A Publication of Warde Medical Laboratory 2012 Volume 22, Number 5 “Quality in Laboratory Diagnosis”

Ethylene GlycolNtei Abudu, Ph.D. Richard S. Bak, Ph.D.

Ethylene glycol is a colorless, odorless, sweet-tasting, viscous liquid. It is

primarily used as an automobile radiator antifreeze. Other uses include de-icing solutions, brake fluid, paints, lacquers, and as a solvent. Ethylene glycol intoxication is

one of the most serious poisonings encountered in clinical toxicology. It is occasionally ingested as a beverage by a debilitated or misguided alcoholic patient and rarely by a child who has taken a sip of the sweet-tasting liquid. The lethal dose in adults is estimated to be

100 mLs. In children, the estimated lethal dose is 1mL per 1kg of body weight.

Chemistry, Absorption, and Metabolism

Ethylene glycol is a simple molecule. It is very similar to ethyl alcohol and its chemical structure is shown in (Fig. 1).

Ethylene glycol is absorbed within 30 minutes of ingestion. Maximal blood concentrations are reached in 1 to 4 hours. The elimination half-life, in the absence of treatment, is 2.5 to 3.0 hours1,2,3.

Unmetabolized ethylene glycol is not toxic. After ingestion, ethylene glycol is oxidized to glycoaldehyde, glycolic acid, glyoxalic acid, and

oxalic acid (Fig 2). These four metabolites are responsible for the compound’s major toxic effects which include1 tissue destruction,

primarily from calcium oxalate tissue deposition, and2 metabolic abnormalities,

specifically a high anion-gap metabolic acidosis, lactic acidosis, and hypocalcemia4.

After ingestion, ethylene glycol is oxidized to four metabolites responsible for the compound’s major toxic effects.

Also In This Issue:

6 Editorial — Your Health — Nonpharmacologic Management of Gout

Fig 1. Structure of ethylene glycol

HO

OH

2

Ethylene Glycol

Clinical Presentation

Toxicity has been described as appearing in three stages5,6. Stage 1 occurs from 0.5 to 12.0 hours. CNS toxicity predominates with inebriation, confusion, nystagmus, paralysis, seizures, and coma. Nausea, vomiting, and papilledema may also occur. An elevated serum osmolarity is usually seen early in this phase. Calcium oxalate crystals may be present.

Stage 2 occurs from 12 to 24 hours postingestation. Cardiopulmonary symptoms predominate with mild tachycardia and hypertension. Other effects include anion gap metabolic acidosis (possibly severe) with compensatory hyperventilation, hypoxia, congestive heart failure, and acute renal distress syndrome.

Stage 3 occurs from 24 to 72 hours postingestion. This renal phase is characterized by flank pain with oliguria,

hematuria, calcium oxaluria, proteinuria, and anemia leading to acute tubular necrosis and renal failure.

Diagnostic Tests

Serum Ethylene Glycol Concentration

The determination of serum ethylene glycol concentration, usually by gas chromatography, is the preferred diagnostic procedure. If ethylene glycol levels are not available within a few hours, treatment should be initiated until the lab results become available. Levels greater than 20 mg/dL are considered toxic, but levels less than 20mg/dL may still indicate a toxic amount if significant time has passed since the ingestion.

Clinical Chemistry Tests

Serum osmolality may be useful if ethylene glycol levels cannot be done. The increased serum osmolarity is due to ethylene glycol and glycoaldehyde. The increase occurs early on and may disappear later as ethylene glycol and glycoaldehyde are metabolized. Thus the osmol gap may decrease despite a worsening toxicity. It should also be noted that an increase osmolality could be caused by other

Ethylene Glycol Pharmacokinetic Data

Vd = 0.5 - 0.8 L/kg

t 1/2, in the absence of treatment 2.5 to 3.0 hours

t 1/2, with ethanol treatment 17 hours

t 1/2, with fomepizole treatment 20 hours

With treatment, ethylene glycol may persist in the serum for up to 5 days and may be detectable

in urine for up to 17 days.

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Fig 2. Metabolism of ethylene glycol

Intracellular Ca2+

Calcium Oxalate

HO OHC

O O

COxalic Acid

H HC

HO

H

O

CGlycoaldehyde

H HC

HO

H

OH

H

CEthylene Glycol

H OHC

HO

H

O

CGlycolic Acid

H OHC

O O

CGlyoxalic Acid

α-OH-β-ketoadipic acid Thiamine

Glycine and benzoic acidPyridoxine

NAD

Alcohol Dehydrogenase

NADH + Pyruvate Lactic acid

NAD

Aldehyde Dehydrogenase

NADH + Pyruvate Lactic acid

O2

Glycolic Acid Dehydrogenase

H2O

O2

Glycolic Acid Dehydrogenase

H2O

4

Ethylene Glycol

conditions such as shock, alcoholic or diabetic ketoacidosis, lactic acidosis or renal failure.

The presence of a high anion gap may be a useful diagnostic clue. The anion gap increases due partially to the formation of pyruvate to lactate in the first two steps of ethylene glycol metabolism7. However, the

absence of an anion gap could be due to individual variability and does not rule out ethylene glycol ingestion.

Serum calcium testing and electrocardiogram monitoring are both

indicated when monitoring an ethylene glycol poisoned patient.

Renal function tests and urinalysis should be done on symptomatic patients.

Calcium oxalate crystals may appear in the urine 4 to 8 hours after ingestion either as the monohydrate crystal (elongated) or the more specific dihydrate crystal (octahedral). These crystals will deposit in almost every tissue of the body including the brain, heart, lungs, kidneys, and urine.

Treatment

The treatment of ethylene glycol poisoning is complex and challenging. Gastric aspiration followed by lavage is useful up to one hour after ingestion. Bicarbonate drip is usually given not only to increase the bicarbonate concentration but also to promote the excretion of glycolic and lactic acids7.

Antidotal therapy is indicated when 1) there is a history or suspicion of ethylene glycol ingestion 2) an unexplained increase in serum osmolarity 3) the presence of oxalate crystals in the urine or 4) ethylene glycol levels above 20 mg/dL4.

Antidotal therapy is based on preventing the alcohol dehydrogenase enzyme from converting ethylene glycol into toxic metabolites (Fig 2). Two competitive inhibitors are currently in clinical use: ethanol and fomepizole.

Ethanol has been the traditional antidote for ethylene glycol toxicity. Ethanol has 100 times the affinity for alcohol dehydrogenase than ethylene glycol. In most cases, a serum ethanol level of 100 to 130 mg/dL is needed to effectively block alcohol dehydrogenase from metabolizing ethylene glycol. When ethanol is administered, serum ethanol concentrations should be monitored every one to two hours to avoid ethanol toxicity.

Fomepizole (Antizol) was approved by the FDA in 1997 for the treatment of ethylene glycol poisoning (Fig 3). It has 500 to 1,000 times the affinity for alcohol dehydrogenase than ethylene glycol. Fomepizole has advantages over

Fig 3. Chemical structure of fomepizole (Antizol)

Antidotal therapy is used to prevent ethylene glycol from converting into toxic metabolites.

CH3

N

NH

5

ethanol in that it is easier to administer, causes no central nervous system depression, and has a longer duration of action. However the cost of the drug is much higher than ethanol (approximately $900.00 per dose).

Thiamine is often given as an adjunct therapy6. Besides the fact that many alcoholics are thiamine deficient, thiamine also prevents the formation of oxalic acid by facilitating the conversion of glycoxylic acid to alpha-hydroxy-beta ketoadipic acid (Fig 2).

Pyridoxine is also given as adjunct therapy. It prevents the formation of oxalic acid by converting glycoxylic acid to

benzoic acid and glycine. (Fig 2).

Hemodialysis should be considered in the patient with severe metabolic acidosis, renal failure, or generally deteriorating condition. Traditonally, it has been recommended to

dialyze the patient when the ethylene glycol level is greater than 50 mg/dL8. However, if the patient is not acidotic, he or she may be treated with antidotal therapy only9.

The endpoint of hemodialysis treatment or antidotal treatment should be a serum ethylene glycol level less than 20 mg/dL, with resolution of acidosis, and the patient should be improving clinically10.

Summary

Ethylene glycol poisoning is a relatively rare event, but when it occurs it is a serious medical emergency. The measurement of ethylene glycol levels in serum and/or urine can confirm the diagnosis and may aid the clinician in both the type and duration of therapy.

References

1. Peterson CD, Collins AJ, Himes JM, et al. Ethylene glycol poisoning: pharmacokinetics during therapy with ethanol and hemodialysis. N Engl J Med 1981;304:21-23

2. Winek CL, Shingleton DP, Shanor SP. Ethylene and diethylene glycol toxicity. J Toxicol Clin Toxicol 1978; 13:297-324.

3. Jacobsen D, Sebastian CS, Blomstrand R, et al. 4-Methylpyrazole: a controlled study of safety in healthy human subjects after single, ascending doses. Metab Clin Exp Res 1988; 12:516-522.

4. http://www.mnpoison.org/index.asp?pageID=155

5. Berman LB, Schreiner GE, Feys J. The nephrotoxic lesions of ethylene glycol. Ann Intern Med 1957; 46:611-619.

6. Kahn HS, Brotchner RJ. A recovery from ethylene glycol (antifreeze) intoxication; A case of survival and two fatalities from ethylene glycol including autopsy findings. Ann Intern Med 1950; 32:284-294.

7. Medicine.med.nyu.edu/…/ethylene%20glycol%20poisoning.pdf

8. Barceloux DG, Krenzelok EP, Olson K, Watson W. American Academy of Clinical Toxicology Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Ad Hoc Committee. J Toxicol Clin Toxicol 1999; 37:537-560.

9. Borron SW, Megarbane B, Baud FJ. Fomepizole in treatment of uncomplicated ethylene glycol poisoning. Lancet 1999; 354:831.

10. Heath A Joliff and Marco L.A. Swilotti. Ethylene Glycol. In Dart RC ed, Medical Toxicology, 3rd ed. Philadelphia Lippincott Williams and Wilkins 2004 p.1228

Hemodialysis is considered when there is severe metabolic acidosis, renal failure, or deteriorating condition.

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Your Health — Nonpharmacologic Management of GoutDanny Wiedbrauk, Ph.D.

In October 2012, the American College of Rheumatology (ACR) published a two-part guideline for the management

and treatment of gout. The first ACR guideline focuses on patient education, diet, lifestyle, treatment objectives, and management of comorbidities1. These recommendations constitute the core therapeutic measures in the management of gout. The second

guideline publication addresses the clinical management of gout2.

Gout is one of the most common rheumatic diseases of adulthood, with 8.3 million affected individuals in the U.S. alone. The incidence of gout has risen 40% from 1990 to 19993 as Americans have become older, heavier4, and experience more comorbidities including hypertension, renal insufficiency, hypertriglyceridemia, hypercholesterolemia, diabetes, obesity, and early menopause that contribute to elevated uric acid/urate levels.

Uric acid is an end-stage by-product of purine metabolism and humans remove urate primarily by renal excretion. Gout develops when uric acid excretion cannot maintain serum urate levels below the saturation point of 6.8 mg/dL. When tissues become supersaturated, the urate salts precipitate, forming needle-like crystals that can cause inflammation and cell destruction. Gout can also be caused by overproduction of urate due to genetic anomalies, malignancies, certain hematologic disorders, chemotherapeutic agents, excessive exercise, and obesity. Gout is associated with considerable morbidity with acute episodes often causing incapacitation. Chronic tissue injury can lead to severe joint destruction and renal impairment.

Management of gout frequently requires pharmacologic intervention to relieve pain, prevent disease progression, and prevent tissue deposition of uric acid. Patient behaviors that reduce uric acid levels and prevent gout-associated comorbidities play an important role in preventing gouty flares and the associated tissue damage. The first part of the ACR guidelines focuses on these behaviors.

The incidence of gout rose 40% from 1990 to 1999 and 8.3 million Americans suffer with the disease.

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Foods to avoid

• Foods that have very high purine levels including hearts, sweetbreads (e.g., pancreas, thymus), liver, and kidney.

• Foods containing high-fructose corn syrup. Consumption of fructose-rich foods and beverages is associated with an increased risk of gout in both men and women.5,6

• Alcohol overuse (more than 2 servings/day for males and 1 serving/day for

females) in patients without symptoms. All alcohol use should be avoided during gout attacks and in cases of advanced gout under poor control. Heavy drinkers are much more likely to have recurrent gout attacks, even with

allopurinol therapy. (Alcohol interferes with the effectiveness of allopurinol.)

Foods to Limit

• Limit serving sizes of beef, pork, lamb and seafood with high purine content such as smelt, sardines, and shellfish.

• Limit servings of naturally sweet fruit juices, table sugar, sweetened beverages, and desserts.

• Limit table salt including salt in sauces and gravies.

• Limit Alcohol intake (particularly beer, but also wine and spirits) in all gout patients. These beverages can elevate uric acid levels and precipitate attacks of gout.

Foods that are encouraged

• Low-fat or non-fat dairy products. Dairy products are relatively low in dietary purines. Milk also contains uricosuric factors, such as orotic acid, which may promote renal uric acid excretion.

• Vegetables

• Maintaining a high level of hydration with water is helpful in avoiding gouty flares and the formation of kidney stones.

The diagnosis of gout may be a good time to start a low-cholesterol, low-fat diet.

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William G. Finn, M.D., Medical DirectorRichard S. Bak, Ph.D., Operations Director

Direct Correspondence to:

Editor: The Warde ReportWarde Medical Laboratory300 Textile RoadAnn Arbor, MI 48108

734-214-0300 / Toll free 1-800-876-6522Fax 734-214-0399www.wardelab.com

Your Health — Nonpharmacologic Management of Gout

Behavior Modification Recommendations

• Weight loss in those who are overweight can lower uric acid levels.

• Smoking cessation

• Moderate exercise can reduce uric acid levels and associated comorbidities.

• Because of the association of gout with atherosclerosis, the diagnosis of gout may be a good time to start a low- cholesterol, low-fat diet. This type of diet can reduce uric acid levels and lower the risk of atherosclerosis.

Patient lifestyle choices have an important role in preventing gouty flares and the comorbidities associated with gouty attacks. Choose wisely.

Literature Cited

1. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64:1431-1446.

2. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64:1447-1461.

3. Terkeltaub RA. Gout: Recent advances and emerging therapies. Rheumatic Disease Clinics Update. 2008;3(1):1-9.

4. Kim KY, Ralph Schumacher H, Hunsche E, Wertheimer AI, Kong SX. A literature review of the epidemiology and treatment of acute gout. Clin Ther. Jun 2003;25(6):1593-617.

5. Choi HK, Willett W, Curhan G. Fructose-rich beverages and risk of gout in women. JAMA. Nov 24 2010;304(20):2270-8.

6. Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ. Feb 9 2008;336(7639):309-12.