Review Article

Effect of chronic alcohol consumption on the development and

progression of non-alcoholic fatty liver disease (NAFLD)
Helmut K. Seitz1, Sebastian Mueller2, Claus Hellerbrand3, Suthat Liangpunsakul4
1
Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany; 2Department of Medicine (Gastroenterology & Hepatology),
Salem Medical Centre, Heidelberg, Germany; 3Department of Internal Medicine I, University Hospital Regensburg, Germany; 4Division of
Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana, USA
Correspondence to: Helmut K. Seitz, MD, AGAF. Professor of Medicine. Gastroenterology and Alcohol Research, Department of Medicine, University
of Heidelberg, Salem Medical Centre, Heidelberg, Germany. Email: [email protected].

Abstract: A number of epidemiologic studies show a protective effect of light to moderate daily alcohol
consumption on the development of non-alcoholic fatty liver disease (NAFLD). Although these small
amounts of ethanol may prevent fatty liver, they may also be a risk factor for other diseases such as breast
and colon cancer. Those individuals who have underlying hepatic steatosis or non-alcoholic steatohepatitis
(NASH) should not use ethanol chronically since the data available at present do not support a beneficial
effect of alcohol in this situation. Especially overweight and obese individuals may be more susceptible
towards alcohol even at moderate doses. Animal experiments show a negative effect of ethanol on liver
histology in either dietary or genetic NASH models. In addition, patients with NASH reveal a significant
increased risk for hepatocellular cancer (HCC) even with social alcohol consumption. Thus, subjects with
underlying NASH should abstain from alcohol at any amounts.

Keywords: Alcohol; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH)

Submitted Aug 06, 2014. Accepted for publication Oct 29, 2014.
doi: 10.3978/j.issn.2304-3881.2014.12.01
View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.12.01

Introduction triglycerides and fatty acids primarily due to the change

in the redox state of the hepatocyte following ethanol
Sufficient evidence has been accumulated that alcoholic
oxidation with increased triglyceride synthesis and decreased
liver disease (ALD) and non-alcoholic fatty liver disease
ß-oxidation of fatty acids (5). In NAFLD the metabolic
(NAFLD) share at least some pathogenetic mechanisms
syndrome with hyperinsulinemia and high circulating
in their development (1-3). This is especially true for the levels of free fatty acids are the predominant reason for
progression of fatty liver to hepatic inflammation with the hepatocellular fat accumulation (3,6). This metabolic
involvement of gut derived endotoxins, cytokine secretion syndrome is characterized by obesity, diabetes mellitus
from Kupffer cells and oxidative stress. Both diseases (DM), hypertension and disturbances in fat metabolism.
start with simple fatty liver, progress with inflammatory Interestingly it has been shown that moderate alcohol
reaction to alcoholic steatohepatitis (ASH)/non-alcoholic ingestion has a beneficial effect on peripheral insulin
steatohepatitis (NASH), and end up with cirrhosis of resistance and thus a positive effect in patients with type II
the liver and hepatocellular cancer (HCC). Also both DM (7).
entities have similar pattern of liver injury and may be In the last years a number of epidemiologic publications
indistinguishable on liver biopsy (4). occurred in which the effect of moderate alcohol
However, the cause of the development of fatty liver in consumption on the risk to develop NASH as well as on the
ALD and NAFLD is different. In ALD a major reason for progression of NASH has been investigated. Furthermore,
hepatic fat accumulation is a change in the metabolism of some experimental data also exist studying the same

© HepatoBiliary Surgery and Nutrition. All rights reserved. www.thehbsn.org HepatoBiliary Surg Nutr 2015;4(3):147-151
148 Seitz et al. Effect of alcohol in non-alcoholic fatty liver disease

question. The purpose of this brief review is to update the the rapid ethanol metabolizing allele ADH1C*1,1) resulting
knowledge on this issue with a final recommendation based in increased acetaldehyde levels have an increased cancer
on the up to date literature. risk when they consume more than 30 grams of ethanol per
day (14). In addition, some pre-existing conditions such as
hepatitis C (15), as well as borderline hypertension (16) or
How much ethanol results in fatty liver?
some metabolic disorders (17) may deteriorate with chronic
The dose threshold of alcohol for its hepatotoxic effects alcohol ingestion even at small amounts.
varies. It depends on a variety of factors including genetics,
ethnicity, and gender (2). The safety levels of drinking as
Epidemiological studies analyzing the effect of
endorsed by the European Association for the Study of the
alcohol on the risk to develop NAFLD
Liver (EASL) and the American Association for the Study of
the Liver (AASLD) are defined as 30 and 20 g of alcohol per A number of epidemiologic studies from the United States,
day in man and woman, respectively (2,8). The Asian Pacific Europe, and Japan have demonstrated that moderate
for the Study of the Liver (APASL) Guideline recommends alcohol consumption may have a beneficial effect on the
less than 20 g of alcohol per day in man and 10 g of alcohol development of NAFL, primarily through the improvement
per day in women (9). Taken together, it is the acceptance in peripheral insulin resistance.
that daily ethanol intake of less than two drinks in man A prospective study of 109,690 women (age 25 to 42 years)
and less than one drink in woman are considered as ‘safe’ showed a nonlinear and inverse relationship between alcohol
and such levels should not lead to hepatic steatosis (10,11), consumption and risk of type 2 DM (7). Compared with
and in fact these cut off levels are also arbitrarily used to lifelong abstainers, the odds of individuals who consumed
differentiate ALD from NAFLD in most clinical trials. <5, <15, <30, and >30 g of ethanol per day and the risk
However, there are other factors such as baseline body of developing type 2 DM were 0.8, 0.67, 0.42, and 0.78,
weight, which should be taken into consideration in clinical respectively. The take home message of this study is that
practice; especially on what we normally consider as “safety light to moderate, but not have alcohol consumption has a
drinking”. In a study by Bellentani et al. using a large cohort protective effect against the development of DM (7).
of subjects in Northern Italy (12), the authors found that In another study from the U.S. using the data from the
subjects with underlying obesity had a higher prevalence of Third National Health and Nutrition Examination Survey
hepatic steatosis, as determined by ultrasonography, when (NHANES) found a reduced prevalence of NAFLD in
compared to lean controls who consumed alcohol in the subjects with modest wine consumption at the maximum of
same range subjects with a daily intake of more than 60 g 10 grams per day (18).
of alcohol and a body mass index (BMI) of over 25 kg/m2 In a cross sectional study (n=5,599) from Japan (19),
revealed a fatty liver in more than 90%. Gunji et al. also found an inverse association between light
It is important to note that the recommended levels of a (40-140 g of alcohol per week) and moderate alcohol
‘safety drink’ are derived when we use liver pathology as the consumption (140-280 g per week) and a prevalence of
end point. These levels of drinking in fact have been shown hepatic steatosis, as diagnosed by ultrasound (19). The results
to have adverse effects which might lead to breast (13) and of this study (19) are in accordance with another Japanese
colon (14) cancers. Although these relatively small amounts study (20) which showed a low prevalence of fatty liver in
of ethanol seem safe for the liver, they may be harmful for subjects who drank less than 20 g of ethanol on 1-3 days
other organs and tissues. In this context major concern per week. The protective effect of light to moderate alcohol
has been raised with respect to the alcohol related risk for consumption on hepatic steatosis was recently confirmed in a
breast (13) and colorectal cancer (14). Such associations are meta-analysis involving 43,175 subjects (21).
mainly extrapolated from several epidemiologic studies, Epidemiological data also support the protective role
which have the pitfalls with multiple potential confounding of moderate alcohol consumption on the liver, when using
factors. At present, there are no reporting data on what the serum transaminases activity as the endpoint. In a study of
minimal threshold of alcohol consumption is deem to be safe 1,177 male subjects without underlying liver disease the
against the risk of developing breast cancer. With respect to authors found that light (70-140 g per week) to moderate
colon cancer it was shown that individuals with an alcohol (140-280 g per week) alcohol consumption was associated
dehydrogenase (ADH) 1C polymorphism (homozygote for with lower levels of serum transaminases activity as

© HepatoBiliary Surgery and Nutrition. All rights reserved. www.thehbsn.org HepatoBiliary Surg Nutr 2015;4(3):147-151
HepatoBiliary Surgery and Nutrition, Vol 4, No 3 June 2015 149

compared to controls (22). On the other hand, drinking increased with increasing BMI for each alcohol drinking
alcohol in the higher range (>3 drinks per day), as expected, level (29).
was associated with an elevation of ALT and AST by 8.9 Lastly, there was a retrospective study suggesting an
and 21-fold, respectively, when controlling for covariates increasing risk for HCC in patients with underlying NASH
such as BMI (23). who consumed alcohol in moderate amounts (30).
Despite the pitfall in the study design of several of these
epidemiological studies, existing data support the notion
Experimental (animal) studies analyzing the
that light to moderate drinking might be protective against
effect of alcohol on NAFLD development and
diabetes and hepatic steatosis in healthy subjects.
progression

We have investigated the effect of a rather low intake of

Effect of alcohol on subjects with a histological
ethanol (16% of total calories) on the progression of a
diagnosis of NAFLD
high fat diet-induced NASH model in Sprague Dawley
Besides from the above mentioned epidemiological studies, rats (31). We found an increased number of inflammatory
the effect of alcohol drinking on the underlying hepatic foci and apoptosis due to the additional intake of ethanol.
histopathology in subjects with the firm diagnosis of These histological features were found to be associated
NAFLD has been reported. Kwon et al. found that regular with elevated mRNA expression of Fas/FasL and cleaved
alcohol consumption was associated with less severe fatty caspase 3 protein. Our data suggest that moderate alcohol
liver disease (24). intake can augment the inflammation as well as apoptosis in
In a study by Cotrim et al. in 132 morbidity obese individuals rodents with underlying NASH.
undergoing bariatric surgery, there was no relationship To further study the underlying mechanism, we next
between alcohol consumption and liver histopathology, investigated the effect of alcohol using the above model on
however, light to moderate alcohol consumption SIRT1 activity, adiponectin/ Adiponectin receptor (AdipoR)
was inversely associated with insulin resistance (25). related signaling and lipid metabolism (32). Ethanol
Dixon et al. have shown that morbidly obese patients with increased hepatic nuclear SIRT1 protein but decreased its
moderate alcohol consumption undergoing bariatric surgery deacetylation activity. SREBP-1c protein expression and
in fact had a lower prevalence of steatohepatitis, even though FAS mRNA levels were significantly upregulated, while
such findings did not persist in the multivariate analysis DGAT1/2 and CPT-l mRNA levels were downregulated in
controlling for confounders such as diabetes or insulin the livers of ethanol-fed rats in addition to the high fat diet.
resistance (26). Lastly, Dunn et al. reported that modest Ethanol had no effect on AipoR2 and their downstream
alcohol ingestion was associated with a lesser degree of signaling, plasma adiponectin, free fats acids, and
severity of NASH as well as of fibrosis when 252 lifetime adiponectin expression in adipose tissue. These data show
non-drinkers were compared to 331 modest drinkers with that the inhibitory effect of alcohol on SIRT1 deacetylase
a normal BMI (27). Moderate drinkers had a significantly activity exacerbated hepatic inflammation and apoptosis in
lower risk for hepatic fibrosis (ORs 0.58, 95% CI, 0.41-0.77) rats with pre-existing NASH.
and ballooning of hepatocytes (ORs 0.67, 95% CI, 0.48-0.92), Also in a further study in mice we observed joint
when compared to non-drinkers. pathological effects of chronic alcohol administration in
Despite the positive effect of moderate drinking on liver drinking water (up to 5%) and feeding a NASH-inducing
histology in NAFLD, there are some studies reporting high fat diet (33). The high fat diet induced hepatic
negative outcomes. A study by Ekstedt et al. found an triglyceride accumulation and expression of proinflammatory
accelerated progression of fibrosis over more than years genes while the effects of alcohol alone were less pronounced.
in patients with NAFLD who drank moderate amounts However, in combination with the high fat diet, alcohol
of alcohol (28). The findings from the population based significantly enhanced proinflammatory gene expression.
NHANES-3 study also showed that the likelihood of Furthermore, a combination of both alcohol and high fat
hepatic injury was higher at increasing body weight even diet led to marked induction of hepatic fibrosis compared
when the levels of alcohol consumption were as low as to isolated effects of alcohol or high fat diet alone on
2 drinks a day. In this report by Ruhl and Everhart, the profibrogenic gene expression and extracellular matrix
prevalence of elevated serum transaminases activities has deposition in liver tissue. Moreover, endotoxin levels in

© HepatoBiliary Surgery and Nutrition. All rights reserved. www.thehbsn.org HepatoBiliary Surg Nutr 2015;4(3):147-151
150 Seitz et al. Effect of alcohol in non-alcoholic fatty liver disease

the portal circulation were significantly elevated in mice to Helmut K. Seitz and Sebastian Mueller.
that received alcohol or a high fat diet and were further Disclosure: The authors declare no conflict of interest.
significantly increased in those animals receiving both. The
high fat diet alone and in combination with alcohol resulted
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Cite this article as: Seitz HK, Mueller S, Hellerbrand C,

Liangpunsakul S. Effect of chronic alcohol consumption on
the development and progression of non-alcoholic fatty liver
disease (NAFLD). HepatoBiliary Surg Nutr 2015;4(3):147-151.
doi: 10.3978/j.issn.2304-3881.2014.12.01

© HepatoBiliary Surgery and Nutrition. All rights reserved. www.thehbsn.org HepatoBiliary Surg Nutr 2015;4(3):147-151