Case Report

Diethylene Glycol Poisoning From Transcutaneous Absorption

Elisabetta Devoti, MD, Elisabetta Marta, MD, Elena Belotti, MD, Laura Bregoli, MD,
Francesca Liut, MD, Paolo Maiorca, MD, Valentina Mazzucotelli, MD, and
Giovanni Cancarini, MD

A case of transcutaneous diethylene glycol poisoning with severe acute kidney injury, but a positive
outcome, is described. A man without significant medical history was admitted to our hospital due to anuria,
gastrointestinal symptoms, and hypertension. Ultrasonography excluded vascular damage and postrenal
obstruction. Laboratory tests showed acute kidney injury and metabolic acidosis with increased anion gap;
hemodialysis therapy was started. The brother of the patient reported that the patient had been smearing his
skin with brake fluid containing diethylene glycol to treat a “dermatitis.” Only supportive therapy was given due
to the lack of a specific antidote. Continuous venovenous hemofiltration was performed. The kidney biopsy
showed acute toxic proximal tubulonecrosis, without deposition of oxalate crystals. His neurologic condition
worsened dramatically; supportive care was continued. Over time, acute kidney injury and neurologic damage
gradually improved; 33 days after admission, he went to a rehabilitation unit for 5 months, with complete
clinical recovery. Historically, diethylene glycol has been the cause of large-scale poisonings from ingestion of
contaminated drugs. The clinical evolution is unpredictable. Treatment is not well defined; early hemodialysis
treatment reduces levels of toxic metabolites, and fomepizole could be useful in cases with an early diagnosis.
A comparison of the characteristics of diethylene glycol versus ethylene glycol poisoning is given.
Am J Kidney Dis. 65(4):603-606. ª 2015 by the National Kidney Foundation, Inc.

INDEX WORDS: Diethylene glycol; ethylene glycol; acute kidney injury; acute renal failure; poisoning;
intoxication.

D iethylene glycol, a clear, colorless, and odorless

substance present in many industrial products,
causes toxicity if ingested. In the past, it has been
substituted in pharmaceutical preparations in place of
more expensive but nontoxic substances, causing
mass poisoning 12 times during the last 70 years.1-3
Diethylene glycol poisoning leads to kidney failure,
peripheral neuropathy, and liver toxicity.4
This case report describes a rare case of trans-
cutaneous diethylene glycol poisoning with severe
clinical course.
CASE REPORT
A 29-year-old African man who was a nonsmoker, spoke Italian
fluently, reported no misuse of alcohol or illicit drug use, and had
no significant medical history came to our hospital experiencing
nausea, abdominal pain, weakness, hyporexia, hypertension (blood
pressure, 170/100 mm Hg), and anuria. Physical examination
findings were unremarkable. Laboratory test results indicated
severe kidney failure (serum creatinine, 15.5 mg/dL; estimated
glomerular filtration rate, 4.3 mL/min/1.73 m2 estimated using the
CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration]
equation5), metabolic acidosis (bicarbonate, 16.4 mEq/L) with
mildly elevated anion gap (23 mmol/L), and high levels of serum
lipase (3,027; reference, , 216 IU/L), transaminases (serum
alanine aminotransferase, 98 IU/L; serum aspartate aminotrans-
ferase, 100; reference range, 5-50 IU/L), and C-reactive-protein
(131; reference, ,5 mg/L). Renal and Doppler sonography
excluded chronic kidney disease, urinary tract obstruction, renal
artery stenosis, and renal vein thrombosis. Laboratory test results
for the more likely infectious and immunologic diseases were
negative.
Hemodialysis therapy was started immediately. Due to a pro-
longed bleeding time, kidney biopsy was delayed until day 6 after
admission. Soon after the biopsy, the patient’s brother reported that
the patient had been smearing his skin with brake fluid for the past
few months to treat a “dermatitis.” The patient confirmed this, but
denied accidental or intentional ingestion. The brake fluid was class
DOT3 (Department of Transportation), with a mean diethylene
glycol concentration of 10%. Only supportive therapy was given
due to the lack of a specific antidote for diethylene glycol. Over the
next 3 hours, the patient developed progressive drowsiness, hy-
potension (systolic blood pressure, 100 mm Hg), and respiratory
failure requiring intubation and ventilator support in the intensive
care unit. Lumbar puncture excluded meningitis. Continuous
venovenous hemofiltration was performed from days 7 to 12.
The kidney biopsy specimen exhibited normal glomeruli and
vessels and acute toxic proximal tubular necrosis without oxalate
crystals, findings that supported the differential diagnosis of
diethylene glycol intoxication. Laboratory analyses found only
traces of diethylene glycol in urine, but the samples had been
collected after some dialysis sessions. Laboratory methods for
detecting metabolites of diethylene glycol were not available.
Over the next several days, the patient’s neurologic situation
progressively worsened: ascending paralysis with disappearance of
limb, head, and eye movements; areflexia; loss of corneal,
vestibulo-ocular, and gag reflexes, and absence of auditory evoked
potentials; electroencephalography showed depression of activity
From the Operative Unit of Nephrology, A.O. Spedali Civili di
Brescia and University of Brescia, Brescia, Italy.
Received May 21, 2014. Accepted in revised form July 9, 2014.
Originally published online November 4, 2014.
Address correspondence to Elisabetta Devoti, MD, U.O.
Nefrologia, A.O. Spedali Civili di Brescia, Piazzale Spedali Civili,
1, 25123 Brescia, Italy. E-mail: devotielisabetta@gmail.com
 2015 by the National Kidney Foundation, Inc.
0272-6386
http://dx.doi.org/10.1053/j.ajkd.2014.07.032

Am J Kidney Dis. 2015;65(4):603-606 603

 Devoti et al

in the cerebral cortex; and Glasgow Coma Scale score was 3. Table 1. Chemical and Physical Characteristics of Ethylene
Supportive care was continued. Later, progressive improvements Glycol and Diethylene Glycol
in kidney and neurologic function occurred. At 33 days after
admission, the patient’s serum creatinine level was 1.26 mg/dL Ethylene Glycol Diethylene Glycol
(estimated glomerular filtration rate, 89 mL/min/1.73 m2) and the
patient was transferred to a rehabilitation unit. At discharge, after Molecular C2H6O2 C4H10O3
5 months, his neurologic recovery was almost complete, having formula
recovered his ability to walk, speak, and hear. Structure HO-CH2-CH2-OH HO-CH2-CH2-O-
CH2-CH2-OH
DISCUSSION Molecular 62.07 106.12
Diethylene glycol has been involved in many weight (Da)
medication-associated mass poisonings, mainly due to Solubility Water soluble Water soluble
oral ingestion of acetaminophen or other contami- Appearance Viscous hygroscopic Viscous hygroscopic
liquid; colorless; liquid; colorless;
nated drugs. The first report was in 1937 in the United odorless; sweetish odorless; sweetish
States: 105 patients died after having ingested Elixir taste taste
Sulphanilamide, which was marketed without a prior Contained in Automobile coolants; Antifreeze; brake fluids;
toxicity test.6,7 This event led to creation of the heat transfer fluids; cosmetics; lubricants;
Federal Food, Drug, and Cosmetic Act, which re- precursor to paper; inks; textiles;
quires that drug producers must demonstrate safety polyester (bottle); adhesives; packaging
used in bottling; materials; adhesives,
before selling a product.8 To our knowledge, there is runway deicers solvents
only one report in the literature of topical intoxication;
5 patients with second- and third-degree burns
involving 7% to 62% of the body surface area were the other patients usually remain dialysis dependent.
treated with silver sulfadiazine cream for 4 to 24 days. Renal ultrasound shows enlarged or swollen kidneys
Between days 3 and 6, they developed anuria and and, less frequently, atrophic kidneys. The degree of
neurologic deterioration and died despite supportive kidney injury can predict the neurologic evolution. The
care. The cream contained diethylene glycol and the coexistent hepatic damage is expressed by trans-
autopsy revealed renal lesions suggestive of dieth- aminase level elevation. Hypertension, tachycardia,
ylene glycol intoxication.3 and pancreatitis are frequent.
The kinetics of diethylene glycol in humans is not The third phase is characterized by neurologic
known: the available information derives from damage, mainly of the peripheral nervous system (eg,
experimental studies in animals. Diethylene glycol is areflexia, loss of visual and auditory functions, and
absorbed rapidly in the gastrointestinal tract; trans- motor deficit). Sometimes inspiratory muscle weak-
cutaneous absorption is minimal through intact skin. ness with respiratory depression or coma occurs.
No report of respiratory absorption is described. After The clinical evolution is unpredictable: long-term
absorption, diethylene glycol is distributed widely resolution, permanent neurologic or kidney damage,
throughout the most perfused organs. fulminant ascending paralysis, and death have been
Diethylene glycol is metabolized in the liver. It is described.1,13-16
oxidized to 2-hydroxyetoxyacetaldehyde by alcohol Renal damage in diethylene glycol poisoning is due
dehydrogenase and then to 2-hydroxyethoxyacetic acid to necrosis of the proximal tubules of cortical neph-
by aldehyde dehydrogenase. 2-Hydroxyethoxyacetic rons. Severe vacuolation and swelling of epithelial
acid is oxidized further to diglycolic acid. Diethylene cells cause obstruction of the lumen.1,17,18 The
glycol is not metabolized to ethylene glycol; this mechanism of renal diethylene glycol toxicity is not
is why calcium oxalate crystals, typical of ethylene completely known. The oldest studies hypothesized
glycol intoxication, are not found after diethylene that it was not due to diethylene glycol itself, but to its
glycol poisoning (Tables 1 and 2).1,9-12 metabolites, 2-hydroxyethoxyacetic acid and digly-
The clinical course of diethylene glycol poisoning colic acid.19,20 Diglycolic acid has a molecular
has 3 phases. The first phase is characterized by structure similar to some endogenous compounds;
altered mental status and gastrointestinal symptoms, therefore, after glomerular filtration, it is transported
such as vomiting, nausea, abdominal pain, and some- into the proximal tubular cells by apical sodium
times diarrhea. dicarboxylate transporters (NaDC-1) or organic anion
The second phase usually starts after 1 to 3 days, transporters. Diglycolic acid reaches elevated con-
depending on the diethylene glycol dose and other centrations in the tubular cells, where it inhibits a
coingestants (eg, ethanol inhibits diethylene glycol citric acid cycle enzyme, thus blocking adenosine
metabolism). Oliguric or anuric acute kidney failure triphosphate (ATP) production and causing cell death.
with metabolic acidosis is typical. Death can occur 2 to Inhibition of diglycolic acid transporters in tubular
7 days after the onset of anuria in untreated patients; cells blocks diglycolic acid–induced toxicity.4,21 This

604 Am J Kidney Dis. 2015;65(4):603-606

Diethylene and Ethylene Glycol

Table 2. Clinical Characteristics of Ethylene Glycol and Diethylene Glycol Poisoning

Ethylene Glycol Diethylene Glycol

Toxicokinetics
Absorption GI tract: rapid (1-4 h); skin: minimal; GI tract: rapid (0.2-2 h); damaged skin or contact
respiratory tract: minimal with large surface area; no data about the
respiratory tract (likely low)
Distribution Volume of distribution: 0.5-0.8 L/kg Volume of distribution: 0.5-1 L/kg
Metabolism Liver: ethylene glycol metabolized to glycolic Liver: 70%-80% of diethylene glycol metabolized
acid and oxalic acid; glycine and a-hydroxy- to 2-hydroxyethoxyacetic acid and diglycolic
b-ketoadipate acid
Elimination Liver: 80%; kidney: 20% Kidney: 50%-85%; liver: 2%-50%

Toxic substances/metabolites
Minimal lethal dose for humans
Mechanism of toxicity
Main clinical manifestations
Biopsy findings
Diagnosis
Management
Data drawn from references.1,8-12
Abbreviations: 2-HEAA, 2-hydroxyethoxyacetic acid; GI, gastrointestinal.
Glycolaldehyde and glycolic acid; glyoxylic
and oxalic acid
1.4-1.5 mL/kg body weight
Metabolic acidosis due to glycolic and lactic
acid; calcium oxalate deposition
3 stages (starting 0.5-12 h after ingestion); 1:
central nervous system depression, coma;
2: cardiopulmonary manifestations; 3: acute
kidney injury
Renal tubular necrosis; deposition of calcium
oxalate crystals
Clinical history; increased osmolal gap; severe
“high anion gap acidosis”; calcium oxalate
crystals in urine (4-40 h after ingestion);
measurement of ethylene glycol in plasma/
urine; hypocalcemia (due to precipitation of
calcium oxalate)
Supportive care; antidotes: fomepizole,
ethanol; suggested, but efficacy not proved:
thiamine, pyridoxine, magnesium,
hemodialysis
Diethylene glycol; 2-hydroxyethoxyacetic acid
(2-HEAA); diglycolic acid
Undefined: no reports specify dose/weight;
affected by coingestants; estimated to be
w1 mL/kg body weight
Not fully elucidated: diglycolic acid–related tissue
damage? 2-HEAA–related metabolic acidosis?
3 stages (starting 0.5-3 d after ingestion); 1: GI
symptoms; 2: acute kidney and liver injury; 3:
central nervous system depression and
peripheral neuropathy; other possible
manifestations: pancreatitis, tachycardia,
hyperkalemia and mild hyponatremia
Renal tubular necrosis; no deposition of calcium
oxalate crystals
Clinical history; slightly increased osmolal gap;
moderate “high anion gap acidosis”; no calcium
oxalate crystal in urine; measurement of
diethylene glycol in plasma/urine
Supportive care; suggested, but efficacy not
proved: fomepizole, ethanol, acetylcysteine,
thiamine, pyridoxine, hemodialysis/
hemodiafiltration

is why it is now considered the true toxic metabolite
of diethylene glycol.
Diagnosis of diethylene glycol poisoning is difficult.
It usually is based on medical history and clinical
presentation and can be confirmed by measurement of
diethylene glycol in biological samples if this labora-
tory test is available.22 In the first hours, an increased
osmolal gap, sometimes .20 mOsm/L, could assist in
the diagnosis, suggesting the presence of an unknown
low-molecular-weight substance. Later, due to meta-
bolism of diethylene glycol to 2-hydroxyethoxyacetic
acid, the osmolal gap becomes normal, but the anion
gap increases, resulting in metabolic acidosis.23
Treatment of diethylene glycol poisoning is
extremely difficult due to incomplete knowledge about
its toxicity. Because the toxic effect is due to the me-
tabolites of diethylene glycol, it has been proposed to
attempt to reduce their formation using the alcohol
dehydrogenase inhibitor fomepizole, as in ethylene
glycol poisoning. Fomepizole reduces urinary excre-
tion of 2-hydroxyethoxyacetic acid and diglycolic
acid.10,19 Fomepizole has been used to treat children
with glycol intoxication, with good outcomes.24 He-
modialysis has been used, but there is no evidence of a
real benefit. Overall, there is still no specific evidence-
based treatment.10
In conclusion, diethylene glycol intoxication usually
is associated with ingestion of counterfeit drugs, so it
could be a public health threat, particularly considering
the spread of the illegal internet drug market. Estimated
counterfeit drug diffusion varies from 1% to 15% all
over the world and .50% in parts of Africa and
Asia.25
After diethylene glycol poisoning, death occurs in
more than two-thirds of patients.1 Many of the sur-
vivors do not recover kidney function and some pa-
tients had neurologic sequelae.26 All 5 patients with
transcutaneous diethylene glycol poisoning reported

Am J Kidney Dis. 2015;65(4):603-606 605


in the literature died.3 Our patient survived with
almost full recovery of kidney and neurologic func-
tion. This positive outcome could have been due to
lower absorption through the skin, although his clin-
ical picture was comparable to previous reports of
diethylene glycol ingestion. A possible positive effect
on the outcome could have been the immediate start
of dialysis therapy and the appropriate supportive
treatment in the intensive care unit.
ACKNOWLEDGEMENTS
Support: None.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
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