• Information
  1. Epidemiology
  2. Diseases Associated with Alcoholism
  3. Metabolism of Ethanol
  4. Screening for Alcohol Abuse
  5. Hangover
  6. EtOH Withdrawal
  7. Therapy for Withdrawal
  8. Alcoholic Liver Disease
  9. Abstinence

A. Epidemiology

1. Normal Drinking [15]
   1. 60% of Americans (112 million people over age15) drink at least once/month
   2. Hazardous alcohol drinking in USA present in ~5% of women and ~15% of men
   3. One drink equals 12 ounces (oz) of beer, 6 oz of wine, 1 oz of hard liquor
   4. Note 1 oz = 30mL
   5. Three drinks per day increases risk for all cause mortality in men and women
   6. Thus, mortality associated with alcohol intake follows J-shaped curve
   7. Maximal mortality reductions associated with 0.5-1 drink per day
2. Mild to Moderate Alcohol Consumption [15]
   1. USDA Guideline for moderate drinking: 2 drinks per day for men, 1 per day for women
   2. Mild use of alcohol is beneficial: improves all-cause morbidity and mortality ~20%
   3. Mild to moderate intake in men associated with reduced risk of myocardial infarction [4]
   4. Mild to moderate alcohol intake associated with reduced risk of any-cause stroke [5]
   5. Associated reduced risk and delayed onset in persons >55-65 years old [6,7]
   6. Mild to moderate alcohol consumption (1-2 drinks per day men, 1/2-1 drink per day for women) associated with ~50% reduced risk for developing heart failure [8]
   7. Moderate alcohol intake (1-3 drinks/day) reduces DM2 risk ~30-50% [9]
   8. Wine may provide benefits beyond alcohol content [10]
   9. Mild to moderate alcohol consumption also reduces systemic inflammatory markers [11]
   10. No or marked alcohol consumption increases systemic inflammatory markers (CRP) [11]
3. Complications of Moderate Alcohol Use
   1. Even moderate drinking can cause or exacerbate some medical problems
   2. Low amounts of alchol can induce an "urge to drink" in humans
   3. This urge to drink appears to be mediated through serotonergic neurons [12]
   4. Problems include obesity, hypertension, sleep disorders, higher risk for certain cancers
   5. Increased risk of motor vehicle accidents, falls, and other injuries
   6. Alcohol is a known teratogen and excess should not be consumed during pregnancy
   7. Alcohol affects multiple body systems and interacts with many over the counter (OTC) and prescription drugs
   8. Hangover can be associated with decreased cognitive and other performance [13]
   9. Elevated risk of stroke with heavy alcohol use [5]
   10. Elevated risk of complications, poor outcomes when hospitalized for other illnesses [3]
4. Alcohol Abuse
   1. Consumption that increases risks for illness or injury, without physical addiction, and continued consumption in the presence of adverse consequences
   2. Binge drinking, consumption of a large number of drinks in a short time period
   3. Common among young adults, 17-30 year olds, especially during college years
   4. More common among males but also occurs among females
   5. Greatly increases risk for trauma and death
   6. Greatly increases complications and risks in intensive care unit [3]
   7. Risky drinking: drinking when it will increase the risk of injury or harm to another
   8. Especially while driving, boating, operating heavy machinery
   9. Risky drinking: drinking more than a moderate amount often, but without physical dependence
   10. Some experts consider risky drinking to be an early, interruptable stage of alcoholism
   11. Thus it is very important to inquire about the drinking habits of all patients
   12. About 8 million persons in USA dependent on alcohol (are therefore abusers) [14]
5. Alcoholism
   1. Excessive alcohol consumption in the presence of serious adverse events, and
   2. Lack of control over drinking, tolerance to the effects of alcohol, and withdrawal
6. Genetics and Alcoholism
   1. Genetic predisposition to alcoholism appear distinct from those of other abuses
   2. Polymorphisms in alcohol dehydrogenase 3 (ADH3) gene associated with various complications of alcoholism as well as benefits with mild alcohol intake [16]
   3. Slow metabolizer (ADH3 g2g2) allele associated with increased risk of alcoholism [16]
   4. Serotonin transporter and GABA-receptor polymorphisms may be associated with response to EtOH
   5. Previously reported dopamine receptor associations with alcoholism have not been replicated
7. Problems Associated with Alcoholism
   1. Screening
   2. Diagnosis of Alcoholism
   3. Detoxification
   4. Treatment and Prevention
   5. Referral
   6. Longitudinal Followup
   7. Primary care physicians should coordinate care in most cases [2]
8. About 85,000 deaths each year in USA associated with alcohol abuse [1]

B. Diseases Associated with Alcoholism

1. Gastrointestinal Irritation
   1. Gastritis and Gastric Ulcers
   2. Esophagitis
2. Pancreatitis
   1. Acute Pancreatitis
   2. Chronic pancreatitis with complications
   3. Pancreatic carcinoma (associated with chronic pancreatitis)
3. Metabolic Abnormalities
   1. Increased NADH/NAD ratio leads to:
   2. Increased conversion of acetaldehyde to beta-hydroxybutyrate (BHB) AND to
   3. Lactic acidosis - increased lactate synthesis from reduction of pyruvate
   4. Folate Deficiency: Mean Corpuscular Volume (MCV) >105 fL
   5. Iron Deficiency (may be due to gastrointestinal bleed)
   6. Thiamin Deficiency - may be exacerbated by glucose therapy; always give thiamin first
   7. Note that chronic liver disease may also cause an increased MCV
   8. Alcoholic Ketoacidosis
   9. Decreased urinary excretion of uric acid (due to lactate inhibition)
   10. EtOH Anemia: slightly increased MCV (~103 fL)
4. Hepatitis
   1. Fatty Liver (enlarged)
   2. Cirrhosis (Micronodular or Laenec's)
   3. Cirrhosis linked to increased risk of hepatocellular carcinoma
5. Buccal Hyperplasia
6. Neurologic Disease
   1. Encephalopathy: Wernicke type, Hepatic encephalopathy (usually cirrhotic)
   2. Cerebellar Degeneration
   3. Nutritional polyneuropathy (peripheral)
   4. Seizures
   5. Increased stroke risk with heavy alcohol intake: 1.6X for ischemic, 2.2X for hemorrhagic stroke [5]
7. Wernicke's Encephalopathy
   1. Due to Thiamine (Vitamin B1) deficiency
   2. Mental Confusion, nystagmus, ophthalmoplegia, gait ataxia
   3. Medical Emergency
   4. Requires immediate thiamin 50mg iv (or im) to prevent further brain damage
   5. Thiamine should be given before other iv infusions (or Wernicke's may be exacerbated)
   6. Often with Korsakoff's Syndrome - gross disturbance in recent memory
8. Seizures
   1. Alcoholic (during intake)
   2. Withdrawal (24-60 hours after intake)
   3. Delirium Tremens (usually 48-96 hours post intake)
   4. Trauma (focus)
9. Myopathy
   1. Skeletal muscle weakness and atrophy
   2. Dilated cardiomyopathy - women appear more susceptible than men [17]
   3. Usually requires >10 years of heavy drinking (>80gm/d alcohol consumption)
   4. Men with alcoholic cardiomyopathy who reduce alcohol consumption to <60gm/d have no increased risk (versus abstinence) [18]
10. Increased Cancer Risk
    1. Esophageal cancer - particularly with smoking
    2. Hepatocellular cancer - mainly with cirrhosis
    3. Slightly increased risk of breast cancer in women
11. Fetal Alcohol Syndrome [19]
    1. Exposure to EtOH during pregnancy
    2. First trimester exposure probably: bland face, microcephaly, retardation
    3. Later exposure probably: behavioral abnormalities
    4. Timing and peak level of EtOH most important
    5. Newborns with syndrome may have withdrawal symptoms, tremors, hypotonia
    6. Neuroligc abnormalities, septal defects, renal hypoplasia also occur
    7. Abstinance from EtOH generally recommended during pregnancy
12. Other
    1. Poor Dentition
    2. Trauma
    3. Internal Bleeding
    4. Increased risk of serious infection - pneumonia, aspiration, tuberculosis
    5. Increased risk (>2 fold) of developing ARDS with chronic alcohol abuse versus none
    6. Depression
    7. Hangover (see below)
13. Mild alcohol ingestion raises HDL cholesterol and reduces myocardial infarction risk

D. Metabolism of Ethanol

1. Ethanol is oxidized by alcohol dehydrogenase producing acetaldehyde
   1. Acetaldehyde is converted to acetate by aldehyde dehydrogenase
   2. Two NAD molecules are reduced to NADH in the course of these reactions
   3. Two variants of Alcohol dehydrogenase with rapid metabolizer phenotypes are known
   4. These two variants are associated with initially higher levels of acetaldehyde
2. High NADH levels favor conversion of pyruvate to lactate leading to lactic acidosis
   1. High lactic acid levels inhibit renal urate excretion leading to hyperuricemia
   2. High NADH levels also oppose gluconeogenesis, Krebs cycle, and fatty acid oxidation
   3. Inhibition of gluconeogenesis predisposes to hypoglycemia and seizures
3. Alcohol Dehydrogenase (ADH) [16]
   1. Three ADH isoenzymes exist in humans: ADH1, AHD2, ADH3
   2. ADH2 and ADH3 are polymorphic
   3. In white populations, ADH3 alleles occur as g1 and g2 with 2.5X different kinetics
   4. Persons with g1g1 (40%) have most rapid kinetics, g1g2 mid (45%), g2g2 (~15%) slowest
   5. G1G1 associated with increased risk of oropharyngeal cancer and end-organ damage
   6. G2G2 associated with increased risk of alcoholism itself
   7. G2G2 with mild alcohol consumption associated with reduced myocardial infarction risk
4. Acetaldehyde
   1. Inhibts repair of alkylated nucleoproteins
   2. Promotes cell death by depleting cells of glutathione (an anti-oxidant)
   3. Binds tubulin leading to inhibition of protein secretion and hepatocyte ballooning
   4. Crosses placenta, impairs fetal fetal DNA methylation, leads to fetal alcohol syndrome
   5. Normally metabolized to acetate by aldehyde dehydrogenase (ALDH)
   6. Low ALDH (mainly Asians) lead to higher blood aldehyde and toxic effects
   7. These toxic effects probably prevent alcoholism in their hosts
5. Induction of microsomal ethanol-oxidizing system (MEOS)
   1. Long term ethanol consumption induces MEOS
   2. This permits metabolic tolerance to alcohol
   3. This oxidizing system can convert many substances to very toxic agents
   4. Acetaminophen (Tylenol®), isoniazid, cocaine are converted to toxic molecules
   5. The MEOS also generates toxic oxygen species
   6. Depletion of reduced glutathione and anti-oxidant vitamins contributes to toxicity
   7. Short term alcohol consumption competes with other drugs for MEOS

D. Screening for Alcohol Abuse

1. Multiple Questionnaires have been developed for screening for alcohol abuse
   1. CAGE Questionnaire
   2. Self Administered Alcoholism Screening Test (SASST)
   3. Alcohol Use Disorders Identification Test (AUDIT)
   4. Michigan Alcohol Screening Test (MAST)
2. The CAGE Questions have been most widely adopted
   1. C: Have you ever tried to Cut Down on your drinking ?
   2. A: Do you get Angry when people talk to you about your drinking ?
   3. G: Have you ever felt Guilty about drinking ?
   4. E: Do you ever have an "Eye Opener" in the morning ?
   5. In general, CAGE should be used to screen, followed by quantity / frequency questions
3. Family history of alcoholism increases risk for alcoholic dependence
4. Minimental status examination (MMSE) should be performed on all potential alcoholics [21]
5. Neurobehavioral Effects of Alcohol Associated with Alcoholic Dependence [21]
   1. Stimulation, induction of pleasure
   2. Sedation
   3. Tolerance
   4. Withdrawal
   5. Craving

E. Hangover [13]

1. Symptoms
   1. Headache
   2. Tremulousness
   3. Nasea and diarrhea
   4. Fatigue
2. Decreased Performance:
   1. Occupational
   2. Cognitive
   3. Visual-spatial skills
   4. Diffuse slowing on electroencephalography is seen
3. Usually problematic in light to moderate drinkers
4. Pathophysiology
   1. Dehydration - EtOH acutely inhibits antidiuretic hormone (ADH) release
   2. Hormonal alterations - cortisol increase, others
   3. Dysregulated cytokine pathways (increased "inflammatory" cytokines)
   4. Metabolic acidosis
5. Treatment
   1. Rehydration
   2. Prostaglandin inhibition - usually with NSAIDs (caution with gastric toxicity)
   3. High doses of vitamin B6 - unknown mechanism
   4. Adequate glucose - "deserts" prior to sleeping may be helpful
   5. Antihistamines may also be helpful (particularly with anticholinergic activity)

F. EtOH Withdrawal [3,14]
[Figure] "Alcohol Withdrawal Symptoms"

1. Minor Symptoms
   1. Occur 1-2 days after withdrawal
   2. Usually after stopping chronic EtOH use
2. Major Symptoms
   1. Occur in 1-2% of EtOH abusers
   2. Cannot predict which persons will develop major symptoms
   3. History of delirium tremens increases risk of recurrence
3. Pathophysiology of Withdrawal
   1. GABA (g-aminobutyric acid) levels are down-regulated with chronic alcohol use
   2. Excitatory glutamate receptors (NMDA) are down-regulated as well with chronic alcohol
   3. When alcohol is withdrawn, glutamate levels increase and NMDA up-regulates
   4. GABA levels do not increase as quickly as glutamate with alcohol withdrawal
   5. Result is high level of generalized CNS stimulation with reduced inhibitory pathways
   6. Similar symptoms occur with withdrawal from benzodiazepines [14]
4. Symptomatic Changes
   1. Autonomic Nervous System Dysfunction: nausea and vomiting
   2. Increased sympathetic outflow: Locus ceruleus (norepinephrine) activation
   3. Neuronal Excitation: Seizures
   4. Mental Clouding: hallucinations, delirium
5. Mnemonic for withdrawal: "THE DTs"
   1. Tremulousness - 8-12 hours
   2. Hallucinations - 24-48 hours
   3. Epilepsy (Seizures) - 8-24 hours
   4. Delirium
   5. Tremors with Delirium - >48 hours after EtOH stopped
   6. Note that EtOH level is not necessarily zero (0) during withdrawal
6. Delirium Tremens (DTs)
   1. Occurs in about 20% of persons in inner city emergency rooms with alcohol dependence
   2. Medical emergency requiring intensive care monitoring
   3. Adequate sedation is crucial
   4. Control of cardiovascular system

G. Therapy for Withdrawal [3,14]

1. Inhibit Sympathetic Discharge
   1. Benzodiazapines - will reduce sympathetic discharge as well as incidence of DTs
   2. Clonidine 0.2mg po or patch as needed; excellent for hypertension, tachycardia
   3. Clonidine is unlikely to reduce risk of DTs or seizures
   4. ß-Blockers - improve vital signs and reduce cravings, propranol qid or atenolol qd
   5. ß-Blockers are especially useful with esophageal varices
2. Prevent (Reduce) Withdrawal [22]
   1. Sedative hypnotics (mainly benzodiazepines) reduce mortality and duration of delirium in alcohol withdrawal syndrome [22]
   2. Benzodiazapines are first line; prevent or reduce seizures and improve mortality [22]
   3. Benzodiazapines orally prevent delirium tremons
   4. Originally recommended standing dose with taper over 3-7 days
   5. Clear that "as needed" dosing, liberally, for inpatients, is preferred regimen
   6. Dosing for symptoms (prn) leads to less medication and shorter hospitalization
   7. Note: Thiamine 100-250mg IV should be given in all initial treatments of alcohol withdrawal
3. Specific Benzodiazepines
   1. Lorazepam 2mg IV after acute alcohol related seizure reduces second seizures 90% [23]
   2. Lorazepam (Ativan® 1-2mg q2-4 hours prn) IM or IV, OR
   3. Oxazepam (Serax® 15-30mg q4-6 hours prn; may be used as outpatient), OR
   4. Chlordiazepoxide (Librium® 25-50mg q6-8 hours prn; may be used as outpatient)
   5. Diazepam (Valium®, caution: long half life with active metabolites)
   6. Caution with long acting agents in elderly and hepatic dysfunction
4. Carbamazepine (Tegretol®)
   1. May be used as adjunctive therapy for seizures with benzodiazepines
   2. Also reduces severity of other withdrawal symptoms
5. Fluid resuscitation - most alcoholics are dehydrated
6. Nutritional Supplementation
   1. Thiamine 100mg IV - give first; prior to any glucose to prevent acute Wernicke Syndrome
   2. Glucose 1 Amp D50 - give after thiamine as glycogen stores are depleted
   3. Folate 1mg iv qd
   4. Multivitamins
   5. Check magnesium levels; often low in alcoholics
7. Metabolic Acidosis [3]
   1. ~25% of alcoholics will have metabolic acidosis (with anion gap) on hospital admission
   2. Due lactic acidosis and alcoholic ketoacidosis, in addition to other disorders
   3. Also calculate osmolar gap for possible methanol or ethylene glycol ingestion
   4. Fluid replacement, possible use of bicarbonate, as needed to correct acidosis
   5. Carefully monitor serum potassium levels as pH adjustments are made
8. Baclofen [24]
   1. GABA-B receptor agonist used for spacticity
   2. Single 10mg oral dose suppresses alcohol withdrawal symptoms
9. Specific guidelines have been developed by American Society of Addictive Medicine

H. Alcoholic Liver Disease

1. Pathophysiology
   1. Metabolism via alcohol dehydrogenase (ADH) and MEOS (induced by EtOH)
   2. Toxic effects of metabolites (such as acetaldehyde), highly reactive with biomolecules
   3. Acetaldehyde (CH3CHO) is made from EtOH oxydation (CH3CH2OH)
2. Pathology
   1. Fatty Liver - can begin within days of heavy drinking
   2. Alcohol induced cirrhosis - often occurs in absence of hepatitis intermediate
   3. Cirrhosis results from reduction in collagen degradation
   4. Fibrosis results from necrosis of liver cells with inflammation
3. Symptoms
   1. Hepatomegaly, Jaundice
   2. Ascites, Encephalopathy
4. Effects on Liver
   1. AST mildly increased; ALT may not be increased
   2. Typically AST:ALT > 2 (EtOH induces AST)
   3. Jaundice may occur in early moderate or severe disease
   4. Fatty liver (steatohepatitis) change can lead to hepatomegaly and eventually liver failure
   5. Micronodular cirrhosis and fatty liver may be seen on biopsy specimens

I. Abstinence [2,21,25]

1. Difficult for most persons
2. Family history of alcoholism predicts recurrent alcoholism
3. Social reinforcement of abstinence is critical to most patients
   1. Alcoholics Anonymous (AA) is most often used
   2. Motivational enhancement therapy has been advocated
   3. AA and other motivational treatment programs are probably equally effective
4. Drugs to Maintain Abstinence [26]
   1. Disulfiram
   2. Naltrexone
   3. Acamprosate
   4. Unapproved but probably effective: baclofen, nalmefene (Revex®), topiramate (Topamax®)
5. Disulfiram (Antabuse®)
   1. Irreversibly inhibits acetaldehyde dehydrogenase
   2. Causes a severe reaction when taken with alcohol
   3. Use is widespread, but data proving efficacy are lacking
   4. Controlled trials have failed to show a benefit; agent is NOT recommended
6. Naltrexone (Revia®) [27]
   1. An opioid receptor antagonist used for treating opioid dependence
   2. Also FDA approved for treating alcohol dependence
   3. Randomized study shows that naltrexone does NOT improve abstinence rates in men with chronic severe alcoholism when combined with psychosocial support [28]
   4. Reduces craving in abstinent patients
   5. Blocks reinforcing effects of alcohol in patients who do drink
   6. Blocks alcohol-induced release of dopamine in the nucleus accumbens
   7. Can be used as adjunct to counselling in a primary care setting [30]
   8. Superior to acamprosate, and as good or better than combined behavioral intervention [30]
   9. Dose is 50mg po qd and acts for ~24 hours
   10. Duration of treatment usually 10-12 weeks
   11. Agent should not be started until patient is alcohol (and opiate) free
   12. Long acting (exteneded release) intramuscular naltrexone formulation (Vivitrol®) given monthly reduces heavy drinking in patients who are abstinent on initiation of drug [30,31]
   13. Adverse effects - mild nausea, mild sedation, may cause mild hepatitis
   14. Drug interactions - with thioridazine can increase sedation; avoid hepatotoxic drugs
7. Acamprosate (Campral®) [26]
   1. Interaction with glutamate (NMDA) receptors and calcium channels
   2. Agonist activity at GABA receptor; antagonizes NMDA receptors
   3. Multiple studies have shown that acamprosate prevents some relapses
   4. No benefit in a large study employing 3000mg/day [32]
   5. Excreted unchanged in the urine
   6. Dose is 666mg po tid; reduce by 50% in patients with renal dysfunction
   7. About as effective as disulfiram or naltrexone; may be combined with either
   8. Diarrhea (10%) and headache (20%) are main side effects
8. Baclofen [33,34]
   1. GABA-B receptor agonist
   2. Muscle relaxant with alcohol abstinence properties
   3. In alcoholic with cirrhosis, 71% achieved and maintained abstinence versus 29% of placebo
   4. Dosing for alcohol abstinence is 5mg po tid x 3 days, then 10mg po tid
9. Topiramate (Topamax®) [20,29]
   1. May inhibit mesocorticolimbic dopamine release through its GABA activity
   2. Also inhibits glutamate function and may antagonize alcohol's rewarding effects
   3. Placebo versus 25mg up to 300mg qd (two major studies)
   4. Reduced heavy drinking days 16.2% versus placebo [20]
   5. Topiramate reduced drinks per day and increased abstinent days
   6. Topiramate also reduced craving and was generally well tolerated
   7. Paresthsia (50%), taste perversion (23%), anorxia (20%), concentration difficulties (15%)
10. Isradipine (DynaCirc®)
    1. A dihydropyridine calcium channel blocker for hypertension
    2. Very effectively blocks craving in alcoholics
    3. In small studies, appears to be more effective than naltrexone
    4. Dose is 2.5mg po bid, same as that for hypertension
11. Serotonin (5-HT) Type 3 Antagonists [12]
    1. Densely distributed type 3 5-HT receptors found in limbic system
    2. These neurons can regulate release of dopamine, involved in "addiction"
    3. Urge to drink can be ameliorated by ondansetron, a 5-HT3 receptor antagonist
    4. Ondansetron 4µg/kg bid is an effective treatment for early onset alcoholism
12. Desipramine
    1. High rates of depression in alcoholics suggest use of anti-depressants
    2. In alcoholics without depression, desipramine did not reduce alcohol abuse
    3. In alcoholics with depression, despiramine increased abstinance from alcohol

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