ALCOHOL

Contents
Absorption, Metabolism, and Physiological Effects
Effects of Consumption on Diet and Nutritional Status

Absorption, Metabolism, and Physiological Effects

R Rajendram, R Hunter, and V Preedy, King’s College London, London, UK
r 2013 Elsevier Ltd. All rights reserved.

This article is a revision of the previous edition article by

R. Rajendram, R. Hunter, V. Preedy and T. Peters, volume 2,
pp 48–57, r 2005, Elsevier Ltd.

Glossary Catalase Catalase is a common enzyme found in nearly

Alcohol dehydrogenase Alcohol dehydrogenase (ADH) is all living organisms. The main action is the decomposition
an enzyme that couples oxidation of ethanol to reduction of of hydrogen peroxide (H2O2) to water. It can also oxidize
nicotinamide adenine dinucleotide (NAD þ ) to NADH. ethanol in a reaction that requires H2O2.
ADH has a wide range of substrates and functions, including First-pass metabolism of ethanol First-pass metabolism
dehydrogenation of steroids and oxidation of fatty acids. of ethanol reduces the concentration of ethanol before it
Aldehyde dehydrogenase Aldehyde dehydrogenase reaches the systemic circulation.
(ALDH) is an enzyme that couples oxidation of Microsomal ethanol oxidizing system The microsomal
acetaldehyde to reduction of NAD þ . The presence of ALDH ethanol oxidizing system (MEOS) is another pathway of
in tissues may reduce the toxic effects of acetaldehyde. ethanol metabolism. The key enzyme of the MEOS is
Blood ethanol concentration Blood ethanol cytochrome P4502E1 (CYP2E1). This pathway requires
concentration is commonly used as a measure of oxidation of NADPH to NADP þ.
intoxication. It is commonly expressed as mg l1, g dl1, or
mmol l1.

After caffeine, ethanol is the most commonly used recreational in most organs of the body. Some data have suggested that
drug worldwide. Alcohol is synonymous with ethanol, and alcohol may be beneficial in the reduction of ischemic heart
drinking often describes the consumption of beverages con- disease.
taining ethanol. In the United Kingdom (UK), a unit of al- Many of the effects of alcohol correlate with the peak
cohol (standard alcoholic drink; Table 1) contains 8 g of concentration of ethanol in the blood during a drinking ses-
ethanol (ethyl alcohol). The Department of Health, the Na- sion. It is therefore important to understand the factors that
tional Institute for Clinical Excellence (NICE), and several of influence the blood ethanol concentration (BEC) achieved
the medical Royal Colleges in the UK have recommended from a dose of ethanol.
sensible limits for alcohol intake based on these units of al-
cohol. However, as the amount of ethanol in one unit or a
standard alcoholic drink varies throughout the world (Table 2
and Table 3), the unit system does not allow international Physical Properties of Ethanol
comparisons. Recommendations for sensible limits for alco-
hol intake also vary worldwide. Ethanol is produced from the fermentation of glucose by
Despite these guidelines, the quantity of alcohol consumed yeast. Ethanol (Figure 1) is highly soluble in water due to its
varies widely. Many enjoy the pleasant psychopharmacological polar hydroxyl (OH) group. The nonpolar (C2H5) group en-
effects of alcohol. However, some experience adverse reactions ables ethanol to dissolve lipids and thereby disrupt biological
due to genetic variation of enzymes that metabolize alcohol. membranes. As a relatively uncharged molecule, ethanol
Misuse of alcohol undoubtedly induces pathological changes crosses cell membranes by passive diffusion.

40 Encyclopedia of Human Nutrition, Volume 1 http://dx.doi.org/10.1016/B978-0-12-375083-9.00005-2

 Alcohol: Absorption, Metabolism, and Physiological Effects 41

Absorption and Distribution of Alcohol Alcohol continues down the GI tract until absorbed. The
ethanol concentration therefore decreases down the GI tract.
The basic principles of alcohol absorption from the gastro- There is also a concentration gradient of ethanol from the
intestinal (GI) tract and subsequent distribution are well lumen to the blood. The concentration of ethanol is much
understood. Beverages containing ethanol pass down the higher in the lumen of the upper small intestine than in
esophagus into the stomach. The endogenous flora of the GI plasma (Table 4). Alcohol diffuses passively across the cell
tract can also transform food into a ‘cocktail0 containing several membranes of the mucosal surface into the submucosal space
alcohols including ethanol. This is particularly important if there and then the submucosal capillaries.
are anatomical variations in the upper GI tract (e.g., diverticulae). Absorption occurs across all of the GI mucosa but is fastest
in the duodenum and jejunum. The rate of gastric emptying is
the main determinant of absorption because most ethanol is
Table 1 Unit system of ethanol content of alcoholic beveragesa
absorbed after leaving the stomach through the pylorus.
Beverage containing ethanol Units of ethanol

Half pint of low-strength beer (284 ml) 1 Polar hydroxyl group

Pint of beer (568 ml) 2
500 ml of high-strength beer 6
Pint of cider 2 H H
One glass of wine (125 ml) 1 H C C O H
Bottle of wine (750 ml) 6
H H
One measure of spirits (e.g., whisky, gin, vodka) 1
Bottle of spirits (e.g., vodka 750 ml) 36
a
Nonpolar carbon backbone
The unit system is a convenient way of quantifying consumption of ethanol and offers
a suitable means to give practical guidance. However, there are several problems with Figure 1 Chemical Structure of Ethanol (Ethyl Alcohol).
the unit system. The ethanol content of various brands of alcoholic beverages varies
considerably (for example, the ethanol content of beers/ales is in the range 0.5–9.0%
so a pint may contain 2–5 units) and the amounts of alcohol consumed in homes bear Table 4 Approximate ethanol concentrations in the gastrointestinal
little in common with standard measures. Similarly, variations in the strength (9–14%) tract and in the blood of a 70 kg male after consumption of 7 units of
and serving size (125–250 ml or more) of wine makes quantization of self reported alcohola
intakes rather difficult.
Site Ethanol concentration

Table 2 Geographical variation in the amount of ethanol in one g dl1 mmol l1
unit
Stomach 8 1740
Country Amount of ethanol (g) Jejunum 4 870
Ileum 0.1–0.2 22–43
Sweden 20 Blood (15–120 minutes after dosage) 0.1–0.2 22–43
Japan 19.75 a
United States 14 Ethanol appears in the blood as quickly as 5 minutes after ingestion and is rapidly
Australia and New Zealand 10 distributed around the body. A dose of 0.8 g ethanol per kg body weight (56 g ethanol
United Kingdom 8 (7 units) consumed by a 70 kg male) should result in a blood ethanol concentration of
100–200 mg dl1 (22–43 mmol l1) between 15 and 120 minutes after dosage.
The unit system does not permit international comparisons. Highest concentrations occur after 30–90 minutes.

Table 3 UK guidelines for the consumption of alcohola

Men (units) Women (units)

b c
Weekly Daily Weeklyb Dailyc

Low risk 0–21 3–4 0–14 2–3

Hazardous 22–50 Z4 15–35 Z3
Harmful 450 435 Z1–2d
a
Guidelines regarding the consumption of alcohol are designed to reduce harm. The Royal Colleges’ (1995) guidelines are for weekly consumption rates, and the Department of
Health’s (1995) guidelines are for daily consumption.
b
Recommendations of the Working Group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners (UK).
c
Recommendations of the Department of Health (UK).
d
Consumption of alcohol may increase the risk of miscarriage so NICE recommends that when pregnant or trying to conceive, women should be advised to abstain from alcohol
completely for at least the first 3 months of pregnancy. Women who wish to drink while pregnant, should be advised not to get drunk or binge drink (drink over 7.5 UK units during
a single session). They should be advised to limit their intake to no more than 1 or 2 UK units of alcohol once or twice a week. How much alcohol is safe during pregnancy is
uncertain, but there is no evidence that this low level of alcohol intake harms the fetus. However, many other countries recommend that women should abstain from alcohol while
pregnant, trying to conceive or breastfeeding.
42 Alcohol: Absorption, Metabolism, and Physiological Effects

Alcohol diffuses from the blood into tissues across capil- wide range of substrates and functions, including de-
lary walls. Ethanol concentration equilibrates between blood hydrogenation of steroids and oxidation of fatty acids.
and the extracellular fluid within a single pass. However,
equilibration between blood water and total tissue water may
take several hours, depending on the cross-sectional area of Alcohol Dehydrogenase Isoenzymes
the capillary bed and tissue blood flow.
Ethanol enters most tissues but its solubility in bone and ADH is a zinc metalloprotein with five classes of isoenzymes
fat is negligible. Therefore, in the postabsorption phase, the that arise from the association of eight different subunits
volume of distribution of ethanol reflects total body water. into dimers (Table 5). These five classes of ADH are the
Thus, for a given dose, BEC will reflect lean body mass. products of five gene loci (ADH1–5). Class 1 isoenzymes
generally require a low concentration of ethanol to achieve
‘half-maximal activity0 (low Km), whereas class 2 isoenzymes
Metabolism of Alcohol have a relatively high Km. Class 3 ADH has a low affinity
for ethanol and does not participate in the oxidation of
The rate at which alcohol is eliminated from the blood by ethanol in the liver. Class 4 ADH is found in the human
oxidization varies from 6 to 10 g h1. This is reflected by the stomach and class 5 has been reported in liver and stomach.
BEC, which falls by 9–20 mg dl1 h1 after consumption of Whereas the majority of ethanol metabolism occurs in the
ethanol. After a dose of 0.6–0.9 g per kg body weight without liver, gastric ADH is responsible for a small portion of ethanol
food, elimination of ethanol is approximately 15 mg dl oxidation.
blood1 h1. However, many factors influence this rate and
there is considerable individual variation.
Absorbed ethanol is initially oxidized to acetaldehyde
(Figure 2) by one of three pathways (Figure 3): H H H O
H C C O H C C
1. Alcohol dehydrogenase (ADH)–cystosol
H H H O−
2. Microsomal ethanol oxidizing system (MEOS)–endo-
plasmic reticulum
3. Catalase–peroxisomes Acetaldehyde Acetate
Figure 2 Chemical structures of acetaldehyde and acetate, the
Alcohol Dehydrogenase products of ethanol metabolism. Acetaldehyde and acetic acid/acetate
are the current preferred or common names for these chemicals.
ADH couples oxidation of ethanol to reduction of nicotina- However, some texts may use their systematic names, i.e., ethanal
mide adenine dinucleotide (NAD þ ) to NADH. ADH has a and ethanoic acid, respectively.

Alcohol Hepatocyte Acetaldehyde

dehydrogense
Ethanol Acetaldehyde NAD+ dehydrogense
Alcohol
NADH + H+
NAD+ NADH + H+
Cytosol
Acetate
Mitochondria

Ethanol
Microsomal ethanol oxidizing system
H2O2
Catalase
2H2O NADH + H+ Oxidized Ethanol

NADPH O2
Acetaldehyde cytochrome p450 CYP2E1
reductase H2O

NADP+ Reduced Acetaldehyde

Endoplasmic reticulum

Figure 3 Pathways of ethanol metabolism.

 Alcohol: Absorption, Metabolism, and Physiological Effects 43

Table 5 Classes of alcohol dehydrogenase isoenzymes

Class Subunit Location Km (mmol l1)a Vmax

1
ADH1 a Liver 4 54
ADH2 b Liver, lung 0.05–34 
ADH3 g Liver, stomach 0.6–1.0 

2
ADH4 p Liver, cornea 34 40

3
ADH5 w Most tissues 1000 

4
ADH7 s, m Stomach, esophagus, other mucosae 20 1510

5
ADH6 F Liver, stomach 30 

a
Km supplied is for ethanol; ADH also oxidizes other substrates.
Reliable data not available.
Source: Reproduced with permission from Kwo PY and Crabb DW (2002) Genetics of ethanol metabolism and alcoholic liver disease. In: Sherman DIN, Preedy VR, and Watson RR
(eds.) Ethanol and the Liver. Mechanisms and Management, pp. 95–129. London: Taylor & Francis.

Table 6 Classes of aldehyde dehydrogenase isoenzymes

Class Structure Location Km (mmol l1)a

1
ALDH1 a4 Cytosolic
Many tissues: highest in liver 30
2
ALDH2 a4 Mitochondrial
Present in all tissues except red blood cells 1
Liver4kidney4muscle4heart
a
Km supplied is for acetaldehyde; ALDH also oxidizes other substrates.
Source: Reproduced with permission from Kwo PY and Crabb DW (2002) Genetics of ethanol metabolism and alcoholic liver disease. In: Sherman DIN, Preedy VR, and Watson RR
(eds.) Ethanol and the Liver. Mechanisms and Management, pp. 95–129. London: Taylor & Francis.

Catalase P4502E1 (CYP2E1). Chronic alcohol use is associated with a

4- to 10-fold increase of CYP2E1 due to increases in mRNA
Peroxisomal catalase, which requires the presence of hydrogen
levels and rate of translation.
peroxide (H2O2), is usually of little significance in the me-
tabolism of ethanol. Metabolism of ethanol by ADH inhibits
catalase activity because H2O2 production is inhibited by the
reducing equivalents (NADH) produced by ADH. However, Acetaldehyde Metabolism
metabolism of ethanol by catalase may be more significant if
Acetaldehyde is highly toxic but is rapidly converted to acetate.
the other pathways for ethanol metabolism are inhibited, for
This conversion is catalyzed by aldehyde dehydrogenase
example, by mitochondrial damage in a chronic alcoholic.
(ALDH) and is accompanied by reduction of NAD þ
(Figure 3). There are several isoenzymes of ALDH (Table 6).
The most important are ALDH1 (cytosolic) and ALDH2
Microsomal Ethanol Oxidizing System
(mitochondrial). The presence of ALDH in most tissues may
Chronic administration of ethanol with nutritionally adequate reduce the toxic effects of acetaldehyde.
diets increases clearance of ethanol from the blood. In 1968, In alcoholics, the oxidation of ethanol is increased by in-
the MEOS was identified. The MEOS has a higher Km for duction of MEOS. However, the capacity of mitochondria to
ethanol (8–10 mmol l1) than ADH (0.2–2.0 mmol l1) so at oxidize acetaldehyde is reduced. Hepatic acetaldehyde there-
low BEC, ADH is more important. However, unlike the other fore increases with chronic ethanol consumption. A significant
pathways, MEOS is highly inducible by chronic alcohol con- increase of acetaldehyde in hepatic venous blood reflects the
sumption. The key enzyme of the MEOS is cytochrome high tissue level of acetaldehyde.
44 Alcohol: Absorption, Metabolism, and Physiological Effects

Metabolism of Acetate distribution of ethanol reflects total body water. Because the
bodies of women contain a greater proportion of fat, it is not
The final metabolism of acetate derived from ethanol remains
surprising that the BEC is higher in women. However, gender
unclear. However, some important principles have been
differences in the gastric metabolism of ethanol may also be
elucidated:
relevant.
1. The majority of absorbed ethanol is metabolized in the
liver and released as acetate. Acetate release from the liver
increases 212 times after ethanol consumption. Period Over which the Alcohol is Consumed
2. Acetyl-CoA synthetase catalyzes the conversion of acetate to
Rapid intake of alcohol increases the concentration of
acetyl-CoA via a reaction requiring adenosine triphosphate.
ethanol in the stomach and small intestine. The greater
The adenosine monophosphate produced is converted to
the concentration gradient, the faster the absorption of
adenosine in a reaction catalyzed by 50 -nucleosidase.
ethanol and therefore peak BEC. If alcohol is consumed
3. Acetyl-CoA may be converted to glycerol, glycogen, and
and absorbed faster than the rate of oxidation, then BEC
lipid, particularly in the fed state. However, this only
increases.
accounts for a small fraction of absorbed ethanol.
4. The acetyl-CoA generated from acetate may be used to
generate adenosine triphosphate via the Kreb’s cycle.
5. Acetate readily crosses the blood–brain barrier and is actively Effects of Food on Blood Ethanol Concentration
metabolized in the brain. The neurotransmitter acetyl- The peak BEC is reduced when alcohol is consumed with or
choline is produced from acetyl-CoA in cholinergic neurons. after food. Food delays gastric emptying into the duodenum.
6. Both cardiac and skeletal muscle are very important in the This attenuates the sharp early rise in BEC seen when alcohol
metabolism of acetate. is taken on an empty stomach. Food also increases elimin-
Based on these observations, future studies on the effects of ation of ethanol from the blood. The area under the BEC/time
ethanol metabolism should focus on skeletal and cardiac curve (AUC) is reduced (Figure 4). The contributions of
muscle, adipose tissue, and the brain. various nutrients to these effects have been studied, but small,
often conflicting, differences have been found. It appears that
the caloric value of the meal is more important than the
Nonoxidative Metabolism of Alcohol precise balance of nutrients.
In animal studies ethanol is often administered with other
Nonoxidative metabolism of alcohol, which results in formation nutrients in liquid diets. The AUC is less when alcohol is given
of ethyl esters from fatty acids occurs in several organs which in a liquid diet than with the same dose of ethanol in water.
lack an oxidative system to metabolize alcohol (e.g., pancreas, The different blood ethanol profile in these models may affect
heart, and adipose tissue). These organs often develop alcohol- the expression of pathology.
induced disease so fatty acid ethyl esters may play a role in the However, food increases splanchnic blood flow, which
pathogenesis of the lesions induced by alcohol consumption. maintains the ethanol diffusion gradient in the small intestine.
The nonoxidative metabolism of ethanol may be more signifi- Food-induced impairment of gastric emptying may be par-
cant if the other pathways for ethanol metabolism are inhibited. tially offset by faster absorption of ethanol in the duodenum.

Blood Ethanol Concentration

100
Blood ethanol concentration (mg dl−1)

The relationship between BEC and the effects of alcohol is 90

complex and varies between individuals and with patterns of 80 Dosing after overnight fast
drinking. Many of the effects correlate with the peak concen-
70 Dosing after breakfast
tration of ethanol in the blood and organs during a drinking
session. Other effects are due to products of metabolism and 60
the total dose of ethanol ingested over a period of time. These 50
two considerations are not entirely separable because the 40
ethanol concentration during a session may determine which
30
pathways of ethanol metabolism predominate.
It is of considerable clinical interest to understand what 20
factors increase the probability of higher maximum ethanol 10
concentrations for any given level of consumption.
0
0 1 2 3 4 5 6
Time (hours)
Factors Affecting Blood Ethanol Concentration
Figure 4 Blood ethanol concentration curve after oral dosing of
Gender Differences in Blood Ethanol Concentration ethanol. A subject ingested 0.8 g kg1 ethanol over 30 minutes either
after an overnight fast or after breakfast. The peak blood ethanol
Women achieve higher peak BEC than men given the same concentration and the area under the curve are reduced if ethanol is
dose of ethanol per kilogram of body weight. The volume of consumed with food.
 Alcohol: Absorption, Metabolism, and Physiological Effects 45

Beverage Alcohol Content and Blood Ethanol Concentration Physiological Effects of Alcohol
The ethanol concentration of the beverage consumed
Ethanol or the products of its metabolism affect nearly all
(Table 7) affects ethanol absorption and can affect BEC. Ab-
cellular structures and functions.
sorption is fastest when the concentration is 10–30%. Below
10%, the low ethanol concentration in the GI tract reduces
diffusion and the greater volume of liquid slows gastric Effects of Alcohol on the Central Nervous System
emptying. Concentrations above 30% irritate the GI mucosa
Ethanol generally decreases the activity of the central
and the pyloric sphincter, increasing secretion of mucus and
nervous system. In relation to alcohol, the most important
delaying gastric emptying. Some evidence has shown that even
neurotransmitters in the brain are glutamate, gamma-amino-
low concentrations of ethanol (e.g., 4%, as found in beer) may
butyric acid (GABA), dopamine, and serotonin.
cause minor lesions in the gastric mucosa though they may be
Glutamate is the major excitatory neurotransmitter in the
insignificant pathologically.
brain. Ethanol inhibits the N-methyl-D-aspartate (NMDA)
subset of glutamate receptors. Ethanol thereby reduces the
excitatory effects of glutamate. GABA is the major inhibitory
First-Pass Metabolism of Ethanol
neurotransmitter in the brain. Alcohol facilitates the action of
The AUC is significantly lower after oral dosing of ethanol the GABA-a receptor, increasing inhibition. Changes to these
than after intravenous or intraperitoneal administration. receptors seem to be important in the development of toler-
The total dose of intravenously administered ethanol is ance of and dependence on alcohol.
available to the systemic circulation. The difference between Dopamine is involved in the rewarding aspects of alcohol
AUCoral and AUCiv represents the fraction of the oral dose consumption. Enjoyable activities such as eating or use of other
that was either not absorbed or metabolized before entering recreational drugs also release dopamine in the nucleus
the systemic circulation (first-pass metabolism (FPM)). The accumbens of the brain. Serotonin is also involved in the reward
ratio of AUCoral to AUCiv reflects the oral bioavailability of processes and may be important in encouraging alcohol use.
ethanol. The most obvious effects of ethanol intoxication on the
The investigation of ethanol metabolism has primarily central nervous system begin with behavior modification (e.g.,
focused on the liver and its relationship to liver pathology. cheerfulness, impaired judgment, and loss of inhibitions).
However, gastric metabolism accounts for approximately 5% These excitatory effects result from the disinhibition described
of ethanol oxidation and 2–10% is excreted in the breath, previously (inhibition of cells in the brain that are usually
sweat, or urine. The rest is metabolized by the liver. inhibitory).
After absorption, ethanol is transported to the liver in the As a result of these effects, it is well recognized that
portal vein. Some is metabolized by the liver before reaching operating vehicles such as cars or heavy machinery under
the systemic circulation. However, hepatic ADH is saturated at the influence of ethanol is unsafe. However, the BEC after
a BEC that may be achieved in an average-size adult after consumption of a specific amount of ethanol and the im-
consumption of one or two units. If ADH is saturated by pairment caused by a specific BEC vary significantly between
ethanol entering the liver from the systemic circulation via the individuals. Despite this variation, BEC is used to define in-
hepatic artery, ethanol in the portal blood must compete for toxication and provide a rough measure of impairment for
binding to ADH. Although hepatic oxidation of ethanol can- legal purposes because it is an objective measurement that is
not increase once ADH is saturated, gastric ADH can signifi- difficult to contest.
cantly metabolize ethanol at the high concentrations in the Most countries have set maximum legally permissible
stomach after initial ingestion. If gastric emptying of ethanol is BEC levels for drivers to reduce harm from ‘drink driving.’
delayed, prolonged contact with gastric ADH increases FPM. Governments define these level after reviewing the available
Conversely, fasting, which greatly increases the speed of gastric evidence. However, the definition of what is safe or
emptying, virtually eliminates gastric FPM. acceptable varies between countries (Table 8). These BEC

Table 7 Alcohol content of selected beverages

Beverage Alcohol content

a
g dl1 (%) b
mmol l1 b
mol l1

Low-strength beers 3–4 650–870 0.65–0.87

High-strength beers 8–9 1740–1960 1.74–1.96
Wine 7–14 1520–3040 1.52–3.04
Brandy 35–45 7610–9780 7.61–9.78
Vodka 35–50 7610–10870 7.61–10.87
Gin 35–50 7610–10870 7.61–10.87
Whisky 35–75 7610–16300 7.61–16.30
a
Data obtained by reviewing the alcohol content of various beverages as stated on the product label.
b
Data calculated from the information obtained from reviewing the alcoholic content of various beverages as stated on the product label.
46 Alcohol: Absorption, Metabolism, and Physiological Effects

Table 8 Legal limits of blood ethanol concentrations for drivinga hypothalamic neurons (which secrete vasopressin) has also
been described in chronic alcoholics, suggesting long-term
Legal limitb Blood ethanol
consequences for fluid balance. Plasma atrial natriuretic pep-
concentration
tide, increased by alcohol consumption, may also increase
mg dl1 mmol l1 diuresis and resultant dehydration.
Alcoholism also affects the hypothalamic–pituitary–gonadal
The Czech Republic, and Hungary 0 0 axis. These effects are further exacerbated by alcoholic liver
Norway and Sweden 20 4.3 disease. There are conflicting data regarding the changes
Japan, Russian Federation, and Uraguay 30 6.45
observed. Testosterone is either normal or decreased in men,
France, Germany, Italy, and Australia 50 11
but it may increase in women. Estradiol is increased in men
United Kingdom,c United States, and Canada 80 17
and women, and it increases as hepatic dysfunction deterior-
a
Ethanol impairs judgment and coordination. It is well recognized that driving under the ates. Production of sex hormone-binding globulin is also
influence of ethanol is unsafe. However, the definition of what is safe or acceptable varies perturbed by alcohol.
between countries and can change as a result of social, political, or scientific influences. The development of female secondary sexual characteristics
b
Legislation regarding legal limits of blood ethanol for driving may change. in men (e.g., gynecomastia and testicular atrophy) generally
c
In the UK, the legal limit is currently 80 mg dl1 but the recently published North
only occurs after the development of cirrhosis. In women, the
Review of Drink and Drug Driving Law strongly recommended that this limit be
hormonal changes may reduce libido, disrupt menstruation,
reduced to 50 mg dl1.
or even induce premature menopause. Sexual dysfunction is
also common in men with reduced libido and impotence.
thresholds range from zero tolerance (0.0 mg ml1) to Fertility may also be reduced, with decreased sperm counts
0.8 mg ml1. and motility.
Some countries are considering the potential social benefits
of lowering BEC limits. However, opponents cite factors such
as the drinking culture, convenience, the unpalatability of Effects of Alcohol on Muscle
tighter legislation and the impact on the alcohol industry.
Myopathy is common, affecting up to two-thirds of all alco-
The effects of ethanol are dose dependent (Table 9) and
holics. It is characterized by wasting, weakness, and myalgia
further intake causes agitation, slurred speech, memory loss,
and improves with abstinence. Histology correlates with
double vision, and loss of coordination. This may progress to
symptoms and shows selective atrophy of type II muscle fibers.
depression of consciousness and loss of airway protective re-
Ethanol causes a reduction in muscle protein and ribonucleic
flexes, with danger of aspiration, suffocation, and death.
acid content. The underlying mechanism is unclear, but rates
This sequence of events is particularly relevant in the
of muscle protein synthesis are reduced, whereas protein
hospital setting, where patients may present intoxicated with a
degradation is either unaffected or inhibited. Attention has
reduced level of consciousness. It is difficult to determine
focused on the role of acetaldehyde adducts and free radicals
whether there is coexisting pathology such as an extradural
in the pathogenesis of alcoholic myopathy.
hematoma or overdose of other drugs in addition to ethanol.
Although measurement of BEC is helpful (Table 9), it is safest
to assume that alcohol is not responsible for any disturbance
Alcohol and Nutrition
in consciousness and to search for another cause.
The nutritional status of alcoholics is often impaired. Some of
the pathophysiological changes seen in alcoholics are direct
consequences of malnutrition. However, in the 1960s, Charles
Neuroendocrine Effects of Alcohol
Lieber demonstrated that many alcohol-induced pathologies,
Alcohol activates the sympathetic nervous system, increasing including alcoholic hepatitis, cirrhosis, and myopathy, are
circulating catecholamines from the adrenal medulla. Hypo- reproducible in animals fed a nutritionally adequate diet.
thalamic–pituitary stimulation results in increased circulating Consequently, the concept that all alcohol-induced path-
cortisol from the adrenal cortex and can, rarely, cause a ologies are due to nutritional deficiencies is outdated and
pseudo-Cushing’s syndrome with typical moon-shaped face, incorrect.
truncal obesity, and muscle weakness. Alcoholics with pseudo- Myopathy is a direct consequence of alcohol or acetalde-
Cushing’s show many of the biochemical features of Cushing’s hyde on muscle and is not necessarily associated with
syndrome, including failure to suppress cortisol with a 48-h malnutrition. Assessment of nutritional status in chronic al-
low-dose dexamethasone suppression test. However, they coholics using anthropometric measures (e.g., limb circum-
may be distinguished by an insulin stress test. In pseudo- ference and muscle mass) may be misleading in the presence
Cushing’s, the cortisol rises in response to insulin-induced of myopathy.
hypoglycemia, but in true Cushing’s there is no response to Acute or chronic ethanol administration impairs the ab-
hypoglycemia. sorption of several nutrients, including glucose, amino acids,
Ethanol affects hypothalamic osmoreceptors, reducing biotin, folate, and ascorbic acid. There is no strong evidence
vasopressin release. This increases salt and water excretion that alcohol impairs absorption of magnesium, riboflavin, or
from the kidney, causing polyuria. Significant dehydration pyridoxine, so these deficiencies are probably due to poor
may result particularly with consumption of spirits containing intakes. Hepatogastrointestinal damage (e.g., villous injury,
high concentrations of ethanol and little water. Loss of bacterial overgrowth of the intestine, pancreatic damage, or
 Alcohol: Absorption, Metabolism, and Physiological Effects 47

Table 9 Relationship between amount of athanol consumed, blood ethanol concentration (BEC) and effect of ethanol on the central nervous
system

Alcohol consumeda (UK units) Possible BEC Effect

1–5 10–50 mg dl1 No obvious change in behavior

2–11 mmol l1
2–7 30–100 mg dl1 Increased self-confidence; loss of inhibitions
7–22 mmol l1 Impaired judgment, attention, and control
Euphoria Mild sensorimotor impairment, delayed reaction times
Sociability Legal limits for driving generally fall within this range (see Table 8)
8–15 90–250 mg dl1 Loss of critical judgment
20–54 mmol l1 Impairment of perception, memory, and comprehension
Reduced visual acuity
Reduced coordination, impaired balance
Drowsiness

11–20 180–300 mg dl1 Disorientation

39–65 mmol l1 Exaggerated emotional states
Disturbances of vision and perception of color, form, motion, and depth
Confusion Increased pain threshold
Further reduction of coordination, staggering gait, slurred speech
15–25 250–400 mg dl1 Loss of motor functions
54–87 mmol l1 Markedly reduced response to stimuli
Marked loss of coordination, inability to stand/walk
Stupor Incontinence
Impaired consciousness
22–30 350–500 mg dl1 Unconsciousness
76–108 mmol l1 Reduced or abolished reflexes
Incontinence
Coma Cardiovascular and respiratory depression (death possible)
38 4600 mg dl1
4130 mmol l1 Respiratory arrest
Death
a
Approximate amounts of alcohol required by a 70 kg male to produce the corresponding blood ethanol concentration (BEC) and intoxicating effects of ethanol. One UK unit of
alcohol contains 8 g of ethanol. It should be noted that these theoretical data are provided for illustrative purposes only. The BEC and the effects after consumption of ethanol are
dependent on several factors and varies significantly between individuals.
Source: Adapted with permission from Morgan MY and Ritson B (2003) Alcohol and Health: A Handbook for Students and Medical Practitioners, 4th edn. London: Medical Council
on Alcohol.

cholestasis) may impair the absorption of some nutrients such The beneficial, cardioprotective effects of alcohol con-
as the fat-soluble vitamins (A, D, E, and K). In contrast, iron sumption have been broadcast widely. This observation is
stores may be adequate as absorption is increased. based on population studies of mortality due to ischemic
heart disease, case–control studies, and animal experiments.
However, there is no evidence from randomized controlled
Effects of Alcohol on the Cardiovascular System trials. The apparent protective effect of alcohol may therefore
result from confounding factors. For example, the diets are
Alcohol affects both the heart and the peripheral vasculature. different to those of nondrinkers. Even the diets of beer
Acutely, alcohol causes peripheral vasodilatation, giving a false drinkers are different from those of wine drinkers. Further-
sensation of warmth that can be dangerous. Heat loss is rapid more, on the population level, the burden of alcohol-induced
in cold weather or when swimming, but reduced awareness morbidity and mortality far outweighs any possible cardio-
leaves people vulnerable to hypothermia. The main adverse vascular benefit.
effect of acute alcohol on the cardiovascular system is the
induction of arrhythmias i.e., ‘Holiday Heart’. These are
often harmless and experienced as palpitations but can rarely
Effects of Alcohol on Liver Function
be fatal. Chronic ethanol consumption can cause systemic
hypertension and congestive cardiomyopathy. Alcoholic car- Fundamental to the effects of ethanol is the liver, in which
diomyopathy accounts for up to one-third of dilated cardio- 60–90% of ethanol metabolism occurs. Ethanol displaces
myopathies but may improve with abstinence or progress many of the substrates usually metabolized in the liver. Me-
to death. tabolism of ethanol by ADH in the liver generates reducing
48 Alcohol: Absorption, Metabolism, and Physiological Effects

equivalents. ALDH also generates NADH with conversion of accumulates after ethanol administration, with plasma levels
acetaldehyde to acetate. The NADH:NAD þ ratio is increased, up to 20 times higher in people with ALDH2 deficiency. Even
with a corresponding increase in the lactate:pyruvate ratio. If small amounts of alcohol produce a rapid facial flush, tachy-
lactic acidosis combines with a b-hydroxybutyrate predomin- cardia, headache, and nausea. Acetaldehyde partly acts
ant ketoacidosis, the blood pH can fall to 7.1 and hypo- through catecholamines, although other mediators have been
glycemia may occur. Severe ketoacidosis and hypoglycemia implicated, including histamine, bradykinin, prostaglandin,
can cause permanent brain damage. However, in general the and endogenous opioids.
prognosis of alcohol-induced acidosis is good. Lactic acid also This is similar to the disulfiram reaction due to the rise of
reduces the renal capacity for urate excretion. Hyperuricemia is acetaldehyde after inhibition of ALDH. Disulfiram is used
further exacerbated by alcohol-induced ketosis and acetate- therapeutically to encourage abstinence in alcohol rehabili-
mediated purine generation. Hyperuricemia explains, at least tation programs. The aversive effects of acetaldehyde may re-
in part, the clinical observation that alcohol misuse can pre- duce the development of alcoholism and the incidence of
cipitate gout. cirrhosis in ‘flushers.0 However, some alcoholics with ALDH2
The excess NADH promotes fatty acid synthesis and in- deficiency and, presumably, higher hepatic acetaldehyde levels
hibits lipid oxidation in the mitochondria, resulting in fat develop alcoholic liver disease at a lower intake of ethanol
accumulation. Fatty changes within the liver are usually than controls.
asymptomatic but can be seen on ultrasound or computed
tomography scanning, and they are associated with abnormal
liver toxicity tests (e.g., raised activities of serum g-glutamyl Effects of Acetaldehyde
transferase, aspartate aminotransferase, and alanine transa-
Acetaldehyde is highly toxic and can bind cellular constituents
minases). The supposition that most of the hepatic damage in
(e.g., proteins including CYP2E1, lipids, and nucleic acids) to
alcoholism is due to increases in the NADH:NAD ratio per se is
produce harmful acetaldehyde adducts. Adduct formation
somewhat outdated. Now, molecular and cellular processes
changes the structure and the biochemical properties of the
and acetaldehyde toxicity have been shown to be major con-
affected molecules. The new structures may be recognized as
tributors to the disease process.
foreign antigens by the immune system and initiate a dam-
Progression to alcoholic hepatitis involves invasion of the
aging response.
liver by neutrophils with hepatocyte necrosis. Giant mito-
Adduct formation leads to retention of protein within
chondria are visible and dense cytoplasmic lesions (Mallory
hepatocytes, contributing to the hepatomegaly, and several
bodies) are seen. Alcoholic hepatitis can be asymptomatic but
toxic manifestations, including impairment of antioxidant
usually presents with abdominal pain, fever, and jaundice,
mechanisms (e.g., decreased glutathione (GSH)). Acetalde-
or, depending on the severity of disease, patients may have
hyde thereby promotes free radical-mediated toxicity and
encephalopathy, ascites, and ankle edema.
lipid peroxidation. Binding of acetaldehyde with cysteine
Continued alcohol consumption may lead to cirrhosis.
(one of the three amino acids that comprise GSH) or GSH
However, not all alcoholics progress to cirrhosis. The reason
also reduces liver GSH content. Chronic ethanol adminis-
for this is unclear. It has been suggested that genetic factors
tration significantly increases rates of GSH turnover in rats.
and differences in immune response may play a role.
Acute ethanol administration inhibits GSH synthesis and
In alcoholic cirrhosis there is fibrocollagenous deposition,
increases losses from the liver. Furthermore, mitochondrial
with scarring and disruption of surrounding hepatic
GSH is selectively depleted and this may contribute to the
architecture. There is ongoing necrosis with concurrent re-
marked disruption of mitochondria in alcoholic cirrhosis.
generation. Alcoholic cirrhosis is classically said to be micro-
nodular, but often a mixed pattern is present. The underlying
pathological mechanisms are complex and are the subject of
debate. Induction of the MEOS and oxidation of ethanol by Effects of Acetate
catalase result in free radical production. Glutathione (a free
radical scavenger) is reduced in alcoholics, impairing the The role of acetate in alcohol-induced pathology is not well
ability to dispose of free radicals. Mitochondrial damage understood. The uptake and utilization of acetate by tissues
occurs, limiting their capacity to oxidize fatty acids. Perox- depend on the activity of acetyl-CoA synthetase. Acetyl-CoA
isomal oxidation of fatty acids further increases free radical and adenosine are produced from the metabolism of acetate.
production. These changes eventually result in hepato- Acetate crosses the blood–brain barrier easily and is actively
cyte necrosis, and inflammation and fibrosis ensue. Acetalde- metabolized in the brain. Many of the central nervous system
hyde also contributes by promoting collagen synthesis and depressant effects of ethanol may be blocked by adenosine
fibrosis. receptor blockers. Thus, acetate and adenosine may be im-
portant in the intoxicating effects of ethanol.
Ethanol increases portal blood flow, mainly by increasing
Alcohol and Facial Flushing
GI tract blood flow. This effect is reproduced by acetate.
Genetic variations in ADH and ALDH may explain why par- Acetate also increases coronary blood flow, myocardial con-
ticular individuals develop some of the pathologies of alco- tractility, and cardiac output. Acetate inhibits lipolysis in adi-
holism and others do not. For example, up to 50% of pose tissue and promotes steatosis in the liver. The reduced
Orientals have a genetically determined reduction in ALDH2 circulating free fatty acids (a source of energy for many tissues)
activity (‘flushing0 phenotype). As a result, acetaldehyde may have significant metabolic consequences. Thus, some of
 Alcohol: Absorption, Metabolism, and Physiological Effects 49

the effects of alcohol may be due to acetate, though this area is Jones AW (2000) Aspects of in-vivo pharmacokinetics of ethanol. Alcoholism:
under explored. Clinical & Experimental Research 24: 400–402.
Kwo PY and Crabb DW (2002) Genetics of ethanol metabolism and alcoholic liver
disease. In: Sherman DIN, Preedy VR, and Watson RR (eds.) Ethanol and the
Liver. Mechanisms and Management, pp. 95–129. London: Taylor & Francis.
See also: Alcohol: Effects of Consumption on Diet and Lader D and Meltzer H (2002) Drinking: Adults’ Behaviour and Knowledge in 2002.
London: Office for National Statistics.
Nutritional Status. Liver Disorders: Nutritional Management
Lieber CS (2000) Alcohol: Its metabolism and interaction with nutrients. Annual
Review of Nutrition 20: 395–430.
Mezey E (1985) Effect of ethanol on intestinal morphology, metabolism and
function. In: Seitz HK and Kommerell B (eds.) Alcohol Related Diseases in
Gastroenterology, pp. 342–360. Berlin: Springer-Verlag.
Further Reading Morgan MY and Ritson B (2003) Alcohol and Health: A Handbook for Students and
Medical Practitioners, 4th edn. London: Medical Council on Alcohol.
Department of Health (1995) Sensible Drinking: The Report of an Inter-Departmental National Institute for Health and Clinical Excellence (2008) Antenatal care: Routine
Working Group. London: Department of Health. care for the healthy pregnant woman. NICE clinical guideline 62.
Gluud C (2002) Endocrine system. In: Sherman DIN, Preedy VR, and Watson RR Peters TJ and Preedy VR (1999) Chronic alcohol abuse: Effects on the body.
(eds.) Ethanol and the Liver. Mechanisms and Management, pp. 472–494. Medicine 27: 11–15.
London: Taylor & Francis. Rajendram R and Preedy VR (2005) Effect of Alcohol Consumption on the Gut.
Haber PS (2000) Metabolism of alcohol by the human stomach. Alcoholism: Digestive Diseases 23: 214–221.
Clinical & Experimental Research 24: 407–408. Royal Colleges (1995) Alcohol and the heart in perspective. Sensible limits
Henderson L, Gregory J, Irving K, and Swan G (2003) The National Diet and reaffirmed. A Working Group of the Royal Colleges of Physicians, Psychiatrists
Nutrition Survey: Adults aged 19–64 years. Energy, Protein, Carbohydrate, Fat and General Practitioners. Journal of the Royal College of Physicians of London
and Alcohol Intake, Vol. 2. London: TSO. 29: 266–271.
Israel Y, Orrego H, and Carmichael FJ (1994) Acetate-mediated effects of ethanol.
Alcoholism: Clinical & Experimental Research 18(1): 144–148.