The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Dan L. Longo, M.D., Editor

Alcohol Use in Patients with Chronic Liver

Disease
Daniel Fuster, M.D., Ph.D., and Jeffrey H. Samet, M.D., M.P.H.​​

G
lobally, alcohol consumption is the seventh leading risk fac- From the Internal Medicine Service, Ad-
tor for both death and the burden of disease and injury.1 Alcohol use ac- diction Unit, Hospital Universitari Ger-
mans Trias i Pujol, Universitat Autonoma
counts for 6.8% of age-standardized deaths in men and 2.2% in women, de Barcelona, Badalona, Spain (D.F.); and
with a disproportionate effect on young people.1 The overall costs associated with the Clinical Addiction Research and Edu-
alcohol use represent more than 1% of the gross national product in high- and cation Unit, Section of General Internal
Medicine, Department of Medicine, Bos-
middle-income countries, with the costs of social harm (e.g., violence and road ton Medical Center and Boston University
accidents) being far greater than health costs alone.2 In short, except for tobacco, School of Medicine, the Grayken Center
alcohol accounts for a higher burden of disease than any other drug.3 In this review, for Addiction, Boston Medical Center, and
the Department of Community Health
we discuss the effects of alcohol use on various forms of liver disease, as well as Sciences, Boston University School of
the assessment and treatment of alcohol use in patients with chronic liver disease. Public Health — all in Boston ( J.H.S.).
Address reprint requests to Dr. Samet at
Boston University Schools of Medicine
A l c ohol ic L i v er Dise a se and Public Health, 801 Massachusetts
Ave., 2nd Fl., Boston, MA 02118, or at
Alcohol use is a major cause of preventable liver disease worldwide, and alcoholic ­jsamet@​­bu​.­edu.

liver disease is the main alcohol-related chronic medical illness.4,5 Globally, per N Engl J Med 2018;379:1251-61.
capita alcohol consumption is strongly correlated with the rate of death due to DOI: 10.1056/NEJMra1715733
Copyright © 2018 Massachusetts Medical Society.
liver cirrhosis.6 Alcohol-related and viral hepatitis–related liver disease are not
mutually exclusive; nevertheless, it is plausible that with the advent of direct-acting
antiviral agents for chronic hepatitis C virus (HCV),7 alcohol will again become the
most prominent driver of liver disease worldwide. Alcoholic liver disease is the
leading cause of liver transplantation in Europe4 and the second-leading cause of
liver transplantation in the United States, after HCV-related liver disease.8
Alcoholic liver disease encompasses several histopathologic changes, from simple
steatosis to alcoholic steatohepatitis, progressive liver fibrosis (which usually
starts in the perivenular area of the hepatic lobule), cirrhosis, and liver cancer.8
Rather than being distinct stages of the disease, these features can coexist in the
same person.8 Once steatohepatitis is established, liver damage is not totally re-
versible with abstinence from alcohol, but abstinence can ameliorate portal hyper-
tension.8 Acute alcoholic hepatitis is a severe complication that can occur at any
point in the course of alcoholic liver disease and is associated with liver failure
and with short-term mortality as high as 40%.9
Patients with alcoholic liver disease, as opposed to those with other forms of
liver disease, often have at least a 20-year history of regular consumption of alco-
hol above the threshold of 20 g of pure alcohol per day for women and 30 g for
men.4,6 In most persons who consistently drink more than 60 g per day (i.e., ap-
proximately four standard drinks, with a standard drink [i.e., 12 oz of beer, 5 oz
of wine, or 1.5 oz of 80-proof liquor] containing approximately 14 g of alcohol)
for as little as 2 years, liver steatosis will develop,10 which is reversible with cessa-
tion of alcohol intake. Although cirrhosis will not develop in all patients who
consume alcohol above those thresholds,6 higher levels of consumption are associ-

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 The n e w e ng l a n d j o u r na l
ated with more advanced forms of liver dis-
ease.8,11 The dose–response curve representing
the level of alcohol intake and the occurrence of
liver disease is exponential, with the risk of liver
disease being significantly higher among women
who consume two to three drinks per day and
men who consume three to four drinks per day
than among persons with no alcohol intake.6,8,11
Several authors have studied the association
between lifetime drinking history and the oc-
currence of alcoholic liver disease.12,13 Not all
patterns of drinking have resulted in alcoholic
liver disease. In a study from Denmark, daily
drinking was associated with an increased risk
of alcoholic cirrhosis.14 In a study from the
United Kingdom, patients with alcoholic liver
disease were more likely to have a pattern of
regular (daily or almost daily) heavy drinking
than of episodic heavy drinking or binge drink-
ing.12 A recent study from Iceland showed simi-
lar results in women with alcohol-use disorder
but showed that men were more likely than
women to engage in binge drinking.13 The effect
of binge drinking, which is becoming more
prevalent among adolescents and young adults
worldwide,15 on the development and severity of
alcoholic liver disease has received little attention
in the literature.4,16 A higher frequency of binge
drinking seems to be associated with a higher
risk of liver disease, independent of average alco-
hol intake, an effect that is more apparent in
patients with the metabolic syndrome than in
those without the syndrome.17
A l c ohol a s a L i v er T ox in
The causal association between alcohol intake
and alcoholic liver disease has been well docu-
mented,8 yet liver cirrhosis develops in only 10 to
20% of heavy drinkers.18 Even though alcohol
consumption is a major factor in the develop-
ment of liver disease, several cofactors facilitate
liver damage.19
Other conditions, including HCV infection,
diabetes mellitus, and obesity are common co-
existing conditions associated with faster pro-
gression of fibrosis.8 In addition, genetic factors,
such as mutations in patatin-like phospholipase
domain–containing 3 (PNLAP3) and transmem-
brane 6 superfamily, member 2 (TM6SF2), are
predisposing factors in the development of alco-
holic liver disease.20
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of m e dic i n e
Alcohol intake promotes accumulation of ac-
etaldehyde and other reactive oxygen moieties in
the liver, a process associated with oxidative
stress, impaired hepatocyte metabolism, and cell
death.21 Alcohol consumption also promotes the
growth of intestinal gram-negative bacteria and
increases intestinal permeability, consequences
that raise the levels of lipopolysaccharide, also
known as endotoxin, in the peripheral blood.22
An excess amount of lipopolysaccharide reach-
ing the liver can activate Kupffer cells, thus gen-
erating free radicals and inflammatory cytokines
that lead to the initiation of necroinflammation
and fibrotic changes in the liver.23 Endotoxin
also activates quiescent hepatic stellate cells,
which are the main fibrogenic cell type of the
injured liver, thereby stimulating the secretion of
proinflammatory cytokines and the initiation and
progression of liver fibrosis.24 The pathogenic
changes involved in alcohol-related liver disease
are depicted in Figure 1.
Effec t of A l c ohol Use
The effect of alcohol use in patients with liver
disease is multidimensional. Figure 2 summa-
rizes the effects of alcohol consumption on the
four most prevalent forms of liver disease, which
are also outlined below.
HCV-Related Liver Disease
Counterintuitively, adults with HCV infection tend
to consume greater amounts of ethanol than
other adults.25 Adults with HCV infection are
more than twice as likely as those without HCV
infection to regularly consume more than one
alcoholic drink per day (35% vs. 14%) and al-
most 8 times as likely to regularly consume
more than three drinks per day (19% vs. 2%).26
Alcohol use is associated with more persis-
tent HCV infection and more extensive liver
damage than no alcohol use, because of interac-
tions between alcohol use and HCV that affect
immune responses, cytotoxicity, and oxidative
stress.27 In addition, alcohol use may have an
effect on HCV viral replication in certain sub-
groups of patients.28 No safe level of alcohol
consumption has been determined for patients
with HCV, and even those who drink moderate
amounts of alcohol can have progressive liver
fibrosis.27 A meta-analysis showed that the rela-
tive risk of progression to liver cirrhosis or de-
 Alcohol Use in Patients with Chronic Liver Disease

Lipid peroxidation
DAMPs Steatosis
LIVER Neutrophils
Neutrophils and macrophages
Stellate
and macrophages
cells
Hepatocyte
Progressive ↑Iron damage
liver fibrosis deposits

Kupffer
Reactive cells
oxygen species
Cytokines Reactive
oxygen species
↑Bile Cytokines
acids

PAMPs
BONE

Change in Gut
microbiome bacteria
composition
ALCOHOL

INTESTINE

↑Intestinal
↑LPS
permeability

Figure 1. Diagram of Alcohol-Related Liver Injury.

Alcohol-related liver injury is characterized by oxidative stress, leading to lipid peroxidation and steatosis, increased
iron deposits, hepatocyte damage, and cell death leading to the release of damage-associated molecular patterns
(DAMPs). These features are associated with liver inflammation, activation of Kupffer cells and stellate cells, liver
regeneration process modifications, and progressive liver fibrosis. In addition, alcohol use promotes a change in
microbiome composition, an increase in intestinal permeability, and translocation of bacterial products (endotoxin
and pathogen-associated molecular patterns [PAMPs]) that also activate Kupffer cells, with the release of inflamma-
tory cytokines further increasing liver inflammation and fibrosis progression. LPS denotes lipopolysaccharide.

compensated liver disease was 2.3 times as high
among patients with HCV who drank alcohol as
the risk among abstainers.29
HCV infection in patients with alcohol-use
disorder is associated with poorer outcomes,
such as longer hospital stays and higher in-hos-
pital mortality, than in patients with alcohol-use
disorder who do not have HCV infection.30 This
association may be partially explained by group
differences in coexisting conditions or behaviors
associated with poorer survival; however, even in
studies that have accounted for those factors,
HCV infection in patients with alcohol-use dis-
order is associated with elevated overall and liver-
related mortality.31 Among patients with alcohol-
use disorder who are admitted to the hospital
for detoxification, mortality is higher if the pa-
tients have HCV infection than if they do not,
especially in younger patients and patients who
also have human immunodeficiency virus (HIV)
infection.32
In the era of interferon-based antiviral ther-
apy for HCV infection, alcohol consumption was
associated with lower odds of a sustained viro-
logic response, mainly owing to lower adherence
to the medication.27 In the era of direct-acting
antiviral agents, alcohol use is still a major con-
tributor to decompensated cirrhosis in HCV-
infected patients,33,34 but it does not appear to
mitigate achievement of sustained virologic sup-
pression.7 Abstinence from alcohol is not required
for treatment, and its ongoing use should not be
a contraindication for treatment; nevertheless, it
seems prudent to recommend that patients stop

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Hepatitis C Virus Infection

Increased infection exposure
and persistence
More extensive liver damage
Faster progression of liver
fibrosis
Higher mortality

Hepatitis B Virus Infection

Increased risk of hepatocellular
carcinoma

Alcohol Use Nonalcoholic Fatty Liver Disease

Greater prevalence of steatosis
and abnormal liver test
Increased fibrosis progression
Increased risk of hepatocellular
carcinoma

Hereditary Hemochromatosis
Increased iron overload
Increased fibrosis progression

Figure 2. Effects of Alcohol Use on Various Forms of Chronic Liver Disease.

the use of alcohol if they plan to undergo anti- normal liver-function test results41 and hepatic
viral therapy for HCV infection. steatosis42 in obese patients who are also heavy
drinkers is significantly greater than the likeli-
Hepatitis B Virus–Related Liver Disease hood in heavy drinkers who are not obese. Some,
Alcohol use increases hepatitis B virus (HBV) but not all, observational studies have reported
replication in mice, increases HBV surface anti- beneficial effects on cardiovascular outcomes of
gen levels in humans, and delays the clearance low or moderate alcohol consumption in patients
of HBV.35 Alcohol use is associated with an in- with nonalcoholic fatty liver disease.43 Currently,
creased risk of progression of liver fibrosis and there are no guidelines on how to counsel pa-
of the occurrence of hepatocellular carcinoma in tients with nonalcoholic fatty liver disease about
patients with HBV-related cirrhosis.36 Correspond- alcohol use, but abstinence should be the goal,
ingly, the presence of HBV infection is associat- since heavy alcohol intake, or even low or moder-
ed with the development of hepatocellular carci- ate alcohol consumption in those with the meta-
noma and liver-related death in patients with bolic syndrome,44 is associated with increased
alcoholic liver disease.37 Even though one cross- fibrosis progression.43
sectional study involving patients with chronic
HBV infection showed that the prevalence of Hereditary Hemochromatosis
advanced fibrosis in those who reported drink- Alcohol consumption is associated with increased
ing 1 to 20 g of alcohol per day was similar to iron overload and faster progression to liver cir-
the prevalence in those who abstained,38 alcohol rhosis in patients with hereditary hemochromato-
consumption should be kept to a minimum in sis. This condition is characterized by increased
patients with HBV infection.39 absorption of iron, which generates reactive oxy-
gen species and causes peroxidation of cell mem-
Nonalcoholic Fatty Liver Disease branes, cell damage, and liver injury.45 Alcohol
Nonalcoholic fatty liver disease is a consequence has an additive effect on liver damage; in one
mainly of obesity and the metabolic syndrome. study, which was controlled for age, 61% of pa-
In the Global North, nonalcoholic fatty liver dis- tients with hemochromatosis who drank more
ease is one of the leading causes of liver trans- than 60 g per day had severe fibrosis or cirrhosis
plantation because of the high prevalence of as compared with 7% of those who drank lower
these clinical conditions.40 The likelihood of ab- amounts.46

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 Alcohol Use in Patients with Chronic Liver Disease

Table 1. Summary of Pharmacologic Treatment Recommendations for Patients with the Alcohol Withdrawal Syndrome
and Liver Disease.

Drug Dosage Use in Patients with Liver Disease

Diazepam 10–20 mg orally every 1–2 hr as needed until Yes, but avoid use in patients with poor synthetic
symptoms are minimal* function, decompensated cirrhosis, or both
Chlordiazepoxide 50 mg orally every 1–2 hr as needed until Yes, but avoid use in patients with poor synthetic
symptoms are minimal* function, decompensated cirrhosis, or both
Lorazepam† 2 mg orally every 1–2 hr as needed until symp- Yes
toms are minimal*
Oxazepam† 30 mg orally every 1–2 hr as needed until Yes
symptoms are minimal*

* An initial dose regardless of symptoms can be considered in high-risk patients (i.e., those with prior seizures or multiple
alcohol detoxifications).
† When the patient’s symptoms are minimal, consider a taper to avoid benzodiazepine withdrawal.

Acute-on-Chronic Liver Failure
Alcohol use is one of the most common triggers
of acute decompensation in persons with chronic
liver disease, which is known as acute-on-chronic
liver failure and is associated with organ failure
and short-term mortality.47 Nevertheless, acute-
on-chronic liver failure precipitated by alcohol
has a better prognosis than liver failure pre-
cipitated by infections or upper gastrointestinal
bleeding.48
Information about the effect of alcohol con-
sumption on less prevalent forms of liver disease
(e.g., Wilson’s disease and autoimmune and cryp-
togenic liver disease) is scarce, but the use of
alcohol, which is a hepatotoxin in patients with
another cause of chronic liver disease, seems un-
wise. In addition, alcohol can be an underrecog-
nized factor in the exacerbation of these forms
of liver disease.39
A sse ssmen t of A l c ohol Use
Assessment of alcohol use is appropriate for any
person with liver disease, given the elevated risks
of alcohol-related hepatotoxicity. The Alcohol Use
Disorders Identification Test (AUDIT) is a vali-
dated tool for identifying alcohol-use disorder in
patients.49 It is recommended by both American
and European guidelines,4,8 but it can be difficult
to use in a clinical setting because of its length,
unless it is administered before the clinical visit.
A shorter version exists (AUDIT-C),50 which is
another option. Also, the National Institute on
Alcohol Abuse and Alcoholism single-question
screening tool has been validated for the screen-
ing of unhealthful alcohol use (i.e., the spectrum
from risky use to alcohol-use disorder) in the
primary care setting.51 The question is, “How
many times in the past year have you had X or
more drinks in a day?,” where X is five for men
and four for women, and a response of one or
more times is considered positive and merits
further assessment.
In fact, there is no known safe threshold of
alcohol consumption for patients with chronic
liver disease, especially those with HCV infec-
tion, obesity, or the metabolic syndrome. If a
threshold exists, it is probably very low, and even
alcohol use that does not reach the risky range
can be detrimental.29,39 Abstinence from alcohol
intake improves clinical outcomes in patients
with chronic liver disease and is associated with
survival benefits even after the development of
cirrhosis.52 Therefore, complete abstinence is the
clinical goal for patients with alcohol-use disor-
der and liver disease, especially those in whom
liver cirrhosis has already developed.4
T r e atmen t of the A l c ohol
W i thdr awa l S y ndrome
Patients with alcohol-use disorder are at risk for
the alcohol withdrawal syndrome after discon-
tinuation of or decrease in frequent heavy alco-
hol consumption.4 The cornerstone of treatment
for the alcohol withdrawal syndrome is the use
of benzodiazepines53,54 (Table 1). Long-acting
benzodiazepines (e.g., diazepam and chlordiaz-
epoxide) protect against seizures and delirium,
but short- and intermediate-acting benzodiaz-

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 The n e w e ng l a n d j o u r na l
epines (e.g., lorazepam and oxazepam), which
presumably have efficacy similar to long-acting
benzodiazepines, are safer for patients with poor
synthetic liver function, because the drugs are
associated with a reduced risk of toxic effects
due to medication accumulation resulting from
slow hepatic catabolism.54 Lorazepam metabo-
lites are eliminated by the kidney rather than the
liver, which makes the drug particularly useful in
patients with chronic liver disease. As a second-
line therapy, phenobarbital can be used for the
treatment of withdrawal, but it is not recom-
mended in patients with liver disease.54 For un-
complicated withdrawal, carbamazepine and
oxcarbazepine can help mitigate symptoms, but
the evidence for their use is of lower quality than
that for benzodiazepines.4,54
Given that benzodiazepines may precipitate
and worsen hepatic encephalopathy, other drugs
such as baclofen, clonidine (which can in turn
ameliorate tachycardia and hypertension in asso-
ciation with the alcohol withdrawal syndrome),
gabapentin, and topiramate have been proposed
as alternatives in patients with alcoholic liver
disease,54 but the quality of the data supporting
their use is still poor.55 Alcohol use for therapeu-
tic purposes does not have an empirical basis
in the treatment of the alcohol withdrawal syn-
drome.
Pr e v en t ion of R el a pse a nd
Promo t ion of A bs t inence
Nonpharmacologic Therapies
In patients with liver disease, brief intervention
and motivational interviewing (which involves
nonconfrontational counseling by the clinician
to encourage choices that are consistent with the
patient’s long-term goals) can be used to reduce
alcohol use that does not qualify as alcohol-use
disorder.56 Also, feedback around abnormal liver-
test results has been associated with decreased
alcohol use in patients who are at risk for
chronic liver disease.57
A recent systematic review advocated the use
of cognitive behavioral therapy and motivational
enhancement therapy as effective psychosocial
interventions that can be implemented in com-
bination with pharmacotherapy and comprehen-
sive medical care.58 Data supporting the use of
contingency management58 — or more intensive
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of m e dic i n e
forms of treatment provision, such as chronic
care management or collaborative care59,60 — are
still inconclusive. In addition, the paucity of data
concerning the combination of pharmacologic
and nonpharmacologic treatment for alcohol-use
disorder in patients with chronic liver disease
limits evidence-based recommendations from
extending beyond those for patients without liver
disease. Several nonpharmacologic strategies for
relapse prevention can be implemented in pri-
mary care.61 These include establishing a support-
ive patient–physician relationship; scheduling
regular follow-up visits; mobilizing family sup-
port; suggesting involvement in 12-step programs;
developing a plan to recognize, cope with, and
manage early relapse; facilitating positive life-
style changes; and treating coexisting conditions
that can trigger relapse.61
Pharmacologic Therapies
Three medications (naltrexone, disulfiram, and
acamprosate) have been approved by the Food
and Drug Administration for the treatment of
alcohol-use disorder56 (Table 2), and a newer drug
(nalmefene) has been approved in many Euro-
pean countries for the reduction of alcohol con-
sumption.62 However, few clinical trials examine
the effectiveness of these drugs against alcohol-
use disorder in patients with advanced liver dis-
ease, and most of the recommendations are
based on research that involved patients without
overt liver disease.63 In general, patients with
minor or mild forms of liver disease can be
treated with any of the approved medications,
but caution should be exercised with the admin-
istration of disulfiram and naltrexone in patients
who have cirrhosis, especially if it is decompen-
sated or if the patient has features suggestive of
synthetic dysfunction.
Disulfiram inhibits acetaldehyde dehydroge-
nase action, thus provoking what is known as
the acetaldehyde syndrome (facial flushing, nau-
sea, vomiting, tachycardia, and hypotension) when
disulfiram is consumed with alcohol.64 Disulfi-
ram has been approved for promoting absti-
nence since the 1950s, given its potential as a
deterrent for alcohol consumption. Open-label
studies have shown promising results, but evi-
dence of its efficacy has been mixed in clinical
trials.54 A meta-analysis that reviewed random-
ized clinical trials published up to 2011 showed
 Alcohol Use in Patients with Chronic Liver Disease

Table 2. Summary of Pharmacologic Treatment Recommendations for Patients with Alcohol-Use Disorder and Liver
Disease.

FDA-Approved for
Treatment of Alcohol-
Drug Dosage Use Disorder* Use in Patients with Liver Disease
Naltrexone 50 mg orally once a day or 380 mg intra- Yes Yes, but use with caution in patients
muscularly monthly for ≥4 mo with acute hepatitis and decom-
pensated cirrhosis
Disulfiram 250–500 mg once a day for ≥3 mo Yes No
Acamprosate 666 mg three times a day† Yes Yes
Baclofen 10 mg three times a day; ≤80 mg once No Yes‡
a day
Gabapentin 900–1800 mg once a day No Data are limited§
Ondansetron 1–16 μg per kg of body weight twice a day No Data are limited¶
Topiramate 300 mg once a day No Data are limited‖
Varenicline 2 mg once a day No Data are limited

* FDA denotes Food and Drug Administration.

† In patients who weigh less than 60 kg, the recommended dose of acamprosate is 333 mg four times a day (two 333-mg
pills with breakfast, one with lunch, and one with dinner).
‡ Studies of the efficacy of baclofen have had mixed results.
§ Gabapentin can be addictive.
¶ Liver toxicity has been reported with the use of ondansetron.
‖ The side effects of topiramate may mimic the symptoms of hepatic encephalopathy.

that only 6 of 11 trials showed a significant effect
of disulfiram on abstinence.65 Disulfiram treat-
ment is more efficacious in patients who are
committed to maintaining abstinence and when
it is provided in a monitored fashion, since treat-
ment failure has been attributed to patients’ deci-
sion to stop the medication so that alcohol use
can be restarted.64 Treatment should be given for
at least 3 months, and it is not uncommon to
maintain treatment for a year or more Table 2.54
The use of disulfiram is contraindicated in pa-
tients with liver cirrhosis, especially in those with
synthetic dysfunction, given that liver failure lead-
ing to death or liver transplantation has been re-
ported.66 Liver toxicity has also occurred in patients
with no previous liver problems, so monitoring
of liver enzymes during treatment is highly recom-
mended.67
Naltrexone is a mu-opioid and kappa-opioid
receptor antagonist that reduces alcohol-related
dopamine release in the nucleus accumbens and
reduces the reward sensation, thus making pa-
tients less motivated to drink.68 There is mixed
evidence around markers that predict a favorable
response to naltrexone treatment, such as male
sex, a positive family history of alcoholism, high
levels of craving, and a polymorphism of the
opioid receptor gene OPRM1.69 In clinical trials,
naltrexone use is associated with lower rates of
relapse of alcohol consumption as compared with
placebo and a higher percentage of days of ab-
stinence.70 Treatment for at least 4 months is
indicated, with monthly follow-up for up to a
year.71 Hepatotoxicity is rare with the use of nal­
trexone at the recommended doses, but elevated
liver enzyme levels are not uncommon.71 Naltrex-
one use is formally contraindicated in patients
with acute hepatitis or liver failure and should
be used with caution in patients with active liver
disease (i.e., patients who present with liver en-
zyme levels that are greater than the upper limit
of the normal range), since high doses of the
drug (≥100 mg daily) can lead to liver enzyme
levels of more than five times the upper limit of
the normal range and the margin of separation
between the apparently safe dose and the dose
causing hepatic injury appears to be small.63,72
Because of the risk of injection-site hematomas,
naltrexone injections should not be given to pa-
tients with advanced chronic liver disease who
have a low platelet count or prolonged prothrom-
bin time. In addition, the use of naltrexone for

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 The n e w e ng l a n d j o u r na l
alcohol-use disorder is contraindicated in patients
with concomitant opioid-use disorder who are
receiving treatment with such mu-opioid ago-
nists as methadone or buprenorphine.
Acamprosate is believed to act as an N-methyl-
d-aspartate receptor antagonist and a modulator
of γ-aminobutyric acid (GABA) type A receptor73
and to reduce symptoms of protracted absti-
nence. Results in clinical trials have been mixed,74
but meta-analytical data show that acamprosate
reduces alcohol intake in mild-to-moderate forms
of alcohol-use disorder75 and can be safely used
in patients receiving opioid treatment.75 Acam-
prosate has no hepatic metabolism. It could be
considered safe, but it has not formally been
tested in patients with advanced forms of liver
disease.63 Its dose should be adjusted in patients
with chronic kidney disease, and its use is con-
traindicated when creatinine clearance is less
than 30 ml per minute.54 In addition, long-term
administration of acamprosate could increase
the risk of encephalopathy because of the drug’s
antagonism of the glutamate receptor.63
Nalmefene is a mu-opioid and delta-opioid
receptor antagonist and a kappa-opioid receptor
partial agonist that has been approved in Europe
for the reduction of heavy drinking.62 Nalmefene
has a longer half-life than naltrexone, and there
is no evidence of hepatotoxicity associated with
nalmefene,63 but questions have been raised about
its overall efficacy.76 The following two cautions
are noteworthy with respect to its use in persons
with liver disease: there is an absence of data
involving patients with advanced liver disease,
and abstinence — and not just the reduction of
alcohol consumption, which is nalmefene’s in-
tended use — is the preferred treatment goal for
patients with liver disease.8
Baclofen is a selective GABA type B receptor
antagonist used to control spasticity.4,54 There is
no evidence of an association between baclofen
use and liver toxicity, and the drug has been
formally tested in patients with clinically signifi-
cant liver disease, including patients with HCV,
in both clinical trials and open-label studies,
with mixed results.63,77-79 Even though it has not
been formally approved for the treatment of
alcohol-use disorder by regulatory agencies, its
off-label use is common in France.4
Four other treatments that have been tested
in patients with alcohol-use disorder include
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of m e dic i n e
gabapentin, ondansetron, topiramate, and vareni-
cline.54,80 Gabapentin can be addictive in some
patients, but in clinical trials its use is associ-
ated with abstinence, fewer days of heavy drink-
ing, and fewer relapse-related symptoms (e.g.,
insomnia, dysphoria, and craving).81 Given their
minimal to nonexistent hepatic metabolism, on-
dansetron and topiramate could be safely used
in patients with alcoholic liver disease.63 How-
ever, topiramate should be used with caution in
patients with hepatic encephalopathy, since its
side effects of memory loss and concentration
problems may confound a patient’s clinical course
and treatment. Cases of liver toxicity have been
reported with the use of ondansetron; however,
this relationship with ondansetron is not clearly
determined.63 Limited evidence suggests that
varenicline may be effective in reducing alcohol
craving and of overall alcohol consumption, but
it has not been tested in patients with active
liver disease.82 So far, evidence is not strong
enough to support widespread use of these four
drugs in patients with alcoholic liver disease.54
Treatment details are given in Table 2. Except for
the known interaction between alcohol and di-
sulfiram, there are no relevant interactions be-
tween alcohol and the drugs used for the treat-
ment of alcohol-use disorder.
A l c ohol Use a nd L i v er
T r a nspl a n tat ion
The allocation of organs to patients with alco-
holic liver disease currently involves consider-
ation of urgency and usefulness. Patients with
alcoholic liver disease who are candidates for
liver transplantation are often stigmatized and
not referred for evaluation, since some physicians
consider alcoholic liver disease a self-inflicted
disease. It is notable, however, that graft survival
rates in patients with alcoholic liver disease are
similar to those in patients with other causes of
end-stage liver disease.83
Most guidelines promote the 6-month alcohol-
abstinence rule as a prerequisite for receipt of a
liver transplant, not only to establish the likeli-
hood of long-term abstinence after liver trans-
plantation but also to permit some patients to
recover from decompensated liver disease through
the decrease of portal hypertension, thus obviat-
ing the need for liver transplantation.4 However,
 Alcohol Use in Patients with Chronic Liver Disease

empirical data regarding this approach are mixed.83 C onclusions a nd F ur ther

Moreover, interpreting sobriety in patients who
are eligible for liver transplantation might be
challenging, since sometimes the assessment is
based on reports by the patient.83 Referral of
patients to physicians who are specialists in ad-
diction is an option when consideration of fur-
ther treatment to increase the chances of suc-
cessfully remaining abstinent is needed.
Rates of relapse to any alcohol consumption
among liver-transplant recipients vary widely
among studies.83 Only a return to heavy drinking
after transplantation is associated with poor out-
comes, and this pattern of drinking is reported
in only 20% of patients.83
A case–control study showed that rapid liver
transplantation would improve survival among
patients with severe alcoholic hepatitis who did
not have a response to medical therapy.84 In the
study, recidivism in alcohol use was less than
15%. These data could be informative in consid-
eration of the development of an alternative ap-
proach for persons with alcohol-use disorder
and liver failure, which has been explored re-
cently by other groups, with promising results.85
Dir ec t ions
Alcohol use is common among patients with
liver disease and is associated with poor out-
comes. Advanced liver disease can complicate
the pharmacologic treatment of alcohol-use dis-
order and alcohol withdrawal syndrome. Medi-
cations approved for alcohol-use disorder are
prescribed to a minority of patients, yet they
could be used by patients with chronic liver dis-
ease. Abstinence from alcohol should be encour-
aged in patients with chronic liver disease. Liver
transplantation could be considered for patients
who abstain from alcohol and present with pro-
gressive liver failure. It would be wise to expand
alcohol-use disorder treatment in everyday clini-
cal practice to include treatment in patients with
advanced liver disease.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Richard Saitz, M.D., M.P.H., for his critical review
of an earlier version of the manuscript, and Kristina King,
M.P.H., for her assistance with development of earlier versions
of the manuscript and figures.

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