Alcohol Toxicity

Updated: Dec 15, 2016
  • Author: Michael D Levine, MD; Chief Editor: Jeter (Jay) Pritchard Taylor, III, MD  more...
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Overview

Background

Although any alcohol can be toxic if ingested in large enough quantities, the term toxic alcohol has traditionally referred to isopropanol, methanol, and ethylene glycol. [1] Prompt recognition and treatment of patients intoxicated with these substances can reduce the morbidity and mortality associated with these alcohols.

This article discusses not only the three toxic alcohols but also ethanol. For discussion of the individual agents, see Methanol Toxicity and Ethylene Glycol Toxicity; for discussion of pediatric ethanol ingestion, see Ethanol Toxicity. Ethanol withdrawal is a serious and potentially life-threatening problem, which is discussed in Withdrawal Syndromes.

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Pathophysiology

Ethanol

Ethyl alcohol (ethanol; CH3 -CH2 -OH) is a low molecular weight hydrocarbon that is derived from the fermentation of sugars and cereals. It is widely available both as a beverage and as an ingredient in food extracts, cough and cold medications, and mouthwashes.

Ethanol is rapidly absorbed across both the gastric mucosa and the small intestines, reaching a peak concentration 20-60 minutes after ingestion. Once absorbed, it is converted to acetaldehyde. This conversion involves three discrete enzymes: the microsomal cytochrome P450 isoenzyme CYP2E1, the cytosol-based enzyme alcohol dehydrogenase (ADH), and the peroxisome catalase system. Acetaldehyde is then converted to acetate, which is converted to acetyl Co A, and ultimately carbon dioxide and water. [2]

Genetic polymorphisms coding for alcohol dehydrogenase, the amount of alcohol consumed, and the rate at which ethanol is consumed all affect the speed of metabolism. As a general rule, ethanol is metabolized at a rate of 20-25 mg/dL in the nonalcoholic but at an increased rate in chronic alcoholics.

Isopropanol

Isopropyl alcohol (isopropanol; CH3 -CHOH-CH3) is a low molecular weight hydrocarbon. It is commonly found as both a solvent as well as a disinfectant. [3] It can be found in many mouthwashes, skin lotions, rubbing alcohol, and hand sanitizers. Because of its widespread availability, lack of purchasing restrictions, and profound intoxicating properties, it is commonly used as an ethanol substitute.

Isopropanol is rapidly absorbed across the gastric mucosa and reaches a peak concentration approximately 30-120 minutes after ingestion. Isopropanol is primarily metabolized via alcohol dehydrogenase to acetone. A small portion of isopropanol is excreted unchanged in the urine. The peak concentration of acetone is not present until approximately 4 hours after ingestion. The acetone produces CNS depressant effects and a fruity odor on the breath. [4]

Methanol

Methyl alcohol (methanol; CH3 OH) is widely used as an industrial and marine solvent and paint remover. It is also used in photocopying fluid, shellacs, and windshield-washing fluids. Although toxicity primarily occurs from ingestion, it can also occur from prolonged inhalation or skin absorption. [5, 6, 7] Methanol is rapidly absorbed from the gastric mucosa, and achieves a maximal concentration 30-90 minutes after ingestion. [8]

Methanol is primarily metabolized in the liver via alcohol dehydrogenase into formaldehyde. Formaldehyde is subsequently metabolized via aldehyde dehydrogenase into formic acid, which ultimately is metabolized to folic acid, folinic acid, carbon dioxide, and water. A small portion is excreted unchanged by the lungs.

Formic acid is responsible for the majority of the toxicity associated with methanol. Without competition for alcohol dehydrogenase, methanol undergoes zero-order metabolism, and is thus is excreted at a rate of 8.5 mg/dL/h to 20 mg/dL/h. Once methanol experiences competitive inhibition, from either ethanol or fomepizole, the metabolism changes to first order. In this later scenario, the excretion half-life ranges from 22-87 hours.

Ethylene glycol

Ethylene glycol (CH2 OH-CH2 OH) is an odorless, colorless, sweet-tasting liquid, which is used in many manufacturing processes. Domestically, it is probably most commonly encountered in antifreeze. It is absorbed somewhat rapidly from the gastrointestinal tract, and peak concentrations are observed 1-4 hours after ingestion. [7]

Ethylene glycol itself is nontoxic, but it is metabolized into toxic compounds. Ethylene glycol is oxidized via alcohol dehydrogenase into glycoaldehyde, which then undergoes metabolism via aldehyde dehydrogenase into glycolic acid. [9] The conversion to glycolic acid is somewhat rapid. In contrast, the conversion of glycolic acid to glyoxylic acid is slower and is the rate-limiting step in the metabolism of ethylene glycol.

Glyoxylic acid is subsequently metabolized into several different products, including oxalic acid (oxalate), glycine, and alpha-hydroxy-beta-ketoadipate. The conversion to glycine requires pyridoxine as a cofactor, while the conversion to alpha-hydroxy-beta-ketoadipate requires thiamine as a cofactor. The oxalic acid combines with calcium to form calcium oxalate crystals.

In the presence of normal renal function and no competitive inhibition for alcohol dehydrogenase, the excretion half-life of ethylene glycol is approximately 3 hours. However, in the presence of fomepizole or ethanol, alcohol dehydrogenase undergoes competitive inhibition, and the resulting excretion half-life increases to approximately 17-20 hours.

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Epidemiology

Frequency

Alcohol intoxication is common in modern society, largely because of its widespread availability. More than 8 million Americans are believed to be dependent on alcohol, and up to 15% of the population is considered at risk. In some studies, more than half of all trauma patients are intoxicated with ethanol at the time of arrival to the trauma center. In addition, ethanol is a common coingestant in suicide attempts.

Mortality/Morbidity

Acute intoxication with any of the alcohols can result in respiratory depression, aspiration, hypotension, and cardiovascular collapse.

Ethanol

In 2014, 6026 single exposures to ethanol in beverages, with 219 major outcomes and 15 deaths, were reported to US Poison Control Centers. There were 3508 non-beverage exposures, with 13 major outcomes and 4 deaths; ethanol-based hand sanitizers accounted for 18,322 single exposures, with 11 major outcomes and no deaths, and ethanol-containing mouthwashes accounted for 6,539 single exposures, with 20 major outcomes and two deaths. [10]

Ethanol poisoning is typically caused by high-intensity binge drinking (ie, consumption of a very large amount of alcohol during an episode of binge drinking). Approximately 38 million US adults report binge drinking an average of four times per month and consuming an average of eight drinks per episode. In 2010–2012, an annual average of 2,221 ethanol poisoning deaths (8.8 deaths per 1 million population) occurred in persons aged ≥15 years in the United States. Of those deaths, 1,681 (75.7%) involved adults aged 35–64 years, and 1,696 (76.4%) involved men. [22]

Although many patients present with ethanol intoxication as their sole issue, many other patients have ethanol intoxication as part of a larger picture. Thus, the morbidity is often from coingestants or coexisting injuries and illnesses.

Long-term use results in hepatic and gastrointestinal injuries. Coma, stupor, respiratory depression, hypothermia, and death can result from high concentrations of acute ethanol intoxication. Chronic alcoholics, as well as children, are at risk for hypoglycemia.

Isopropanol, methanol, and ethylene glycol

In 2014, 15,334 single exposures to isopropanol (from sources including rubbing alcohol, cleaning agents, and hand sanitizers) were reported to US Poison Control Centers. Of these, 60 patients were classified as experiencing "major" morbidity, with one patient dying. [10]

In the same year, 1,610 single exposures to methanol, including automotive products, and 5,552 exposures to ethylene glycol were reported. Of those intoxicated with methanol, 16 patients were classified as experiencing "major" disability, and 9 additional patients died. For those patients who were intoxicated with ethylene glycol, 141 patients were classified as having "major" disability, with an additional 16 patients dying. [10] It is important to recognize that these numbers likely underestimate the true incidence of exposure, however, because of both a failure to recognize the ingestion as well as a failure to report the suspected or known ingestion to a poison control center.

The primary toxicity with isopropanol is CNS depression. These CNS manifestations can include lethargy, ataxia, and coma. In addition, isopropanol is irritating to the GI tract. Therefore, abdominal pain, hemorrhagic gastritis, and vomiting can be observed. Unlike methanol and ethylene glycol, isopropanol does not cause a metabolic acidosis.

The toxicity with methanol occurs from both the ensuing metabolic acidosis, as well as the formate anion (formic acid) itself. [11] Although the eye is the primary site of organ toxicity, in the later stages of severe methanol toxicity, specific changes can occur in the basal ganglia as well. Pancreatitis has been reported following methanol ingestion. Hyperventilation will occur as a compensatory mechanism to counteract the acidosis.

As previously stated, ethylene glycol itself is nontoxic. The majority of the metabolic acidosis occurs from glycolic acid. One form of morbidity occurs when oxalate combines with calcium to form calcium oxalate crystals, which accumulate in the proximal renal tubules, thereby inducing renal failure. Hypocalcemia can ensue, and cause coma, seizures, and dysrhythmias. Autopsy studies have confirmed that the calcium oxalate crystals are deposited not only in the kidneys but in many other organs, including the brain, heart, and lungs.

Age

Ethanol intoxication is common in older teenagers through adulthood. The toxic dose for an adult is 5 mg/dL, whereas the toxic dose in a child is 3 mg/dL. Children are at higher risks of developing hypoglycemia following a single ingestion than are adults.

Most isopropanol ingestions occur in children younger than 6 years. Most methanol and ethylene glycol ingestions occur in adults older than 19 years.

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