Case Report

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


Authors' Affiliation:
Department of Emergency Medicine
500 University Drive
The Milton S. Hershey Medical Center
The Pennsylvania State University
Hershey, PA 17033

Correspondence:
Keith K. Burkhart, MD
Telephone #: 717-531-7057
Fax #: 717-531-4441
Email: kburkhart@psu.edu

Abstract

Objective: To present cases in which the acute and chronic co-ingestion of iron may have enhanced acetaminophen-induced hepatotoxicity.

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.

Introduction

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 Reports

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 of anesthesia.

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.

Discussion

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 acetaminophen hepatotoxicity.2-8

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 exhalation.5 Glutathione depletion more than doubled this enhancement.

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 general.18

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.

Conclusions

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.

References

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  16. Rumack BH: Acetaminophen Hepatotoxicity: The First 35 Years. Int J Med Toxicol 2002;5(2):5
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