Bioethics Paper

Treatment of Alcohol Use Disorder in Patients with Alcoholic
Liver Disease

Lorenzo Leggio, M.D., Ph.D., M.Sc.1,2 and Mary R. Lee, M.D.1

1Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National
Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National
Institutes of Health, Bethesda, MD

2Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown
University, Providence, RI

Abstract

Alcohol is a leading cause of liver disease worldwide. Although alcohol abstinence is the crucial

therapeutic goal for patients with alcoholic liver disease, these patients have less access to

psychosocial, behavioral and/or pharmacological treatments for alcohol use disorder. Psychosocial

and behavioral therapies include 12-step facilitation, brief interventions, cognitive behavioral

therapy, and motivational enhancement therapy. In addition to medications approved by the Food

and Drug Administration (FDA) for alcohol use disorder (disulfiram, naltrexone and acamprosate),

recent efforts to identify potential new treatments have yielded promising candidate

pharmacotherapies. Finally, more efforts are needed to integrate treatments across disciplines

toward patient-centered approaches in the management of patients with alcohol use disorder and

alcoholic liver disease.

Keywords

alcohol use disorder; liver disease; alcoholic liver disease; treatment

INTRODUCTION

Despite the mortality and morbidity resulting from alcohol use disorder(1), <10% of patients receive treatment for alcohol use disorder(2). There is a paucity of clinical trials in patients with alcoholic liver disease and little integration of addiction specialists into the medical Contact information: [email protected] (L. Leggio) and [email protected] (M.R. Lee), Section on Clinical Psychoneuroendocrinology, and Neuropsychopharmacology, NIAAA & NIDA, NIH, 10 Center Drive (10CRC/15330), Room 1-5429, Bethesda, MD 20892-1108, Phone: +1 301 435 9398. AUTHOR CONTRIBUTIONS Both authors contributed equally to all aspects of this manuscript. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author manuscript Am J Med. Author manuscript; available in PMC 2018 February 01. Published in final edited form as: Am J Med. 2017 February ; 130(2): 124–134. doi:10.1016/j.amjmed.2016.10.004. A u th o r M a n u scrip t A u th o r M a n u scrip t A u th o r M a n u scrip t A u th o r M a n u scrip t teams that care for these patients. This deficiency reflects nihilism, stigma, and a failure to link behavioral and traditional medical research. ALCOHOL USE DISORDER Neurobiology of Alcohol Use Disorder Alcohol use disorder is characterized by loss of control over alcohol consumption accompanied by changes in brain regions responsible for the execution of motivated behaviors, e.g.: midbrain, limbic and prefrontal cortex(3). Positive and negative reinforcement mechanisms play a role in the maladaptive pattern of alcohol consumption. As the severity of alcohol use disorder worsens, negative reinforcement mechanisms predominate where negative affective state is relieved by alcohol consumption, thus leading to relapse. Alcohol’s reinforcing effects are primarily mediated by dopamine, opioid peptides, gamma- aminobutyric-acid, and endocannabinoids(4), while negative reinforcement involves increased recruitment of corticotropin-releasing factor and glutamatergic systems, and down-regulation of gamma-aminobutyric-acid transmission(3, 4). Screening and Diagnosis of Alcohol Use Disorder Screening instruments for problematic drinking include the Cut down-Annoyed-Guilty- Eye opener (CAGE) and the Alcohol Use Disorders Identification Test (AUDIT) (Tables 1 and 2) (5, 6). The CAGE is short, may be easily implemented in primary care settings and assesses consequences of drinking. The latter makes it less sensitive as a screening tool for at-risk drinking and gives inconsistent results across different ethnicities(7). The AUDIT actually quantifies alcohol consumption and has been validated across different ethnicities(7). There is a brief version of the AUDIT, developed for use in primary care settings(8). The diagnosis of alcohol use disorder, set forth in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), is defined as a problematic pattern of drinking leading to clinically significant impairment and distress for at least 12 months (Table 3)(9). The gold standard to quantify alcohol consumption is the Timeline Followback, a semi- structured interview that is used mostly in research settings(10). Objective biomarkers of alcohol use are blood, breath or urine ethanol levels which are highly specific but only reflect very recent use. Ethyl glucuronide, a conjugated ethanol metabolite, is detected in urine several days after drinking and can be used reliably in regular drinkers(11). However, for a single drinking episode, the window of detection depends on the quantity of alcohol consumed.(12, 13) Carbohydrate-deficient transferrin (CDT) is a desialylated isoform of transferrin, increases with chronic heavy alcohol intake and is the most specific marker of alcohol use(14); however its sensitivity is limited, particularly in women, end-stage liver disease and overweight/obese individuals(15). Increased serum liver enzymes, alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transferase (GGT), are markers of inflammation and oxidative stress, and have low specificity for detecting alcohol use. Moderate drinking may cause elevations in liver enzymes in obese but not normal weight individuals(13); notably, ALT is more sensitive to Leggio and Lee Page 2 Am J Med. Author manuscript; available in PMC 2018 February 01. A u th o r M a n u scrip t A u th o r M a n u scrip t A u th o r M a n u scrip t A u th o r M a n u scrip t BMI and GGT to alcohol consumption. Phosphatidylethanol is an abnormal phospholipid generated from phosphatidylcholine in the presence of ethanol and is positive in blood more than 2 weeks after ethanol is cleared from the body(16). It is more sensitive than ethyl glucuronide for identification of current drinking(12) and is more sensitive compared to GGT and CDT(17). A combination of CDT with GGT improves the sensitivity of detecting heavy drinking without loss in specificity(13). CLINICAL STAGES OF ALCOHOLIC LIVER DISEASE The risk for alcoholic liver disease rises with increasing daily alcohol consumption with a threshold of 12–22 g/day in women and 24–46 g/day in men(18), however, this relationship is not dose-dependent(19). There are individual differences and risk factors, including genetic predisposition, age, gender, metabolic syndrome, diabetes, obesity, smoking, iron overload, and chronic hepatitis B or C(20, 21) that modify risk. Alcoholic liver disease comprises several forms ranging from relatively mild and reversible steatosis (fatty liver) and alcoholic hepatitis, to fibrosis and finally cirrhosis and hepatic failure(22). Fatty liver develops in about 90% of individuals who drink >60g/day of alcohol

and is generally reversible with 4–6 weeks abstinence(23, 24). About 25% of patients with

alcohol use disorder develop alcoholic hepatitis. Treatments for alcoholic hepatitis (e.g.:
prednisone and pentoxifylline) may have limited efficacy(25), which further highlights the

critical importance of treating the underlying alcohol use disorder(26). The severity of

alcoholic hepatitis can range from mild to severe and can be superimposed on chronic liver

disease(27). Prospective studies indicate that the recent, rather than lifetime alcohol

consumption, predicts alcoholic cirrhosis(19, 28, 29). While treatments for alcoholic liver

disease have been extensively reviewed elsewhere(30–34), this review (Box 1) focuses on

the treatment of the underlying problem in these patients, i.e. alcohol use disorder.

Box 1

Review Criteria

In April 2016, we searched PubMed using the following search terms: ‘alcohol use

disorder’, ‘liver disease’, ‘alcoholic liver disease’, ‘treatment’. The references from initial

papers identified were searched to identify additional references. We focused only on

papers written in English.

TREATMENT FOR ALCOHOL USE DISORDER IN PATIENTS WITH

ALCOHOLIC LIVER DISEASE

Despite evidence that outcomes improve with integration of psychosocial and medical

care(35), there are almost no randomized studies for behavioral and/or pharmacological

treatments in patients with alcohol use disorder and alcoholic liver disease. Alcohol

abstinence is the most important therapeutic goal for patients with alcoholic liver disease, as

abstinence can improve outcome at all stages of disease(36–38).

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Psychosocial and behavioral treatments

Brief interventions (Table 4) are a counseling strategy that can be delivered by a health care

provider during a 5–10 minute medical office visit. The intervention is aimed at educating

the patient about problematic drinking, increasing motivation to change behavior, and

reinforcing skills to address problematic drinking(39). In primary care settings, studies

support the use of brief interventions to reduce drinking(40, 41) particularly when the

intervention is repeated over multiple visits with follow-up telephone consultations(39).

Although brief interventions are not sufficient by themselves in those with very heavy use or

dependence(42), they can reinforce other therapeutic approaches such as compliance to

medications(43) and/or referral to treatment programs(44, 45). This approach is typically

referred to with the acronym SBIRT: screening, brief intervention and referral to

treatment(26, 46).

Specific psychosocial and behavioral therapies for alcohol use disorder include 12-step

facilitation, cognitive behavioral therapy (CBT), and motivational enhancement therapy

(MET). Twelve-step facilitation is abstinence-based, and involves participation in Alcoholics

Anonymous meetings. The program is grounded in acceptance, spirituality and moral

inventories (47). CBT focuses on identifying triggers and maladaptive behaviors that

engender relapse. The approach encourages coping mechanisms to allow replacement of

alcohol-laden with alcohol-free circumstances(48). MET seeks to frame the decision to stop

or modify drinking in terms of a dilemma and helps the patient work through the dilemma

by “rolling with the resistance” to change (49). Lastly, mobile phone applications are

beginning to be used to support reduction in risky drinking(50).

It is not established if any of these therapies is superior. Indeed, the Matching Alcoholism

Treatments to Client Heterogeneity (MATCH) trial(51) showed that they are equivalent.

Similarly, the United Kingdom Alcohol Treatment Trial compared social/network therapy to

MET and found no difference in outcome(52). The large Combining Medications and

Behavioral Interventions (COMBINE) study examined whether combining medications and

a behavioral intervention improves drinking outcomes in patients with alcohol use

disorder(53). The intervention was a combination of all three interventions used in the

MATCH trial. In addition, COMBINE tested Medical Management, an intervention that

focuses on medication compliance, management of side-effects and goals toward harmful

drinking reduction and/or abstinence(54). The results showed that combination of the

behavioral intervention with medications was superior to medication alone and that

naltrexone combined with Medical Management can be a cost-effective way to treat alcohol

use disorder(53).

Clinical research on the use of psychosocial and behavioral treatments for alcohol use

disorder in patients with liver disease is limited. A landmark study integrating treatment for

both alcoholic liver disease and alcohol use disorder was conducted by Lieber and

colleagues(55). In this study, addition of a brief intervention to a pharmacologic treatment

trial for liver fibrosis resulted in a significant reduction in alcohol drinking. Other studies

examined behavioral approaches like CBT and MET for alcohol abstinence in patients with

alcoholic liver disease and these studies were recently reviewed systematically (13 studies;

N = 1,945) by Khan and colleagues(35). While psychosocial interventions alone were not

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effective in maintaining abstinence, combining comprehensive medical care and behavioral

approaches such as CBT and MET did increase abstinence rates. This indicates that the use

of integrated care to treat alcohol use disorder in the context of alcoholic liver disease may

lead to better outcomes.

Pharmacological treatments: management of alcohol detoxification

Alcohol withdrawal syndrome is characterized by a constellation of acute symptoms, which

may include anxiety, tremors, nausea, insomnia, and in severe cases seizures and delirium

tremens(56). Delirium tremens may occur at any time during withdrawal, most commonly

between 48–72 hours of abstinence. While up to 50% of alcoholic individuals manifest

alcohol withdrawal symptoms after stopping drinking, only a small percentage requires

medical treatment. The severity of withdrawal is typically measured with ranked scales such

as the Clinical Institute Withdrawal Assessment for Alcohol—revised (CIWA-Ar) (Table 5)

(57). While CIWA-Ar scores ≥8 but ≤15 indicate a potential need for a pharmacological

treatment, an alcohol withdrawal syndrome with a CIWA-Ar score >15 must be treated

pharmacologically. Benzodiazepines are the mainstay of treatment as they are the only class

of medications that reduces the risk of withdrawal seizures and/or delirium tremens.

In alcoholic patients with alcoholic liver disease, lorazepam or oxazepam are preferred as

they do not undergo phase I biotransformation, rather, undergo only glucuronidation which

is preserved even if liver function is compromised. Benzodiazepines may be administered on

a fixed or symptom-triggered schedule. In patients with alcohol use disorder and liver

disease, a symptom-triggered schedule (i.e. only when symptoms exceed a threshold of
severity) is preferred, with assessment at least every 4 hours or more frequently if

withdrawal symptoms are present. This strategy requires close and expert monitoring to

ensure appropriate medication is provided and is preferable as it avoids unnecessary dosing

of sedative hypnotic medication. Finally, it is important to distinguish withdrawal symptoms

from those of alcohol intoxication or hepatic encephalopathy as benzodiazepines should not

be administered in the latter cases. Other factors to consider are supportive care including

fluid and electrolyte balance. Caution is needed in preventing the precipitation of Wernicke’s

encephalopathy, especially in those patients with end-stage liver disease who present with

encephalopathy. Since prolonged glucose supplementation without the addition of thiamine

can be a risk factor for the development of Wernicke’s encephalopathy, thiamine

supplementation should be given promptly(58).

Pharmacological treatments to promote abstinence and prevent relapse

Consistent with the increasing knowledge of the neurobiology of addictions(3, 4),

medications have been developed (Table 6)(59). In the US, acamprosate, disulfiram and

naltrexone (oral and intramuscular) are approved by the Food and Drug Administration

(FDA) for treatment of alcohol use disorder. A recent meta-analysis supports the efficacy of

naltrexone and acamprosate, but not disulfiram, for alcohol use disorder(60). Efforts have

also been made to test other pharmacotherapies as potential new treatments for alcohol use

disorder. These medications are FDA-approved for other indications, some of them have

shown efficacy for alcohol use disorder in Phase 2/3 trials, but are not FDA-approved for

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alcohol use disorder. Among them, the most promising are baclofen, gabapentin,

ondansetron, topiramate and varenicline(59).

There is, however, a lack of formal clinical trials that have tested the role of

pharmacotherapies in patients with alcohol use disorder and alcoholic liver disease (26).

Although hepatotoxicity with naltrexone is rare(61), naltrexone could induce liver injury and

is contraindicated in patients with liver diseases as specified in an FDA ‘‘black box”(26).

Acamprosate has not formally been tested either in patients with alcoholic liver disease,

however it is the preferable FDA-approved medication in this population as it does not

undergo hepatic metabolism; there are no reports of hepatotoxicity.

Baclofen, gabapentin, ondansetron, topiramate and varenicline have no evidence of liver

toxicity, therefore they might also be useful in patients with alcohol use disorder and

alcoholic liver disease (see Table 6 for details). However, only baclofen has been formally

tested in patients with alcohol use disorder and clinically significant alcoholic liver disease

in a randomized controlled trial (62, 63) and in observational studies(64, 65); as such,

although further research with baclofen is needed, its potential utility for treatment of

alcohol use disorder in hepatology settings has been highlighted(66, 67). Unexplored are the

combinations of pharmacotherapies and behavioral treatments and of different medications

in patients with alcohol use disorder and alcoholic liver disease.

Liver Transplantation

Liver transplantation represents a life-saving treatment for patients with end-stage liver

disease. Patients with alcohol use disorder must demonstrate 6 months’ abstinence to be

placed on a liver transplant waiting list. Relapse to drinking results in removal from the list

with the requirement to demonstrate another 6 months’ abstinence for relisting, a timeframe

that is often incompatible with the prognosis of these patients. While 6 months abstinence is

commonly required, few transplant programs include treatment programs for alcohol use

disorder(68). One-year relapse rates range from 67 to 81%(69) in patients with alcoholic

liver disease therefore, effective, ongoing rehabilitation for alcohol addiction is necessary to

achieve sustained abstinence(70). Of note, liver transplantation without the 6-month

abstinence requirement has been used to treat patients with severe, acute alcoholic hepatitis

who fail to respond to steroid therapy(71, 72). Liver transplantation in this population results

in long-term survival benefits with recidivism to drinking at rates comparable or below those

liver transplant patients who were required to have 6 months abstinence. For an extensive

review on the management of alcohol use disorder in patients requiring liver transplant,

see(68).

SHIFTING CLINICAL LANDSCAPE: COMORBIDITIES IN PATIENTS WITH

ALCOHOL USE DISORDER AND ALCOHOLIC LIVER DISEASE

There is a shifting clinical landscape of alcoholic liver disease which includes a younger age

at presentation and increasing comorbid obesity(73). By contrast, with the emergence of

efficacious direct acting antiviral (DAA) drugs for Hepatitis C (HCV)(74), the comorbid

etiology of alcohol use disorder and HCV will diminish in importance. Alcohol can be a

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singular etiology of liver disease or can be one of several etiologies, as is the case for

example, with comorbid viral hepatitis and/or obesity-related non-alcoholic steatohepatitis.

Comorbidity of HCV and alcohol confers a poorer prognosis (20). HCV is the most common

blood borne pathogen in the US with an estimated 2.7 million persons living with chronic

HCV infection(75). The prevalence of HCV is 3- to 30-fold higher in alcoholic individuals

compared with the general population(76). Alcoholism represents an independent risk factor

for HCV infection(77, 78). Concomitant alcohol use accelerates HCV disease progression.

While the threshold level of drinking responsible for this progression is not well-

established(20), the two conditions have a synergistic effect(79). As a consequence, there are

no safe levels of alcohol consumption in HCV-infected individuals, therefore alcohol

abstinence is necessary for optimal treatment of HCV infection, especially in this new era of

effective treatments for HCV.

Alcohol-induced symptoms of depression, anxiety, and insomnia are common and often

indistinguishable from a primary psychiatric disorder(80). However, these abate with

abstinence, usually within a month, though there is a protracted abstinence syndrome that

can persist for months(81). Treatment for these symptoms is sometimes required. This may

be particularly challenging in those patients with alcohol use disorder and HCV infection

who are taking DAAs, which are substrates as well as inhibitors of cytochrome P450 3A4

and P-glycoprotein. There are clinically important drug-drug interactions between these

drugs and common medications used to treat withdrawal (e.g., alprazolam; midazolam),
sleep problems (e.g., zolpidem; trazodone), and psychiatric symptoms (e.g., escitalopram; St
John’s Wort; carbamazepine)(82).

Finally, obesity increases risk for all stages of alcoholic liver disease(83). Prospective cohort

studies show that alcohol use disorder and obesity exert a greater than additive effect on

development of liver disease and share a common pathophysiology(84). Treating alcohol use

disorder in obese patients with liver disease and obesity will be integral to the management

of these patients. As HCV decreases in importance as an etiology for liver disease(85),

alcohol use disorder and non-alcoholic steatohepatitis will be the most common etiologies

for end-stage liver disease. As such, patients with alcohol use disorder will be prominent

among those seen in hepatology practices.

CONCLUSIONS

Alcohol abstinence represents the cornerstone in the treatment of alcoholic liver disease. The

clinical literature summarized here indicates that treatments for patients with alcoholic liver

disease exist and providing these treatments is critical. To this end, it is important to educate

physicians in addiction medicine (86). The National Institute on Alcohol Abuse and

Alcoholism has developed several professional education materials for health care

providers(87). Figure 1 outlines multimodal treatments based on the severity of alcoholic

liver disease.

These treatment approaches for alcohol use disorder help patients, including those with

alcoholic liver disease, reduce alcohol consumption, achieve abstinence and prevent relapse.

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Integration of addiction medicine into the multidisciplinary teams that care for these patients

may improve outcomes.

Acknowledgments

The authors would like to thank: Lisa Farinelli, Section on Clinical Psychoneuroendocrinology and
Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism (NIAAA) and National Institute
on Drug Abuse (NIDA), for providing support with the preparation of the manuscript; Melinda Moyer and Fred
Donodeo, Communications and Public Liaison Branch, NIAAA, for technical assistance with the preparation of the
figure; Dr. David Kleiner, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, for
providing comments on the figure; and Karen Smith, National Institutes of Health (NIH) Library, for bibliographic
assistance. The work was supported by NIH intramural funding ZIA-AA000218 (Section on Clinical
Psychoneuroendocrinology and Neuropsychopharmacology; PI: Leggio), jointly supported by NIAAA and NIDA.

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