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).
Leggio and Lee Page 3
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
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
Leggio and Lee Page 4
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
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
Leggio and Lee Page 5
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
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
Leggio and Lee Page 6
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
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.
Leggio and Lee Page 7
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
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.
References
1. Nutt DJ, King LA, Phillips LD. Independent Scientific Committee on Drugs. Drug harms in the UK:
a multicriteria decision analysis. Lancet. 2010; 376(9752):1558–65. [PubMed: 21036393]
2. Substance Abuse and Mental Health Services Administration (SAMHSA). Results from the 2013
National Survey on Drug Use and Health: Summary of National Findings. Rockville, MD: 2014.
3. Volkow ND, Koob GF, McLellan AT. Neurobiologic Advances from the Brain Disease Model of
Addiction. N Engl J Med. 2016; 374(4):363–71. [PubMed: 26816013]
4. Koob GF, Le Moal M. Addiction and the brain antireward system. Annu Rev Psychol. 2008; 59:29–
53. [PubMed: 18154498]
5. Soderstrom CA, Smith GS, Kufera JA, Dischinger PC, Hebel JR, McDuff DR, et al. The accuracy of
the CAGE, the Brief Michigan Alcoholism Screening Test, and the Alcohol Use Disorders
Identification Test in screening trauma center patients for alcoholism. J Trauma. 1997; 43(6):962–9.
[PubMed: 9420113]
6. Girela E, Villanueva E, Hernandez-Cueto C, Luna JD. Comparison of the CAGE questionnaire
versus some biochemical markers in the diagnosis of alcoholism. Alcohol Alcohol. 1994; 29(3):
337–43. [PubMed: 7945575]
7. Maisto SA, Saitz R. Alcohol use disorders: screening and diagnosis. Am J Addict. 2003; 12(Suppl
1):S12–25. [PubMed: 14972777]
8. Connor JP, Haber PS, Hall WD. Alcohol use disorders. Lancet. 2016; 387(10022):988–98.
[PubMed: 26343838]
9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
(DSM-5). 5. Washington, DC: American Psychiatric Association; 2013.
10. Sobell LC, Sobell MB, Connors GJ, Agrawal S. Assessing drinking outcomes in alcohol treatment
efficacy studies: selecting a yardstick of success. Alcohol Clin Exp Res. 2003; 27(10):1661–6.
[PubMed: 14574238]
11. Allen JP, Wurst FM, Thon N, Litten RZ. Assessing the drinking status of liver transplant patients
with alcoholic liver disease. Liver Transpl. 2013; 19(4):369–76. [PubMed: 23281299]
12. Helander A, Peter O, Zheng Y. Monitoring of the alcohol biomarkers PEth, CDT and EtG/EtS in an
outpatient treatment setting. Alcohol Alcohol. 2012; 47(5):552–7. [PubMed: 22691387]
13. Niemela O, Alatalo P. Biomarkers of alcohol consumption and related liver disease. Scand J Clin
Lab Invest. 2010; 70(5):305–12. [PubMed: 20470213]
14. Anton RF. Carbohydrate-deficient transferrin for detection and monitoring of sustained heavy
drinking. What have we learned? Where do we go from here? Alcohol. 2001; 25(3):185–8.
[PubMed: 11839464]
15. Fagan KJ, Irvine KM, McWhinney BC, Fletcher LM, Horsfall LU, Johnson L, et al. Diagnostic
sensitivity of carbohydrate deficient transferrin in heavy drinkers. BMC Gastroenterol. 2014;
14:97. [PubMed: 24885510]
Leggio and Lee Page 8
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
16. Nanau RM, Neuman MG. Biomolecules and Biomarkers Used in Diagnosis of Alcohol Drinking
and in Monitoring Therapeutic Interventions. Biomolecules. 2015; 5(3):1339–85. [PubMed:
26131978]
17. Hartmann S, Aradottir S, Graf M, Wiesbeck G, Lesch O, Ramskogler K, et al. Phosphatidylethanol
as a sensitive and specific biomarker: comparison with gamma-glutamyl transpeptidase, mean
corpuscular volume and carbohydrate-deficient transferrin. Addict Biol. 2007; 12(1):81–4.
[PubMed: 17407500]
18. Becker U, Deis A, Sorensen TI, Gronbaek M, Borch-Johnsen K, Muller CF, et al. Prediction of risk
of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology. 1996;
23(5):1025–9. [PubMed: 8621128]
19. Kamper-Jorgensen M, Gronbaek M, Tolstrup J, Becker U. Alcohol and cirrhosis: dose–response or
threshold effect? J Hepatol. 2004; 41(1):25–30. [PubMed: 15246203]
20. Hutchinson SJ, Bird SM, Goldberg DJ. Influence of alcohol on the progression of hepatitis C virus
infection: a meta-analysis. Clin Gastroenterol Hepatol. 2005; 3(11):1150–9. [PubMed: 16271348]
21. Addolorato G, Mirijello A, Leggio L, Ferrulli A, Landolfi R. Management of alcohol dependence
in patients with liver disease. CNS Drugs. 2013; 27(4):287–99. …
Delivering a high-quality product at a reasonable price is not enough anymore.
That’s why we have developed 5 beneficial guarantees that will make your experience with our service enjoyable, easy, and safe.
You have to be 100% sure of the quality of your product to give a money-back guarantee. This describes us perfectly. Make sure that this guarantee is totally transparent.
Read moreEach paper is composed from scratch, according to your instructions. It is then checked by our plagiarism-detection software. There is no gap where plagiarism could squeeze in.
Read moreThanks to our free revisions, there is no way for you to be unsatisfied. We will work on your paper until you are completely happy with the result.
Read moreYour email is safe, as we store it according to international data protection rules. Your bank details are secure, as we use only reliable payment systems.
Read moreBy sending us your money, you buy the service we provide. Check out our terms and conditions if you prefer business talks to be laid out in official language.
Read more