Alcoholic
liver disease is one of the most serious medical
consequences of
chronic alcohol use. Moreover, chronic excessive
alcohol use is the single
most important cause of illness and death from
liver disease (alcoholic
hepatitis and cirrhosis) in the United States
(1).
The Normal Liver
Normal liver function is essential to life. The
liver is the largest organ
of the body, located in the upper right section
of the abdomen. It filters
circulating blood, removing and destroying toxic
substances; it secretes
bile into the small intestine to help digest and
absorb fats; and it is
involved in many of the metabolic systems of the
body. Digested food
substances are carried from the intestine
directly to the liver for further
processing. The liver stores vitamins;
synthesizes cholesterol; metabolizes
or stores sugars; processes fats; and assembles
amino acids into various
proteins, some for use within the liver and some
for export. The liver
controls blood fluidity and regulates
blood-clotting mechanisms. It also
converts the products of protein metabolism into
urea for excretion by the kidneys.
Alcoholic Liver Disease
The three alcohol-induced liver conditions are
fatty liver, alcoholic
hepatitis, and cirrhosis.
Some degree of fat deposition usually occurs in
the liver after short-term
excessive use of alcohol. However, fatty liver
rarely causes illness (2).
In some heavy drinkers, alcohol consumption
leads to severe alcoholic
hepatitis, an inflammation of the liver
characterized by fever, jaundice,
and abdominal pain (3). Severe alcoholic
hepatitis can be confused with many serious
abdominal conditions, such as cholecystitis
(inflammation of the gall bladder),
appendicitis, and pancreatitis. It is important
to be aware
of this potential confusion because some of
these other conditions require
surgery, and surgery is contraindicated in
patients with alcoholic hepatitis. These
patients have a high death rate following
surgery.
The most advanced form of alcoholic liver injury
is alcoholic cirrhosis.
This condition is marked by progressive
development of scar tissue that
chokes off blood vessels and distorts the normal
architecture of the liver
(2).
A patient may have only one of the three
alcohol
rehab-induced conditions or any
combination of them. Traditionally, they have
been considered sequentially
related, progressing from fatty liver to
alcoholic hepatitis to cirrhosis.
However, some studies have demonstrated that
alcoholics may progress to
cirrhosis without passing through any visible
stage resembling hepatitis.
Thus, alcoholic cirrhosis can appear
insidiously, with little warning (4).
Fatty liver is reversible with abstinence.
Alcoholic hepatitis may be fatal
but can be reversible with abstinence (5). While
alcoholic cirrhosis is
often progressive and fatal, it can stabilize
with abstinence (3).
Complications of advanced liver disease include
severe bleeding from
distended veins in the esophagus, brain
disorders (hepatic encephalopathy),
accumulation of fluid in the abdomen (ascites),
and kidney failure (6).
Not all liver disease that may occur in
alcoholics is caused by alcohol. In
addition, when alcohol-induced liver disease
does occur, it may be
accompanied by other conditions, not related to
alcohol, that also can cause
liver failure. These include nonalcoholic
hepatitis and exposure to drugs
and occupational chemicals (see below).
Extent of the Problem
Alcohol-related cirrhosis is know n to be
underreported. However, about 44
percent of all deaths caused by cirrhosis in
North America are reportedly
alcohol related (7).
Up to 100 percent of heavy drinkers show
evidence of fatty liver, an
estimated 10 to 35 percent develop alcoholic
hepatitis, and 10 to 20 percent
develop cirrhosis (1).
Daily drinkers are at a higher risk of
developing alcoholic cirrhosis than
are binge drinkers (8). In general, patients
with alcoholic cirrhosis have
been drinking heavily for 10 to 20 years (8-10).
Mortality from cirrhosis in the United States
varies significantly with
gender, race, and age. In 1988, the highest
mortality from cirrhosis
occurred in nonwhite males, followed by white
males, nonwhite females, and
white females (11). Most of the deaths from
alcoholic cirrhosis occur in
people ages 40-65 (11). Thus, alcoholic
cirrhosis kills people in what
should be their most productive years.
How Does Alcohol Damage the Liver?
Currently we do not know how alcohol causes
cirrhosis. However, there are
many mechanisms by which alcohol injures the
liver. Many of these mechanisms are poorly
understood, in part because no simple animal
model has been developed for cirrhosis. In
addition, there is considerable variation among
individuals in susceptibility to alcoholic liver
disease, so that among
people drinking similar amounts, only some
develop cirrhosis.
Diet. Before the 1970's, alcoholic cirrhosis was
believed to arise from
nutritional deficiencies common among heavy
drinkers. Overwhelming evidence subsequently
proved that alcohol itself is toxic to the
liver, even when nutrition is adequate. Today,
it is believed that nutritional effects and
direct alcohol toxicity interact in such complex
ways that the influence of
the two cannot be separated (12).
Genetics. Genetic differences might explain why
some heavy drinkers develop cirrhosis while
others do not. The scar tissue that forms in the
cirrhotic liver is composed of the protein
collagen. It has been suggested that stimulation
of collagen synthesis resulting from activation
of the collagen gene may promote liver scarring
(13). In that case, it might be speculated that
differences in genes for collagen among
individual drinkers may be associated with
differences in the development of alcoholic
cirrhosis.
Free radicals and acetaldehyde. Much of the cell
damage that occurs during
liver degeneration is believed to be caused by
free radicals, highly reactive molecular
fragments, liberated during alcohol metabolism.
The damage caused by free radicals can include
the destruction of essential components of cell
membranes. The cell's natural defenses against
free radicals include the natural chemicals
glutathione (GSH) and vitamin E.
The function of GSH and vitamin E is impaired in
alcoholics. For example,
chronic alcohol ingestion decreased GSH levels
in baboons and humans (14).
Similarly, chronic alcohol feeding significantly
increased damage caused by
free radicals in liver cells of rats maintained
on a diet low in vitamin E
(15).
Acetaldehyde, the primary metabolic product of
alcohol in the liver, appears
to be a key generator of free radicals. Because
of its reactivity,
acetaldehyde can promote membrane damage and can
stimulate the synthesis of collagen to form scar
tissue (16-18).
Nonalcoholic hepatitis. The increased
prevalence of hepatitis C viral
infection in alcoholics might explain some of
the variation in individual
susceptibility to alcoholic liver disease (19).
In addition, chronic
hepatitis C infection is significantly
correlated with the severity of
alcoholic cirrhosis (20) and may influence the
progression of alcoholic
liver disease in some patients (21,22).
The immune system. The immune system
responds or contributes to liver cell damage in
alcohol-induced liver disease in complex ways,
although a causal relationship is unclear.
Acetaldehyde has been shown to attach chemically
to liver proteins. The altered proteins may then
trigger various immune responses (23). Cellular
toxins are released, causing cell damage;
certain proteins are deposited along the liver's
small blood-carrying channels; and specific
white blood cells are activated (24-27).
Liver metabolism. Chronic alcohol
administration has been found to increase the
rate of oxygen metabolism by the liver. In
addition, a series of studies by Israel and
colleagues (28) demonstrated similarities in the
effects of alcohol and thyroid hormone on liver
cells. They called these effects the
"liver hypermetabolic state." As a result of
these studies, propylthio-uracil, a drug used to
treat excessive production of thyroid hormone,
has been tested for the treatment of alcoholic
liver disease (see Treatment below).
Gender. Current evidence suggests that women may
be more susceptible than men to alcoholic liver
disease; more research is necessary to validate
this hypothesis (8,19).
Environmental factors. Chronic alcohol
consumption markedly increases the
liver toxicity of various industrial solvents,
anesthetics, medications, and
vitamins (29,30). For example, acetaminophen
(Tylenol and others), a widely used
over-the-counter pain reliever, is generally
safe when taken in
recommended doses. However, excessive use of
acetaminophen has been
associated with liver toxicity in people
drinking heavily (30-32). Alcohol
also enhances the toxicity of excess vitamin A,
so care must be taken when treating an alcoholic
with a vitamin A deficiency (33).
Treatment
Alcoholic hepatitis. Mortality from
alcoholic hepatitis during the early
weeks of treatment is very high. Although the
evidence is inconsistent,
corticosteroid therapy may improve survival
during the early stages of the
disease in patients with severe alcoholic
hepatitis (34-38). Supplemental
amino acids may improve a patient's nutrition
but not the chances of
survival or progression to cirrhosis (39).
Orrego and colleagues (40) reported that the
drug propylthiouracil (PTU)
improved survival of patients with all types of
alcoholic liver disease.
However, other studies have demonstrated no
benefit from this therapy in
patients with alcoholic hepatitis (41,42).
Abstinence is the cornerstone of therapy for
patients with prolonged
alcoholic hepatitis. Also important are careful
control of diet with
correction of vitamin deficiencies, and
management of medical complications
(38).
If the patient with alcoholic hepatitis lives to
leave the hospital,
abstinence is essential for long-term survival.
Alexander and coworkers (43)
found that more than 80 percent of those who
abstained or markedly reduced
their drinking were alive 7 years later, whereas
only 50 percent who
continued to drink were alive 7 years later.
Alcoholic cirrhosis. Treatment for
cirrhosis is directed at symptoms and
complications, with abstinence a requirement.
For terminally ill patients,
liver transplantation is the only effective
treatment. This procedure in
alcoholic cirrhotic patients has demonstrated
success and survival rates
equal to those for nonalcoholic cirrhotic
patients (44).
Future directions in cirrhosis therapy are
suggested by a study showing that
lecithin protects against the development of
alcohol-induced liver scarring
in baboons (45). This therapy has not yet been
studied in humans.
--------------------------------------------------------------------------------
Alcohol and the Liver--A Commentary by
NIAAA Director Enoch Gordis, M.D.
Abstinence from alcohol is the single most
important component of treatment
for alcoholic liver disease. Continued drinking
will worsen the condition of
patients with this disease and greatly increase
their risk for death.
Physicians who treat alcoholic liver disease, no
matter how competently, and
who do not address their patients' drinking are
practicing bad medicine,
akin to treating an iron-deficiency anemia and
disregarding the colon cancer
that is causing it.
Because many alcohol abusers and most alcoholics
require some form of
treatment to remain abstinent, simply giving
advice to "quit" drinking often
is not sufficient. Physicians who choose not to
manage their patients'
alcohol problems may refer these patients to
specialized alcohol treatment
providers for evaluation and appropriate
treatment. In referring a patient
to appropriate alcohol treatment, physicians
should keep informed of their
patients' progress, as relapse may further
complicate management of the
alcoholic liver disease.
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