View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Digital Commons@Becker Washington University School of Medicine Digital Commons@Becker Open Access Publications 2018 Toxic alcohols Jeffrey A. Kraut University of California, Los Angeles Michael E. Mullins Washington University School of Medicine in St. Louis Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Kraut, Jeffrey A. and Mullins, Michael E., ,"Toxic alcohols." The eN w England Journal of Medicine.378,3. 270-280. (2018). https://digitalcommons.wustl.edu/open_access_pubs/6501 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. The new england journal of medicine Review Article Edward W. Campion, M.D., Editor Toxic Alcohols Jeffrey A. Kraut, M.D., and Michael E. Mullins, M.D.​​ From Medical and Research Services and oisonings by the toxic alcohols (methanol, ethylene glycol, iso- Division of Nephrology, Veterans Health propanol, diethylene glycol, and propylene glycol) can cause cellular dysfunc- Administration Greater Los Angeles 1 (VHAGLA) Healthcare System, and Mem- tion and death, but symptoms may be nonspecific. Delays in diagnosis in- brane Biology Laboratory, David Geffen P 2 crease the risk of irreversible organ damage and death. In this review, we discuss School of Medicine, University of Califor- the mechanisms of toxicity, methods available for diagnosis, and current recom- nia, Los Angeles — both in Los Angeles (J.A.K.); and the Division of Emergency mendations for therapy. Medicine, Washington University School of Medicine, St. Louis (M.E.M.). Address reprint requests to Dr. Kraut at the Divi- Mechanisms of Toxicity sion of Nephrology, VHAGLA Healthcare System, 11301 Wilshire Blvd., Bldg. 500, The toxic alcohols are inebriating but are not directly toxic, except for isopropanol. Rm. 6018, Los Angeles, CA 90073, or at Their toxic effects result from their metabolites. A simplified schema depicting jkraut@ ucla . edu. their primary metabolic pathways is shown in Figure 1A. This article was updated on January 18, Alcohol dehydrogenase catalyzes the first oxidation of the toxic alcohols. The 2018, at NEJM.org.º resulting aldehydes (except for acetone from isopropanol) undergo further oxida- N Engl J Med 2018;378:270-80. tion by aldehyde dehydrogenase to form carboxylic acid metabolites: methanol is DOI: 10.1056/NEJMra1615295 3 3 Copyright © 2018 Massachusetts Medical Society. metabolized to formic acid, ethylene glycol to oxalic and glycolic acid, diethylene glycol to 2-hydroxyethoxyacetic acid and glycolic acid,4 and propylene glycol to D-lactic and L-lactic acid.5 Alcohol dehydrogenase is the critical enzyme that modulates the production of the toxic metabolites. Coingested ethanol, a competi- tive substrate for alcohol dehydrogenase, delays production of the toxic metabo- lites.6 Increased production of lactic acid can result from exposure to the me- tabolites of methanol or ethylene glycol,3,7 but spurious increments in blood lactate may occur with exposure to ethylene glycol metabolites as a result of interference of glycolate with the lactate measurement by point-of-care instruments.8 Epidemiologic Features The intoxications can occur through different means (Table 1). Methanol intoxication most commonly follows ingestion of automotive windshield-washer fluid, indus- trial products, or adulterated liquids,9 but exposure can also occur through pulmo- nary and cutaneous routes.10 Ethylene glycol is most commonly ingested by adults in antifreeze or in adulterated spirits in which ethylene glycol has been added in lieu of ethanol, in an attempt to commit suicide; in children, it is most commonly ingested unintentionally. Isopropanol intoxication usually results from ingestion of rubbing alcohol, hand sanitizer, and various industrial products, but intoxica- tion can also be due to inhalation or absorption through dermal or rectal routes.11 Diethylene glycol intoxication results from ingestion of automotive brake fluids or industrial products, but it usually occurs in outbreaks in which consumer products or oral medications for children contain diethylene glycol in lieu of propylene glycol 270 n engl j med 378;3 nejm.org January 18, 2018 The New England Journal of Medicine Downloaded from nejm.org at WASHINGTON UNIV SCH MED MEDICAL LIB on January 23, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. Toxic Alcohols A Metabolic Pathways of Toxic Alcohols Alcohol Aldehyde Dehydrogenase Dehydrogenase Ethylene glycol Glycoaldehyde Glycolate+H+ Oxalate+H+ HOCH2CH2OH Methanol Formaldehyde Formate+H+ CH3OH Propylene glycol Lactaldehyde Lactate+H+ OH OH H3C 2-Hydroxyethoxy- 2-Hydroxyethoxy- Diethylene glycol Diglycolate+H+ acetaldehyde acetate+H+ O HO OH Isopropanol Acetone OH H3C CH3 Elevated osmolal gap Elevated anion gap B Time Course of Changes in the Osmolal and Anion Gaps 80 40 70 With coingested ethanol O sm ses 60 o ea la cr 30 l g in ap ap d g ec n 50 re io as An es 40 20 Anion Gap (mmol/liter) Osmolal Gap 30 (mOsm/kg of water) 20 10 10 With coingested ethanol 0 0 Hours Figure 1. Metabolic Pathways of Toxic Alcohols and Time Course of Changes in the Osmolal and Anion Gaps with and without Coingested Ethanol. Panel A shows the metabolic pathways of toxic alcohols. Alcohol dehydrogenase and aldehyde dehydrogenase sequen- tially oxidize the toxic alcohols. Alcohol dehydrogenase catalyzes the first oxidation of the toxic alcohols and is an im- portant target for antidotal therapy. The enclosed boxes highlight the putative toxic metabolites. Methanol is metabo- lized to formic acid, ethylene glycol to oxalic and glycolic acid, diethylene glycol to 2-hydroxyethoxyacetic acid and glycolic acid, and propylene glycol to D-lactic and L-lactic acid. Panel B shows the time course of changes in the os- molal and anion gaps with and without coingested ethanol. An increased osmolal gap is prominent early owing to the accumulation of the un-ionized alcohols. As metabolism proceeds, the osmolal gap declines with the formation of ionized metabolites. Conversely, the serum anion gap is lowest before the alcohol is metabolized and increases with the formation of ionized metabolites. The time course of these changes in both parameters varies among the alcohols. They typically evolve over several hours to over a day. Coingested ethanol impedes metabolism (dashed lines) and delays the onset of the high anion-gap acidosis. n engl j med 378;3 nejm.org January 18, 2018 271 The New England Journal of Medicine Downloaded from nejm.org at WASHINGTON UNIV SCH MED MEDICAL LIB on January 23, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. 272 Table 1. Clinical and Laboratory Features of the Toxic Alcohols. Increase in Serum Osmolality per 10-mg/dl Alcohol Type and Increase in Serum Onset of Clinical and Laboratory Molecular Weight Alcohol Concentration Common Sources Common Clinical Features Major Laboratory Features Features* Without With Coingested Coingested Ethanol Ethanol mOsm/kg of water hours after exposure The new england journal england new n engljmed Ethylene glycol, 1.60 Automotive antifreeze, engine Inebriation, acute kidney injury Increased osmolal gap and high 12–24 48–72 62.07 coolants, deicing fluids anion-gap metabolic acidosis, calcium oxalate crystalluria dihydrate (early) and monohy- drate (late) and hypocalcemia, 378;3 lactate gap (discrepancy be- tween findings from a point- of-care analyzer and laboratory nejm.org test) Methanol, 32.04 3.09 Windshield-washer fluid, carbu- Inebriation, abdominal pain, Increased osmolal gap and high 6–24 72–96 retor cleaner, octane boost- decreased vision with anion-gap metabolic acidosis, January 18,2018 ers, racing fuels, camp stove blindness, Parkinson-like increased formate, lactic aci- fuel, adulterated ethanol features (rare) dosis with cellular hypoxia, (“moonshine”) spurious increase in serum of medicine creatinine concentration Propylene glycol, 1.31 Diluent in parenteral medica- Hepatic and renal disease are Increased osmolal gap alone NA NA 76.09 tions, automotive antifreeze uncommon but will predis- (most common finding), un- (marketed as a safer alterna- pose to more severe toxicity explained lactic acidosis, acute tive to ethylene glycol) kidney injury (rare) Diethylene glycol, 0.9 Automotive brake fluids, hydrau- Abdominal pain, nausea and Increased osmolal gap and high 24–48 48–72 106.12 lic fluids, adulterated liquid vomiting, acute pancreati- anion-gap metabolic acidosis, (limited data (limited data medications (e.g., inappro- tis, acute kidney injury acute kidney injury available) available) priate substitution for pro- pylene glycol or glycerin) (most common source) Isopropanol, 60.02 1.66 Rubbing alcohol, hand sanitizers Inebriation, depressed senso- Increased osmolal gap, acetone- 2–4 NA rium, abdominal pain mia, ketonuria * Without or with coingested ethanol indicates the impact of the simultaneous presence of ethanol in the patient. NA denotes not applicable. The New England Journal of Medicine Downloaded from nejm.org at WASHINGTON UNIV SCH MED MEDICAL LIB on January 23, 2018. For personal use only. No other uses without permission.