|Internet Journal of Medical Toxicology
A publication of The American College of Medical Toxicology
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Co-ingestion of Iron May
Enhance Acetaminophen Toxicity
Keith K. Burkhart, MD, FACMT, FAACT, FACEP
Michael Garcia, MD
J Ward Donovan, MD, FACMT, FACEP
Int J Med Toxicol 2003; 6(2):9
Department of Emergency Medicine
500 University Drive
The Milton S. Hershey Medical Center
The Pennsylvania State University
Hershey, PA 17033
Keith K. Burkhart, MD
Telephone #: 717-531-7057
Fax #: 717-531-4441
Objective: To present cases
in which the acute and chronic co-ingestion of iron may have enhanced
Case Series: Two patients
who developed fulminant hepatic failure from acetaminophen. Patient one took a
large single acute overdose that included 57 grams of acetaminophen and 21.5
grams of ferrous sulfate. His 1.25 hours post ingestion serum iron level was 365
mcg/dL and then a five-hour acetaminophen level was 142 mcg/dL. Patient two was
given therapeutic doses of acetaminophen for pain management following coronary
artery bypass grafting. He was given daily iron sulfate, 325 mg three times per
day, for anemia. His acetaminophen dosing was 2.6 g on post-op day 1, 3.9 g on
post-op days 2, 3, and 4, followed by 1.3 g on post-op day 5. Both patients were
given supportive care including intravenous N-acetylcysteine at the hospital.
The acutely poisoned patient manifested fulminant hepatic failure approximately
24 hours after the ingestion and died 77 hours after the ingestion. The
postoperative patient developed hepatorenal failure. A biopsy demonstrated
centrilobular necrosis. This patient went on to a complete recovery.
Conclusions: The concomitant
ingestion of iron acutely or chronically may have the potential to enhance
acetaminophen toxicity. Toxicologists and intensivists should consider the use
of chelators when iron may be a co-ingestant with acetaminophen.
The initiation of N-Acetylcysteine acetylcysteine (NAC)
by eight hours after an ingestion of acetaminophen is generally believed to be
sufficient to prevent acetaminophen-induced mortality.1 Research
suggests that iron may have an important cofactor role in acetaminophen-induced
hepatocellular injury.2-5 In fact iron chelators have been studied as
a treatment modality for acetaminophen.6-8
Case 1: A 25
year old male was witnessed by his wife to ingest acetaminophen 57g, ferrous
sulfate 21.5g, ibuprofen 20g and ethanol. He did not have a history of medical
treatment for alcohol abuse, but his family described him as a heavy binge
drinker. He began vomiting and was transported to the Emergency Department
approximately one hour after the ingestion. The vomitus in the ED was red-tinged
particulate matter that was guaiac positive. Vital signs were: temperature,
35.70C; pulse, 90/min; BP, 125/61 mmHg; and respirations, 20/min. The patient's
mental status was alert, oriented and cooperative. The remainder of his
examination was also normal including his abdomen that included stool negative
for occult blood.
Laboratory evaluation at 1.25 hours post ingestion included acetaminophen 222 mcg/mL, iron 365 mcg/dL, TIBC 384 mcg/dL, and ethanol 109 mg/dL. Serum aminotransferases were within normal limits. The CBC, electrolytes, renal function tests, and coagulation studies were also within normal ranges. An abdominal radiograph did not demonstrate radiopacities. A urine toxicology screen was negative for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, tetrahydrocannabinol, propoxyphene, and tricyclic antidepressants.
Activated charcoal, 50 g, was given with vomiting 30 minutes later. A five hour acetaminophen level was 142 mcg/mL. Therefore, six hours after ingestion, 140 mg/kg NAC was administered by nasogastric tube, after lavage using two liters of normal saline solution. Repeat serum iron remained elevated at 380 mcg/dL. His vomiting and abdominal pain had resolved. Whole bowel irrigation and chelation therapy with deferoxamine were considered, but not performed because of the negative abdominal radiograph, the lack of symptoms, and a mildly elevated serum iron level.
In the ICU the patient was given the next two NAC maintenance doses by nasogastric tube. The patientHe was transferred to the floor and his nasogastric tube was discontinued. For unknown reasons, the fourth and fifth NAC doses were not given. The sixth and seventh NAC doses were given orally. After this dose the patient felt ill, weak and had abdominal pain.
He then refused the eighth NAC dose. Repeat studies done at thirty-one hours after ingestion included AST 13,813 IU/L, ALT 6882 IU/L, bilirubin 4.1 mg/dL, glucose 14 mg/dL and serum iron 287 mcg/dL. Additional laboratory tests at 36 hours were room air ABG: pH, 6.87; pCO2, 16.3 mmHg; pO2, 178 mmHg; bicarbonate 3.0 mEq/L, lactate 26.8 mmol/L, ammonia 452 mg/dL, PT >40 sec, PTT > 150 sec, and fibrinogen 58 mg/dL. Despite transfer to the Toxicology Service and resumption of NAC therapy by the intravenous route, the patient expired 77 hours after ingestion in fulminant hepatic failure.
Case 2: A 47 year old male previously healthy male underwent coronary artery bypass
graft, four days after his admission for congestive heart failure. He was found
to have an ejection fraction of 20%. He had an ALT of 94 IU/L and an LDH of 1611
IU/L. These were believed to be from the congestive heart failure, as a
myocardial infarction was excluded by serial enzyme analysis. The patient
reported a four pack per day smoking history. He also drank 6-8 beers per day.
He did not demonstrate withdrawal symptoms in his hospital course. Coronary
angiography demonstrated multi-vessel disease. On hospital day four he underwent
coronary artery bypass grafting. Post-operatively the patient received no
nutrition, but was given iron sulfate, 325mg po TID. He had an unremarkable
post-op course, until the evening of the fourth post-op day, when he became
disoriented, and hypotensive. On further evaluation he was found to be markedly
acidotic with multiorgan failure. His ALT and AST were 2613 IU/L and 4838 IU/L,
respectively. The acetaminophen level was 15 mcg/mL, 8 hours after the last
dose. His INR was 5.6. His serum lactate was > 15 mmol/L, while the serum
bicarbonate was 16 mmol/L. His serum glucose was 48 mg/dL. His creatinine was
2.5 mg/dL, increased from 0.7 mg/dL the day before this injury. This patient had
post-op orders for multiple acetaminophen containing products, propoxyphene/
acetaminophen 650 mg, acetaminophen 325 mg/oxycodone 5 mg, acetaminophen 325
mg/codeine 30 mg, and acetaminophen 650 mg for fever. The combination of these
multiple prnPRN orders resulted in the patient receiving acetaminophen 2.6 g on
post-op day 1, and 3.9 g on post-op days 2, 3, and 4. An additional 1.3 g was
given on post-op day 5, before the severe hepatotoxicity was recognized. If the
patient had received all prnPRN orders, there was the potential for him to
receive up to eight grams per day. This patient is a starved alcoholic, which
might pose a unique risk factor especially when combined with the complications
The patient was treated for possible sepsis and had an emergent exploratory
laporatomy. No evidence for peritonitis was found. A liver biopsy demonstrated
centrilobular necrosis. His blood, peritoneal, urine, and tracheal cultures all
returned no growth. The following day the ALT and AST were both greater than
4250 IU/L. Lipase was also elevated at 954 U/L. The creatinine increased and
peaked at 3.3 mg/dL. The bilirubin increased to 10.1 mg/dL. Thrombocytopenia
developed with a nadir of 59,000/mcL K/mcL.
Aggressive supportive care included vasopressors and multiple antibiotics for
presumed sepsis. The patient was given a loading dose of N-acetlycysteine
acetylcysteine 140 mg/kg intravenously followed by 17 maintenance doses of 70
mg/kg. He had a full recovery.
Severe toxicity following therapeutic doses is often
questioned because of the reliability of the history. The above case, however,
carries clear hospital documentation. The centrilobular pattern of hepatic
necrosis and rapid recovery without evidence for sepsis or other viral
etiologies makes acetaminophen poisoning the likely diagnosis. This patient had
multiple risk factors that may have made him susceptible to acetaminophen
toxicity. The patient had preexisting hepatic injury (enzyme elevations) from
congestive heart failure. He smoked and consumed alcohol, known inducers of the
cytochrome P450 enzyme system. The patient was in a fasting state, as no
nutritional supplements were provided, and was also catabolic secondary to
post-surgical healing.9 These points made; it is unknown what the
patientís glutathione and cytochrome P450 content were at the time of
acetaminophen exposure. Hepatitis tends to increase glutathione levels, while
steatosis, which this patient did not have, decrease levels.10,11
While fasting or food restriction may lower glutathione levels, it also lowers
cytochrome P450 content such that there still may be a balance in favor of
enough glutathione to handle P450 generated
N-acetyl-p-benzoquinoneimine.12-16 Rumack provides a more detailed
review of these nutritional factors in Acetaminophen Hepatotoxicity: The First
35 Years, http://www.ijmt.net/ijmt/5_2/ellenhorn/ellenhorn.pdf.16
Finally the iron may have had
a role as detailed below.
Death from a single acute ingestion of acetaminophen
rarely occurs, when NAC therapy is started by eight hours after a single acute
ingestion.1 The first patient had NAC therapy started by six hours
after ingestion, but after receiving three scheduled doses he missed the next
two doses. While his death may be attributed to this fact alone, much research
suggests that the co-ingested iron may have contributed.2-8 Although,
the patient's level at five hours was above the 150 mcg/mL treatment line, it
was not in the high probability range for hepatotoxicity. Concomitant ethanol
administration in a mouse model has been shown to be
hepatoprotective.17 Ibuprofen is also hepatotoxic and therefore may
have had a role in this outcome. Finally, as outlined below under experimental
conditions, iron has been demonstrated to have a role in the mediation of
Iron appears to be an important catalyst in the
oxidative metabolism and toxicity of acetaminophen. The first one-electron
oxidation step in the metabolism of acetaminophen consists of a hydrogen
abstraction from the acetylamino nitrogen and/or the hydroxyl group. The
substrate radicals formed recombine with a P450 iron-bound hydroxyl radical to
either yield oxygenated metabolites, or undergo a second hydrogen abstraction
forming dehydrogenated products.2 In the presence of ferric iron,
both superoxide dismutase and catalase in the presence of ferric iron prevent
cell death from acetaminophen.3 This cytoprotection suggests a role
for hydroxyl radicals generated by an iron catalyzed Haber-Weiss reaction in
acetaminophen hepatotoxicity. Hydrogen peroxide has also been implicated as a
cofactor in the flavoenzyme oxidation of acetaminophen.4 In a mouse
model, the combined treatment of acetaminophen and ferrous ion led to a
nine-fold increase in lipid peroxidation measured by ethane
Glutathione depletion more than doubled this
Deferoxamine has beenis hepatoprotective in a number of
animal trials of acetaminophen poisoning.6 Dexrazoxane, another iron
chelator, has also demonstrated benefit against iron-based oxygen free
radical-induced oxidative stress caused by a number of toxins including
acetaminophen.7 The prevention of hepatic necrosis provided by
deferoxamine in a rat model did not prevent glutathione depletion.8
Therefore, hepatic survival or cell death from acetaminophen may ultimately
depend upon factors that follow glutathione depletion. Because of iron's
catalytic role in free radical reactions, iron chelators have been suggested as
antioxidant therapy in the treatment of fulminant hepatic failure in
This case lead to a number of changes in pharmacy practice to assure that a
patient would not receive more than four grams of acetaminophen a day while in
the hospital. Computer flags have been placed in the pharmacy. When an order for
an acetaminophen product is received, the pharmacist is reminded to check for
other orders to check for the daily dose. Stickers have been placed on all
acetaminophen products to remind the administering nurse that the patient should
not receive more than four grams of acetaminophen in any day. Finally, no more
than three doses of a PRN order for a patient are made available to the
nursing staff at any one time.
Research certainly suggests a significant role for
iron as a cofactor in acetaminophen-induced hepatotoxicity. Clearly, it
is speculation that iron played a role in our two patients. We do believe
that further research is needed on the role of iron in acetaminophen
hepatotoxicity and to define a potential protective role for deferoxamine, especially when
iron is a co-ingestant in acetaminophen poisoning. Finally, hospital pharmacies
should institute practices that prevent patients from receiving more than
recommended doses of as needed, PRN, medications.
- Smilkstein MJ, Knapp GL, Kulig KW et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: Analysis of the National Multicenter Study (1976-1985). N Engl J Med 1988;319:1557-1562.
- Koymans L, Donne-Op den Kelder GM, te Koppele JM, et al. Generalized cytochrome P450-mediated oxidation and oxygenation reactions in aromatic substrates with activated N-H, O-H, C-H, or S-H substituents. Xenobiotica 1993;23:633-648.
- Kyle ME, Miccadei S, Nakae D, et al. Superoxide dismutase and catalase protect cultured hepatocytes from the cytotoxicity of acetaminophen. Biochem Biophys Res Commun 1987;149:889-896.
- Van Steveninck J, Koster JF, Dubbelman. Xanthine oxidase-catalyzed oxidation of paracetamol. Biochem J 1989;259:633-637.
- Younes M, Cornelius S, Seigers CP. Ferrous ion supported in vivo lipid peroxidation induced by paracetamol-its relation to hepatotoxicity. Res Commun Chem Pathol Pharmacol 1986;51:89-99.
- Sakaida I, Kayano K, Wasaki, et al: Protection against acetaminophen-induced liver injury in vivo by an iron chelator, deferoxamine. Scand J Gastroenterol 1995;30:61-67.
- Hasinoff BB, Hellmann K, Herman EH, et al. Chemical, biological and clinical aspects of dexrazoxane and other bisdioxopiperazines. Curr Med Chem 1998;5:1-28.
- Nakae D, Oakes JW, Farber JL. Potentiation in the intact rat of the hepatotoxicity of acetaminophen by 1,3-bis(2-chloroethyl)-1-nitrosourea. Arch Biochem Biophys 1988;267:651-659.
- Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994:272:1845-1850.
- Poulsen HE, Ranek L, Andreasen PB. The hepatic glutathione content in liver diseases. Scand J Clin Lab Invest 1981;41:573-576.
- Siegers CP, Bossen KH, Younes M, Mahlke R, Oltmanns D. Glutathione and glutathione-S-transferases in the normal and diseased human liver. Pharmacol Res Commun 1982;14:61-72.
- Schenker S, Speeg KV, Jr., Perez A, Finch J. The effects of food restriction in man on hepatic metabolism of acetaminophen. Clin Nutr 2001;20:145-150.
- Schoene B, Fleischmann RA, Remmer H, von Oldershausen HF. Determination of drug metabolizing enzymes in needle biopsies of human liver. Eur J Clin Pharmacol 1972;4:65-73.
- Newman TJ, Bargman GJ. Acetaminophen hepatotoxicity and malnutrition. Am J Gastroenterol 1979;72:647-650.
- Rumack BH, Holtzman J, Chase HP. Hepatic drug metabolism and protein malnutrition. J Pharmacol Exp Ther 1973;186:441-446.
- Rumack BH: Acetaminophen Hepatotoxicity: The First 35 Years. Int J Med Toxicol 2002;5(2):5
- Thummel KE, Slattery JT, Nelson SD, et al: Effect of ethanol on hepatotoxicity of acetaminophen in mice and on reactive metabolite formation by mouse and human liver microsomes. Tox Applied Pharmacol 1989:100:391-397.
- Evans PJ, Evans RW, Bomford A, et al. Metal ions catalytic for free radical reactions in the plasma of patients with fulminant hepatic failure. Fre Radic Res 1994;20:139-144.
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