Medical Disorders of Alcoholism

1058
THE NEW ENGLAND JOURNAL OF MEDICINE
SEMINARS IN MEDICINE
OF THE
BETH ISRAEL HOSPITAL, BOSTON
JEFFREY S. FLIER, M.D., Editor

LISA H. UNDERHILL, Assistant Editor
MEDICAL DISORDERS OF ALCOHOLISM

CHARLES SAUL LIEBER, M.D.
LCOHOL is the most frequently abused drug

throughout the world. In the United States, it is
consumed regularly by about half the adult population,
and about 15 to 20 million people are alcoholics. Alcoholism claims 100,000 lives annually and carries an annual price tag of more than $100 billion.1 Among persons admitted to general hospitals, 20 to 40 percent
have alcohol-related problems, and among the elderly,
alcohol-related hospitalizations are as numerous as
those due to myocardial infarction.2
Alcohol permeates all tissues of the body and affects
most vital functions, because it is a small molecule soluble in both water and lipids.3 The liver is the organ
most severely affected by alcoholism. In some urban areas, cirrhosis (usually a complication of alcoholism) is
the fourth most frequent cause of death among people
25 to 64 years of age.4 In a prospective survey of 280
alcoholics, more than half of those with cirrhosis and
two thirds of those with cirrhosis and alcoholic hepatitis died within 48 months after enrollment.5 This outcome is worse than that of many cancers, and there is
a widespread belief that not much can be done about
it. However, new insights into the pathophysiology of
alcoholism have led to earlier diagnosis and new treatment strategies, permitting the initiation of therapeutic
and preventive efforts before alcohol-induced tissue
damage becomes irreversible.
SYSTEMIC EFFECTS
OF
ALCOHOL
Alcohol and Nutrition
Unlike other drugs, ethanol is a substantial source of

energy, with 7.1 kcal (29.7 kJ) per gram, a value that exceeds the energy content of carbohydrates or proteins.
On average, ethanol accounts for half an alcoholics caloric intake. It therefore displaces normal nutrients,
causing malnutrition (Fig. 1), including deciencies of
From the Alcohol Research and Treatment Center, Veterans Affairs Medical
Center and Mount Sinai School of Medicine, Bronx, N.Y. Address reprint requests to Dr. Lieber at the Alcohol Research and Treatment Center, Veterans Affairs Medical Center, 130 West Kingsbridge Rd., Bronx, NY 10468.
Supported in part by grants from the National Institutes of Health (AA03508,
AA05934, and AA07275) and the Department of Veterans Affairs.
Oct. 19, 1995
folate, thiamine, and other vitamins. Secondary malnutrition also occurs through malabsorption due to gastrointestinal complications, such as pancreatic insufciency (Fig. 1) and impaired hepatic metabolism of
nutrients. In addition, alcohol promotes the degradation of nutrients, as exemplied by its effects on vitamin
A.3 Although ethanol is rich in energy, long-term consumption of up to 2000 calories per day in the form of
alcohol does not produce the expected gain in body
weight.6 This decit can be attributed, in part, to the
poor yield of energy produced from fat oxidation in
damaged mitochondria and to microsomal pathways
that oxidize ethanol without conserving chemical energy (Fig. 2).
Toxic Effects of Alcohol Oxidation
Oxidation of ethanol through the alcohol dehydrogenase pathway produces acetaldehyde, which is converted to acetate; both reactions reduce nicotinamide
adenine dinucleotide (NAD) to NADH (Fig. 2). Excess
NADH causes a number of metabolic disorders,3 including hyperlactacidemia, which contributes to acidosis and reduces urinary excretion of uric acid. This
latter abnormality leads to secondary hyperuricemia,
which is aggravated by alcohol-induced ketosis and the
acetate-mediated breakdown of ATP and generation of
purines (Fig. 2). NADH also opposes gluconeogenesis
(thereby favoring hypoglycemia), raises a-glycerophosphate levels, and inhibits the Krebs cycle and fatty-acid
oxidation. The inhibition of fatty-acid oxidation favors
steatosis and hyperlipidemia involving all lipid classes,
including high-density lipoprotein (HDL).
The acetaldehyde produced by the oxidation of ethanol also has toxic effects (Fig. 2), inhibiting the repair
of alkylated nucleoproteins,7 decreasing the activity of
key enzymes, and markedly reducing oxygen utilization
in mitochondria damaged by long-term ethanol consumption.8 Moreover, acetaldehyde promotes cell death
by depleting the level of reduced glutathione, inducing
lipid peroxidation, and increasing the toxic effect of free
radicals. By binding to the tubulin of microtubules, acetaldehyde blocks the secretion of proteins. The increases in protein, lipid, water,9 and electrolytes cause hepatocytes to enlarge or balloon, a hallmark of alcoholic
liver disease. Acetaldehydeprotein adducts promote
collagen production and may also act as neoantigens,
which stimulate an immune response.10,11 Acetaldehyde
crosses the placenta, impairs fetal DNA methylation,12
and may contribute to the fetal alcohol syndrome, the
most preventable congenital abnormality.13
Interaction between Ethanol and Other Chemicals
Long-term consumption of ethanol induces the microsomal ethanol-oxidizing system.14 Liver-biopsy specimens from subjects who have recently drunk alcohol
have a 5- to 10-fold increase in levels of cytochrome
P-4502E1, the key enzyme in the oxidation of ethanol,15
and an increase in the corresponding messenger RNA
(mRNA).16 The induction of this oxidizing system contributes to the metabolic tolerance of ethanol in alco-
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Vol. 333
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SEMINARS IN MEDICINE OF THE BETH ISRAEL HOSPITAL, BOSTON
holics and also affects the metabolism of other drugs

(Fig. 3). When alcohol was consumed for several weeks
by volunteers, the blood clearance of meprobamate, pentobarbital, propranolol, antipyrine, tolbutamide, warfarin, diazepam, and rifamycin was increased.3 This effect persisted for days or weeks.
Clinically, the most important feature of cytochrome
P-4502E1 is its extraordinary capacity to convert many
foreign substances into highly toxic metabolites. These
agents include industrial solvents (e.g., bromobenzene
and vinylidene chloride), anesthetic agents (e.g., enurane and methoxyurane), commonly used medications
(e.g., isoniazid and phenylbutazone), illicit drugs (e.g.,
cocaine), and over-the-counter analgesic agents (e.g.,
acetaminophen), all of which are substrates for or inducers of cytochrome P-4502E1. Therapeutic amounts
of acetaminophen (2.5 to 4 g per day) can cause hepatic
injury in alcoholics. In animals given ethanol for long
periods, hepatotoxic effects peak after its withdrawal,17
when ethanol is no longer competing for the microsomal pathway (Fig. 3A) but levels of the toxic metabolite
are at their highest (Fig. 3D). Thus, alcoholics are most
vulnerable to the toxic effects of acetaminophen shortly
after drinking, when the need for analgesia is greatest
1059
because of withdrawal symptoms. The effects of acetaminophen, ethanol, and fasting are synergistic,18 because all three deplete the level of reduced glutathione,
a scavenger of toxic free radicals. Ethanol inhibits the
synthesis of reduced glutathione, and the selective loss
of the compound from liver mitochondria19 contributes
to the striking alcohol-induced impairment of those
organelles. Cytochrome P-4502E1 also generates toxic
species of active oxygen, which, in concert with a decrease in the level of reduced glutathione, promote injury by inactivation of enzymes and peroxidation of lipids.
In patients with cirrhosis, hepatic depletion of a-tocopherol,20 a major antioxidant, potentiates this effect.
In contrast to the long-term consumption of ethanol,
which induces the hepatic metabolism of drugs (Fig.
3D), short-term consumption inhibits their metabolism
(Fig. 3A) because of direct competition for cytochrome
P-4502E1.3 Methadone exemplies this dual interaction: 50 percent of methadone users are also alcohol
abusers. Whereas long-term consumption of ethanol
increases the hepatic microsomal metabolism of methadone, short-term consumption inhibits microsomal
demethylation of methadone and increases its concentrations in the brain and liver. The combined intake of
Impaired
activation,
utilization, and
detoxification
Direct toxic effects
Ethanol
Empty calorie
Increased
degradation
Malnutrition
Maldigestion
Malabsorption
Figure 1. Organ Damage in the Alcoholic.

The direct toxic effects of ethanol on various organs (red arrows) interact with malnutrition (green arrows) due to dietary deciencies
or to maldigestion, malabsorption, increased degradation, or impaired activation of nutrients, as well as altered hepatic detoxication.
1060
Oct. 19, 1995
Ethanol (CH3CH2OH)
Physical dependence?
Immunologic
stimulation?
Secondary malnutrition
Toxic
effects
Primary
malnutrition
Organelle
dysfunction?
Hypoxic damage
Membrane alterations
Vitamins
Proteins
Usable energy
Microsomal induction
ADH
Cytochrome P-450
Metabolic
derangements
O2
P-4502E1
Activation of
hepatotoxins
and carcinogens
MEOS
Acetaldehyde
(CH3CHO)
Acetate
Acetone metabolism
P-4504A1
ATP degradation
Impaired lipolysis
Increased -hydroxylation, peroxisomal
b-oxidation, L-FABP and FA esterification
Accelerated metabolism of drugs,

increased degradation of testosterone
and retinoids, energy wastage
Adverse
effects
NADH
Fatty liver and

hyperlipidemia
Hypoproteinemia
Hypoglycemia
Hypoglucuronidation
Hyperlactacidemia
Hyperuricemia
Increased collagen
synthesis
Covalent binding to protein

Microtubular impairment
(plus protein retention and hepatocyte swelling)
Lipid peroxidation
Pyridoxine depletion
Increased collagen synthesis
Inhibition of DNA repair
Stimulation of immunologic reactivity?
Hyperglycemia?
Impairment of mitochondrial electron-transport chain
Figure 2. Toxic and Metabolic Disorders Caused by Ethanol Abuse.

Most of the toxic and metabolic disorders that result from long-term ethanol abuse can be explained on the basis of the metabolism
of ethanol by alcohol dehydrogenase (ADH) and the associated generation of reduced NADH or by the microsomal ethanol-oxidizing
system (MEOS), with the induction of cytochrome P-4502E1 and other microsomal enzymes, as well as by the toxic effects of acetaldehyde produced by both pathways, primarily in the liver. FA denotes fatty acids, and L-FABP liver
fatty-acidbinding protein.
ethanol and tranquilizers or barbiturates may also increase drug levels dangerously.
In view of the opposite effects of immediate and
long-term alcohol consumption, the net effect of concomitant alcohol and drug use in a given long-term alcohol consumer is difcult to predict. It varies with the
amounts used, the relative afnity of alcohol and the
other drug (or drugs) for the microsomal detoxication
process, and the severity of the underlying liver injury,
which may offset the enzyme induction.
Ethanol, Carcinogens, and Vitamin A
Alcohol abuse is associated with cancers of the alimentary and respiratory tracts and possibly with breast
cancer.21 One contributory factor is the activation of
carcinogens through the induction of cytochrome
P-4502E1 (Fig. 2). Alcohol also enhances the mutagenicity of tobacco-derived products. A third contributing
factor is vitamin A deciency,22 which long-term ethanol consumption induces in part by accelerating hepatic
microsomal degradation of retinol.23 Epidemiologic
studies have shown a link between vitamin A deciency
and cancer; indeed, vitamin A is essential to the integrity of mucosal linings and opposes the activation of
carcinogens.21 However, the effect of prophylactic supplementation is complicated, because ethanol can potentiate liver damage caused by excessive vitamin A.24
Although beta carotene, the precursor of vitamin A, is
less toxic, studies in primates have shown that its toxic

effects are also enhanced by alcohol.25 Furthermore,
beta carotene increases the risk of pulmonary cancer in
smokers,26 an effect related to an interaction between
beta carotene and alcohol (Taylor PR: personal communication). Thus, vitamin A or beta carotene supplementation must be used cautiously in alcoholics.
Effects of Sex, Hormones, Age, and Heredity on Alcohol
Toxicity
Traditionally, women drink less than men, but the

gap is narrowing, especially between young women and
men.27 For a given amount of alcohol consumed, blood
levels are higher in women than in men for two reasons: the smaller body size of women and the distribution of alcohol in a smaller water space in women28 because of their higher proportion of fat. Furthermore,
among people under the age of 50 years, women have
less gastric alcohol dehydrogenase activity than men;
with less alcohol broken down in the stomach, a proportionally larger amount enters the bloodstream.28,29
Alcohol abuse decreases gastric alcohol dehydrogenase
activity even further, possibly because of gastritis. The
higher blood alcohol levels in normal women as compared with normal men28 and in alcoholic women and
men as compared with normal women and men28 are
inversely related to gastric alcohol dehydrogenase activity. The inhibition of gastric alcohol dehydrogenase
1061
Alcohol
Drugs
Alcohol
Alcohol
dehydrogenase
Microsomes
Alcohol
dehydrogenase
Acetaldehyde
Metabolites
Stomach
Liver
Acetaldehyde
Alcohol
dehydrogenase
Acetaldehyde
C
Liver
by aspirin30 and some histamine H2-receptor blockers31-33

also results in corresponding increases in blood ethanol levels.32-35 There is now a consensus that these
drugs increase blood alcohol levels in most persons
who consume small amounts of alcohol (0.15 g per kilogram of body weight, which is less than the amount of
alcohol in a drink).32-34 Although these increases may
be too small to affect function,32,34 their importance lies
in the fact that social drinkers commonly consume
several drinks in succession. When this pattern was
mimicked by volunteers taking cimetidine (Fig. 4),
blood alcohol increased cumulatively to levels that do
affect function36 and are considered unsafe for driving
in some countries. This observation is of practical importance, since social drinking is widespread and H2receptor blockers are among the most commonly prescribed drugs worldwide.
Alcohol dehydrogenase activity, measured in vitro, is
of course only one determinant of ethanol metabolism
in vivo, and discrepancies between in vitro and in vivo
measurements are not uncommon. For example, hepatic alcohol dehydrogenase activity, which testosterone
and its derivatives depress,37 is signicantly higher in
women than in men up to the age of 50 to 53 years.38
Another factor is the delay in gastric emptying during
the luteal phase of the menstrual cycle in women.
Liver injury is more frequent39 and progresses fast40
er among women than among men with similar histories of alcohol abuse. Daily consumption of 40 to 60 g
of alcohol in men,41,42 as compared with only 20 g in
women,41 signicantly increased the incidence of cirrhosis in a well-nourished population. Female hormones such as estrogens (endogenous and exogenous
e.g., oral contraceptives) can impair various liver
functions. Furthermore, women have higher ethanolinduced acetaldehyde levels than men.43 Hormones
may also inuence the pathologic response to ethanol
in other tissues; alcoholic women may have a higher
risk of breast cancer44 and gastric ulcers than women
who do not drink.45 The degree of brain shrinkage in
women is similar to that in men,46 even with a signicantly shorter ethanol exposure.
Accordingly, a level of alcohol consumption considered moderate in men is not necessarily moderate in
women. Moderate drinking is now dened as not more
than two drinks per day for men but only one drink
per day for women,47 with a drink dened as 12 oz (354
ml) of regular beer, 5 oz (148 ml) of wine, or 11/ 2 oz
(44 ml) of distilled spirits (80 proof), each containing
about 14 g of ethanol.
The effects of alcoholism in the elderly are generally
underestimated. As compared with younger persons,
the elderly may drink less alcohol, but for a given level
of consumption, their blood alcohol levels are higher
because of decreased body uids. Moreover, in a study
of patients with alcoholic cirrhosis, the mortality rate at
one year was 50 percent among those who were over
60 years of age, as compared with 7 percent among
the younger patients.48 The effect of social drinking on
intellectual capacities is also related to age49; psychological testing has shown that as blood alcohol levels
Blood
Blood
No. 16
Stomach
Vol. 333
Alcohol
Drugs
Alcohol
dehydrogenase
Microsomes
Acetaldehyde
Metabolites
D
Figure 3. EthanolDrug Interactions Involving the Alcohol Dehydrogenase Pathway and Liver Microsomes.
The metabolism of drugs by liver microsomes is inhibited (broken line) in the presence of high concentrations of ethanol, in
part through competition for a common microsomal detoxication process (Panel A). Gastric alcohol dehydrogenase activity
is inhibited by drugs (Panel B). After long-term alcohol abuse,
gastric alcohol dehydrogenase activity and ethanol metabolism
are decreased (Panel C). In addition, after long-term consumption of alcohol, hepatic metabolism of ethanol and drugs, as
well as drug (and other hepatotoxin) activation, is increased
because of microsomal induction (bold arrows and circle) (Panel
D). Shaded areas in Panels A and D denote high blood
alcohol levels.
increase, perception and attention decrease progressively, and older subjects perform less well at all blood
alcohol levels. In addition, interactions between alcohol
and the psychotropic medications frequently used by
the elderly often cause problems.
Heredity inuences the development of alcoholism in
both men50 and women,51 an effect that has been attributed to the gene for the dopamine D2 receptor.52 Individual differences in the rate of ethanol metabolism and
the severity of alcohol-induced liver disease50 are, in
part, genetically determined. Levels of gastric alcohol
dehydrogenase also differ among ethnic groups. An alcohol dehydrogenase isoenzyme (s-alcohol dehydrogenase), which is present in gastric mucosa but not in
the liver,32 is absent or markedly decreased in 80 percent of Japanese persons.53 This deciency is notable
because the Japanese are susceptible to gastric cancer,
and the isoenzyme oxidizes carcinogen products.
ALCOHOLIC LIVER INJURY
Pathogenesis
Because of its intrinsic toxicity, alcohol can injure

the liver even in the absence of dietary deciencies.3
Fatty liver, the rst manifestation of alcoholic liver dis-
1062
Oct. 19, 1995
without an apparent intermediate

stage of alcoholic hepatitis, both in
alcoholics54,55 and in baboons given
40
alcohol.56 Indeed, independently of
necrosis and inammation, alcohol
directly affects lipocytes in the liver
30
(also called stellate, Ito, or fat-storing cells), causing the deposition of
20
collagen, the characteristic protein
of the brous tissues. Long-term alcohol consumption transforms lipo10
cytes into collagen-producing myobroblast-like cells.57,58 In vitro, these
0
cells respond to acetaldehyde with a
0
30
60
90
120 150 180 210 240 270 300
further increase in collagen59 and its
mRNA.60
Minutes
Phospholipids, the backbone of
Figure 4. Mean (SE) Blood Alcohol Levels after Repeated Oral Consumption of
all
cellular membranes, are the priSmall Doses of Ethanol.
mary
targets of peroxidation and can
Nine volunteers were given four small doses of ethanol (each dose, 0.15 g per kilobe strikingly altered by ethanol.61 In
gram of body weight, which is less than one drink) before and after the administrababoons given alcohol, phosphatition of cimetidine (400 mg twice a day for seven days). In all nine subjects, blood
alcohol levels increased after the administration of cimetidine, and in two subjects,
dylcholine was generally depleted in
the peak level exceeded 50 mg per deciliter. The effect of cimetidine on repeated
the liver56 and especially in liver midrinking was signicant (P0.01 by two-way analysis of variance for repeated meastochondria,62 causing a marked deures). (Adapted from Gupta et al.36)
crease in cytochrome oxidase activity and oxygen consumption. This
ease, can begin to develop within days after heavy
deciency was correctable in vitro by replenishing the
drinking and is followed by early brosis (Fig. 5), which
culture with phospholipid.62 When the alcohol-fed baboons were given polyenylphosphatidylcholine, a polyin turn can be associated with alcoholic hepatitis, leadunsaturated phospholipid mixture extracted from soying to the irreversible damage caused by severe brosis
beans, hepatic phosphatidylcholine and the activity of
and, subsequently, to cirrhosis. The various clinical
phosphatidylethanolamine methyltransferase were remanifestations of alcoholic liver disease have been well
stored, the number of transformed lipocytes was redocumented and are not reviewed here.
duced, and alcoholic cirrhosis was prevented.56
Fibrosis as a result of necrosis and inammation
Cirrhosis, which results from an imbalance between
is thought to be the underlying mechanism of alcoholthe degradation and production of collagen, may repreic cirrhosis. However, cirrhosis commonly develops
sent the failure of degradation to keep pace with synthesis. Indeed, in transformed lipocytes, polyenylphosphatidylcholine suppresses the acetaldehyde-mediated
increase in collagen accumulation, most likely by stimulating collagenase activity.63 The role of collagenase
has also been shown indirectly in humans by the correlation between the severity of alcoholic brosis and the
activity of a circulating collagenase inhibitor, the tissue
inhibitor of metalloproteinase.64
Cytokines such as transforming growth factor b and
tumor necrosis factor a also stimulate brogenesis. Tumor necrosis factor a may contribute to the anorexia
and muscle wasting associated with severe liver disease.65
Derangements of the immune system occur in alcoholic liver disease,66 but whether they are a consequence or a cause of the liver injury remains debatable.
Figure 5. Liver-Biopsy Specimen from a Patient with Alcoholic
Viral hepatitis due to hepatitis B or C virus commonly
Fatty Liver and No Evidence of Alcoholic Hepatitis.
accompanies chronic hepatitis in alcoholics. Even in the
There is a brous rim around the terminal hepatic venule (perivenular brosis), with some brous strands surrounding adjaabsence of risk factors such as intravenous drug abuse,
cent sinusoids and hepatocytes (perisinusoidal and pericellular
portal or lobular inammation is strongly associated
brosis). Once these lesions appear, there is a rapid progreswith the hepatitis C virus in alcoholics,67 suggesting
sion to more severe stages of disease, including cirrhosis, with
that alcohol may favor the acquisition, replication, or
continued drinking (chromotropeaniline blue stain, 280).
(Courtesy of Dr. F. Paronetto.)
persistence of the virus, which can potentiate associat50
Blood Ethanol Level (mg/dl)
Ethanol
Before cimetidine
After cimetidine
Vol. 333
No. 16
ed liver disorders, including brosis. No specic antiviral therapy is currently available, since interferon alfa
is contraindicated in alcoholic patients.
Treatment and Prevention
The treatment of alcoholic liver disease should address the psychological and behavioral problems that
underlie the excessive drinking. A better understanding
of how alcohol affects the liver now permits early and
direct intervention to prevent or counteract the effects
of alcohol. Biochemical markers (such as g-glutamyltranspeptidase and carbohydrate-decient transferrin)
and screening for signs of medical complications help
to overcome denial (which is common among alcoholics) by facilitating the early detection of heavy drinking.
Since cirrhosis develops in only a minority of heavy
drinkers (10 to 30 percent), it is useful to focus therapeutic efforts on patients with hepatic lesions that
presage cirrhosis, such as perivenular brosis (Fig. 5).54
Agents that replenish reduced glutathione, such as
S-adenosylmethionine, can be effective in the initial
stages of alcohol-induced liver injury.68 In patients with
hepatic encephalopathy or a high value for Maddreys
discriminant function (based on the prothrombin time
and bilirubin level), prednisolone improves short-term
survival.69 Oxandrolone may benet moderately malnourished patients.70 Propylthiouracil has been suggested for the treatment of alcoholic hepatitis,71 and colchicine for alcoholic cirrhosis,72 but additional controlled
trials are needed to establish their efcacy. Finally, liver
transplantation, originally not an option for patients
with alcoholic liver disease, is now being considered for
alcoholics who have stopped drinking.73
EFFECT OF ALCOHOL ON OTHER ORGAN SYSTEMS
Alcohol abuse is associated with acute erosive gastritis. Chronic gastritis in alcoholics is due primarily to
Helicobacter pylori infection and generally resolves with
the eradication of the microbe.74 Diarrhea is common
in alcoholics for a variety of reasons, including the exacerbation of lactase deciency, especially in people of
African descent.75
Heavy drinking for at least 10 years may cause a cardiomyopathy with myocardial hypertrophy and brosis.3 Binges may result in arrhythmias. The vasopressor
effect of ethanol may explain the association between
long-term consumption of alcohol and hypertension.
Alcoholics have elevated levels of plasma homocysteine,76 which has been linked to premature vascular
disease. The rate of mortality is higher among heavy
drinkers (those who consume four or more drinks a
day) than among abstainers, but moderate drinkers
(those who consume one to two drinks per day) have a
lower mortality rate than abstainers.77 Possible reasons
for the presumably protective coronary effect of alcohol
include increased HDL,3 enhanced brinolysis,78 and
decreased platelet aggregation (because of the acetaldehyde-mediated increase in prostacyclins79 or wine
congeners80). However, factors other than alcohol could
account for the apparent protection, because it has also
1063
been found in people who have only one drink per

week77 or per month.81
CONCLUSIONS
Alcohol-related medical disorders affect virtually all
tissues of the body and represent a major but neglected
public health issue. Although overall alcohol use is decreasing, consumption is increasing among young people, and more active intervention is needed to reduce
the staggering costs to society associated with alcoholism. Thus far, interventions have focused on the prevention and treatment of alcohol abuse, withdrawal
therapy, and treatment of severe medical complications, such as the sequelae of cirrhosis. There is an obvious need, however, for arresting or reversing alcoholinduced organ damage at earlier stages. This might be
accomplished through systematic efforts to detect precursor lesions and to boost the bodys defenses against
the toxic effects of ethanol. We must also develop treatments that prevent irreversible liver damage, such as
those that have been effective in primates.56 Even small
decreases in the frequency or duration of hospitalization would offset the costs of early detection, intervention, and required research, not to mention the priceless benet of reducing human suffering.
DISCUSSION
DR. JEFFREY FLIER: Would you comment further on
a possible genetic basis for the propensity to abuse alcohol and the genes that may increase or modify the
toxic effects of alcohol?
DR. LIEBER: It is important to identify a gene that
may be related to the propensity for alcoholism. Studies
of siblings and adoptees have established the existence
of genetic factors, but their exact nature is still eluding
us. As I mentioned, dopamine-related genes have been
implicated,52,82 but this view is being revised.83 Individual differences in the rate of ethanol metabolism may
also be genetically controlled. Furthermore, genetic factors inuence the severity of alcohol-induced liver disease. Indeed, the frequency of an alcohol dehydrogenase 3 allele has been found to differ in patients with
alcohol-related end-organ damage (including cirrhosis)
and matched controls, suggesting that genetically determined differences in alcohol metabolism may explain
differences in the susceptibility to alcohol-related disease (possibly through the enhanced generation of toxic metabolites),84 but this hypothesis has recently been
questioned.85 Similarly, a signicant association between a particular restriction-fragmentlength polymorphic haplotype and alcoholic cirrhosis has been
reported86 but not conrmed.87
DR. CHAIM MAYMEN: Would you comment on the
nature of alcohols effects on the central and peripheral
nervous system?
DR. LIEBER: The precise mechanisms whereby alcohol and associated nutritional (thiamine and pyridoxine) deciencies affect brain structure and function are
too complex to be discussed in detail in the context of
this review, but detailed accounts are available else-
1064
where.3 There is a clear change in brain size, with unquestionable atrophy. Other studies pertain to the effects of alcohol on brain function. Alcohol, unlike other
drugs, has no specic brain receptors, but it may affect
some of the other ones, such as ATP and L-glutamate
receptors. Alcohol permeates the membranes of the
brain and uidizes them. Some studies link the membrane rigidity that develops in response to the uidizing effect of alcohol with the development of the symptoms of alcohol withdrawal. This hypothesis has
become somewhat less popular because moderate uctuations in temperature can produce the same changes
in uidity. At this time, we do not have as good an understanding of the effects of alcohol on the brain as we
do for the liver. Recent studies have shown that cytochrome P-4502E1 is present in specic areas of the
brain.88 As I discussed, this system metabolizes ethanol
and produces acetaldehyde, which has striking effects
on the central nervous system. Obviously, it is now just
a matter of time until we have mapped the various areas of the brain that are specically affected by alcohol.
DR. BOOKER BUSH: Are there insights into the basis
of alcohol-induced pancreatitis and cardiomyopathy?
DR. LIEBER: Various theories have been proposed to
explain alcohol-induced pancreatitis,3 including oxidative damage mediated by free radicals. The problem
with pancreatitis is the lack of good experimental models. The diagnosis of alcoholic cardiomyopathy is one of
exclusion.3 We still lack specic and easily performed
tests to identify the disorder. Some of the metabolic effects that have been demonstrated in other tissues may
apply to the heart as well, including the toxic effects of
fatty-acid ethyl esters.89
DR. SARAH K. WARD: What is the accepted medical
denition of alcoholism, and does this denition take
into account the sexual differences you discussed?
DR. LIEBER: A common denition of alcoholism is
based on the social, psychological, or medical complications of alcohol abuse (impaired functioning in society and altered health) or signs of dependence, tolerance of large amounts of alcohol, and craving and
symptoms on withdrawal.3 Since the denition pertains
to symptoms rather than absolute amounts of alcohol,
it applies to both sexes.
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THE NEW ENGLAND JOURNAL OF MEDICINE

JEFFREY S. FLIER, M.D., Editor