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

2015 John Wiley & Sons Ltd


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 language publications and excluded reviews and
less (5), and it is the only stage of ALD completely case reports. Eligible studies were limited to those
reversible with the abstinence, although in 510% focusing on long-term therapy of ALD, i.e. more
of patients the progression to liver fibrosis may than 1 month, in clinical setting. From the huge
happen despite abstinence (7). Conversely, during literature on this topic, including about 755 studies,
continued alcohol intake (> 40 g/day), steatosis can 75 were selected as eligible including clinical trials
be superimposed by an inflammatory infiltrate, the and meta-analysis.
condition defined as ASH, which may evolve to
fibrosis or cirrhosis in 2040% of patients (8). The
Risk factors
progression to liver fibrosis usually is asymptomatic,
except in the cases of heavy alcohol abuse Alcohol consumption
(> 100 g/daily), in these patients, in fact, may occur The most important risk factor for the ALD develop-
episodes of aggressive alcoholic hepatitis (AH) (9). ment is represented by the duration and amount of
AH is accompanied by jaundice, hepatomegaly, spi- alcohol consumption; nevertheless, a safe threshold
der angiomas and/or non-specific symptoms of liver for these quantities has not reached an universal con-
failure, including fever, anorexia, weight loss, nau- sensus in scientific community (14). In fact, while
sea, vomiting, ascites and encephalopaty (10). Cir- National Institute of Alcohol Abuse and Alcoholism
rhosis is the irreversible end stage of ALD and, as (NIAAA) defines as heavy drinkers men consuming
in other chronic liver disease, exposes the patients > 4 drinks daily (48 g of ethanol) or > 14 weekly
to the risk of hepatic decompensation (ascites, vari- and women consuming > 2 drinks daily (24 g) or
ceal bleeding and encephalopathy) or hepatocellular > 7 weekly, other works indicate as unsafe lower
carcinoma (11). levels of alcohol intake. For example, a meta-analysis
A critical issue in order to change the natural has shown as 25 g of ethanol a day are already suffi-
history of ALD is to identify and treat this disease cient to increase the risk of cirrhosis (15). Moreover,
in the early stages, when the irreversible damages other authors demonstrated a high liver-related mor-
are not yet present (12). It is also essential to know tality among men or women consuming only a daily
the risk factors for the development of ALD, intake of ethanol of 1224 g (16). These levels are
including the drinking habits, in order to identify undoubtedly lower than the limits defined by
as soon as possible the patients needing a more NIAAA, but also of most public health recommenda-
aggressive treatment. Unfortunately, physicians often tions (13). Even the pattern of drinking has been
fail to identify the so-called problem drinkers or identified as risk factor: some evidences indicate that
underestimate alcohol-related problems, and even binge drinking (defined by NIAAA as consumption
more frequently do not provide appropriate recom- of 5 for male or 4 for female drinks in the space
mendations (13). Despite the significant burden of of about 2 h) and drinking outside meals may
ALD on health, the attention of scientific research- increase the risk of ALD (17,18).
ers and the interest of pharmaceutical companies
are profoundly scarce in this field, in comparison Obesity
with other less morbid liver disease (1). As a conse- Epidemiological evidence shows that obesity is a risk
quence, few therapeutic advances have been made factor for developing steatohepatitis or cirrhosis in
in the last 40 years and no new drugs have yet been alcoholics, if compared with non-obese alcoholics or
successfully developed. obese non-alcoholics (19). Moreover an experimental
The aim of this review was to summarise the indicated a potential synergism between alcohol and
available data about the therapy of ALD in clinical obesity through the nitrosative stress mediated by
practice, particularly focusing on chronic alcoholic type I macrophage activation, adiponectin resistance
hepatitis, and update the readership about the novel and accentuated endoplasmatic reticulum and mito-
therapies in this field. chondrial response to stress (20).

Gender
Methods
Given an equal daily alcohol intake, women are
To evaluate the available evidence on pharma- reported to develop ALD faster than men. Moreover,
cotherapy of chronic ALD, we performed a com- a higher risk is reported also for lower quantities of
puter based literature search in PubMed, Scopus, consumption (up to 12 g/day) (21). This increased
Google Scholar and MEDLINE databases using the risk is likely because of lower levels of gastric alcohol
medical subject headings alcoholic liver disease dehydrogenase, synergistic oxidative stress of estro-
and therapy. We limited the research to English gens and higher proportion of body fat (7).

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Pharmacotherapy of alcoholic liver disease 121

Genetics 90% for men and 75% for women (34). A quite
Although the importance of a genetic susceptibility accurate marker is ethyl glucuronide, an alcohol
for advanced ALD has been demonstrated in studies metabolite, findable in urine for 45 days and in the
of twins, no genetic variation has been confirmed as hair for 30 days after last alcohol use, allowing the
a risk factor for ALD (22,23). A recent meta-analysis evaluation of long-term abstinence (35,36).
of 50 casecontrol studies found no association A liver biopsy is not essential in the management
between ALD and SNPs genes coding for alcohol of ALD, but in case of diagnostic uncertainty is a
dehydrogenase (ADH), aldehyde dehydrogenase useful tool to establish the diagnosis and exclude
(ALDH) and cytochrome P450 2E1 (24). Recently other causes of liver diseases (37). Furthermore, dur-
two observational studies showed an association ing severe AH, it is a fundamental tool to evaluate
between the variants of gene patatin-like phospholi- the severity of disease and to differentiate AH from
pase domain-containing protein 3 (PNPLA3) and risk decompensated cirrhosis (38). However, liver biopsy
of alcoholic cirrhosis (25,26). is an invasive procedure with a not negligible mor-
bidity. Published guidelines recommended histologi-
Comorbidities cal confirmation only in patients with aggressive
Finally, liver comorbidities like hepatitis B or C, forms of ALD or in patients with other suspected
non-alcoholic fatty liver disease (NAFLD) and factors of liver damage (13,28). However, no histo-
hemocromatosis may accelerate progression of ALD. logical features are individually pathognomonic of
Among these, several studies have focused on syner- ALD, even if Altamirano et al. recently identified the
gism between hepatitis C and alcohol misuse that histological features associated with severity of AH
may increase 30 times the risk of cirrhosis (27). and proposed a novel histologic scoring system,
Alcoholic Hepatitis Histological Score (AHHS).
AHHS (calculated by stage of fibrosis, bilirubinosta-
Diagnosis and prognosis
sis, polimorphonuclear infiltration and megamito-
The diagnosis of ALD is established with a history of condrial) may be an accurate predictor system to
habitual alcohol intake, physical signs and laboratory stratify patient survival, but this score deserves future
abnormalities suggestive of liver disease. However, investigation (39).
often it is difficult to obtain exact information about The decision to undertake a specific pharma-
alcohol intake for the reluctance of patient to pro- cotherapy in AH is based on the assessment of the
vide an adequate medical history. Physicians under- prognosis. In fact mild and moderate forms of AH
estimate alcohol-related problems especially in the simply respond to abstinence, whereas patients with
early stages, when the disease is fully reversible (15). severe AH (up to 40% of mortality within 6 months)
Usually only in advanced stages it becomes a prob- should be considered for steroid or pentoxifylline
lem of hepatologic interest. therapy. Although at present there are no specific
Quantity-frequency questionnaires can be useful to therapies for chronic ALD, the prognosis of patients
identify patients with high-risk drinking habits. The with advanced ALD, as well as those with others aeti-
Alcohol Use Disorders Identification Test (AUDIT) ologies could be eventually assessed, at least, for the
is recommended by European Association for the evaluation of a possible liver transplantation (LT).
Study of the Liver (EASL) (13) and American Associ- Several scoring system are available to assess the
ation for the Study of Liver Disease (AASLD) (28) as severity and the prognosis of liver disease. Child
gold standard. Compared with simpler CAGE ques- TurcottePugh (CTP) score and Model for End-stage
tionnaire, it is able to identify drinkers at risk who Liver Disease (MELD) are applicable to all aetiologies
are not yet alcohol-dependent providing a measure of cirrhosis, while Madreys Discriminant Function
of alcohol intake (29,30). No individual laboratory (MDF) and Glasgow Alcoholic Hepatitis Score
markers can identify ALD. Usually aminotransferase (GAHS) and Age-Bilirubin-INR-Creatinin (ABIC)
activity is five- to eightfolds elevated with a AST/ score have been proposed exclusively in the setting
ALT ratio typically greater than 2 in 7080% of of AH. MELD score, including serum bilirubin level,
patients (31). Gamma glutamyltransferase (GGT) has creatinine level and international normalisation ratio
a high sensitivity in detecting daily ethanol consump- (INR), is relatively accurate in predicting 3 months
tion > 50 g (73%) and it is often used for early mortality and it is also used to prioritise LT candi-
detection of alcohol misuse (32). Unfortunately, it dates (40,41). MDF, which includes only PT and
loses its specificity for alcohol in advanced liver dis- serum bilirubin, is validated as a reproducible crite-
ease and in obesity (33). Carbohydrate-deficient rion to predict early mortality and select AH patients
transferrin is a new biomarker with high specificity likely to benefit from corticosteroids therapy (42,43).
and combined with GGT its sensitivity increase to Severe form of AH are defined by AASLD as

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Int J Clin Pract, February 2016, 70, 2, 119131
122 Pharmacotherapy of alcoholic liver disease

MDF 32 or MELD 18, with mortality ranging liver disease. In all patients, early management of
from 30% to 60% without therapy (28). Several alcohol abuse or addiction is critical, so available
studies have demonstrated the utility to evaluate pharmacotherapies or psychotherapies should be
early improvement in liver function repeating calcu- provided to ensure the abstinence (28). The drugs
lation of prognostic test during the hospitalisation approved for the treatment of alcohol dependence
(44). A change 2 points in the MELD score or a (AD), are reported in Table 1. ALD can be associated
reduction in serum bilirubin, evaluated by Lille score, with malnutrition, which is related to higher mortal-
in the first week have been shown to predict in-hos- ity rates (49). In patients with cirrhosis, the eventual
pital mortality (45,46). GAHS and ABIC have been complications (i.e. encephalopathy, ascites, variceal
tested against the MDF and CTP demonstrating a bleeding) should be treated in the same way as
higher diagnostic accuracy in predicting 28 days and patients with non-ALD (28). As already described in
90 days outcome, but the proposed cut-offs of these a previous review of our group, in severe forms of
score need to be evaluated (47,48). alcoholic hepatitis specific drug treatments are rec-
ommended, including glucocorticoids (predinisolone
40 mg for 28 days) or pentoxifylline (400 mg orally
Pharmacotherapy
for 4 week) (50). Instead, for the long-term manage-
The optimal pharmacotherapy of chronic alcoholic ment of ALD, specific treatments aimed at stopping
hepatitis is based on the stage and the severity of the 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 Severe liver disease, peripheral 8001200 mg/day in a single dose
of ALDH used in patients highly motivated neuropathy and optical neuritis, for 34 day, then 400 mg/day
Treatment should be integrated metronidazole or paraldehyde use, until the 7th day, then 200 mg/
within a psychotherapeutic psychosis, cardiovascular disease, day for 56 months
programme nursing
Naltrexone Antagonist of j- and Anticraving medication reducing Currently using opioids or acute 50100 mg/day orally or an
l-opioid receptor pleasant effects of alcohol opioid withdrawal, severe liver intramuscular injection of 380 mg
disease, pregnancy. of long-acting formulation every
Treatment should be preceded by 30 days for 36 months
naloxone challenge test (0.2
0.6 mg intravenously or 0.8
subcutaneously)
Nalmefene Antagonist of d- and Indicated during a programme of Currently using opioids or acute Dosages: 18 mg orally as-needed
l-opioid receptor alcohol reduction in patients with opioid/alcohol withdrawal, severe for 6 months
and j-opioid a high drinking risk (60 g/day for liver disease, severe renal
receptor partial man and 40 g/day for woman) impairment (creatinine clearance
agonist and without AWS and/or need of < 30 ml/min)
immediate alcohol detoxification.
Acamprosate N-methyl-D-aspartate Anticraving medication with Severe renal impairment (creatinine Dosages: for patients 60 kg 2
glutamate receptor unknown mechanism of action. clearance < 30 ml/min) tablet of 333 mg in 3 oral
antagonist Indicated for the maintenance of administrations; for patients
abstinence during a psychological < 60 kg two tablets with the
support programme morning meal, one with the
midday meal, and one with the
evening meal
Sodium GABAB receptor Anticraving medication with Poly-drug addiction, psychiatric 50100 mg/kg/day every 46 h for
oxybate agonist alcohol-mimicking property. comorbidities, epilepsy, pregnancy 710 days to treat AWS or initial
Indicated for the suppression of phase of AD; 5075 mg/kg/day
AWS every 68 h for 312 months for
Indicated for the initial phase and long-term treatment of AD
the long-term treatment of AD

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

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Pharmacotherapy of alcoholic liver disease 123

Abstinence
Opioid antagonists
Regardless the stage and the severity of liver dis- Naltrexone (NTX) and nalmefene are two opioid
ease, abstinence still represents the only cornerstone antagonist that controls the craving of alcohol reduc-
of therapy in ALD (51). As previously mentioned, ing its euphoric effects (62). A Cochrane review of
alcoholic fatty liver can be completely reverted after 50 randomised controlled trials (RCTs) and a meta-
46 weeks of discontinuation of alcohol intake (9), analysis of 24 RCTs showed that short-term treat-
but abstinence can also improve clinical outcomes ment with naltrexone reduce the risk of relapse but
through a significant decrease in cirrhosis progres- not prevent the return to drinking (63,64). At dose
sion and portal hypertension (52). In addition, of 50 mg/day NTX has poor hepatotoxicity and good
active alcohol use is a contraindication to LT. The tolerability, with nausea the most common side
risk of recidivism after abstinence is very high in effects (65). Nevertheless, it is contraindicated in
all patients at any time, in fact no risk factors were advanced liver disease. In addition, because of risk of
identified to predict relapse (53). Reported rates of severe withdrawal, NTX may not be provided in
recidivism vary considerably between 0% and 95% patients using opioids (66). Long-acting injectable
(53), partly because of definition used, and, as formulations of NTX were introduced to improve
reported in a meta-analysis of Miller et al. total the medication compliance, allowing a monthly dos-
abstinence rates range from 17% to 35% (54). Sev- ing of drug. Some RCTs, conducted on available for-
eral medications have been tested to prevent alco- mulations, proved their efficacy in decrease heavy
hol relapse and increase the abstinence, but only a drinking rates with well tolerated adverse events,
few are currently approved for the treatment of similar to those of oral formulation, but these find-
AD. ings need to be supported by further investigations
(6770). Nalmefene is a novel opioid antagonist with
ALDH inhibitors a chemical structure similar to naltrexone, and a
The first drug approved for the treatment of AD slightly different mechanism of action, including a
was disulfiram (DF), an irreversible inhibitor of prolonged occupancy of l-opioid receptor (71) and
ALDH. DF, if taken while drinking, increases the a partial agonist effect on j-opioid receptor (72).
concentration of acetaldehyde leading to disulfiram- Three RCTs, conducted on patients taking as-
alcohol reaction that can deter the patients from needed, defined as self-identified high risk of drink-
drinking alcohol again, developing symptoms like ing alcohol situations, nalmefene 18 mg proved its
nausea, flushing, vomit and hypotension. Therefore, efficacy to reduce the number of heavy drinking days
it helps to prevent relapse in compliant patients, as per month and total alcohol consumption (7375).
explained by Soyka and Rosner (55), as there is a In addition, nalmefene has no dose-dependent hepa-
strong relationship between adherence to therapy totoxicity and the more frequently reported adverse
and complete abstinence (56). The data about its symptom is the nausea (76).
efficacy are varied (57), but a recent review showed
that all clinical studies published from 2000 to Acamprosate
2008 confirm the effective therapeutic utility of DF Acamprosate (ACM) is a new drug with structural
and suggesting that low-dose regimen (100 mg/ similarities to the endogenous amino-acid N-acetyl
day), integrated into psychotherapeutic programme, homotaurine, a functional glutamate antagonist (77).
can have better results (58). DF is not recom- Although its exact mechanism of action is not clear,
mended in advanced ALD, and monitoring hepato- ACM, with antagonistic effects on NMDA glutamate
toxicity should be done because of a possible receptors, can restore the balance between excitatory
idiosyncratic dose-independent reaction associated and inhibitory neurotransmission altered after
to this drug (55). Daidzin is a selective reversible chronic alcohol consumption (78,79). Various meta-
inhibitor of mitochondrial ALDH-2. It is an extract analyses confirm the clinical efficacy of ACM in
of Kudzu, a plant used for over 1000 years in tra- reducing withdrawal symptoms, including alcohol
ditional Chinese medicine, which showed to be craving and in maintaining abstinence (80,81). Its
effective in reducing alcohol consumption in a US effect is more considerable on maintenance of absti-
study (59). Daidzin, in the animal model, reduces nence rather than inducing remission, and it should
alcohol intake surprisingly without increasing be used in patients abstinent from alcohol at treat-
acetaldehyde (60). CVT-10216 was synthesised on ment initiation within a comprehensive programme
the basis of Daidzin and it is a promising novel of psychosocial support (82,83). A recent Cochrane
medication for the treatment of AD, but are not review of 24 RCTs showed that ACM reduce signifi-
yet available clinical data (61). cantly the risk of any drinking and significantly

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124 Pharmacotherapy of alcoholic liver disease

increase the cumulative abstinence duration, calculat- effective in controlling AWS (98,99). Moreover, in
ing a number needed to treat of 9 to prevent an two double-blind RCTs, our group showed that
additional recidivism (84). As a consequence of its baclofen, at dose of 3 9 10 mg, is more effective
poor bioavailability, ACM is to be administered at than placebo in inducing and maintaining abstinence
daily dose of 1998 mg (3 9 2 tablets of 333 mg) in as well as reducing alcohol craving and consumption
patients weighing more than 60 kg, and 1332 mg in (100,101), although in another study these data were
patients under 60 kg. Diarrhoea is the most com- not confirmed (102). Furthermore, in two recent
monly side effect but this adverse effect does not studies was demonstrated a baclofen dose-effect rela-
seem to affect adherence to treatment (84). The tionship on the reduction of daily alcohol intake,
results obtained by studies on combination therapy suggesting that the dose of baclofen administered
with DF are still conflicting and at present there are should be tailored to the degrees of the severity of
no evidence to support these compared with a the dependence (103,104). Notably, baclofen is meta-
monotherapy (63,84). bolised in the liver to a smaller extent ( 15%) (93),
for this reason shows an excellent safety and tolera-
GABA-mediated compounds bility in patients with cirrhosis and in combination
Sodium oxybate (SO), a drug already approved for with alcohol (105,106).
the treatment of cataplexy in narcoleptic patients, is With a mechanism of action similar to the baclo-
the sodium salt of c-hydroxybutyric acid, which fen, the anticraving action of topiramate seems to be
exerts an agonistic effect on GABAB receptors simi- linked to the reduction of dopamine release by
larly to alcohol (85). SO proved to be as effective as mesocorticolimbic system (107). Two double-blind
diazepam and chlormethiazole in suppressing alcohol RCTs showed a greater efficacy of topiramate,
withdrawal syndrome (AWS) (86,87). Some RCTs administered to initial dosage of 25 mg/day and pro-
showed that SO is more effective than placebo in gressively increased at maintenance dose of 300 mg/
achieving and maintaining abstinence in approxi- day for 3 months, compared with placebo in decreas-
mately 4070% of patients (88,89). In addition, a ing the percentage of heavy drinking days and
recent Cochrane meta-analysis of 13 RCTs, confirm- increasing cumulative abstinence duration (108,109).
ing the favourable results of comparison with pla- Topiramate has a good tolerability especially when
cebo, concluded that SO is more effective than NTX titrated slowly to a maximum dosage of 300 mg
and DF in maintaining alcohol abstinence and reduc- daily, although an optimal dose has still to be deter-
ing alcohol craving (90). Moreover, two studies have mined and lower dose may be also effective (110).
demonstrated that treatment with SO in combination
with NTX or DF was significantly superior in main- Psychotherapy
taining complete abstinence from alcohol than Beside the pharmacotherapy, as regards the psy-
monotherapy (91,92). SO, at the dosage of 50 chotherapy for abstinence, in literature several evi-
100 mg/kg/day, is generally well tolerated, and the dences show that brief intervention is an effective
most common side effects are drowsiness, dizziness method to reduce alcohol consumption and alcohol-
and asthenia, which do not require drug discontinua- related morbidity and mortality (111,112). Brief
tion, but disappear spontaneously. A controversial interventions include motivational interview and
point is the concern about the possibility of SO counselling for a short period of time. Moreover, a
addiction that has been reported in a small number large RCT (113) showed beneficial in abstinence rates
of patients. A Cochrane review highlighted that of three psychotherapeutic treatments, including
patients with psychiatric comorbidities and poly-drug cognitive-behavioural therapy, 12-step facilitation
addiction have significant risk of developing an therapy and motivational enhancement therapy
addiction or abuse of SO. This data suggest to use (114116).
SO only under strict medical surveillance (90).
Baclofen is a GABAB receptor agonist used for
Nutritional support and
years for treatment of spasticity in neurological dis-
supplementation
orders and it is a new promise in alcohol pharma-
cotherapy (93). With its agonistic effect on the Alcoholic liver disease is often complicated by mal-
postsynaptic GABAergic receptors of dopamine neu- nutrition whose severity is linearly related with the
rons, baclofen reduces the dopamine release by severity of liver disease (49). About 2060% of cir-
mesocorticolimbic system, which, disinhibited by rhotic alcoholic outpatients and almost 100% of hos-
alcohol as well as by opioids and cannabinoids, pitalised patients with AH show a state of
mediates the rewarding effects of these addictive sub- malnutrition (117). The malnutrition in ALD is
stances (9497). As benzodiazepines, baclofen is caused by multiple factors including: (i) a poor

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Pharmacotherapy of alcoholic liver disease 125

dietary intake because of the anorexia and dysgeusia mentioned an improvement in serum bilirubin level,
exacerbated by zinc and magnesium deficiency; (ii) a nitrogen balance and hepatic encephalopathy (124).
disproportionate amount of calories from alcohol However, AASLD recommends that patients with
and subsequent micronutrient and vitamin defi- alcoholic cirrhosis should receive frequent interval
ciency; (iii) impairment of gastrointestinal mucosal feedings, emphasising breakfast and night-time
absorption caused by alcohol; (iv) hypermetabolic/ snacks in order to ensure an oral diet that includes
catabolic state because of the metabolism of alcohol 1.21.5 g of protein/kg per day and 3540 kcal/kg, to
through microsomal oxidation and because of an improve nitrogen balance (28). Cirrhotic patients
increased gut permeability with translocation of gut- should receive at least a diet with normal protein
derived bacteria and endotoxins into circulation pro- intake; in fact, the proteins restriction has not been
voking cytokine-induced inflammatory response shown to have beneficial effects on the prevention of
(117). A relationship between voluntary food intake episodes of encephalopathy (125).
and 6-month mortality was showed by Mendenhall Although, a severe malnutrition can lead to serious
et al. in a study on male veterans with AH, in this complications of liver disease (i.e. encephalopathy,
study patients consuming more than 3000 kcal a day ascites, hepato-renal syndrome), ALD patients are
had virtually no mortality, whereas those consuming also frequent have specific nutritional deficiencies,
less than 1000 kcal showed 80% of mortality (118). including fat-soluble vitamins (A, D, E and K),
A review of 13 studies by Stickel et al. demonstrates folate, thiamine (vitamin B1), vitamin B6, vitamin
the beneficial effect of oral nutritional supplements B12 and elements as zinc and magnesium (Table 2).
or enteral nutrition to improve the survival in Additionally, specific chemical interactions of ethanol
patients with ALD (119). Among these studies, two oxidation at least in part may exacerbate the effects
RCTs showed significant benefits to use a long-term of these deficiencies, for example, acetaldehyde dis-
branched chain amino acids (BCAA) oral supple- places the active form of pyridoxal phosphatase (vita-
mentation therapy (120,121). BCAA, that are valine, min B6). These nutritional deficiencies may develop
leucine and isoleucine, increase the protein synthesis, specific extrahepatic manifestations and complica-
ameliorating peripheral muscle wasting and stimulate tions (i.e. Wernickes encephalopathy or peripheral
hepatic regeneration improving biochemical profiles neuropathy in thiamine deficit; anaemia in folate
and ChildPugh scores (122). Marchesini et al. deficit); therefore, after a regular assessment of
demonstrated a beneficial effect of nutritional sup-
port with BCAA, assessed by frequency of hospital
admission and duration of hospital stay, in 174 Table 2 Possible nutrient deficiencies in ALD
patients with alcohol cirrhosis treated for 1 years Nutrient
(121). Furthermore, in the same study are shown deficiency Possible manifestations
improvements in liver function and nutritional status
in the BCAA group compared with the control Vitamin A Night blindness, dry skin
group, despite the lack of compliance to BCAA sup- Thiamine Wernickes encephalopathy, Korsakoffs
plementation because of the low palatability (121). psychosis, optic neuropathy, peripheral
In another large RCT conducted on 646 patients neuropathy
Acid Folic Megaloblastic anaemia, depression, altered
with decompensated cirrhosis, is showed that the use
methionine metabolism
of BCAA granules supplementation administered for
Vitamin D Osteoporosis, depression
2 years improves event-free survival, the albumin Vitamin E Possible increased susceptibility to liver
concentration and quality of life (120). Granules for- injury, oxidative stress
mulations appear to have a better palatability com- Niacin Pellagra dermatitis, depression,
pared with powdered formulations, thereby hallucinations, vomiting and diarrhoea
improving patient compliance. Enteral nutritional Pyridoxine Hypocromic anaemia
therapy in patients with severe ALD, is preferred for Zinc Skin lesions, anorexia nervosa, oral
its advantages including low cost, maintenance of gut ulceration, impaired immune function,
mucosal integrity, prevention of bacterial transloca- diarrhoea, drepression, hypogonadism,
tion and decreased risk of infections (123). Further- impaired night vision, increased
susceptibility to liver injury
more, nutritional support also reduces the
Magnesium Muscle cramps, lethargy, impaired memory
complications after LT (123).
and cognitive function, glucose intolerance
On the contrary, a recent Cochrane review of 37
Selenium Myopathy, cardiomiopathy, oxidative stress
RCTs not justify completely the use of enteral/par-
enteral nutrition or oral nutritional supplementation
ALD, alcoholic liver disease.
in advanced liver disease, even though the authors

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126 Pharmacotherapy of alcoholic liver disease

patients for mineral and vitamin deficiencies, appro- depression disease, SAMe has also been studied for
priate supplementations must be provided (49). 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
Medical therapy of alcoholic liver
for 2 years compared with placebo (134). Despite
disease
this promising result, a meta-analysis of nine RCTs
Unlike pharmaceutical drugs used to support absti- by Cochrane did not showed any significant benefit
nence, few therapeutic advances have been made in of treatment with SAMe (135). Furthermore a recent
the field of drugs direct acting on the liver. Currently study, evaluating the effect of SAMe treatment
medical therapy has been proven to improve survival (1.2 g/day) compared with placebo for 24 week by
in long-term management; as a consequence, no clinical, biochemical and histological parameters,
therapeutic approach was approved for chronic ALD. concluded that SAMe was not more effective than
Thus, we will briefly discuss the drugs tested until placebo in treatment of ALD (136). Beside SAMe,
now to the long-term treatment of ALD. was also evaluated the polyenylphosphatidyl choline
(PPC), an extract of soybean that was demonstrated
Hepatoprotective agents unable to restore the membrane damage in ALD,
Propylthiouracil (PTU), an antithyroid drug that is and its effectiveness in preventing the progression of
able to protect rat liver against ethanol-induced alter- alcohol-induced liver fibrosis (137). A multicentre
ations, has been tested by Orrego et al. on ALD prospective RCT showed that the treatment with
patients by long-term RCTs (2 years), achieving a 1.5 g 9 3 of PPC for 2 years did not affect the pro-
significant reduction in mortality compared with pla- gression of liver fibrosis (138). At present AASLD
cebo group (126). The same group, through an addi- limits the use of SAMe and PPC exclusively in clini-
tional analysis of this study, provided supplementary cal trials (28).
data on the influence of this outcome by dropouts,
by alcohol consumption and by adverse events in the Complementary medicine
order to enable a better assessment of PTU therapeu- Silymarin is an extract of milk thistle composed by
tic effectiveness (127). The rational use of PTU was mixture of flavinolignans, of which silybin is the
to decrease the hypermetabolic state induced by alco- most active (139). The mechanism of hepatoprotec-
hol (128). Despite this result, a Cochrane meta-ana- tive action of silymarin is not yet clear, but probably
lysis of five short-term treatment PTU RCTs and is because of its antioxidant action, including inhibi-
only one long-term treatment PTU RCT, did not tion of lipid peroxidation and scavenging of free rad-
show any significant effect of PTU on liver-related icals (140). On the basis of its protective activity
mortality, liver complication and liver histology against various hepatotoxic substance showed on
(129). Colchicine is an anti-inflammatory and antifi- experimental animals, several RCTs have tested the
brotic drug, which has also been tested on patients benefits of silymarin in ALD (139). One study, con-
with alcoholic and non-alcoholic liver fibrosis by sev- ducted on cirrhotic patients treated with 140 mg of
eral RCTs. Although some studies showed an efficacy silymarin three times a day, showed a reduction on
of colchicine in improving survival and liver fibrosis mortality compared with placebo group (141). How-
in treated patients (130), most of RCTs disagree with ever, a Cochrane systematic review of 13 RCTs, also
these outcomes (131). Also in this case a systematic because of the poor quality of the studies analysed,
review of 15 RCTs, that include patients with any not found a significant influence of silymarin on the
type of liver fibrosis or cirrhosis, has not reported course of patients with ALD, suggesting the need of
benefit on overall mortality and liver-related mortal- high-quality trials (142). In recent years, increasing
ity, while showed an increased risk of adverse events attention has been paid in the field of herbal medi-
related to colchicine therapy (132). As a consequence cine, as a newly emerging treatment for ALD (143).
of these findings, AASLD not recommends the use of However, despite extensive experimental evidences,
PTU or colchicine in ALD patients. data from clinical trials still were not produced
(143).
Special nutrients
S-adenosyl L-methionine (SAMe) is a precursor of
Liver transplantation
glutathione, the main cellular antioxidant, which is
involved in processes of liver detoxification via mul- In North America and Europe, ALD is the most
tiple mechanisms, including maintenance of mito- common indications for LT (144,145). Nevertheless,
chondrial function and down-regulation of TNF-a only 5% of patients with alcoholic cirrhosis are for-
(133). Already largely used as dietary supplement in mally evaluated for LT, probably because ALD is

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Pharmacotherapy of alcoholic liver disease 127

perceived as a self-induced disease and risk of recidi- way, TNF receptor superfamily, osteopontin, gut
vism to alcohol use still represents the principal ethi- microbiota and LPS, CXC chemokines, endocannabi-
cal concern to support transplantation in alcoholics noids and inflammasome (12). Of these, only few
(146). Recidivism rates, defined as any alcohol seem to have a promising future in the treatment of
intake, varies between 11% and 49% at 35 years chronic alcoholic hepatitis.
after LT (53,146149), but this definition of relapse
does not distinguish the occasional lapses from Probiotics and antibiotics
harmful and addictive drinking (150). In fact the An interesting new therapeutic approach focuses on
rates of patients that revert to heavy alcohol abuse countering the pro-inflammatory action of gut-
are generally lower (1020%) (146,151). The main derived LPS. Probiotics may restore the altered bac-
risk factor for recidivism is the short duration of terial flora of alcoholic cirrhotic patients. A small
alcohol abstinence, so AASLD and EASL recommend, study showed that the administration of Lactobacillus
beside a medical and psychological evaluation, a 6- casei restores the normal neutrophil phagocytic
month period of abstinence before LT as minimal capacity and a RCT showed the efficacy of short-
listing criteria in order to reduce the risk of relapse term supplementation of probiotics (Bifidobacterium
(13,28). Occasionally this time period, in patients and Lactobacillus species) to restore bowel flora and
with early liver disease, may leads to clinical improve liver enzyme levels (159,160). Rifaximin is a
improvements to render LT unnecessary (28). How- non-absorbable antibiotic used in treatment of acute
ever, 6-month rule is not accepted worldwide, espe- hepatic encephalopathy and its role in the treatment
cially because not consider patients with severe AH of ALD is being evaluated. A placebo-controlled RCT
at high risk of death or advanced liver disease, in demonstrated its efficacy in prevention of hepatic
which liver function does not make possible a wait- encephalopathy through modification of gut micro-
ing for 6 months (152). A multicentre study showed biota and another study showed a significant reduc-
that early LT improves the 6-month survival among tion in plasma endotoxin concentration and hepatic
patients with first episodes of severe AH that not venous pressure gradient in patients treated for
responding to medical therapy (153). In this field, as 28 days with rifaximin (161,162).
showed by Addolorato et al. a shorter pre-LT time
may be considered in patients strictly followed by an Caspase inhibitors
alcohol addiction unit, which, inserted within a Some studies have shown that anti-apoptotic caspase
transplant centre, may be a useful resource to reduce inhibitors are able to improve liver function and
the risk of alcohol recidivism both pre and after LT fibrosis in patients with chronic HCV or nonalco-
(149). Furthermore, several evidence in literature holic hepatitis (163,164). In fact, patients with ALD
show that the survival rate at 10 years of follow-up are found high levels of apoptotic hepatocyte, for
in ALD patient after LT is comparable and, at times, this reason these drugs could be a therapeutic option
better than non-ALD patients. Although graft rejec- (165).
tion rates among ALD patients are similar than
non-ALD patients, on the contrary the infections, Osteopontin
cardiovascular events and de novo malignancies are Osteopontin is an extracellular matrix protein, over-
more common in patients with alcoholic cirrhosis, expressed in ALD. A recent study showed that osteo-
and represent the major causes of post-LT mortality pontin mediates the fibrogenic alcohol-induced
(144,154156). The risk of de novo malignancies, 5% effects via HSCs activation (166). Inhibition of osteo-
before LT, increases to 55% after LT, probably as a pontin-mediated pathways might be effective for
consequence of immunosuppressive therapy (157). amelioration of ALD. In this regard, a new study has
So these data confirm the importance of a regular demonstrated on mice model that milk osteopontin,
screening, in particular for skin cancer, and the through its gut protective effects, is effective in pre-
correction of the major risk factors like cigarette venting alcohol hepatotoxicity, averting hepatic
smoking (13,158). inflammation and steatosis. This could be a simple
effective nutritional therapeutic strategy (167).
Future perspectives
Endocannabinoids
The approach to long-term therapy remains one of Endocannabinoids are involved in pathogenesis of
the most difficult challenges in the field of ALD. ALD. In mouse model, activation of cannabinoid
Recently, translational research, using human liver receptor 1 (CB1) on hepatic stellate cells (HSCs)
tissues, has identified novel potential therapeutic increases their fibrogenic activity, while CB1 inhibi-
approaches for AH, including IL-22/STAT-3 path- tion slows the progression of fibrosis and protects

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Int J Clin Pract, February 2016, 70, 2, 119131
128 Pharmacotherapy of alcoholic liver disease

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