80: Ethanol

Ethanol, or ethyl alcohol, is commonly referred to as “alcohol.” This term is somewhat misleading, because there are numerous other alcohols. However, ethanol is probably the most commonly used and abused xenobiotic in the world. Its use is pervasive among adolescents and adults of all ages, socioeconomic groups, and represents a tremendous financial and social cost.^3,197 The ethanol content of alcoholic beverages is expressed by volume percent or by proof. Proof is a measure of the absolute ethanol content of distilled liquor, made by determining its specific gravity at an index temperature. In the United Kingdom, the Customs and Excise Act of 1952 declared proof spirits (100 proof) as those in which the weight of the spirits is 12/13 the weight of an equal volume of distilled water at 51°F (11°C). Thus, 100 proof spirits are 48.24% ethanol by weight or 57.06% by volume. Other spirits are designated over or under proof, with the percentage of variance noted. In the United States, a proof spirit (100 proof) is one containing 50% ethanol by volume.

The derivation of proof comes from the days when sailors in the British Navy suspected that the officers were diluting their rum (grog) ration and demanded “proof” that this was not the case. They achieved this by pouring a sample of grog on black granular gunpowder. If the gunpowder ignited by match or spark, the rum was up to standard, 100% proof that the liquor was at least 50% ethanol. This became shortened to 100 proof (Table 80–1).

In addition to beverages, ethanol is present in hundreds of medicinal preparations used as a diluent or solvent in concentrations ranging from 0.3% to 75%.^{28,44,52,145,152,196} Mouthwashes may contain up to 75%ethanol (150 proof), and colognes typically contain 40% to 60% ethanol (80 to 120 proof).^{15,96,152,166} These products occasionally cause intoxication, especially when unintentionally ingested by children.^31,49,84,198

Veisalgia, “alcohol hangover,” comes from the Norwegian kveis, “uneasiness following debauchery” and the Greek algia, “pain.” The “hangover” syndrome has been attributed to congeners, substances that appear in alcoholic beverages in addition to ethanol and water.^26,33,34 Congeners contribute to the special characteristics of taste, flavor, aroma, and color of a beverage. The combinations and exact amounts of congeners vary with the type of beverage, ranging from 33 mg/L in vodka, to averages of 500 mg/L in some whiskies and as much as 29,000 mg/L in specially aged whiskies or brandies.^26,33,34 The conventional listing of congeners includes fusel oil (a mixture containing amyl, buytyl, propyl, and methyl alcohol), aldehydes, furfural, esters, low molecular weight organic acids, phenols, and other carbonyl compounds, tannins, solids, and a relatively large number of additional organic and inorganic compounds, usually in trace amounts.^26,33

Consumption of illicitly produced ethanol (“moonshine”) has resulted in methanol, lead or arsenic poisoning, and botulism.^{19,46,66,93,110,116,132,149} Incidental lead contamination is also reported in draught beers or wine contained in lead-capped bottles.^173,174 Of historic interest is that the addition of cobalt salts to beer to stabilize the “head” (foam) led to outbreaks of congestive cardiomyopathy among heavy beer drinkers in Canada and Belgium in the 1960s (Chap. 94). The clinical-pathological pattern of this disease is distinct from the classical alcoholic cardiomyopathy.^126,128

Alcoholism is the leading cause of morbidity and mortality in the United States. The prevalence of ethanol dependence in the United States has been relatively stable, at around 6% for men and 2% for women.²⁵ The overall estimated annual cost of US health expenses related to ethanol is $185 billion.¹³⁸ More than 70% of the estimated costs were attributed to lost productivity, most of which resulted from ethanol-related illness or premature death. Most of the remaining estimated costs were expenditures for health care services to treat ethanol induced disorders (14.3%), property and administrative costs of ethanol-related motor vehicle crashes (8.5%), and criminal justice system costs of ethanol-related crime (3.4%). More than 200,000 Americans die annually of alcoholism, far more than those who die of all illicit drugs of abuse combined. Ethanol is the leading cause of mortality in people 15 to 45 years of age. In 2011, there were 9878 ethanol-related traffic fatalities in the United States, which accounted for 31% of total traffic fatalities; 66% of ethanol-impaired driving fatalities involved drivers with blood ethanol concentration 80 mg/dL or higher, 27% were passengers riding with the ethanol-impaired drivers, and 7% were nonoccupants of a motor vehicle.¹³⁷ Drivers aged 21 to 34 accounted for 44%, and drivers between 16 to 20 years accounted for 10% of all ethanol-impaired drivers in fatal crashes. Among 16 to 20 year-old male drivers, an increase of 20 mg/dL in blood ethanol concentration was estimated to more than double the relative risk of fatal single-vehicle crash injury compared with sober drivers of the same age and gender.²⁰⁹ When the blood ethanol concentration ranged from 80 to 100 mg/dL (17–22 mmol/L), 100 to 150 mg/dL (22–33 mmol/L), and greater than 150 mg/dL (33 mmol/L), the relative risk of fatal single-vehicle crash injury was 52, 241 and 15,560, respectively.

The Global Burden of Disease Study identified three effects of ethanol: harmful effects in relation to injuries, harmful effects in relation to disease, and the protective effect in relation to ischemic heart disease.¹³⁸ Overall ethanol accounted for 3.5% of mortality and disability, 1.5% of all deaths, 2.1% of all life years lost, and 6% of all the years lived with disability.¹³⁸ In the United States, according to National Highway Traffic Safety Administration (NHTSA) information, all jurisdictions have enacted per se blood ethanol concentration for adults operating noncommercial motor vehicles.¹³⁷ The term “illegal per se” refers to state laws that make it a criminal offense to operate a motor vehicle at or above a specified ethanol (or drug) concentration in the blood, breath, or urine, which may or may not reflect clinical intoxication (Special Considerations: SC6). For example, although ethanol-tolerant patients may not exhibit impairment even at serum ethanol concentrations greater than 300 mg/dL (65 mmol/L), they are still considered impaired with regard to the laws that governs motor vehicle operation.¹

There is a dose-response relationship between ethanol consumption and risk of death in men aged 16 to 34 and in women aged 16 to 54. Meta-analysis of aggregate data from epidemiologic dose-response ethanol and mortality cohort studies suggests that the level of ethanol consumption at which all-cause risk is lowest is approximately 5 g/d and that ethanol exerts a protective effect (J-shaped dose-response curve) up to a daily intake of approximately 45 g.⁹ It is suggested that sensible drinking of ethanol for men is 8 to 10 g/d up to age 34, 16 to 20 g/d between 34 and 44 years of age, 24 to 30 g/d between 44 and 54 years of age, 32 to 40 g/d up between 54 and 84 years of age, and 40 to 50 g/d over age 85. Women would be advised to limit their drinking to 8 to 10 g/d up to age 44, 16 to 20 g/d between 44 and 74 years of age, and 24 to 30 g/d over age 75.²⁰¹ However, no safe level of prenatal ethanol exposure has been established. The combination of a national tolerance of drinking and heavy advertising of ethanol makes it especially appealing to young people. In a society increasingly concerned with drug abuse, the excessive use of ethanol constitutes a serious and pervasive problem as well as a major health issue.

Ethanol is rapidly absorbed from the gastrointestinal (GI) tract, with approximately 20% absorbed from the stomach and the remainder from the small intestine.¹⁴¹ Factors that enhance absorption include rapid gastric emptying, ethanol intake without food, the absence of congeners, dilution of ethanol (maximum absorption occurs at a concentration of 20%), and carbonation. Under optimal conditions for absorption, 80% to 90% of an ingested dose is fully absorbed within 60 minutes. Factors that delay or decrease ethanol absorption include high concentrations of ethanol (by causing pylorospasm), presence of food, coexistence of GI disease, coingestion of xenobiotics such as aspirin and N-butylscopolamine,^94,146 time taken to ingest the drink, and individual variation. When any of these factors is present, absorption may be delayed for 2 to 6 hours. The relative amount of ethanol that is absorbed from the stomach is determined by the presence of alcohol dehydrogenase (ADH) in the gastric mucosa, which oxidizes a proportion of the ingested ethanol, thus reducing the amount available for absorption. This effect is more pronounced in men than in women and in nonalcoholics than in alcoholics.^11,58 Histamine₂ (H₂) receptor antagonists such as cimetidine and ranitidine inhibit gastric ADH resulting in decreased first-pass metabolism and increase the bioavailability of imbibed ethanol.^{6,22,24,40,51}

Following complete distribution, ethanol is present in body tissues in a concentration proportional to that of the tissue water content. Ethanol freely passes through the placenta, exposing the fetus to ethanol concentrations comparable to that achieved in the mother.

Ethanol is primarily eliminated by the liver, with 2% to 5% excreted unchanged by the kidneys, lungs, and sweat.⁸⁸ Ethanol is metabolized via at least three different pathways: the aforementioned ADH pathway located in the cytosol of the hepatocytes, CYP2E1, a member of the cytochrome P450 mixed-function oxidase system, located on the endoplasmic reticulum, and the peroxidase-catalase system associated with the hepatic peroxisomes (Fig. 80–1).¹⁴¹

For a given ethanol dose, 95% to 98% is metabolized in the liver, first to acetaldehyde by ADH and then further to acetate by aldehyde dehydrogenase (ALDH).⁸⁸ The end products of ethanol oxidation are carbon dioxide and water. The remaining 2% to 5% is excreted unchanged in urine, sweat, and expired air. In addition, less than 0.1% undergoes phase II conjugation reactions to produce ethyl glucuronide and ethyl sulfate, catalyzed by uridine diphosphate-glucuronosyltransferase and sulfotransferase, respectively.^{32,56,76,168,169}

The ADH system is the main pathway for ethanol metabolism and is also the rate-limiting step. ADH is a zinc metalloenzyme that uses oxidized nicotinamide adenine dinucleotide (NAD⁺) as a hydrogen ion acceptor to oxidize ethanol to acetaldehyde. In this process, a hydrogen ion is transferred from ethanol to NAD⁺, converting it to its reduced form NADH. Subsequently, a hydrogen ion is transferred from acetaldehyde to NAD⁺. Under normal conditions acetate is converted to acetylcoenzyme A (acetyl-CoA), which enters the Krebs cycle and is metabolized to carbon dioxide and water. The entry of acetyl-CoA into the Krebs cycle is thiamine dependent (Antidotes in Depth: A24).

The ADH gene family encodes enzymes that metabolize a wide variety of substrates. There are at least seven genetic loci that code for human ADH arising from the association of different subunits, and there are more than 20 ADH isoenzymes.² These ADH forms are divided into five major classes (I–V) according to their subunit, isoenzyme composition, and physicochemical properties.⁸⁹ Two of these gene loci exhibit polymorphism and they both involve class I ADH genes; three alleles exist for ADH2 (ADH1B) [ADH2*1 (ADH1B*1), ADH2*2 (ADH1B*2), and ADH2*3 (ADH1B*3)] and three for ADH3 (ADH1C) [ADH3*1 (ADH1C*1), ADH3*2 (ADH1C*2), and ADH3*3 (ADH1C*3)].³⁰ Class I enzymes are inducible intracellular hepatic enzymes and are believed to play a major role in ethanol metabolism.¹¹³ Class IV ADH6 (σ-ADH) is the major ADH expressed in human gastric mucosa.^11,58 σ-ADH is usually present in non-Asians, whereas in a majority of Pacific Rim Asians, the enzyme activity is either low or not detectable.^11,12,42 The ADH1B*2 allele is present in 90% of Pacific Rim Asians but occurs infrequently in most Caucasians, except for people of Jewish and perhaps Hispanic descent.²⁰² This allele is responsible for the unusually rapid conversion of ethanol to acetaldehyde. People carrying ADH1B*2 alleles are about one-third as likely to be alcoholic compared with people without this allele.²⁰²

In the liver, ADH metabolizes ethanol to acetaldehyde, which is then converted to acetate by mitochondrial NAD-dependent ALDH. Human ALDH is divided into nine major gene families. There is a functional polymorphism of the mitochondrial ALDH2 gene and expression of an inactive form of the ALDH2, glutamate to lysine substitution at position 487 (E487K), results in impaired acetaldehyde metabolizing capacity. The variant allele ALDH2*2 encodes a protein subunit that confers low activity to the enzyme resulting in marked differences in the steady-state kinetic constants, which appears to be most prevalent in Pacific Rim Asians.^{2,30,68,182,183} These metabolic polymorphisms contribute to differences in ethanol and acetaldehyde elimination rate; high activity ADH variants are predicted to increase the rate of acetaldehyde generation, whereas the low activity ALDH2 variant is associated with limited capacity to metabolize this compound and may explain differences in ethanol-related behavior. Asians possessing an atypical ALDH2 gene are more sensitive to acute adverse responses to ethanol and tend to discourage ethanol consumption. Homozygous ALDH2*2 individuals are strikingly sensitive to small dose of ethanol (0.2 g/kg), as evidenced by the intense flushing, pronounced cardiovascular hemodynamic effects, and subjective perception of general discomfort.^{48,68,150,188,192} This effect may also be associated with the ADH2*2 and ADH3*1 allele and is similar to that induced by disulfiram (Chap. 79). The ethanol flushing response may involve prostaglandin and histamine release. Both prostaglandin antagonists (aspirin)¹⁸⁹ and antihistamines (H₁ and H₂)^129,178,185 may attenuate this response.

CYP2E1 is responsible for very little ethanol metabolism in the non tolerant drinker, but becomes more important as the ethanol concentration rises or as ethanol use becomes chronic (Fig. 80–1). CYP2E1 uses reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an electron donor in a complex process that ultimately oxidizes ethanol to acetaldehyde.¹⁰⁴ In this process, hydrogen is abstracted from ethanol and donated to molecular oxygen to form water. Subsequently, acetaldehyde is further oxidized to acetate as hydrogen ion is transferred from acetaldehyde to NADP⁺. The ability of ethanol to induce the CYP2E1 forms the basis for the well-established interactions between ethanol and a host of other xenobiotics metabolized by this system.^41,57 In alcoholics and those with higher ethanol concentrations, cimetidine may also delay ethanol clearance by inhibiting CYP2E1.⁷² However, the increase in blood ethanol concentration from such an interaction is of questionable clinical significance.^5,6,22,23

ADH is saturated at relatively low blood ethanol concentrations. As the system is saturated, ethanol elimination changes from first-order to zero-order kinetics (Chap. 9). In adults, the average rate of ethanol metabolism is 100 to 125 mg/kg/h in occasional drinkers and up to 175 mg/kg/h in habitual drinkers.^18,67 As a result, the average-sized adult metabolizes 7 to 10 g/h and the blood ethanol concentration falls 15 to 20 mg/dL/h (3.26–4.35 mmol/L/h)Tolerant drinkers, by recruiting CYP2E1, may increase their clearance of ethanol to 30 mg/dL/h (6.52 mmol/L/h) or even higher.^{18, 67} Studies of ethanol-intoxicated patients indicate that although the average ethanol clearance rate is about 20 mg/dL/h (4.35 mmol/L/h), there is considerable individual variation (standard deviation of about 6 mg/dL/h (1.30 mmol/L/h).^18,67

Ethanol interacts with a variety of xenobiotics (Table 80–2).^92,196 The most frequent ethanol–drug interactions occur as a result of ethanol-induced increase in hepatic xenobiotic-metabolizing enzyme activity. In contrast, acute ethanol use may inhibit metabolism of other xenobiotics, and this may be due to competitive inhibition of hepatic enzyme activity or a reduction in hepatic blood flow. The interaction between ethanol and disulfiram (Antabuse) is well described, and it can be life threatening (Chap. 79).

Concomitant use of cocaine and ethanol leads to the formation of an active metabolite, cocaethylene, through transesterification of cocaine by the liver.¹⁵⁶ Cocaethylene has a longer half-life than cocaine itself (2 hours vs. 48 minutes), and this may explain some of the delayed cardiovascular effects attributed to cocaine use.^8,203 Both ethanol and cocaethylene inhibit the metabolism of cocaine, thereby prolonging the elimination of cocaine and enhancing its effect (Chap. 78).¹⁴⁷

Case reports and retrospective case series that suggest chronic ethanol consumption may predispose a person to acetaminophen (APAP) hepatotoxicity (Chap. 35),^{47,118,125,167, 211} even when APAP has been taken according to the manufacturer’s recommended dosage of not more than 4 g daily.²¹² Because ethanol induces CYP2E1, the enzyme involved in the metabolism of APAP to its hepatotoxic intermediate, N-acetyl-p-benzoquinone imine, a theoretical basis for this association exists. However, in randomized, placebo-controlled trials where confirmed alcoholics were given APAP 4 g daily or placebo, there were no differences between the two groups with regard to liver enzymes or to their coagulation profile.¹⁶³ Recent fasting, common in alcoholics, was also associated with a predisposition to APAP hepatotoxicity, likely due to depletion of glutathione (Chap. 35).²⁰⁰ However, in a retrospective study, heavy drinkers did not develop more severe hepatoxicity following APAP overdose than nondrinkers.¹¹⁹

Despite the long history of ethanol use and study, no specific receptor for ethanol has been identified, and the mechanism of action leading to intoxication remains the subject of debate.¹⁵¹ Ethanol is known to affect a large number of membrane proteins that participate in signaling pathways such as neurotransmitter receptors, enzymes, and ion channels,^136,194 and there is extensive evidence that ethanol interacts with a variety of neurotransmitters.^50,190,191 The major actions of ethanol involve enhancing the inhibitory effects of γ-aminobutyric acid (GABA) at GABA_A receptors and blockade of the N-methyl-d-aspartate (NMDA) subtype of glutamate, an excitatory amino acid (EAA) receptor.^{37,102,103,194} Animal studies indicate that the acute effects of ethanol result from competitive inhibition of glycine binding to the NMDA receptor and disruption of glutamatergic neurotransmission by inhibiting the response of the NMDA receptor. Persistent glycine antagonism and attenuation of glutamatergic neurotransmission by chronic ethanol exposure results in tolerance to ethanol by enhancing EAA neurotransmission and NMDA receptor upregulation.^{85,135,187,190,191} The latter appears to involve selective increases in NMDA R2B subunit concentrations and other molecular changes in specific brain loci.⁴ The abrupt withdrawal of ethanol thus produces a hyperexcitable state that leads to the ethanol withdrawal syndrome and excitotoxic neuronal death.^16,37,190 GABA-mediated inhibition, which normally acts to limit excitation, is eliminated during the ethanol withdrawal syndrome and further intensifies this excitation. In addition, NMDA receptors function to inhibit the release of dopamine in the nucleus accumbens and mesolimbic structures, which modulates the reinforcing action of addictive xenobiotics such as ethanol.^20,21,177 By inhibiting NMDA receptor activity, ethanol could increase dopamine release from the nucleus accumbens and ventral tegmental area and could thus create dependence. Chronic ethanol administration also results in tolerance, dependence, and an ethanol withdrawal syndrome, mediated, in part, by desensitization and or downregulation of GABA_A receptors (Chaps. 14, 15, and 81).

Chronic alcoholism has multiorgan system effects (Table 80–3), and the relationships between ethanol use, nutrition, and liver disease have been reviewed elsewhere.¹¹⁴ In addition to the harmful effects of ethanol itself such as impairment of protein synthesis, its metabolite, acetaldehyde, is inherently toxic to biologic systems.^{108, 112,193,210} Acetaldehyde directly impairs cardiac contractile function, disrupts cardiac excitation-contractile coupling, inhibits myocardial protein synthesis, interferes with phosphorylation, causes structural and functional alterations in mitochondria and hepatocytes, and inactivates acetyl-CoA. Acetaldehyde can also react with intracellular proteins to generate adducts. Acetaldehyde-protein and DNA adducts promote oxidative stress, lipid peroxidation, hepatic stellae cells activation-associated inflammation and fibrosis, and mutagenesis. Acetaldehyde adducts are believed to be important in the early phase of alcoholic liver disease, and in advanced liver disease they contribute to the development of hepatic fibrosis as well as hepatocellular carcinoma.¹⁷¹

Ethanol metabolism through the CYP2E1 pathway generates highly reactive oxygen radicals, including the hydroxyethyl radical molecule. Elevated oxygen radical concentrations generate a state of oxidative stress, which leads to cell damage. Oxygen radicals can also initiate lipid peroxidation resulting in reactive molecules such as malondialdehyde and 4-hydroxy-2-nonenal. These reactive molecules react with proteins or acetaldehyde to form adducts, which contribute to the development of alcoholic liver injury.³⁸

Oxidation of ethanol generates an excess of reducing potential in the cytosol in the form of NADH with the ratio of NADH to NAD⁺ being dramatically increased. This ratio, also known as the redox potential, determines the ability of the cell to carry on various oxidative processes. The unfavorable change in redox potential due to ethanol metabolism contributes to the development of metabolic disorders, such as impaired gluconeogenesis, alterations in fatty acid metabolism, fatty liver, hyperlipidemia, hypoglycemia, elevated lactate concentration, hyperuricemia (gouty attacks), increased collagen and scar tissue formation associated withalcoholism, and a clinical syndrome of alcoholic ketoacidosis (AKA).

Studies in alcoholic liver disease have focused on Kupffer cell activation by endotoxin that is released by intestinal bacteria. When Kupffer cells are activated, they produce regulatory nuclear factor kappa β (NFκβ) and generate significant amounts of superoxide radicals (O₂^–) and cytokines (tumor necrosis factor and interleukin-8), which is an essential factor in the injury to hepatocytes associated with alcoholic liver disease.^124,199

Ethanol is a selective central nervous system (CNS) depressant at low doses and a general depressant at high doses. Initially it depresses those areas of the brain involved with highly integrated functions. Cortical release leads to animated behavior and the loss of restraint. This paradoxical CNS stimulation is due to disinhibition. In cases of mild intoxication, the signs of ethanol inebriation are quite variable. The patient may be energized and loquacious, expansive, emotionally labile, increasingly gregarious or may appear to have lost self-control, exhibit antisocial behavior, and be ill tempered. As the degree of intoxication increases, there is successive inhibition and impairment of neuronal activity. The patient may become irritable, abusive, aggressive, violent, dysarthric, confused, disoriented, or lethargic. With severe intoxication, there is loss of airway protective reflexes, coma, and increasing risk of death from respiratory depression. An ethanol-naive adult with a blood ethanol concentration of greater than 250 mg/dL (54 mmol/L) is usually comatose.¹

However, the acute effects of ethanol ingestion also depend on the habituation of the drinker. This is mainly due to the development of tolerance, which has both a metabolic (pharmacokinetic) and a functional (pharmacodynamic) component.¹⁸¹ Metabolic tolerance to ethanol is based on enhanced elimination by ADH, and to a greater extent, CYP2E1. Functional tolerance (resistance to the effects of ethanol at the cellular level) is a more important determinant of habituation and is mediated through alterations in GABA_A and NMDA receptors as well as serotonergic (eg, 5-HT_1A) and adrenergic neurons.^{85,97,98, 135,180, 181,182,183,184,185,186,187,188,189,190, and 191} Acute ethanol tolerance is demonstrated by the Mellanby effect, which involves the comparison of physiologic responses or behavioral effects at the same blood ethanol concentration on the ascending and descending limbs of the blood ethanol concentration–versus–time curve. Impairment is greater at a given blood ethanol concentration when it is increasing than for the same blood ethanol concentration when it is falling.^139,195 Although individuals who are acutely intoxicated move through a progressive sequence of events, the association of a particular aspect of intoxication with a specific blood ethanol concentration is not usually possible without knowing the pattern of ethanol use of the patient. Acute ethanol intoxication occurs in habitual drinkers when they raise their ethanol concentration an equivalent amount above baseline, and specific clinical manifestations of inebriation typically occur with significantly higher blood ethanol concentration than in nontolerant individuals. Regardless, the absolute change above baseline may be important.

A patient may present with obvious signs and symptoms consistent with ethanol intoxication that include flushed facies, diaphoresis, tachycardia, hypotension, hypothermia, hypoventilation, mydriasis, nystagmus, vomiting, dysarthria, muscular incoordination, ataxia, altered consciousness, and coma. However, an ethanol-intoxicated patient may present to the emergency department (ED) with a broad range of diagnostic possibilities and should prompt a careful evaluation for a variety of covert clinical and metabolic disorders. A meticulous and systematic approach to the evaluation and management of an inebriated patient will help avoid the potential pitfalls in such a situation.⁶¹ The presence or absence of an odor of ethanol on the breath is an unreliable means of ascertaining if a person is intoxicated or if ethanol was recently consumed.¹³⁴ Diplopia, visual disturbances, and nystagmus may be evident, which may be due to the toxic effects of ethanol or may represent Wernicke encephalopathy. Hypothermia may be exacerbated by environmental exposure, from malnutrition and loss of carbohydrate or energy substrate, and from ethanol-induced vasodilation. Ethanol intoxication can impair cardiac output in patients with preexisting cardiac disease⁶⁹ and induce dysrhythmias such as atrial fibrillation, atrioventricular block, and nonsustained ventricular tachycardia.^45,70,71 The association between ethanol use and cardiac dysrhythmias, particularly supraventricular tachydysrhythmias, in apparently healthy people is called “holiday heart syndrome.”^99,105,127 The syndrome was first described in people with heavy ethanol consumption, who typically presented on weekends or after holidays, and it may also occur in patients who binge but who usually drink little ethanol. The most common dysrhythmia is atrial fibrillation, which usually reverts to normal sinus rhythm within 24 hours. Although the syndrome may recur, the clinical course is benign in patients without anatomic cardiac pathology and specific antidysrhythmic therapy is usually not warranted.^59,71 Acute heavy ethanol drinking may precipitate silent myocardial ischemia in patients with stable angina pectoris.¹⁶² Variant angina is reported to occur in patients following ethanol ingestion at a time when the blood ethanol concentration has decreased to almost zero.^{53,91,122,130,145,165,184} Ethanol-induced seizures are reported in adults but are more frequent in children with ethanol-induced hypoglycemia.^31,84 Patients presenting with acute ethanol intoxication commonly have decreased serum ionized magnesium concentrations, while their total serum magnesium concentration is within the normal range.²⁰⁸ However, total body magnesium may be depleted due to poor dietary intake, decreased GI absorption secondary to ethanol, and renal wasting due to the ethanol-related diuresis.^{54,90,159,172,179}

There are numerous qualitative and quantitative assays for ethanol in biological fluids and exhaled breath. Immunoassay or gas chromatography is commonly used for determination of ethanol in liquid specimens in most hospitals. Hospital laboratory analysis of blood samples for ethanol content is usually based upon serum (liquid portion of whole blood after the cellular components and clotting factors have been removed), or rarely plasma (acellular liquid portion of whole blood). In contrast, forensic casework expresses ethanol concentration in terms of ethanol concentration in whole blood (Special Considerations: SC6).

Ethanol saliva testing is a promising alternative to breath ethanol analysis in the rapid assessment of blood ethanol concentrations in patients regardless of their mental status.^35,175 Fatty acid ethyl esters (FAEEs) may be a highly sensitive test for recent ethanol use.^14,43,176 Because FAEEs remain in the body for at least 24 hours, they may have a role as a marker of recent ethanol use even after ethanol is completely metabolized. However, their availability is limited, and their place in patient management is undefined.

Ethyl glucuronide and ethyl sulfate are nonoxidative direct ethanol metabolites and are excreted for considerably longer time than etha­-nol.^{17,32,75,164,168} Testing for these metabolites in urine has gained popularity as a sensitive method to detect recent ethanol intake and is favored over tests such as γ-glutamyl transferase or carbohydrate-deficient transferrin, particularly by agencies concerned with monitoring an individual for recent ethanol consumption or relapse; confirming abstinence in treatment programs, workplaces, and schools; and providing legal proof of drinking.^74,154 The presence of ethyl glucuronide and ethyl sulfate provides a strong indication of recent drinking even when ethanol is no longer detectable.⁷⁵ However, caution should be applied in the interpretation of ethyl glucuronide testing results. Ethyl glucuronide may be sensitive to degradation or may be synthesized by bacteria (eg, Escherichia coli) such that infected urine may result in either a false negative or false positive test, particularly when specimens have been improperly stored; ethyl sulfate degradation or formation has not been detected under similar conditions.^78,79 Detection windows for ethyl glucuronide and ethyl sulfate after drinking may be limited and dependent on the amount of ethanol consumed. For example, these metabolites are detectable in urine for ≤24 hours after intake of 0.25 g/kg ethanol and ≤48 hours after intake of 0.50 g/kg ethanol.^{32,73,75,81,82,206} Depending on the analytical cutoff limit, unintentional exposure to ethanol-based mouthwash and hand sanitizers may result in a urine positive for ethyl glucuronide or ethyl sulfate.^29,161 There appears to be a marked interindividual variation in the concentration-time profiles for both metabolites. In situations where the times for ethanol intake and urine specimen collection between drinking and sampling are uncertain, it is not possible to link a single ethyl glucuronide and sulfate result to a specific ethanol dose taken at a specific time.⁷⁷ A common cutoff or reporting limit is yet to be determined for urinary ethyl glucuronide and ethyl sulfate when used as ethanol biomarkers.

Laboratory investigations that should be considered for patients with ethanol intoxication include a rapid reagent glucose test, complete blood count, electrolytes, blood urea nitrogen, creatinine, ketones, acetone, lipase, liver enzymes, ammonia, calcium, and magnesium. Patients with an anion gap metabolic acidosis should have urine ketones and a serum lactate concentration determined (Chaps. 19 and 109). High serum acetone concentrations may be indicative of isopropanol intoxication, whereas elevated serum or urinary ketones may be indicative of AKA, starvation ketosis, or diabetic ketoacidosis (DKA). Because the laboratory nitroprusside reaction detects only ketones (acetoacetate and acetone) and not β-hydroxybutyrate, the assay for urinary ketones may be only mildly positive in patients with AKA.

A blood ethanol concentration should be included in the initial laboratory studies.⁸³ If the blood ethanol concentration is inconsistent with the clinical condition of the patient, prompt reevaluation is indicated to elucidate the etiology of the altered mental status including toxic-metabolic (eg, hypoglycemia, electrolyte or acid-base disorder, toxic alcohols, therapeutic or illicit drug overdose, ethanol withdrawal, hepatic encephalopathy, and Wernicke-Korsakoff syndrome), trauma-related, neurologic (eg, postictalcondition), and infectious etiologies. Comatose patients with concentrations below 300 mg/dL (65 mmol/L) and those with values in excess of300 mg/dL (65 mmol/L) who fail to improve clinically during a limited period of close observation should have a head computed tomography (CT) scan, followed by a lumbar puncture if warranted. Because chronically ethanol-tolerant patients are prone to trauma and coagulopathies, both of which can cause intracerebral bleeding, the threshold for head CT scanning should be low.

Ethanol is rapidly absorbed from the GI tract. In situations where recent ingestion (within one hour of presentation), delayed absorption, and concomitant ingestions are under consideration, GI decontamination may be considered. Occasionally, the extremely intoxicated or comatose patient may have severe respiratory depression necessitating endotracheal intubation and ventilatory support.

Any patient with an acute altered mental status mandates immediate investigation and treatment of reversible etiologies such as hypoxia, hypoglycemia, and opioid toxicity. In addition, Wernicke encephalopathy should be considered. Supplemental oxygen should be administered if the patient is hypoxic, and intravenous dextrose (0.5–1.0 g/kg), thiamine 100 mg, and naloxone 0.4 mg should be administered as clinically indicated. Abnormal vital signs should be addressed and stabilized. Patients who are combative and violent should be both physically and then chemically restrained. Randomized clinical trials suggest both benzodiazepine (ie, midazolam) and antipsychotics (ie, droperidol) are effective as “chemical restraints” in the ED setting.^{86,100,121,140} Midazolam has a more rapid onset of action and has a shorter duration of effect compared with droperidol.^{86,100,121,140} Patients receiving midazolam required more additional sedation and required airway management compared with patients receiving droperidol.^86,100,121 Although the efficacy of midazolam and droperidol has been confirmed by multiple studies,^{86,100,121,140} they were not designed to inform about safety, equivalence, or superiority of midazolam and droperidol. Caution should be taken because of additive effects of ethanol and benzodiazepine on respiratory depression. Attempts by those who are significantly clinically intoxicated to sign out against medical advice or attempt to leave should also be prevented (Chap. 141). The fluid and electrolyte status of the patient should be assessed and abnormalities corrected. Multivitamins with folate, thiamine, and magnesium may be added to the maintenance intravenous solution.

A variety of therapies have been advocated either to reverse the intoxicating effects of ethanol or to enhance its elimination. Those proven to be either ineffective or unreliable include coffee, caffeine, naloxone, flumazenil, and rapid intravenous saline loading.^{55,111,142,143,160} Hemodialysis is an effective means of enhancing the systemic elimination of ethanol because of the small volume of distribution and low molecular weight of ethanol. In severe ethanol poisoning resulting in respiratory failure or coma, hemodialysis may be an adjunct treatment to supportive care. However, the risks and benefits of hemodialysis should be considered.

A patient with uncomplicated ethanol intoxication can be safely discharged after a careful observation with social service or psychiatric counseling. An individual should not be discharged while still clinically intoxicated. However, consideration may be given to a situation where the intoxicated patient is discharged to a protected environment under the supervision of a responsible not intoxicated adult. In all cases except allowing a person to drive, the clinical assessment of the patient is more important than the blood ethanol concentration. Indications for hospital admission include persistently abnormal vital signs, persistently abnormal mental status with or without an obvious cause, an overdose with intended self-harm, concomitant serious trauma, consequential ethanol withdrawal, and an associated serious disease process such as pancreatitis or GI hemorrhage.

Chronic alcoholism leads to an organic brain syndrome that is irreversible. The socioeconomic condition of the patient and the ability to comply with a treatment plan are critical in making a disposition. Alcoholics requesting ethanol detoxification can be admitted for rehabilitation. Inpatient detoxification programs differ substantially from outpatient programs, but their most consequential advantages may be that they enforce abstinence, provide more support and structure, and separate the patient from the social surroundings associated with drinking.¹³⁸ For patients who are not admitted, a referral should be offered to Alcoholics Anonymous or another suitable ethanol rehabilitation program.

Hypoglycemia associated with ethanol consumption occurs when ethanol metabolism increases the cellular redox ratio. The higher redox state favors the conversion of pyruvate to lactate, diverting pyruvate from gluconeogenesis (Fig. 80–2). Hypoglycemia typically occurs when there is a reduced caloric intake and only after the hepatic glycogen stores are depleted, as in an overnight fast. The mechanism by which hypoglycemia is associated with ethanol consumption in the well nourished individual is less well defined.

Although the conditions associated with hypoglycemia in adults may also be present in infants and children, children, with their smaller liver, have less glycogen stores than adults and are more likely to develop hypoglycemia. Hypoglycemia associated with ethanol consumption usually occurs in malnourished chronic alcoholics and children. It may also occur in binge drinkers who do not eat. A 22% incidence of hypoglycemia was reported in one retrospective study of children with documented ethanol ingestion.¹⁰⁹ In another retrospective study of children and adolescents, there was a 3.4% incidence of hypoglycemia (serum glucose concentration less than 67 mg/dL {3.7 mmol/L})⁴⁹; children younger than 5 years of age have an increased risk of developing hypoglycemia, and it is the most common reported clinical abnormality related to ethanol ingestion in this age group.^106,107

Clinical Features

Patients with ethanol-associated hypoglycemia usually present with an altered consciousness 2 to 10 hours following ethanol ingestion. Other physical findings include hypothermia and tachypnea. Laboratory findings, in addition to hypoglycemia, usually include a positive blood ethanol concentration, ketonuria without glucosuria, and mild acidosis.

Management

Acute treatment of ethanol-associated hypoglycemia is similar to other causes of hypoglycemia (Chap. 53 and Antidotes in Depth: A12) and should prompt a systematic evaluation for coexisting clinical and metabolic disorders. Hospital admission is indicated as this represents serious metabolic impairment.

The development of AKA requires that a combination of physical and physiologic events occur. The normal response to starvation and depletion of hepatic glycogen stores is for amino acids to be converted to pyruvate. Pyruvate can serve as a substrate for gluconeogenesis, be converted to acetyl-CoA, which can enter the Krebs cycle or can be utilized in various biosynthetic pathways (eg, fatty acids, ketone bodies, cholesterol, and acetylcholine). As described earlier, ethanol metabolism generates NADH, resulting in an excess of reducing potential. This high redox state favors the conversion of pyruvate to lactate, diverting pyruvate from being a substrate for gluconeogenesis. To compensate for the lack of normal metabolic substrates, the body mobilizes fat from adipose tissue and increases fatty acid metabolism as an alternative source of energy. This response is mediated by a decrease in insulin and an increased secretion of glucagon, catecholamines, growth hormone, and cortisol. Fatty acid metabolism results in the formation of acetyl-CoA, and it combines with the excess acetate that is generated from ethanol metabolism to form acetoacetate (Fig. 80–3).⁶⁰ Most of the acetoacetate is reduced to β-hydroxybutyrate due to the excess reducing potential or high redox state of the cell. Volume depletion interferes with the renal elimination of acetoacetate and β-hydroxybutyrate and contributes to the acidosis. An elevated lactate concentration may result from shunting from pyruvate or from hypoperfusion or infection that may coexist with the underlying ketoacidosis.

Clinical Features

Patients with AKA are typically chronic ethanol users, presenting after a few days of “binge” drinking, who become acutely starved because of cessation in oral intake due to binging itself or to nausea, vomiting, abdominal pain from gastritis, hepatitis, pancreatitis, or a concurrent acute illness.^{61, 62, and 63} The patient may appear acutely ill with salt and water depletion, tachypnea, tachycardia, and hypotension. Underlying medical conditions such as sepsis, meningitis, pyelonephritis, or pneumonia may be present, and ethanol withdrawal may develop, all of which should be considered and systematically excluded. The diagnosis of AKA is a diagnosis of exclusion.

The blood ethanol concentration is usually low or undetectable because ethanol intake ceased substantially earlier in the clinical course. The hallmarks of AKA include an elevated anion gap metabolic acidosis with an elevated serum lactate concentration insufficient to account for the gap. However, some patients will have a normal blood pH or may be even alkalemic because of an associated primary metabolic alkalosis due to vomiting and a compensatory respiratory alkalosis (Chap. 19).⁶⁰ When patients with AKA are compared with patients with DKA, those with AKA tended to have a higher blood pH, lower serum potassium and chloride concentrations, and a higher serum bicarbonate concentration.⁶⁴ The etiology of anion gaps in patients with AKA and DKA is very similar, with β-hydroxybutyrate being the primary anion contributor and lactate having a less consequential role.⁶⁴

The nitroprusside test used to detect the presence of ketones in serum and urine may be negative or mildly positive in patients with AKA because the nitroprusside reaction detects only molecules containing ketone moieties. This includes acetone and acetoacetate but not β-hydroxybutyrate. Reliance on the nitroprusside test alone may underestimate the severity of ketoacidosis. Specific assays for β-hydroxybutyrate may be performed in some hospital laboratories and may be available as point-of-care testing at the bedside. The blood glucose may be low or mildly elevated. It is postulated that ethanol-induced hypoglycemia occurs first, causing increased levels of cortisol, growth hormone, glucagon, and epinephrine; this may correct the hypoglycemia and mobilize fatty acids, which are converted to ketones.³⁶ Therefore, alcoholic hypoglycemia and AKA may be sequential events of the same process, depending on the point in this process at which the patient is evaluated.

Management

Treatment should begin with adequate crystalloid fluid replacement, dextrose, thiamine, and folic acid. Supplemental multivitamins, potassium, and magnesium should be instituted on an individual basis. The administration of dextrose will stimulate the release of insulin, decrease the release of glucagon, and reduce the oxidation of fatty acids. Exogenous glucose also facilitates the synthesis of adenosine triphosphate (ATP), which reverses the pyruvate-to-lactate and NAD⁺-to-NADH ratios. The provision of thiamine facilitates pyruvate entry into the Krebs cycle, thus increasing ATP production. Volume replacement restores glomerular flow and improves excretion of ketones and organic acids. Administration of either insulin or sodium bicarbonate in the management of AKA is usually unnecessary.⁶³

During the recovery phase of AKA, β-hydroxybutyrate is converted to acetoacetate. As this process occurs, the nitroprusside test may become more positive because of higher concentrations of acetoacetate, resulting in hyperketonemia and ketonuria, which represents improvement of the metabolic status.

Patients presenting with AKA are manifesting serious metabolic impairment and require hospital admission. They may succumb to other precipitating or coexisting medical or surgical disorders⁶¹ such as occult trauma, pancreatitis, GI hemorrhage or hepatorenal dysfunction, and infections. However, mortality is rare from ethanol-induced ketoacidosis.

Alcoholism is traditionally defined as a chronic, progressive disease characterized by tolerance and physical dependence to ethanol and pathologic organ changes. Alcoholism is a multifactorial, genetically influenced disorder.^{30,80,138,150,157,170,186}

Screening is a preliminary procedure to assess the likelihood that an individual has a substance use disorder or is at risk of negative consequences from alcohol or other xenobiotics use. Whereas screening tools such as the Brief Michigan Alcoholism Screening Test (MAST)¹⁵³ and the CAGE questions¹²³ (Tables 80–4 and 80–5) were initially developed to identify people with active alcohol dependence for referral to treatment, the screening, brief intervention, and referral to treatment (SBIRT) was developed as a public health model designed to provide universal screening, secondary prevention in detecting risky or hazardous substance use before the onset of abuse or dependence, early intervention, and treatment for people who have problematic or hazardous alcohol problems within health care settings.⁷ Based on the Substance Abuse and Mental Health Services Administration (SAMHSA) model, SBIRT allows for universal screening of all patients regardless of an identified disorder, allowing health care professionals to address the spectrum of such behavioral health problems even when the patient is not actively seeking intervention or treatment.

The presence of tolerance and or dependence is not essential for a diagnosis of alcoholism. Emphasis instead is placed on the social and behavioral concomitants of heavy drinking.¹³³ In the ED setting, questions concerning the ability of the patient to function physically and psychologically are just as appropriate as quantifying the amount of ethanol consumed per day.

Alcoholism is commonly associated with affective disorders, especially depression.^131,155 There is a higher rate of alcoholism among patients with bipolar disorder than in the general population, and there may be a genetic relationship between alcoholism and depression.^{95,144,204,205} Ethanol affects mood, judgment, and self-control; creates a clinical condition conducive to violence directed at self and others; and is an important risk factor for suicide. Although many people drink in an attempt to ameliorate their depression, all available evidence suggests that alcoholism adversely affects mood and cognitive ability. Research indicates alcoholism may be partly under genetic control.^{10,95,101,115} Chromosomal linkage analysis has implicated chromosomes 9, 15, and 16 in the genetic predisposition to alcoholism.^13,39,117 Polymorphism in ADH and ALDH genes appears to be a marker for risk of alcoholism.^{27,30,48,186,188} The ADH1B*2, ADH1C*1, and ALDH2*2 alleles are associated with reduced risk of alcoholism. Genetic epidemiologic studies strongly correlate Asians with homozygous ADH1B*2 and ALDH2*2 alleles with reduced ethanol consumption and incidence of alcoholism.^30,150,202 The incidence of both homozygous ADH1B*1 and ALDH2*1 alleles was significantly higher in patients with ethanol dependence and in patients with alcoholic liver disease.

Various strategies are employed to treat alcoholism, including psychosocial interventions, pharmacological interventions, or both. Pharmacologic treatment of ethanol dependence that is of potential collateral toxicologic consequence include opioid antagonists naltrexone, acamprosate, disulfiram, serotonergic agents, and topiramate.^65,87

Although alcoholism is a serious disease with important health and economic consequences, it continues to be underdiagnosed and remains a treatment challenge.^120,207

• Ethanol is widely used in society, and ethanol use problems impose a staggering personal, social, and economic burden on society.

• Domestic violence, child abuse, fires, falls, sexual assault, and other crimes such as robbery and assault, as well as medical consequences such as cancer, liver disease, and heart disease have all been associated with ethanol misuse.

• Ethanol research suggests that genetics may be an important determinant in vulnerability to ethanol dependence.

• Acute ethanol intoxication and alcoholism are among the most common and complex toxicologic and societal problems.

• Patients with acute ethanol intoxication or alcoholism may present with a diversity of clinical problems that challenge the clinician to be meticulous and systematic in the evaluation and management of these patients.

References