REVIEW ARTICLE

Pharmacotherapy of alcoholic liver disease in clinical

practice
V. Rosato,1 L. Abenavoli,2 A. Federico,3 M. Masarone,4 M. Persico4

1
Internal Medicine and
SUMMARY Hepatology Department, Second
Review criteria
The long-term treatment of alcoholic liver disease University of Naples, Naples,
Aims: Alcohol is the most commonly used addictive substance and alcoholic liver
Italy
disease (ALD) is a major cause of chronic liver disease worldwide, responsible for (ALD) is a major challenge in clinical practice. In this 2
Department of Health Science,
review, we summarise the available data about the
47.9% of all liver chronic deaths. Despite ALD has a significant burden on the University Magna Graecia,
therapy of ALD in clinical practice, particularly Catanzaro, Italy
health, few therapeutic advances have been made in the last 40 years, particularly
focusing on chronic alcoholic hepatitis, giving the 3
Gastroenterology and
in the long-term management of these patients. Methods: we searched in readership an up-to-date view about the novel Endoscopy Unit, Second
PubMed, Scopus, Google Scholar, and MEDLINE databases to identify relevant therapies in this field. University of Naples, Naples,
English language publications focused on long-term therapy of ALD. Results: From Italy
4
the huge literature on this topic, including about 755 studies, 75 were selected as Message for the clinic Internal Medicine and
Abstinence remains the cornerstone of the therapy Hepatology Unit, University of
eligible including clinical trials and meta-analysis. Conclusions: Abstinence
Salerno, Baronissi, Italy
remains the cornerstone of ALD therapy but it is also the most difficult therapeutic and several medications were approved to prevent
alcohol relapse and increase the abstinence. Often
target to achieve and the risk of recidivism is very high at any time. Several drugs Correspondence to:
ALD is complicated by a malnutrition status, which is Ludovico Abenavoli MD, PhD,
(disulfiram, naltrexone, acamprosate, sodium oxybate) have proven to be effective
related to higher mortality rates. For the reason Department of Health Sciences,
to prevent alcohol relapse and increase the abstinence, although the psychothera- nutritional status should be evaluated, particularly University Magna Grcia,
peutic support remains crucial. Baclofen seems to be effective to improve absti- considering the vitamin and mineral deficiency. Viale Europa Germaneto,
nence, showing an excellent safety and tolerability. ALD is often complicated by a Orthotropic liver transplant remains the only Catanzaro 88100, Italy
state of malnutrition, which is related to a worst mortality. A nutritional therapy definitive treatment for end-stage alcoholic cirrhosis. Tel.: + 39 0961 3694387
Specific treatments aimed at stopping the progression Fax: + 39 0961 754220
may improve survival in cirrhotic patients, reversing muscle wasting, weight loss
Email: l.abenavoli@unicz.it
and specific nutritional deficiencies. While in aggressive forms of alcoholic hepatitis of fibrosis are not yet approved, but recent studies
have identified novel promising approaches.
are recommended specific drug treatments, including glucocorticoids or pentoxifyl-
line, for the long-term treatment of ALD, specific treatments aimed at stopping the
Disclosures
progression of fibrosis are not yet approved, but there are some future perspective
All the authors have no
in this field, including probiotics and antibiotics, caspase inhibitors, osteopontin conflicts of interest.
and endocannabinoids.

liver cirrhosis was responsible for 47.9% of all liver

Introduction
mm caq eleka ja D kahjadea/
amhqxprm edxjg
Wine was given to men by the son of Semele and Zeus,
as oblivion of evils.
Alceo (630 BC - 560 BC) fr 346 V.
Alcohol represents the oldest and the most diffuse
abused substance. Since the dawn of literature, we
have received testimonies about the alcohol,
described by Alceo as oblivion of evils in this frag-
ment dating back to VI century BC. With its quali-
ties, alcohol, always integrated in our culture, still
remains the most commonly used addictive sub-
stance and most prevalent cause of advanced liver
disease worldwide (1). In 2010, alcohol-attributable
cirrhosis deaths, representing 0.9% of all deaths
because of any cause (2). Alcohol use disorder
(AUD) is defined, by Diagnostic and Statistical
Manual of Mental Disorders 5th edition (DSM-5),
as a problematic patterns of alcohol use leading to
clinically significant impairment or psychological
distress (3). The association between alcohol con-
sumption and fatty liver was described first by Tho-
mas Addison in 1836, but only in 1965, Lieber
et al. identified alcohol as a direct hepatotoxin,
showing that fatty liver is not simply because of
malnutrition (4,5).
The ALD comprises a large spectrum of liver
injuries, ranging from simple steatosis to alcoholic
steatohepatitis (ASH) and cirrhosis. The earliest
response to alcohol consumption is represented by
fatty liver. It occurs in 90% of individuals who

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Int J Clin Pract, February 2016, 70, 2, 119131. doi: 10.1111/ijcp.12764 119
120 Pharmacotherapy of alcoholic liver disease
drink more than 60 g/day of alcohol (6), or even
less (5), and it is the only stage of ALD completely
reversible with the abstinence, although in 510%
of patients the progression to liver fibrosis may
happen despite abstinence (7). Conversely, during
continued alcohol intake (> 40 g/day), steatosis can
be superimposed by an inflammatory infiltrate, the
condition defined as ASH, which may evolve to
fibrosis or cirrhosis in 2040% of patients (8). The
progression to liver fibrosis usually is asymptomatic,
except in the cases of heavy alcohol abuse
(> 100 g/daily), in these patients, in fact, may occur
episodes of aggressive alcoholic hepatitis (AH) (9).
AH is accompanied by jaundice, hepatomegaly, spi-
der angiomas and/or non-specific symptoms of liver
failure, including fever, anorexia, weight loss, nau-
sea, vomiting, ascites and encephalopaty (10). Cir-
rhosis is the irreversible end stage of ALD and, as
in other chronic liver disease, exposes the patients
to the risk of hepatic decompensation (ascites, vari-
ceal bleeding and encephalopathy) or hepatocellular
carcinoma (11).
A critical issue in order to change the natural
history of ALD is to identify and treat this disease
in the early stages, when the irreversible damages
are not yet present (12). It is also essential to know
the risk factors for the development of ALD,
including the drinking habits, in order to identify
as soon as possible the patients needing a more
aggressive treatment. Unfortunately, physicians often
fail to identify the so-called problem drinkers or
underestimate alcohol-related problems, and even
more frequently do not provide appropriate recom-
mendations (13). Despite the significant burden of
ALD on health, the attention of scientific research-
ers and the interest of pharmaceutical companies
are profoundly scarce in this field, in comparison
with other less morbid liver disease (1). As a conse-
quence, few therapeutic advances have been made
in the last 40 years and no new drugs have yet been
successfully developed.
The aim of this review was to summarise the
available data about the therapy of ALD in clinical
practice, particularly focusing on chronic alcoholic
hepatitis, and update the readership about the novel
therapies in this field.
Methods
To evaluate the available evidence on pharma-
cotherapy of chronic ALD, we performed a com-
puter based literature search in PubMed, Scopus,
Google Scholar and MEDLINE databases using the
medical subject headings alcoholic liver disease
and therapy. We limited the research to English
language publications and excluded reviews and
case reports. Eligible studies were limited to those
focusing on long-term therapy of ALD, i.e. more
than 1 month, in clinical setting. From the huge
literature on this topic, including about 755 studies,
75 were selected as eligible including clinical trials
and meta-analysis.
Risk factors
Alcohol consumption
The most important risk factor for the ALD develop-
ment is represented by the duration and amount of
alcohol consumption; nevertheless, a safe threshold
for these quantities has not reached an universal con-
sensus in scientific community (14). In fact, while
National Institute of Alcohol Abuse and Alcoholism
(NIAAA) defines as heavy drinkers men consuming
> 4 drinks daily (48 g of ethanol) or > 14 weekly
and women consuming > 2 drinks daily (24 g) or
> 7 weekly, other works indicate as unsafe lower
levels of alcohol intake. For example, a meta-analysis
has shown as 25 g of ethanol a day are already suffi-
cient to increase the risk of cirrhosis (15). Moreover,
other authors demonstrated a high liver-related mor-
tality among men or women consuming only a daily
intake of ethanol of 1224 g (16). These levels are
undoubtedly lower than the limits defined by
NIAAA, but also of most public health recommenda-
tions (13). Even the pattern of drinking has been
identified as risk factor: some evidences indicate that
binge drinking (defined by NIAAA as consumption
of 5 for male or 4 for female drinks in the space
of about 2 h) and drinking outside meals may
increase the risk of ALD (17,18).
Obesity
Epidemiological evidence shows that obesity is a risk
factor for developing steatohepatitis or cirrhosis in
alcoholics, if compared with non-obese alcoholics or
obese non-alcoholics (19). Moreover an experimental
indicated a potential synergism between alcohol and
obesity through the nitrosative stress mediated by
type I macrophage activation, adiponectin resistance
and accentuated endoplasmatic reticulum and mito-
chondrial response to stress (20).
Gender
Given an equal daily alcohol intake, women are
reported to develop ALD faster than men. Moreover,
a higher risk is reported also for lower quantities of
consumption (up to 12 g/day) (21). This increased
risk is likely because of lower levels of gastric alcohol
dehydrogenase, synergistic oxidative stress of estro-
gens and higher proportion of body fat (7).
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Genetics
Although the importance of a genetic susceptibility
for advanced ALD has been demonstrated in studies
of twins, no genetic variation has been confirmed as
a risk factor for ALD (22,23). A recent meta-analysis
of 50 casecontrol studies found no association
between ALD and SNPs genes coding for alcohol
dehydrogenase (ADH), aldehyde dehydrogenase
(ALDH) and cytochrome P450 2E1 (24). Recently
two observational studies showed an association
between the variants of gene patatin-like phospholi-
pase domain-containing protein 3 (PNPLA3) and risk
of alcoholic cirrhosis (25,26).
Comorbidities
Finally, liver comorbidities like hepatitis B or C,
non-alcoholic fatty liver disease (NAFLD) and
hemocromatosis may accelerate progression of ALD.
Among these, several studies have focused on syner-
gism between hepatitis C and alcohol misuse that
may increase 30 times the risk of cirrhosis (27).
Diagnosis and prognosis
The diagnosis of ALD is established with a history of
habitual alcohol intake, physical signs and laboratory
abnormalities suggestive of liver disease. However,
often it is difficult to obtain exact information about
alcohol intake for the reluctance of patient to pro-
vide an adequate medical history. Physicians under-
estimate alcohol-related problems especially in the
early stages, when the disease is fully reversible (15).
Usually only in advanced stages it becomes a prob-
lem of hepatologic interest.
Quantity-frequency questionnaires can be useful to
identify patients with high-risk drinking habits. The
Alcohol Use Disorders Identification Test (AUDIT)
is recommended by European Association for the
Study of the Liver (EASL) (13) and American Associ-
ation for the Study of Liver Disease (AASLD) (28) as
gold standard. Compared with simpler CAGE ques-
tionnaire, it is able to identify drinkers at risk who
are not yet alcohol-dependent providing a measure
of alcohol intake (29,30). No individual laboratory
markers can identify ALD. Usually aminotransferase
activity is five- to eightfolds elevated with a AST/
ALT ratio typically greater than 2 in 7080% of
patients (31). Gamma glutamyltransferase (GGT) has
a high sensitivity in detecting daily ethanol consump-
tion > 50 g (73%) and it is often used for early
detection of alcohol misuse (32). Unfortunately, it
loses its specificity for alcohol in advanced liver dis-
ease and in obesity (33). Carbohydrate-deficient
transferrin is a new biomarker with high specificity
and combined with GGT its sensitivity increase to
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Pharmacotherapy of alcoholic liver disease 121
90% for men and 75% for women (34). A quite
accurate marker is ethyl glucuronide, an alcohol
metabolite, findable in urine for 45 days and in the
hair for 30 days after last alcohol use, allowing the
evaluation of long-term abstinence (35,36).
A liver biopsy is not essential in the management
of ALD, but in case of diagnostic uncertainty is a
useful tool to establish the diagnosis and exclude
other causes of liver diseases (37). Furthermore, dur-
ing severe AH, it is a fundamental tool to evaluate
the severity of disease and to differentiate AH from
decompensated cirrhosis (38). However, liver biopsy
is an invasive procedure with a not negligible mor-
bidity. Published guidelines recommended histologi-
cal confirmation only in patients with aggressive
forms of ALD or in patients with other suspected
factors of liver damage (13,28). However, no histo-
logical features are individually pathognomonic of
ALD, even if Altamirano et al. recently identified the
histological features associated with severity of AH
and proposed a novel histologic scoring system,
Alcoholic Hepatitis Histological Score (AHHS).
AHHS (calculated by stage of fibrosis, bilirubinosta-
sis, polimorphonuclear infiltration and megamito-
condrial) may be an accurate predictor system to
stratify patient survival, but this score deserves future
investigation (39).
The decision to undertake a specific pharma-
cotherapy in AH is based on the assessment of the
prognosis. In fact mild and moderate forms of AH
simply respond to abstinence, whereas patients with
severe AH (up to 40% of mortality within 6 months)
should be considered for steroid or pentoxifylline
therapy. Although at present there are no specific
therapies for chronic ALD, the prognosis of patients
with advanced ALD, as well as those with others aeti-
ologies could be eventually assessed, at least, for the
evaluation of a possible liver transplantation (LT).
Several scoring system are available to assess the
severity and the prognosis of liver disease. Child
TurcottePugh (CTP) score and Model for End-stage
Liver Disease (MELD) are applicable to all aetiologies
of cirrhosis, while Madreys Discriminant Function
(MDF) and Glasgow Alcoholic Hepatitis Score
(GAHS) and Age-Bilirubin-INR-Creatinin (ABIC)
score have been proposed exclusively in the setting
of AH. MELD score, including serum bilirubin level,
creatinine level and international normalisation ratio
(INR), is relatively accurate in predicting 3 months
mortality and it is also used to prioritise LT candi-
dates (40,41). MDF, which includes only PT and
serum bilirubin, is validated as a reproducible crite-
rion to predict early mortality and select AH patients
likely to benefit from corticosteroids therapy (42,43).
Severe form of AH are defined by AASLD as
122 Pharmacotherapy of alcoholic liver disease

MDF 32 or MELD 18, with mortality ranging
from 30% to 60% without therapy (28). Several
studies have demonstrated the utility to evaluate
early improvement in liver function repeating calcu-
lation of prognostic test during the hospitalisation
(44). A change 2 points in the MELD score or a
reduction in serum bilirubin, evaluated by Lille score,
in the first week have been shown to predict in-hos-
pital mortality (45,46). GAHS and ABIC have been
tested against the MDF and CTP demonstrating a
higher diagnostic accuracy in predicting 28 days and
90 days outcome, but the proposed cut-offs of these
score need to be evaluated (47,48).
Pharmacotherapy
The optimal pharmacotherapy of chronic alcoholic
hepatitis is based on the stage and the severity of the
liver disease. In all patients, early management of
alcohol abuse or addiction is critical, so available
pharmacotherapies or psychotherapies should be
provided to ensure the abstinence (28). The drugs
approved for the treatment of alcohol dependence
(AD), are reported in Table 1. ALD can be associated
with malnutrition, which is related to higher mortal-
ity rates (49). In patients with cirrhosis, the eventual
complications (i.e. encephalopathy, ascites, variceal
bleeding) should be treated in the same way as
patients with non-ALD (28). As already described in
a previous review of our group, in severe forms of
alcoholic hepatitis specific drug treatments are rec-
ommended, including glucocorticoids (predinisolone
40 mg for 28 days) or pentoxifylline (400 mg orally
for 4 week) (50). Instead, for the long-term manage-
ment of ALD, specific treatments aimed at stopping
the progression of fibrosis are not yet approved.

Table 1 Drugs until now approved for the treatment of AD

Mechanisms of
action Clinical use Contraindications Dosage

Disulfiram Irreversible inhibitor Deterrent to alcohol intake to be
of ALDH used in patients highly motivated
Treatment should be integrated
within a psychotherapeutic
programme
Naltrexone Antagonist of j- and Anticraving medication reducing
l-opioid receptor pleasant effects of alcohol
Nalmefene Antagonist of d- and Indicated during a programme of
l-opioid receptor alcohol reduction in patients with
and j-opioid a high drinking risk (60 g/day for
receptor partial man and 40 g/day for woman)
agonist and without AWS and/or need of
immediate alcohol detoxification.
Acamprosate N-methyl-D-aspartate Anticraving medication with
glutamate receptor unknown mechanism of action.
antagonist Indicated for the maintenance of
abstinence during a psychological
support programme
Sodium GABAB receptor Anticraving medication with
oxybate agonist alcohol-mimicking property.
Indicated for the suppression of
AWS
Indicated for the initial phase and
the long-term treatment of AD
Severe liver disease, peripheral
neuropathy and optical neuritis,
metronidazole or paraldehyde use,
psychosis, cardiovascular disease,
nursing
Currently using opioids or acute
opioid withdrawal, severe liver
disease, pregnancy.
Treatment should be preceded by
naloxone challenge test (0.2
0.6 mg intravenously or 0.8
subcutaneously)
Currently using opioids or acute
opioid/alcohol withdrawal, severe
liver disease, severe renal
impairment (creatinine clearance
< 30 ml/min)
Severe renal impairment (creatinine
clearance < 30 ml/min)
Poly-drug addiction, psychiatric
comorbidities, epilepsy, pregnancy
8001200 mg/day in a single dose
for 34 day, then 400 mg/day
until the 7th day, then 200 mg/
day for 56 months
50100 mg/day orally or an
intramuscular injection of 380 mg
of long-acting formulation every
30 days for 36 months
Dosages: 18 mg orally as-needed
for 6 months
Dosages: for patients 60 kg 2
tablet of 333 mg in 3 oral
administrations; for patients
< 60 kg two tablets with the
morning meal, one with the
midday meal, and one with the
evening meal
50100 mg/kg/day every 46 h for
710 days to treat AWS or initial
phase of AD; 5075 mg/kg/day
every 68 h for 312 months for
long-term treatment of AD

AD, alcohol dependence; ALDH, aldehyde deidrogenase; AWS, alcohol withdrawal syndrome.

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Abstinence
Regardless the stage and the severity of liver dis-
ease, abstinence still represents the only cornerstone
of therapy in ALD (51). As previously mentioned,
alcoholic fatty liver can be completely reverted after
46 weeks of discontinuation of alcohol intake (9),
but abstinence can also improve clinical outcomes
through a significant decrease in cirrhosis progres-
sion and portal hypertension (52). In addition,
active alcohol use is a contraindication to LT. The
risk of recidivism after abstinence is very high in
all patients at any time, in fact no risk factors were
identified to predict relapse (53). Reported rates of
recidivism vary considerably between 0% and 95%
(53), partly because of definition used, and, as
reported in a meta-analysis of Miller et al. total
abstinence rates range from 17% to 35% (54). Sev-
eral medications have been tested to prevent alco-
hol relapse and increase the abstinence, but only a
few are currently approved for the treatment of
AD.
ALDH inhibitors
The first drug approved for the treatment of AD
was disulfiram (DF), an irreversible inhibitor of
ALDH. DF, if taken while drinking, increases the
concentration of acetaldehyde leading to disulfiram-
alcohol reaction that can deter the patients from
drinking alcohol again, developing symptoms like
nausea, flushing, vomit and hypotension. Therefore,
it helps to prevent relapse in compliant patients, as
explained by Soyka and Rosner (55), as there is a
strong relationship between adherence to therapy
and complete abstinence (56). The data about its
efficacy are varied (57), but a recent review showed
that all clinical studies published from 2000 to
2008 confirm the effective therapeutic utility of DF
and suggesting that low-dose regimen (100 mg/
day), integrated into psychotherapeutic programme,
can have better results (58). DF is not recom-
mended in advanced ALD, and monitoring hepato-
toxicity should be done because of a possible
idiosyncratic dose-independent reaction associated
to this drug (55). Daidzin is a selective reversible
inhibitor of mitochondrial ALDH-2. It is an extract
of Kudzu, a plant used for over 1000 years in tra-
ditional Chinese medicine, which showed to be
effective in reducing alcohol consumption in a US
study (59). Daidzin, in the animal model, reduces
alcohol intake surprisingly without increasing
acetaldehyde (60). CVT-10216 was synthesised on
the basis of Daidzin and it is a promising novel
medication for the treatment of AD, but are not
yet available clinical data (61).
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Pharmacotherapy of alcoholic liver disease 123
Opioid antagonists
Naltrexone (NTX) and nalmefene are two opioid
antagonist that controls the craving of alcohol reduc-
ing its euphoric effects (62). A Cochrane review of
50 randomised controlled trials (RCTs) and a meta-
analysis of 24 RCTs showed that short-term treat-
ment with naltrexone reduce the risk of relapse but
not prevent the return to drinking (63,64). At dose
of 50 mg/day NTX has poor hepatotoxicity and good
tolerability, with nausea the most common side
effects (65). Nevertheless, it is contraindicated in
advanced liver disease. In addition, because of risk of
severe withdrawal, NTX may not be provided in
patients using opioids (66). Long-acting injectable
formulations of NTX were introduced to improve
the medication compliance, allowing a monthly dos-
ing of drug. Some RCTs, conducted on available for-
mulations, proved their efficacy in decrease heavy
drinking rates with well tolerated adverse events,
similar to those of oral formulation, but these find-
ings need to be supported by further investigations
(6770). Nalmefene is a novel opioid antagonist with
a chemical structure similar to naltrexone, and a
slightly different mechanism of action, including a
prolonged occupancy of l-opioid receptor (71) and
a partial agonist effect on j-opioid receptor (72).
Three RCTs, conducted on patients taking as-
needed, defined as self-identified high risk of drink-
ing alcohol situations, nalmefene 18 mg proved its
efficacy to reduce the number of heavy drinking days
per month and total alcohol consumption (7375).
In addition, nalmefene has no dose-dependent hepa-
totoxicity and the more frequently reported adverse
symptom is the nausea (76).
Acamprosate
Acamprosate (ACM) is a new drug with structural
similarities to the endogenous amino-acid N-acetyl
homotaurine, a functional glutamate antagonist (77).
Although its exact mechanism of action is not clear,
ACM, with antagonistic effects on NMDA glutamate
receptors, can restore the balance between excitatory
and inhibitory neurotransmission altered after
chronic alcohol consumption (78,79). Various meta-
analyses confirm the clinical efficacy of ACM in
reducing withdrawal symptoms, including alcohol
craving and in maintaining abstinence (80,81). Its
effect is more considerable on maintenance of absti-
nence rather than inducing remission, and it should
be used in patients abstinent from alcohol at treat-
ment initiation within a comprehensive programme
of psychosocial support (82,83). A recent Cochrane
review of 24 RCTs showed that ACM reduce signifi-
cantly the risk of any drinking and significantly
124 Pharmacotherapy of alcoholic liver disease
increase the cumulative abstinence duration, calculat-
ing a number needed to treat of 9 to prevent an
additional recidivism (84). As a consequence of its
poor bioavailability, ACM is to be administered at
daily dose of 1998 mg (3 9 2 tablets of 333 mg) in
patients weighing more than 60 kg, and 1332 mg in
patients under 60 kg. Diarrhoea is the most com-
monly side effect but this adverse effect does not
seem to affect adherence to treatment (84). The
results obtained by studies on combination therapy
with DF are still conflicting and at present there are
no evidence to support these compared with a
monotherapy (63,84).
GABA-mediated compounds
Sodium oxybate (SO), a drug already approved for
the treatment of cataplexy in narcoleptic patients, is
the sodium salt of c-hydroxybutyric acid, which
exerts an agonistic effect on GABAB receptors simi-
larly to alcohol (85). SO proved to be as effective as
diazepam and chlormethiazole in suppressing alcohol
withdrawal syndrome (AWS) (86,87). Some RCTs
showed that SO is more effective than placebo in
achieving and maintaining abstinence in approxi-
mately 4070% of patients (88,89). In addition, a
recent Cochrane meta-analysis of 13 RCTs, confirm-
ing the favourable results of comparison with pla-
cebo, concluded that SO is more effective than NTX
and DF in maintaining alcohol abstinence and reduc-
ing alcohol craving (90). Moreover, two studies have
demonstrated that treatment with SO in combination
with NTX or DF was significantly superior in main-
taining complete abstinence from alcohol than
monotherapy (91,92). SO, at the dosage of 50
100 mg/kg/day, is generally well tolerated, and the
most common side effects are drowsiness, dizziness
and asthenia, which do not require drug discontinua-
tion, but disappear spontaneously. A controversial
point is the concern about the possibility of SO
addiction that has been reported in a small number
of patients. A Cochrane review highlighted that
patients with psychiatric comorbidities and poly-drug
addiction have significant risk of developing an
addiction or abuse of SO. This data suggest to use
SO only under strict medical surveillance (90).
Baclofen is a GABAB receptor agonist used for
years for treatment of spasticity in neurological dis-
orders and it is a new promise in alcohol pharma-
cotherapy (93). With its agonistic effect on the
postsynaptic GABAergic receptors of dopamine neu-
rons, baclofen reduces the dopamine release by
mesocorticolimbic system, which, disinhibited by
alcohol as well as by opioids and cannabinoids,
mediates the rewarding effects of these addictive sub-
stances (9497). As benzodiazepines, baclofen is
effective in controlling AWS (98,99). Moreover, in
two double-blind RCTs, our group showed that
baclofen, at dose of 3 9 10 mg, is more effective
than placebo in inducing and maintaining abstinence
as well as reducing alcohol craving and consumption
(100,101), although in another study these data were
not confirmed (102). Furthermore, in two recent
studies was demonstrated a baclofen dose-effect rela-
tionship on the reduction of daily alcohol intake,
suggesting that the dose of baclofen administered
should be tailored to the degrees of the severity of
the dependence (103,104). Notably, baclofen is meta-
bolised in the liver to a smaller extent ( 15%) (93),
for this reason shows an excellent safety and tolera-
bility in patients with cirrhosis and in combination
with alcohol (105,106).
With a mechanism of action similar to the baclo-
fen, the anticraving action of topiramate seems to be
linked to the reduction of dopamine release by
mesocorticolimbic system (107). Two double-blind
RCTs showed a greater efficacy of topiramate,
administered to initial dosage of 25 mg/day and pro-
gressively increased at maintenance dose of 300 mg/
day for 3 months, compared with placebo in decreas-
ing the percentage of heavy drinking days and
increasing cumulative abstinence duration (108,109).
Topiramate has a good tolerability especially when
titrated slowly to a maximum dosage of 300 mg
daily, although an optimal dose has still to be deter-
mined and lower dose may be also effective (110).
Psychotherapy
Beside the pharmacotherapy, as regards the psy-
chotherapy for abstinence, in literature several evi-
dences show that brief intervention is an effective
method to reduce alcohol consumption and alcohol-
related morbidity and mortality (111,112). Brief
interventions include motivational interview and
counselling for a short period of time. Moreover, a
large RCT (113) showed beneficial in abstinence rates
of three psychotherapeutic treatments, including
cognitive-behavioural therapy, 12-step facilitation
therapy and motivational enhancement therapy
(114116).
Nutritional support and
supplementation
Alcoholic liver disease is often complicated by mal-
nutrition whose severity is linearly related with the
severity of liver disease (49). About 2060% of cir-
rhotic alcoholic outpatients and almost 100% of hos-
pitalised patients with AH show a state of
malnutrition (117). The malnutrition in ALD is
caused by multiple factors including: (i) a poor
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dietary intake because of the anorexia and dysgeusia
exacerbated by zinc and magnesium deficiency; (ii) a
disproportionate amount of calories from alcohol
and subsequent micronutrient and vitamin defi-
ciency; (iii) impairment of gastrointestinal mucosal
absorption caused by alcohol; (iv) hypermetabolic/
catabolic state because of the metabolism of alcohol
through microsomal oxidation and because of an
increased gut permeability with translocation of gut-
derived bacteria and endotoxins into circulation pro-
voking cytokine-induced inflammatory response
(117). A relationship between voluntary food intake
and 6-month mortality was showed by Mendenhall
et al. in a study on male veterans with AH, in this
study patients consuming more than 3000 kcal a day
had virtually no mortality, whereas those consuming
less than 1000 kcal showed 80% of mortality (118).
A review of 13 studies by Stickel et al. demonstrates
the beneficial effect of oral nutritional supplements
or enteral nutrition to improve the survival in
patients with ALD (119). Among these studies, two
RCTs showed significant benefits to use a long-term
branched chain amino acids (BCAA) oral supple-
mentation therapy (120,121). BCAA, that are valine,
leucine and isoleucine, increase the protein synthesis,
ameliorating peripheral muscle wasting and stimulate
hepatic regeneration improving biochemical profiles
and ChildPugh scores (122). Marchesini et al.
demonstrated a beneficial effect of nutritional sup-
port with BCAA, assessed by frequency of hospital
admission and duration of hospital stay, in 174
patients with alcohol cirrhosis treated for 1 years
(121). Furthermore, in the same study are shown
improvements in liver function and nutritional status
in the BCAA group compared with the control
group, despite the lack of compliance to BCAA sup-
plementation because of the low palatability (121).
In another large RCT conducted on 646 patients
with decompensated cirrhosis, is showed that the use
of BCAA granules supplementation administered for
2 years improves event-free survival, the albumin
concentration and quality of life (120). Granules for-
mulations appear to have a better palatability com-
pared with powdered formulations, thereby
improving patient compliance. Enteral nutritional
therapy in patients with severe ALD, is preferred for
its advantages including low cost, maintenance of gut
mucosal integrity, prevention of bacterial transloca-
tion and decreased risk of infections (123). Further-
more, nutritional support also reduces the
complications after LT (123).
On the contrary, a recent Cochrane review of 37
RCTs not justify completely the use of enteral/par-
enteral nutrition or oral nutritional supplementation
in advanced liver disease, even though the authors
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Pharmacotherapy of alcoholic liver disease 125
mentioned an improvement in serum bilirubin level,
nitrogen balance and hepatic encephalopathy (124).
However, AASLD recommends that patients with
alcoholic cirrhosis should receive frequent interval
feedings, emphasising breakfast and night-time
snacks in order to ensure an oral diet that includes
1.21.5 g of protein/kg per day and 3540 kcal/kg, to
improve nitrogen balance (28). Cirrhotic patients
should receive at least a diet with normal protein
intake; in fact, the proteins restriction has not been
shown to have beneficial effects on the prevention of
episodes of encephalopathy (125).
Although, a severe malnutrition can lead to serious
complications of liver disease (i.e. encephalopathy,
ascites, hepato-renal syndrome), ALD patients are
also frequent have specific nutritional deficiencies,
including fat-soluble vitamins (A, D, E and K),
folate, thiamine (vitamin B1), vitamin B6, vitamin
B12 and elements as zinc and magnesium (Table 2).
Additionally, specific chemical interactions of ethanol
oxidation at least in part may exacerbate the effects
of these deficiencies, for example, acetaldehyde dis-
places the active form of pyridoxal phosphatase (vita-
min B6). These nutritional deficiencies may develop
specific extrahepatic manifestations and complica-
tions (i.e. Wernickes encephalopathy or peripheral
neuropathy in thiamine deficit; anaemia in folate
deficit); therefore, after a regular assessment of
Table 2 Possible nutrient deficiencies in ALD
Nutrient
deficiency Possible manifestations
Vitamin A Night blindness, dry skin
Thiamine Wernickes encephalopathy, Korsakoffs
psychosis, optic neuropathy, peripheral
neuropathy
Acid Folic Megaloblastic anaemia, depression, altered
methionine metabolism
Vitamin D Osteoporosis, depression
Vitamin E Possible increased susceptibility to liver
injury, oxidative stress
Niacin Pellagra dermatitis, depression,
hallucinations, vomiting and diarrhoea
Pyridoxine Hypocromic anaemia
Zinc Skin lesions, anorexia nervosa, oral
ulceration, impaired immune function,
diarrhoea, drepression, hypogonadism,
impaired night vision, increased
susceptibility to liver injury
Magnesium Muscle cramps, lethargy, impaired memory
and cognitive function, glucose intolerance
Selenium Myopathy, cardiomiopathy, oxidative stress
ALD, alcoholic liver disease.
126 Pharmacotherapy of alcoholic liver disease
patients for mineral and vitamin deficiencies, appro-
priate supplementations must be provided (49).
Medical therapy of alcoholic liver
disease
Unlike pharmaceutical drugs used to support absti-
nence, few therapeutic advances have been made in
the field of drugs direct acting on the liver. Currently
medical therapy has been proven to improve survival
in long-term management; as a consequence, no
therapeutic approach was approved for chronic ALD.
Thus, we will briefly discuss the drugs tested until
now to the long-term treatment of ALD.
Hepatoprotective agents
Propylthiouracil (PTU), an antithyroid drug that is
able to protect rat liver against ethanol-induced alter-
ations, has been tested by Orrego et al. on ALD
patients by long-term RCTs (2 years), achieving a
significant reduction in mortality compared with pla-
cebo group (126). The same group, through an addi-
tional analysis of this study, provided supplementary
data on the influence of this outcome by dropouts,
by alcohol consumption and by adverse events in the
order to enable a better assessment of PTU therapeu-
tic effectiveness (127). The rational use of PTU was
to decrease the hypermetabolic state induced by alco-
hol (128). Despite this result, a Cochrane meta-ana-
lysis of five short-term treatment PTU RCTs and
only one long-term treatment PTU RCT, did not
show any significant effect of PTU on liver-related
mortality, liver complication and liver histology
(129). Colchicine is an anti-inflammatory and antifi-
brotic drug, which has also been tested on patients
with alcoholic and non-alcoholic liver fibrosis by sev-
eral RCTs. Although some studies showed an efficacy
of colchicine in improving survival and liver fibrosis
in treated patients (130), most of RCTs disagree with
these outcomes (131). Also in this case a systematic
review of 15 RCTs, that include patients with any
type of liver fibrosis or cirrhosis, has not reported
benefit on overall mortality and liver-related mortal-
ity, while showed an increased risk of adverse events
related to colchicine therapy (132). As a consequence
of these findings, AASLD not recommends the use of
PTU or colchicine in ALD patients.
Special nutrients
S-adenosyl L-methionine (SAMe) is a precursor of
glutathione, the main cellular antioxidant, which is
involved in processes of liver detoxification via mul-
tiple mechanisms, including maintenance of mito-
chondrial function and down-regulation of TNF-a
(133). Already largely used as dietary supplement in
depression disease, SAMe has also been studied for
liver disease and a RCT indicated a significant
improvement of survival and delay of liver transplan-
tation in ALD patients treated with SAMe 1.2 g/day
for 2 years compared with placebo (134). Despite
this promising result, a meta-analysis of nine RCTs
by Cochrane did not showed any significant benefit
of treatment with SAMe (135). Furthermore a recent
study, evaluating the effect of SAMe treatment
(1.2 g/day) compared with placebo for 24 week by
clinical, biochemical and histological parameters,
concluded that SAMe was not more effective than
placebo in treatment of ALD (136). Beside SAMe,
was also evaluated the polyenylphosphatidyl choline
(PPC), an extract of soybean that was demonstrated
unable to restore the membrane damage in ALD,
and its effectiveness in preventing the progression of
alcohol-induced liver fibrosis (137). A multicentre
prospective RCT showed that the treatment with
1.5 g 9 3 of PPC for 2 years did not affect the pro-
gression of liver fibrosis (138). At present AASLD
limits the use of SAMe and PPC exclusively in clini-
cal trials (28).
Complementary medicine
Silymarin is an extract of milk thistle composed by
mixture of flavinolignans, of which silybin is the
most active (139). The mechanism of hepatoprotec-
tive action of silymarin is not yet clear, but probably
is because of its antioxidant action, including inhibi-
tion of lipid peroxidation and scavenging of free rad-
icals (140). On the basis of its protective activity
against various hepatotoxic substance showed on
experimental animals, several RCTs have tested the
benefits of silymarin in ALD (139). One study, con-
ducted on cirrhotic patients treated with 140 mg of
silymarin three times a day, showed a reduction on
mortality compared with placebo group (141). How-
ever, a Cochrane systematic review of 13 RCTs, also
because of the poor quality of the studies analysed,
not found a significant influence of silymarin on the
course of patients with ALD, suggesting the need of
high-quality trials (142). In recent years, increasing
attention has been paid in the field of herbal medi-
cine, as a newly emerging treatment for ALD (143).
However, despite extensive experimental evidences,
data from clinical trials still were not produced
(143).
Liver transplantation
In North America and Europe, ALD is the most
common indications for LT (144,145). Nevertheless,
only 5% of patients with alcoholic cirrhosis are for-
mally evaluated for LT, probably because ALD is
2015 John Wiley & Sons Ltd
Int J Clin Pract, February 2016, 70, 2, 119131

perceived as a self-induced disease and risk of recidi-
vism to alcohol use still represents the principal ethi-
cal concern to support transplantation in alcoholics
(146). Recidivism rates, defined as any alcohol
intake, varies between 11% and 49% at 35 years
after LT (53,146149), but this definition of relapse
does not distinguish the occasional lapses from
harmful and addictive drinking (150). In fact the
rates of patients that revert to heavy alcohol abuse
are generally lower (1020%) (146,151). The main
risk factor for recidivism is the short duration of
alcohol abstinence, so AASLD and EASL recommend,
beside a medical and psychological evaluation, a 6-
month period of abstinence before LT as minimal
listing criteria in order to reduce the risk of relapse
(13,28). Occasionally this time period, in patients
with early liver disease, may leads to clinical
improvements to render LT unnecessary (28). How-
ever, 6-month rule is not accepted worldwide, espe-
cially because not consider patients with severe AH
at high risk of death or advanced liver disease, in
which liver function does not make possible a wait-
ing for 6 months (152). A multicentre study showed
that early LT improves the 6-month survival among
patients with first episodes of severe AH that not
responding to medical therapy (153). In this field, as
showed by Addolorato et al. a shorter pre-LT time
may be considered in patients strictly followed by an
alcohol addiction unit, which, inserted within a
transplant centre, may be a useful resource to reduce
the risk of alcohol recidivism both pre and after LT
(149). Furthermore, several evidence in literature
show that the survival rate at 10 years of follow-up
in ALD patient after LT is comparable and, at times,
better than non-ALD patients. Although graft rejec-
tion rates among ALD patients are similar than
non-ALD patients, on the contrary the infections,
cardiovascular events and de novo malignancies are
more common in patients with alcoholic cirrhosis,
and represent the major causes of post-LT mortality
(144,154156). The risk of de novo malignancies, 5%
before LT, increases to 55% after LT, probably as a
consequence of immunosuppressive therapy (157).
So these data confirm the importance of a regular
screening, in particular for skin cancer, and the
correction of the major risk factors like cigarette
smoking (13,158).
Future perspectives
The approach to long-term therapy remains one of
the most difficult challenges in the field of ALD.
Recently, translational research, using human liver
tissues, has identified novel potential therapeutic
approaches for AH, including IL-22/STAT-3 path-
2015 John Wiley & Sons Ltd
Int J Clin Pract, February 2016, 70, 2, 119131
Pharmacotherapy of alcoholic liver disease 127
way, TNF receptor superfamily, osteopontin, gut
microbiota and LPS, CXC chemokines, endocannabi-
noids and inflammasome (12). Of these, only few
seem to have a promising future in the treatment of
chronic alcoholic hepatitis.
Probiotics and antibiotics
An interesting new therapeutic approach focuses on
countering the pro-inflammatory action of gut-
derived LPS. Probiotics may restore the altered bac-
terial flora of alcoholic cirrhotic patients. A small
study showed that the administration of Lactobacillus
casei restores the normal neutrophil phagocytic
capacity and a RCT showed the efficacy of short-
term supplementation of probiotics (Bifidobacterium
and Lactobacillus species) to restore bowel flora and
improve liver enzyme levels (159,160). Rifaximin is a
non-absorbable antibiotic used in treatment of acute
hepatic encephalopathy and its role in the treatment
of ALD is being evaluated. A placebo-controlled RCT
demonstrated its efficacy in prevention of hepatic
encephalopathy through modification of gut micro-
biota and another study showed a significant reduc-
tion in plasma endotoxin concentration and hepatic
venous pressure gradient in patients treated for
28 days with rifaximin (161,162).
Caspase inhibitors
Some studies have shown that anti-apoptotic caspase
inhibitors are able to improve liver function and
fibrosis in patients with chronic HCV or nonalco-
holic hepatitis (163,164). In fact, patients with ALD
are found high levels of apoptotic hepatocyte, for
this reason these drugs could be a therapeutic option
(165).
Osteopontin
Osteopontin is an extracellular matrix protein, over-
expressed in ALD. A recent study showed that osteo-
pontin mediates the fibrogenic alcohol-induced
effects via HSCs activation (166). Inhibition of osteo-
pontin-mediated pathways might be effective for
amelioration of ALD. In this regard, a new study has
demonstrated on mice model that milk osteopontin,
through its gut protective effects, is effective in pre-
venting alcohol hepatotoxicity, averting hepatic
inflammation and steatosis. This could be a simple
effective nutritional therapeutic strategy (167).
Endocannabinoids
Endocannabinoids are involved in pathogenesis of
ALD. In mouse model, activation of cannabinoid
receptor 1 (CB1) on hepatic stellate cells (HSCs)
increases their fibrogenic activity, while CB1 inhibi-
tion slows the progression of fibrosis and protects
128 Pharmacotherapy of alcoholic liver disease

against ethanol-induced steatosis and hepatocellular
damage (168). Unfortunately, the therapeutic appli-
cations of antagonists CB1 are limited by their neu-
ropsychiatric side effects (168). Instead the
cannabinoid receptor 2 (CB2) mediates protective
effects by reducing hepatocyte steatosis and regulat-
ing the inflammatory activity of LPS on Kupffer cells
(169). Moreover, recent studies on mice model
shown that CB2 agonist reduced voluntary alcohol
intake (170). These data identify CB2 agonist as
promising therapeutic drugs for ALD management.
Conclusions
ALD is a relevant and, in some circumstances, com-
pletely reversible cause of liver-related morbidity and
mortality. Despite its significant burden on health-
care no major advance has been made in the man-
agement of ALD, especially in the field of long-term
treatments. Abstinence remains the basis of the cure
and the only certain way to improve the overall sur-
vival, being able to decrease portal hypertension and
cirrhosis progression. Nevertheless, some medications
are currently approved for the treatment of ALD,
and good clinical practice should provide a pharma-
cological treatment combined with psychotherapeutic
approach in order to support abstinence. Malnutri-
tion is a common presentation in ALD, especially
in alcoholic cirrhosis, thus a nutritional support
should be also considered as essential in the patient
management. Even if some medications, such as cor-
ticosteroids and pentoxifylline, are currently recom-
mended for the treatment of liver imbalance of AH,
no effective treatments have been yet approved for
the long-term management of ALD. Indeed, despite
some encouraging results of RCTs carried on PTU,
colchicine, SAMe or silymarin, no specific pharmaco-
logical agents have clearly demonstrated a survival
benefit. LT remains the only definitive treatment for
end-stage alcoholic cirrhosis, in patients with ade-
quate social support providing a 6-month period of
abstinence, but the organ availability is still the
major limiting factor. Very interestingly, some recent
studies on new drugs preliminary suggested a good
efficacy in the long-term treatment of ALD, but, to
the date, most of the results were obtained in animal
models or translational research models. Unfortu-
nately, these results have not yet been confirmed in
randomised clinical trials on human and it is difficult
to assess the real potential of these drugs in long-
term care of ALD at the moment.
Acknowledgements
This research did not receive specific funds.
We are very grateful to Dr. Valentina Peta,
Department of Health Science, University Magna
Graecia, of Catanzaro Italy, for technical assistance
to write this manuscript.
Authors contribution
Valerio Rosato wrote the manuscript; Ludovico Abe-
navoli wrote and revise the manuscript; Mario
Masarone, Alessandro Federico participated to study
conception and design, data analysis and interpreta-
tion, article drafting and revising it critically for
important intellectual content, and gave final
approval for publication. Marcello Persico is respon-
sible for the overall content as guarantor.

8 Sorensen TI, Orholm M, Bentsen KD et al. by general medical providers: results from a
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Paper received October 2015, accepted October 2015