508e2519

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Narrative Review

Beverages and Non-alcoholic fatty liver disease (NAFLD): Think before

you drink
Jyoti Chhimwal a, b, Vikram Patial a, b, Yogendra Padwad a, b, *
a
Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur,
176061, H.P., India
b
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India

a r t i c l e i n f o s u m m a r y

Article history: Background & aims: Beverages and Non-alcoholic fatty liver disease (NAFLD) both the terms are asso-
Received 29 October 2020 ciated with westernized diet and sedentary lifestyle. Throughout recent decades, dietary changes have
Accepted 3 April 2021 boosted demand of beverages to meet the liquid consumption needs, among which rising consumption
of several calorie-rich beverages have increased the risk of fatty liver disease. Meanwhile, certain bev-
Keywords: erages have capacity to deliver many unanticipated health benefits thereby reducing the burden of
Beverage
NAFLD and metabolic diseases. The present review therefore addresses the increasing interconnections
NAFLD
between beverages intake among population, dietary patterns and the overall effect of these beverage on
NASH
Fibrosis
the development and prevention of NAFLD. Methods
Inflammation In the present review, some frequently consumed beverage groups have been analyzed in light of their
Sugar-sweetened beverages role in the advancement and prevention of NAFLD, including sugar sweetened, hot and alcoholic bev-
erages. The nutritional composition of different beverages makes the progression of NAFLD distinctive.
Results: The ingestion of sugar-rich beverages has demonstrated the metabolic burden and in all cases,
raises the risk of NAFLD, while intake of coffee and tea has decreased this risk without any significant
adverse effects. In some cases, low to moderate alcohol intake has been shown to minimize the risk of
advanced fibrosis and NAFLD-mortality.
Conclusion: Together, this review discusses and supports work on new dietary approaches and clinical
studies to accomplish nutrition-oriented NAFLD care by improving the drinking habits.
© 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction NAFLD is often associated with many other pathologies

Non-alcoholic fatty liver disease (NAFLD) is among the most
frequent causes of chronic liver injury worldwide evidenced by the
excessive aggregation of large fat droplets in hepatocytes, called as
hepatic steatosis and is detected either by contrast enhanced ul-
trasound, computed tomography and magnetic resonance imaging
or histological examinations [1]. Hepatic steatosis along-with
lobular inflammation and swallowing of hepatocytes defines
Non-alcoholic steatohepatitis (NASH), followed by progressive
fibrosis/cirrhosis then to hepatocellular carcinoma [2] (Fig. 1).
* Corresponding author. Pharmacology and Toxicology Laboratory, Dietetics &
Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology,
Palampur, 176061, H.P., India.
E-mail address: yogendra@ihbt.res.in (Y. Padwad).
including obesity, diabetes, cardiovascular and metabolic disorders
[3]. Accompanying the pandemics of obesity and the metabolic
disorders, NAFLD is quickly turning into the main cause of altered
liver functions in western nations, and within the next two decades
NASH will turn into the leading cause for end-stage liver ailment
and hepatocellular carcinoma [4]. Approximately 3e15% of NASH
cases develop cirrhosis and about 4e27% of NASH cases with
cirrhosis turn into HCC [5]. Ludwig and his colleagues first pro-
posed the idea of NAFLD in 1980, during their study on patients
with a pathological resemblance to alcohol-induced fatty liver
disease without any previous history of alcohol consumption [6].
Lifestyle and dietary habits may contribute to both protective
and hazardous role in the advancement and progression of NAFLD
[7]. Dietary patterns of the population across the globe have
extensively changed in the last two decades, with increased con-
sumption of saturated fats and carbohydrates rich food products
and beverages. Excess intake of refined foods and sedentary

https://doi.org/10.1016/j.clnu.2021.04.011
0261-5614/© 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
J. Chhimwal, V. Patial and Y. Padwad Clinical Nutrition 40 (2021) 2508e2519

Abbreviations IL Interleukins
LDL Low Density Lipoproteins
ACC Acetyl-CoA Carboxylase MDA Malondialdehyde
ALP Alanine Phosphatase NAFLD Non-Alcoholic Fatty Liver Disease
ALT Alanine Aminotransferase NASH Non-Alcoholic Steatohepatitis
AST Aspartate Aminotransferase NF-kB Nuclear Factor KappaB
BMI Body Mass Index PPAR Peroxisome Proliferator-Activated Receptors
ChREBP Carbohydrate Response Element Binding Protein ROS Reactive Oxygen Species
ECM Extracellular Matrix SCD Stearoyl-CoA desaturase
FAS Fatty Acid Synthase SREBP Sterol Receptor Element Binding Protein
FFA Free Fatty Acids SSB Sugar-Sweetened Beverages
GGT Gamma-glutamyltransferase TG Triglycerides
HCC Hepatocellular Carcinoma TGF-b Transforming Growth Factor-b
HDL High Density Lipoproteins TLR-4 Toll-like receptor-4
HFCS High Fructose Corn Syrup TNF-a Tumor Necrotic Factor-a
HSC Hepatic Stellate Cells

lifestyle has prompted the occurrence of metabolic disorders, e.g.,
obesity, type 2 diabetes mellitus (T2DM), cardiovascular diseases
and NAFLD [8]. However, diet is an important factor in metabolic
regulation, growing evidences have clearly shown that many di-
etary components are strictly engaged in the pathogenesis of
NAFLD.
Beverages have grown as a significant proportion of the west-
ernized diet over the past two decades and have contributed
significantly to an increase in energy consumed in liquid form [9].
Beverages include a wide variety of drinks, e.g., alcoholic beverages,
carbonated and fruit drinks with added sugar (sugar-sweetened
beverages), diet drinks, energy drinks and tea/coffee-based drinks.
Several studies have been carried out to elucidate the effect of
beverages on human health. An extended set of studies have shown
that intake of some calorie-rich beverages does not minimize the
consumption of solid food in order to preserve energy balance. It is
predicted that high intakes of sugar-rich beverages may lead to a
positive energy balance without energy compensation and there-
fore encourage weight gain [9]. Quite a few studies in animals as
well as in humans have indicated that chronic consumption of
refined sugars, especially fructose, may lead to NAFLD [10]. Con-
sumption of fructose rich diet is found to be associated with an
increased level of triglycerides, abdominal fat, blood pressure, in-
sulin resistance, and decreased levels of HDL-cholesterol which
may trigger the progression of NAFLD and obesity [11]. Apart from
sugar-sweetened beverages, coffee and tea are the most frequently
used non-alcoholic beverages, consumed primarily for taste and
flavour, but often considered healthy for several organs including
the liver [12]. Despite of unhealthy effects of sugar-sweetened
beverages and energy drinks, there are some evidences that the

Fig. 1. Schematic diagram illustrating the spectrum of NAFLD progression. The four stages of NAFLD development includes simple steatosis, NASH, fibrosis/cirrhosis and HCC.

2509
J. Chhimwal, V. Patial and Y. Padwad
consumption of some beverages like tea, coffee and alcoholic drinks
to some extent may impart several benefits in liver diseases
[13e15]. It is however very hard to describe the role of all kinds of
beverages, we have categorized most frequently consumed bever-
ages as sugar-sweetened beverages, hot beverages including tea
and coffee and alcoholic beverages. Therefore, this review intended
to systematically evaluate observational studies available on the
overall effect of these beverages on the progression and prevention
of NAFLD/NASH. We will first illustrate the pathophysiology of
NAFLD and summarize the consumption trend of above-mentioned
beverages across the globe. Secondly, the possible role of these
beverages in the development and prevention of NAFLD will be
outlined. Ultimately, we will look at the nutritional therapeutic
approaches in the prevention of NAFLD.
2. Non-alcoholic fatty liver disease (NAFLD): epidemiology
and pathophysiology of disease
NAFLD is best described by evidence of hepatic steatosis in the
absence of triggers for auxiliary hepatic fat accumulation such as
side effects of certain medications, chronic alcohol use and peculiar
endocrine conditions [1]. The assessed prevalence of NAFLD is
around 25e35% worldwide with a gender bias affecting approxi-
mately 30e40% of men and 15e20% of the women population [16].
In the United States, the predominance of NAFLD has jumped from
18% to 31% since 1991 to 2012. Recent data confirm an increased
prevalence in cases of NAFLD/NASH globally as it has a strong as-
sociation with lifestyle related ailments such as obesity and type 2
diabetes [17]. In India, NAFLD is believed to affect 9e32% of the
human population, with a higher occurrence amongst obese and
diabetic patients [5]. In UK, the assessed predominance of NAFLD
among type 2 diabetic people was observed to be around 42.6%
[16]. NAFLD is among the three leading causes of cirrhosis and can
also be linked to hepatocellular carcinoma (HCC). In addition,
NAFLD is a cardiovascular risk factor as well [18]. A recent report
highlights close relationship between NAFLD and the metabolic
syndromes, associating visceral obesity, dyslipidemia, insulin
resistance and arterial hypertension [3]; conveys the widely
accepted belief that NAFLD is the hepatic representation of
Fig. 2. Schematic diagram illustrating an overview of the ‘two-hit hypotheses’ in the progression of NAFLD. Determination of the first hit is based on chronic exposure to fat and
carbohydrate-rich diets that can promote fat deposition in the liver and adipose tissues, resulting in increased accumulation of triglycerides and oxidative stress. The second hit
disrupt cellular redox homeostasis and facilitate gut dysbiosis leading to the activation of proinflammatory cytokines which further promote stellate cells activation and ultimately
hepatic fibrosis.
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Clinical Nutrition 40 (2021) 2508e2519
metabolic syndrome [7]. The molecular basis of NAFLD develop-
ment is not well understood but is generally attributed to the
occurrence of insulin resistance, malfunctioned lipid metabolism,
oxidative stress, inflammation, apoptosis and necrosis [19]. The
initial stage of NAFLD is hepatic steatosis, i.e., more than 5% of
hepatocytes are covered with the deposition of cytoplasmic tri-
glycerides in the form of macro- and micro-vesicular lipid vacuoles.
Triglycerides accumulated in hepatocytes resulting from a dis-
balance in triglyceride acquisition and eradication that appears as a
consequence primarily from (i) an unbalanced calorie-rich diet, (ii)
increased triglyceride production, or (iii) increased peripheral
lipolysis [20]. The majority of surplus hepatic lipid content comes
from increased peripheral lipolysis [21], resulting from adipose
tissue insulin resistance associated with obesity [22]. Decreased
fatty acid oxidation and inability to secrete lipoproteins addition-
ally add to hepatic fat accumulation [23]. However, the involve-
ment of hepatocellular injury, inflammatory cytokine infiltration
and/or collagen deposition can enable NASH and fibrosis to prog-
ress from simple steatosis [20].
The pathogenic evolution of NASH is a complex and multifac-
torial process involving different metabolically active sites. The
“two hits hypothesis” suggests that several different processes may
contribute to inflammation of the liver. Insulin resistance and he-
patic fatty acid build-up contributed to the primary hit that in-
fluences mitochondrial fatty acids oxidation and allowing free
radical generation [24]. Secondary hits constitute oxidative stress
due to generation of free radicals, inflammatory state (NASH)
triggered by gut endotoxins engaging Toll-like receptor- 4 (TLR-4)
in hepatic inflammatory Kupffer cells and overproduction of cyto-
kines and endoplasmic reticulum stress results in mitochondrial
dysfunction [25] (Fig. 2).
Alteration of hepatic cytochrome P450 Cyp2E1/Cyp4A enzyme
activity also plays a significant role in disease progression and
fibrogenesis [26]. According to previous finding several genetic and
dietary factors also contributes in the progression of NAFLD [27].
Cytokines, adipokines and immune cells are the key drivers of
NAFLD which initiate the pathogenic cascade of inflammation,
fibrosis and consequently tumorigenesis by facilitating a cross-talk
between adipose tissue, gut and the liver. Therefore, NAFLD can no
J. Chhimwal, V. Patial and Y. Padwad
longer be considered as an exclusive hepatic disease, as many other
organs play a crucial part in the advancement of hepatic steatosis
and inflammation [2].
3. Beverages consumption pattern across the world
Beverages are both alcoholic and non-alcoholic drinkable liquid
products intended to human consumption and constitute a sub-
stantial portion of the food industry. Wines, beers and spirits are
the most common examples of alcoholic beverages, while non-
alcoholic beverages comprise of fruit juices, carbonated and non-
carbonated sweetened drinks and hot beverages like tea and coffee
[28]. Choices for beverages have grown ever more rapidly since
human first created settlements. Water and milk were the most
commonly consumed beverages for the last 11,000 years of that
evolutionary history [29]. Besides water and milk, traditional low-
alcoholic or non-alcoholic fermented beverages constitute an in-
tegral part of ancient food culture of China and many other Euro-
pean countries [30]. A wide variety of new options appeared
extremely rapidly in the last-half century. Moreover, new alterna-
tives such as carbonated drinks, sport drinks, energy drinks,
fruit juices and other alcoholic beverages containing high calories
like hard lemonades have also been introduced to conventional
drinks [29].
Beverages are considered as a functional food because, regard-
less of the basic health benefits of certain drinks, they help to
maintain optimum health due to some well-known health-pro-
moting macro or micro-molecules they contain [31]. Food and
Agriculture organization has tracked increase in the availability of
beverages by more than 20% over the last four decades [32]. Ac-
cording to Euromonitor 2014 report, non-alcoholic beverage in-
dustry with a market size of 531.3 billion dollars in 2013 is one of
the leading industries in the world [33]. In 2006, a population-
based study of United States suggested a noticeable difference in
the consumption of beverages on the basis of sex, age and ethnicity
of the population. In which, the consumption of beverages was
found higher in males rather than females. Regardless of their age
groups, African-Americans consumed substantially more fruit
drinks whereas white and Mexicans-Americans consumed more
carbonated soft drinks and milk respectively [34]. Another
population-based study on systematic assessment of beverage
intake in 187 Countries showed the sugary beverage consumption
was highest among the population of age between 20 and 39 years
whereas milk intakes were highest in older adults (age 60 or above)
globally. Consumption of fruit juice was found independent of the
age factor. Heterogeneity was also found in the consumption of
each beverage by region. For example, Caribbean region and
Australia accounts for highest consumption of sugar sweetened
beverages (SSB) and fruit juices respectively. Likewise, central Latin
America and Europe are largest consumers of milk and compara-
tively, consumption of all of these beverages is least in the East Asia
and Oceania [35].
From the last two decades, calorie-rich beverages have replaced
health-promoting beverages. In the category of non-dairy and non-
alcoholic drinks, water, fruit juice and sugar sweetened soft drinks
are most commonly consumed drinks across the population. The
consumption of 100% juice and Milk decreased dramatically as
people grow, while consumption of SSB increased sharply [36].
Regular soft drinks have become the most popular choice among all
beverages globally with an increase in consumption rate of
9.5e11.4 gallons per person annually from 1997 to 2010 [37]. Ac-
cording to a recent report, in the United Sates the spending on the
carbonated beverages (non-diet and diet beverages) was found
approximately 52% of the total budget. Rest of the 48% was shared
by water (12.93%), coffee and tea (~13.73%), and other caloric
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Clinical Nutrition 40 (2021) 2508e2519
beverages (~21.14%) [38]. Coming to alcoholic beverages, the
biggest increase was in beer consumption, which increased by
nearly 5 gallons per person per year [29]. In 2016, 57% of the world's
population (considering only 15þ years) did not consume alcohol
in the past 12 months including those who had ceased alcohol
consumption (12.5%) and who has never consumed alcohol (44.5%),
whereas 43% of the population are current drinkers [39]. Beverages
are an integral part of food and widely consumed across the world.
As stated above, in non-alcoholic beverages category, a substantial
rise in the consumption of sugar-sweetened beverages was found
which may draw a negative energy balance therefore may increase
the risk of NAFLD and metabolic diseases. Again, adults are more
vulnerable to developing NAFLD, as the consumption of both
alcoholic and non-alcoholic beverages rises with age. Although
beverages can constitute an important source of energy, if
consumed in large quantities may increase the risk of weight gain,
obesity and fatty liver and create significant public health and
safety problems in nearly all countries.
4. NAFLD diagnostics in pre-/clinical studies
NAFLD is the primary causes of chronic liver diseases world-
wide. The condition goes unnoticed in the earlier phases leading
to hepatic fibrosis and poor prognosis. Early diagnosis is the key
to preventing the disease by taking dietary precautions and
increasing physical activity. The changes in the serum injury
markers are the easiest way to detect hepatic disease. ALT and
AST are the most commonly used markers; however, ALT is
considered more specific to the liver. The elevated level of ALT
also has a direct correlation with age, body mass index, lipid
profile (triglycerides, LDL and HDL) and blood glucose levels
[40,41]. Alkaline phosphatase and albumin are also considered
markers in patients with liver fibrosis. Steatosis may progress to
hepatic inflammation, and there are various markers to detect the
inflammatory condition, including TNF-a, IL6, C-reactive protein,
adipokines, adiponectin, leptin, and thrombocytopenia. Other
structural maker used to detect NAFLD are cytokeratin-18,
collagen 7s, a-SMA and Fibrinogen-like protein 2 (FGL2) [42].
However, these surrogate markers have the limitation of repeat-
ability, simplicity, and accuracy. These may indicate whether the
disease is improving or worsening, but they often fail to reflect
the actual change in liver fat. Furthermore, their reliability in
predicting liver fat score in interventional trials is still unclear
[41,43]. Therefore, these markers should be used in conjunction
with the gold standard methods such as radiological diagnosis
using ultrasonography and magnetic resonance-based technolo-
gies and liver biopsy in interventional studies. In preclinical
research and clinical trials, the histopathology based semi-
quantitative scoring method is also used to diagnose the disease
[44] (Table 1). Recently, many omics and microbiota-based
markers are also suggested for NAFLD diagnosis, but they still
require standardization before implantation.
5. Effect of different beverages in NAFLD: fundamental
studies and mechanistic insights
Experimental evidences suggest that effects of these beverages
on NAFLD are mediated through the key bioactive molecules
possessed by them. These molecules are thought to be prime
regulators of crucial pathways associated with lipogenesis,
oxidation of fatty acids, inflammation, fibrosis and even tumori-
genesis. In this section, we have tried to comprehend the effects of
major classes of beverages on NAFLD and their respective mech-
anism of action in the light of various key clinical (Table 2) and
preclinical studies.
J. Chhimwal, V. Patial and Y. Padwad Clinical Nutrition 40 (2021) 2508e2519

Table 1
Criteria for scoring the hepatic lesions in NAFLD.

Score Steatosis Lobular infiltration (no. of foci/200X field) Ballooning degeneration

0 <5% None None

1 5e33% <2 Few
2 >33%e66% 2e4 Large no. of cells
3 >66% >4 e

5.1. Effect of sugar-sweetened beverages (SSBs) on NAFLD
5.1.1. Sugar-sweetened beverages (SSBs) promote NAFLD by
increasing hepatic de novo lipogenesis and decreasing b-oxidation
of fatty acids
Some regular examples of Sugar-sweetened beverages (SSB)
are soft drinks, packed fruit juices, sports drinks, energy drinks,
sweetened milk and all other drinks to which sugar has been
added. The key risk factors said to be associated with daily intake
of sugar-sweetened beverages are obesity, cardiovascular disease
and the metabolic syndrome [8] and recently increased accu-
mulation of visceral and hepatic fat, regardless of additional life
style factors [45]. Increased intake of sugar and caramel like
coloring complexes may promote insulin resistance, lipid perox-
idation and liver inflammation [46]. Recent evidences suggest
that increased consumption of sugar-loaded soft drinks might
have boosted the risk of NAFLD. Lee et al. (2020) reported that
daily intake of different SSBs over a period of three months
resulted in metabolic dysfunction, weight gain and hepatic stea-
tosis in mice [47]. The SSBs typically contain high-fructose corn
syrup (HFCS) in a very high extent, which elevates triglycerides
and blood glucose level [48]. Several mechanisms have been
postulated by which fructose may promote fat accumulation in
liver. In liver fructose is primarily metabolized to pyruvate, which
further converted into acetyl CoA, finally providing a substrate for
de novo lipogenesis [49]. SREBP-1c and ChREBP, two major
transcription factors primarily involve in de novo lipogenesis
were also found to be regulated by fructose. Fructose may also
promote hepatic fat accumulation through mitochondrial
dysfunction and abrogating b-oxidation of fatty acids [50] (Fig. 3).
Another important element of added sugar in SSB is glucose,
which can promote hepatic fat accumulation directly or by con-
verting into fructose through polyol pathway (under hypergly-
cemic condition) in the liver [51].
5.1.2. Clinical observations
SSBs and fructose intake have been found to associate with an
increased incidence of NAFLD in several epidemiological studies. In
2007, a cross-sectional analysis based on interview, biochemical
analysis and radiological examination of the Israeli adults (n ¼ 375)
reported a correlation of NAFLD with higher consumption of meat
and sugar loaded soft drinks [52]. Another study in 2009 reported
that patients with NAFLD seems to consume more sugar-sweetened
soft drinks compared to individuals considered as healthy controls
[46]. In another cross-sectional analysis carried out on middle-age
adults, a significant dose dependent association was observed

Table 2
Association between beverage consumption and NAFLD (Population-based studies and meta-analysis).

Type of beverage No. of Time Type of study Manifestations Reference

Participants Period

SSB 31 6 months Cross-sectional study [ALT, [GGT, [Glucose, [Fasting insulin, [TG, [HDL, [MDA [45]
SSB 375 14 months Cross-sectional study [ALT& AST, [Glucose, [Insulin, [TG [51]
SSB 2634 3 years Cohort study [ Body weight, [ALT, [Liver fat content [52]
SSB 1944 4 years Cohort study [ Body weight [53]
SSB 47 6 months Randomized controlled trial [ Plasma uric acid, [ liver fat content [56]
SSB 16 6 months Randomized controlled trial [ Liver fat content, [ Body weight [57]
Coffee 155 18 months Retrospective cross-sectional study YLiver stiffness, YFibrosis [75]
Coffee & Herbal Tea 2424 32 months Rotterdam population study, YLiver stiffness [76]
prospective cohort
Coffee 782 4 years Cross-sectional study YAST, YAdvance fibrosis [77]
Coffee 195 20 months Cohort study YAST, YNASH score, YFibrosis [78]
Coffee 245 6 months Case-control study YFatty liver, YALP, YTotal cholesterol, YLDL-C [79]
Coffee 2786 3 years Multiethnic cohort study YChronic liver disease severity [82]
Coffee & Caffeinated 400 1 year Cohort study YALT, YFibrosis [83]
drinks
Coffee 916 1 year Cohort study No association observed [84]
Green coffee extract 48 8 weeks Double-blind, placebo-controlled, YBMI, YTG, YTotal cholesterol, [HDL [85]
randomized clinical trial
Green coffee extract 44 8 weeks Double-blind, placebo-controlled, YAST, YTG, YTotal cholesterol, YOxidative stress, Yinsulin [86]
randomized clinical trial resistance
Green Tea 17 12 weeks Double-blind, controlled, YBody weight, YALT, YOxidative stress, YLiver fat content [88]
randomized clinical trial YBody fat, [Liver to spleen ratio
Green Tea (Extract) 80 3 months Double-blind, placebo-controlled, YALT, YAST, YALP [102]
randomized clinical trial
Green Tea 80 12 weeks Double-blind, placebo-controlled, YBody weight, YBMI, YALT, YAST, YTG, YLDL-C, [103]
randomized clinical trial [HDL-C, YInflammation
Moderate alcohol 11,754 6 years Cross-sectional analysis YALT, YTG, YBMI [15]
Moderate alcohol 582 2 years Cross-sectional analysis YSteatosis, YInflammation, YFibrosis progression [109]
Moderate alcohol 178 15 years Cross-sectional analysis YInflammatory gene expression, YBallooning of [111]
hepatocytes, YFibrosis
Moderate alcohol 4568 22 years Prospective Cohort Study YMortality in patients with NAFLD [113]
Moderate alcohol 285 2 years Longitudinal cohort study No improvement observed [114]

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J. Chhimwal, V. Patial and Y. Padwad
Fig. 3. Schematic representation of different aspects and mechanism of action of different kind of beverages in the progression and prevention of NAFLD. Beverages can influence
the progression of NAFLD via regulating multiple pathways i.e., hepatic de novo lipogenesis, mitochondrial b-oxidation, inflammation and intestinal dysbiosis.
between SSB consumption and fatty liver disease. After adjusting
for age, sex, BMI, total calorie intake and other lifestyle factors, the
study revealed a 55% greater risk of NAFLD in daily SSB consumers
than non-consumers along-with significantly higher level of liver
fat among obese persons compared to normal weight participants.
Furthermore, high levels of ALT were found frequently among SSB
consumers [53]. Additionally, the regular consumption of sugar-
sweetened beverages, especially when taken between meals, may
increase the risk of childhood obesity, indicating a positive rela-
tionship between the consumption of SSB and NAFLD, as obesity is
a risk factor for NAFLD [54]. A population-based study in 2008 re-
ported that individuals with NAFLD consume sugar-sweetened
beverages two times more than the average intake [55]. The role
of fructose rich beverages in the progression of NAFLD has also been
investigated in a large-scale survey of 427 NAFLD patients. After
adjustments for age, gender, BMI and total caloric intake, the re-
searchers concluded that the intake of fructose rich beverages on a
regular basis, was associated with a much higher level of hepatic
fibrosis in both younger and older age groups [56]. Several ran-
domized controlled trials (RCTs) have also been conducted to assess
the impact of SSBs on NAFLD. It has been reported that 1 L/day
consumption of sugar sweetened soda for 6 months had led to a
substantial rise in hepatic lipid content [57]. Another study re-
ported that overfeeding with carbohydrates or SSBs increases he-
patic lipid content by 27% in overweight adults [58]. Moreover, a
small-scale intervention study published recently found that 6
weeks of fructose restriction reduced hepatic lipid content in
NAFLD patients as compared to isocaloric control group [59]. The
level of ketohexokinase (KHK), the key initiating enzyme in fructose
metabolism was also found elevated in the liver biopsies of NAFLD
patients compared to controls [55]. The finding was evident from
the latest study which documented the impact of fructose on KHK
upregulation in rat liver [60]. Additionally, intake of both the sugars
glucose plus fructose collectively called as sucrose may exacerbate
the disease to a great extent. One study found that overfeeding with
either glucose or sucrose drink for four days increases de novo
lipogenesis by 200e300% in lean women [61]. The above findings
suggest that higher intake of SSB contribute to the expansion of
chronic diseases such as obesity, diabetes and finally NAFLD.
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Clinical Nutrition 40 (2021) 2508e2519
However, there are only few intervention studies with a small
sample size available; therefore, more prospective randomized
controlled trials and intervention studies with large population size
are required in this direction.
5.2. Effect of coffee consumption on NAFLD
5.2.1. Coffee & caffeinated drinks improve intestinal barrier
functioning, facilitate hepatic autophagy and inhibits hepatic
stellate cells (HSC) activation
Being the most popular beverage worldwide, consumption of
coffee has significantly increased over the last decade. According to
recent research, nearly 85 percent of the American population
drinks coffee at least once a day to improve mental alertness and
reduce fatigue [62]. Recent studies have shown that coffee has
beneficial effects against type 2 diabetes and metabolic syndromes
[63,64]. However, several studies have contradicted its effect
against metabolic syndrome. A cross-sectional analysis including
1040 participants reported an increased risk of metabolic syn-
drome and blood pressure with higher consumption of coffee [65]
whereas; no significant association was reported by Shin et al.
(2017) [66].
Eventually, coffee seems to protect against a variety of hepatic
disorders, including liver fibrosis, cirrhosis and HCC owing to the
anti-oxidant and anti-fibrotic potential of different biologically
active compounds it possesses [67]. Calabro et al. (2020) recently
summarized the benefits of coffee consumption on NAFLD [68].
Several preclinical findings on rodent models suggested the pro-
tective role of coffee against NAFLD. Coffee as well as caffeine
ingestion, was found to ameliorate the development of hyper-
triglyceridemia and fatty liver in spontaneously diabetic mice [69].
Vitaglione et al. (2019) demonstrated that coffee supplementation
could reverse NAFLD by reducing ALT, macrovesicular steatosis and
ballooning of hepatocytes [70]. The protective mechanism of action
of coffee against NAFLD is believed to be mediated primarily by
different bioactive components it contains. The anti-fibrotic effect
of coffee is thought to exert by caffeine mediated antagonism of
adenosine receptor A2a which further leads to hepatic stellate cells
inactivation (Fig. 2) [71], whereas the beneficial effect of
J. Chhimwal, V. Patial and Y. Padwad
decaffeinated coffee on the development of NASH was mediated
through inhibition of intestinal nitric oxide synthase (NOS) protein
and restoration of intestinal barrier functioning [72]. Chlorogenic
acid, an important component of regular coffee reduces the prev-
alence of NAFLD possibly by improving the gut barrier functioning,
facilitates hepatic autophagy and decreases hepatic inflammation
through TLR4 pathway [73e75] (Fig. 3).
5.2.2. Clinical observations
The association between the prevalence of NAFLD and coffee
intake (usually 3-4cups/day) was investigated in several cohort
studies including patients diagnosed with chronic liver damage
[76e80] (Table 2). A meta-analysis including 20,064 subjects from
two caseecontrol and four cross-sectional randomized trials re-
ported that regular intake of coffee caffeine might substantially
mitigate the risk of hepatic fibrosis in patients diagnosed NAFLD
[81]. A large population-based research carried out on a cohort of
18,550 individuals by National Health and Nutrition Examination
Surveys (NHNES), United States, reported a favorable effect of
caffeine intake against NAFLD, as identified by the altered levels of
liver enzymes Aspartate Aminotransferase (AST) and Alanine
Aminotransferase (ALT) [82]. The above findings were evident by a
recent multiethnic cohort study revealing the association of
reduced NAFLD risk with coffee drinking [83]. Also, in patients with
NASH, increased coffee intake also leads to a significant reduction
in the risk of advanced fibrosis [84]. The total calories consumption
as well as other lifestyle factor were compensated with coffee
intake in the above stated findings. Conflicting data on the associ-
ation between the intake of coffee and the severity of liver damage
in patients with NAFLD were also reported. A large cohort study of
South Italian people suggested that coffee intake was not associated
with any lower probability of hepatic steatosis in either non-
alcoholic or alcoholic forms of fatty liver [85].
However, some randomized controlled trials have shown that
coffee may protect against NAFLD, confirming the accuracy of the
previously reported cohort studies and meta-analyses. Two studies
reported that green coffee extract supplementation improved the
liver enzymes status, insulin resistance, glucose as well as lipid
metabolism and BMI of people with NAFLD, suggesting that it could
be effective in alleviating NAFLD [86,87]. In summary, coffee sup-
plementation therefore yielded some promising results in NAFLD
patients, which should be explored in future trials. Nevertheless,
there are differences among findings over the coffee drinking and
NAFLD status, possibly due to the demographic factors, methods
used to estimate coffee drinking, total calorie intake and severity of
the disease.
5.3. Effect of tea consumption on NAFLD
5.3.1. Tea consumption ameliorates NAFLD by inhibiting
inflammation and lipogenesis and facilitating b-oxidation of fatty
acids
Tea cultivation began first in China and later in Japan, but in the
15th-17th centuries its commercial cultivation spread to Indonesia,
the Indian subcontinent and Europe, and now it is second most
frequently consumed drink worldwide after water. Green, oolong
and black tea are all extracted from Camellia sinensis leaves and
buds, but due to differences in post-harvest processing, they vary in
their polyphenol content [88]. Catechins (flavan-3-ols) including
EGCG (Epigallocatechin gallate) are the major polyphenols that
constitute about 20% of the total flavonoids found in green tea
leaves [89]. Green tea consumption has been found to decrease the
plasma levels of aminotransferases, triglycerides and improve BMI
in children aged between 10 and 16 [90]. A close relationship be-
tween these variables and NAFLD supports the belief that tea
2514
Clinical Nutrition 40 (2021) 2508e2519
consumption can safeguard against NAFLD. Previously, in-vivo
findings have also shown that green tea prevents intestinal ab-
sorption of dietary lipids, decreases build-up of lipids in the liver
and adipose tissue, and has antioxidant properties [91]. GTE has
been found to protect against hepatic steatosis and associated
injury in the mouse model of NAFLD. Bruno et al. (2008) demon-
strated a protective effect of GTE against NAFLD in spontaneously
diabetic mice showing a decrease in hepatic lipid aggregation and
injury without altering hepatic antioxidant level [92]. Recent
studies have suggested that GTE treatment diminishes inflamma-
tion in steatohepatitis by reducing pro-inflammatory signals
through Tumor necrosis factor receptor 1 (TNFR1) and TLR4. TNFR1
and TLR4 further activates NF-kB and causes liver injury [93,94]
(Fig. 3). GTE administration has also been shown to protect against
NAFLD in diet-cum-chemical induced NASH in rats by reducing
serum levels of liver enzymes, lipid peroxidation and oxidative
stress [95]. In comparison, efficacy of EGCG alone is well docu-
mented against various in-vivo model of NAFLD and associated
disorders [96]. Additionally, green tea catechins were shown to
facilitate hepatic lipid metabolism. Elevated mRNA expression of
enzymes involved in mitochondrial b-oxidation, i.e., acyl-CoA oxi-
dase and acyl-CoA dehydrogenase were detected in the liver of the
catechin administered mice [97]. Oxidative breakdown of fatty
acids by catechins is believed to serve as a defense mechanism
against NAFLD. In addition, it also possesses the property of natural
iron chelator. EGCG administration in patients was discovered to
minimize nonheme iron absorption by 27% [98]. Increased level of
hepatic iron was found to be associated with NASH in patients [99];
therefore, targeting iron absorption by catechins could be an
effective therapy for NAFLD. Similarly, theaflavin from black tea has
led to a reduction in liver steatosis, oxidative stress, inflammation
and apoptosis against ischemia-reperfusion injury in NAFLD
induced mice [100].
5.3.2. Clinical observations
The effectiveness of green tea and its components in preventing
NAFLD in both animals and humans was summarized previously
[40]. Recently, a meta-analysis was performed on four studies
comprising a total of 234 subjects. The results of this pooling
analysis revealed a significant reduction in liver enzymes (ALT and
AST) concentration and total lipid profile after green tea adminis-
tration [101]. Multiple randomized controlled trials have been
conducted to address concerns about the efficacy of green tea in
humans. Findings of a small randomized controlled study incor-
porating 17 NAFLD patients aged 20e70 years revealed that daily
consumption of green tea with high-density catechins ameliorated
hepatic fat content and inflammation in patients with NAFLD by
reducing oxidative stress [89]. Another intervention study revealed
that patients with NAFLD who took a 550 mg green tea tablet daily
for three months had lower BMI, fasting blood sugar, and serum
AST than those who took a placebo [102]. In another placebo-
controlled, double-blind, randomized clinical trial including 80
participants, green tea extract (GTE) supplementation was found to
decrease liver enzymes in patients with NAFLD [103]. Improvement
in body weight, BMI, lipid profile and inflammatory markers were
also reported after twice a day ingestion of 500 mg capsule of green
tea extract (GTE) [104]. It is now evident from these studies that tea
consumption may help to improve the status of patients with
NAFLD.
5.4. Effect of alcoholic drinks on NAFLD
NAFLD by definition is a fatty liver condition due to factors other
than excessive alcohol consumption. The clinical trial for NAFLD
consider ~14 drinks per week as threshold for excessive alcohol
J. Chhimwal, V. Patial and Y. Padwad
intake and consumption below this is considered as moderate. The
American Association for the Study of Liver Diseases (AASLD) also
recommended that moderate alcohol intake in NAFLD patient do
not cause any significant effect on the progression of disease [105].
Interestingly, several epidemiological studies have reported a
negative correlation between moderate alcohol consumption and
prevalence of metabolic syndrome as well as cardiovascular dis-
orders [106,107]. Consumption of modest alcohol can, therefore,
have an advantageous effect on NAFLD. In pre-clinical settings,
there is a limited data available over the beneficial effect of mod-
erate alcohol in animal model of NAFLD [108,109]. However, there
are a number of observational studies that summaries the impact of
moderate to low alcohol intake on biopsy proven NAFLD.A cross-
sectional analysis carried-out by United States of America on
17,763 individuals of age 21 years. The result of the study
demonstrated that moderate consumption of alcohol (up to 10g of
alcohol/day) reduces the serum level of ALT in the individuals
suspected for NAFLD [15]. Similarly, Dunn et al. (2012) in their study
with patients having biopsy-proven NAFLD reported less severity of
disease in modest drinkers in contrast to non-drinkers along with
lower odds for fibrosis [110]. Data from a meta-analysis of 43,175
individuals showed that modest alcohol consumption (40g of
alcohol/day) significantly decreases the risk of NAFLD by 31% with
an about 50% decrease in the risk of developing fibrosis [111]. The
results of these findings were supported by evidence from several
recent studies. In 2018, Yamada et al. investigated that light con-
sumption of alcohol (20g of ethanol/day) significantly reduced
ballooning and fibrosis in NAFLD patients when compared to those
who did not drink alcohol. However, no significant difference was
observed in steatosis or inflammation score among the groups. The
mechanistic insight has shown that the effect was mediate through
decrease in hepatic expression of TLR4 (Toll-like receptor 4) along
with a decreased serum level of TNF-a in the light alcohol con-
sumer group (Fig. 3) [112]. TLR4 mediates progression of hepatic
inflammation and fibrosis was previously explained by Aoyama
et al. (2010) [113]. Hajifathalian et al. (2019) collected data over a
span of 12 years on National Health and Nutrition Examination
Survey (NHNES) participants with NAFLD and linked them to the
National Death Index to monitor the survival rate. The result of this
long-term cohort study has provided the evidence of patients’
survival with modest alcohol consumption (up to 15 g of alcohol/
day), whereas drinking over 1.5 drinks (>21 g of alcohol/day) per
day increases all-cause mortality [114]. Interestingly, several other
reports on alcohol consumption and NAFLD contradict the benefit
of light drinking in NAFLD. A recent finding of Ajmera et al. (2018)
demonstrated that no significant improvement in liver steatosis
and serum AST was observed in NAFLD patients with moderate
drinking (20 g of ethanol/day) as compared to non-drinkers [115],
though exacerbating effect of moderate alcohol consumption still
remains unclear from the results. Despite being a major cause of
chronic liver failure, alcohol consumption may provide a beneficial
effect against NAFLD, depending on the amount of intake.
6. Future directions toward lifestyle modifications and
nutritional approaches
With a sedentary lifestyle and changes in eating habits, NAFLD
prevalence has increased, and the identification of appropriate
treatment for NAFLD is an important public health objective. Till
date, no effective pharmacological interventions have been estab-
lished to reverse the course of disease, however, in western coun-
tries many drugs are being clinically tested for the treatment of
NAFLD [103]. So far, changes in lifestyle and dietary improvements
are the primarily established treatment guidelines for NAFLD
(Fig. 4).
2515
Clinical Nutrition 40 (2021) 2508e2519
Fig. 4. An overview of the lifestyle modifications and nutritional approaches to
decrease the course of NAFLD on the basis of clinical and observational trials.
Dietary interventions avoid the side effects of medicines and
their metabolic and physiological burden on human body. For
NAFLD and NASH, lifestyle interventions such as improved eating
habits, increased physical activity along with weight loss are often
recommended that may improve steatosis, dyslipidemia, insulin
resistance, and cardiovascular risk and cut back hepatic inflam-
mation and injury [116]. Sugar-sweetened beverages are a major
driver of the metabolic syndromes and contribute to our diet more
calories than any other food item. Therefore, targeting sugar-
sweetened beverages are important in order to create a healthy
environment. Recently, several natural sweeteners such as hoodia,
stevia, trehalose, D-tagatose and D-psicose have been reported to
facilitate weight loss and may protect against NAFLD, insulin
resistance and can be implemented in replacement of added sugar
in SSBs to appease the craving for sweet taste without consequent
energy consumption [117]. Based on experimental and clinical ev-
idence Green and Syn (2019) summarized the association of non-
caloric sweetener consumption with low incidences of MetS
including NAFLD [118]. However, intervention studies with human
subjects are urgently needed to be more conclusive.
Apart from avoiding SSB, introduction of healthy beverage in
diet could play a substantial role in altering the disease patho-
genesis. Many dieticians recommend consuming low-fat flavoured
milk and 100% fruit juices in small portions. A cross-sectional
observational study conducted on 136 participants revealed that
consumption of low-fat dairy products was higher among healthy
individuals compared to patients with NAFLD [119]. However, a
single study showed that when people were randomly assigned to
drink isocaloric milk instead of SSBs, they had lower incidences of
fatty liver [57]. Also, cocoa based floured milk contributed to
minimize oxidative stress in NASH patients [120] therefore could be
considered as healthy beverage option. Similarly, 100% fruit juice
contains considerable amounts of natural sugar but also imparts
several health benefits due to the phytochemicals they possess.
Orange and whole grape juices enriched with anthocyanins and
polyphenols improved hepatic steatosis in mice therefore could be
a promising dietary alternative to prevent fatty hepatic disease
[121,122]. As previously mentioned, dietary supplementation of
J. Chhimwal, V. Patial and Y. Padwad
resveratrol which is significant constituent of grape juice and red
wine could be an effective therapy in patients with NAFLD
[123,124]. Several human intervention studies from past also sug-
gested the beneficial effects of fruit juices against NAFLD [125,126].
Moreover, fiber rich beverages viz. Fruit and vegetable smoothies
and other functional drinks could be implemented in diet but un-
availability of data regarding their use in NAFLD limits this possi-
bility. A much deeper knowledge of the role of these substances in
the therapeutic intervention of metabolic disorder such as obesity,
diabetes and NAFLD and their underlying mechanism could enable
new targets for treating these diseases.
7. Conclusion
Based on the available observational and interventional evi-
dences it can be stated that sugar-sweetened beverages when
consumed in excess are likely to be key driving factors of NAFLD
and its long-term consequences. Conversely, regular coffee and tea
intake found to be associate with low disease prevalence; however,
future studies are necessary to determine the intake amount and
type(s) of tea/coffee to achieve more advantageous hepatic out-
comes. Similarly, there are several evidences to support a recom-
mendation for moderate alcohol consumption in NAFLD but its
potential to influence liver as well as cardiovascular health cannot
be overlooked. Therefore, choosing beverage with potential health
benefit can help a person to avoid metabolic disorders like NAFLD.
In conclusion, more human interventional studies in larger popu-
lation are needed to establish a better understanding of the inter-
connection between these beverages and spectrum of NAFLD.
Authors contributions
Jyoti Chhimwal: Conceptualization, Visualization, Writing-
Original draft preparation. Vikram Patial: Visualization, Supervi-
sion, Writing - Review & Editing. Yogendra Padwad: Conceptual-
ization, Supervision, Funding acquisition, Writing- Reviewing and
Editing.
Conflicts of interest
None.
Acknowledgement
The Authors thanks the Director, CSIR-Institute of Himalayan
Bioresource Technology, Palampur, India for his motivation and
incessant support. JC is deeply obliged to CSIR, India for Ph.D.
Fellowship and AcSIR, India for Ph.D. registration. The authors
would like to acknowledge CSIR, India for financial support pro-
vided through project MLP0204 and MLP0155.
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