Case Report
Acute Acetaminophen Toxicity: Report of a Case
Shahrokh C. Bagheri, DMD, MD; Michael L. Beckley, DDS; and Sam E.
Farish, DMD
Copyright 2001 Journal of the California Dental Association.
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A case of acetaminophen overdose in a patient presenting with a mandible fracture is presented to illustrate the clinical scenario, pathophysiology, and treatment of acute toxicity with this commonly used over-the-counter medication.
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Acetaminophen (N-acetyl-p-aminophenol) is an over-the-counter analgesic and antipyretic agent that has gained tremendous popularity in the past three decades due to its presumed safety and low toxicity, especially when compared to the gastrointestinal side effects of aspirin and other NSAIDS. It is the most widely used and recommended nonprescription analgesic and antipyretic medication in the United States.1 The drug was first discovered at Johns Hopkins University in 1877, but it was not marketed in the United States until 1950, replacing phenacetin. The association between the excessive use of phenacetin and the development of renal failure is well-documented.2 In the United Kingdom, overdose is commonly seen in young adults.3 The first reported case of acute acetaminophen-induced hepatic necrosis after massive overdose was reported in 1966.4 Acetaminophen hepatotoxicity is well-recognized5,6 and is observed with ingestion of massive doses as a result of accidental ingestion or attempted suicide. In the previous decade, it was reported to be the No. 1 cause of acute hepatic necrosis and a major method of attempted suicide in the United Kingdom.7 Currently, acetaminophen is implicated in 15 percent to 30 percent of deliberate self-poisoning in the United Kingdom.8
For adults, the recommended daily dosage is not to exceed 4 grams. The minimum acute toxic dose (minimum single dose required to produce toxic effects) is 5 to 15 grams (10 to 30 500 mg tablets). The acute lethal dose (minimum single dose required to cause death) ranges from 13 to 25 grams.6 Almost 50 percent of adults develop fatal liver damage at an oral dose of 250 mg/kg (17.5 g in a 70 kg adult) and 100 percent at 350 mg/kg (24.5 g in a 70 kg adult).9 Chronic hepatic enzyme microsomal induction, as in chronic alcoholism or barbiturate use, and concomitant ingestion of acetaminophen can cause severe hepatic damage at oral doses of less than 10 grams.10-13
Case Report
A 64-year-old male was referred to the Oral and Maxillofacial Surgery Department at the Atlanta Veterans Affairs Medical Center. His chief complaint was pain in his lower jaw. He reported being assaulted 11 days prior to admission. Past medical history was remarkable for spleenectomy secondary to previous abdominal trauma, prostate cancer, cigarette smoking, and alcoholism. The patient stated that he was not taking any medications and was homeless.
Physical examination revealed right facial pain along the inferior border of the mandible with opening and closing. The patient also had tenderness to palpation in his left preauricular region and decreased sensation in his right chin and lip. Abdominal examination was positive for tenderness to palpation in the right upper quadrant. Radiographic evaluation revealed a right mandibular body and left subcondylar fractures. Admission labs were significant for elevated LDH (2116 u/l) (normal: 71-207u/l), AST (SGOT) (233 u/l) (normal: 4-140 u/l), and total bilirubin (1.7 mg/dl) (normal: 0.3-1.4 mg/dl), which are consistent with nonspecific parenchymal liver damage. The patient was admitted for evaluation of elevated liver enzymes and treatment of mandibular fractures. Subsequent hepatitis serology was negative.
During the second hospital day, upon further questioning, the patient admitted to consuming 36 tablets of 500 mg acetaminophen (18 grams) with acute ethanol ingestion in a period of two days prior to admission. On the third hospital day, the following values were obtained: LDH 129 u/l, AST (SGOT) 115 u/l, total bilirubin 0.5 mg/dl, which are consistent with recovery from the prior hepatic insult.
Discussion
In recent years, acetaminophen has gained wide acceptance as an over-the-counter medicine and in prescription-combination medications for the treatment of pain and fever. It is also found in many commonly available cold medications, sleep aids, and allergy-relief medicines. Prescription use of acetaminophen is usually found in combination with other pharmaceuticals for the treatment of pain (Table 1). Many patients take medications containing acetaminophen on a daily basis. It is not uncommon for patients to be unaware of the potential complications their over-the-counter medications may pose when combined with prescription medications. This lack of awareness can result in significant morbidity and mortality in otherwise healthy patients and especially in those who have compromised hepatic function.
The initial presentation of acute lethal acetaminophen overdose can be asymptomatic or may present with mild gastrointestinal irritation including nausea and vomiting. The latter presentation is more commonly observed in children. Twenty-four to 48 hours after ingestion, a latent period is observed characterized by a false sense of well-being. Signs of progressive hepatic encephalopathy (disturbances in consciousness, hyperreflexia, asterixis, and, rarely, seizures) may develop three to four days after ingestion. Liver dysfunction may manifest itself in a variety of clinical symptoms. However, jaundice, fetor hepaticus, and hepatic encephalopathy are usual. Centrilobar hepatic necrosis may extend to involve the entire lobule. In some cases, there is evidence of concurrent renal and myocardial damage.14 Death from hepatic failure occurs four to 18 days after ingestion. Patients with suspected acute acetaminophen overdose should be rapidly referred to the emergency department for prompt medical attention including plasma acetaminophen levels, liver function tests, induced emesis, and subsequent administration of activated charcoal and/or N-acetyl-L cysteine. Induced emesis and N-acetyl-L cysteine are most effective if provided within four to six hours and 10 hours after ingestion respectively.6 Patients should be closely monitored several days after ingestion for development of symptoms of hepatic encephalopathy. In patients who recover, liver function tests progressively return to normal several days after ingestion.
About 5 percent of acetaminophen is excreted unchanged by the kidneys. The glucoronic sulfate pathway of the liver metabolizes the greater fraction of the drug. A smaller portion is metabolized by the hepatic microsomal oxidase system into a toxic metabolite, N-acetyl-p-benzoquinoneimine, that is rapidly conjugated by glutathione. In toxic overdose, depletion of hepatic glutathione leads to the accumulation of N-acetyl-p-benzoquinoneimine, which mediates hepatic necrosis due to electrophilic attack of nearby structures in hepatocytes. N-acetyl-L cysteine is used as an antidote since it is a precursor of glutathione and therefore facilitates the conjugation of the toxic intermediate (Figure 1).6
Dentists and other health care professionals frequently manage patients with pain. A careful history and a high index of suspicion are essential to reduce the significant morbidity and mortality associated with excessive acetaminophen ingestion.
Questions that are designed to identify patients with compromised liver function should be a routine part of the patient evaluation. Patients should be alerted to the fact that acetaminophen (Tylenol) can be harmful and that it only takes eight extra-strength tablets to reach the maximum daily dose. Patients with compromised liver function as in chronic alcoholism have a decreased ability to clear acetaminophen and are more prone to toxic injury. Conversely, acute alcohol ingestion in an otherwise healthy individual will actually induce the hepatic microsomal oxidase system and increase the removal of the toxic ingredient from plasma. In this case report, the patient neglected to report self-medication with acetaminophen despite initial questioning during the history and physical. Markedly elevated liver function tests led to the discovery of acetaminophen-induced hepatotoxicity. Fortunately, the patient recovered successfully; and no residual hepatic damage was observed. However, the literature is replete with cases of hepatic necrosis after acute acetaminophen overdose.15-17
Authors
Shahrokh C. Bagheri, DMD, MD, is a resident in the Department of Surgery, Division of Oral and Maxillofacial Surgery, at Emory University School of Medicine.
Michael L. Beckley, DDS, is a former intern in the Department of Surgery, Division of Oral and Maxillofacial Surgery, Emory University School of Medicine.
Sam E. Farish, DMD, is a staff oral and maxillofacial surgeon at the Department of Veterans Affairs Medical Center in Atlanta, Ga.
References
1. Rose SR, Subtleties of managing acetaminophen poisoning. Am J Hosp Pharm 51:3065-8, 1994.
2. Katzung BG, Basic and Clinical Pharmacology, 5th ed. Appelton and Lange, Norwalk, Conn, 1992, p 505.
3. Dubose TD Jr, Molony DA, et al, Nephrotoxicity of non-steroidal anti-inflammatory drugs. Lancet 344:515-8, 1994.
4. Davidson DGD, Eastham WN, Acute liver necrosis following overdose of paracetamol. Br Med J 2:497-9, 1966.
5. Black M, Acetaminophen hepatotoxicity. Gastroenterology 78:382-92, 1980.
6. Ellenhorn MJ, Schonwald S, et al, Ellenhorn’s Medical Toxicology: Diagnosis and Treatment of Human Poisoning, 2nd ed. Williams and Wilkins, Baltimore, 1997, pp 180-95.
7. Henry J, Volans G, Analgesics: II -- Paracetamol. Br Med J 289:907-8, 1984.
8. Loeb DS, Ahlquist DA, Talley NJ, Management of gastroduodenopathy associated with the use of non-steroidal anti-inflammatory drugs. Mayo Clin Proc 67:354-64, 1992.
9. Prescott LF, Critchley JAJH, The treatment of acetaminophen poisoning. Ann Rev Pharmacol Toxicol 23:87-101, 1983.
10. Pirotte JM, Apparent potentiation by phenobarbital of hepatotoxicity from small doses of acetaminophen. Ann Intern Med 101:403, 1984.
11. Fleckenstein JL, Nyquil and acute hepatic necrosis. N Eng J Med 313:48, 1985.
12. Licht H, Seeff LB, Zimmerman HJ, Apparent potentiation of acetaminophen hepatotoxicity by alcohol. Ann Intern Med 92:511, 1980.
13. McClain CJ, Kromhout JP, et al, Potentiation of acetaminophen hepatotoxicity by alcohol. J Am Med Assoc 244:251-3, 1980.
14. Kumar V, Cotran RS, Robbins SL, Basic Pathology, 5th ed. Saunders, Philadelphia, 1992, pp 229.
15. Johnson MW, Friedman PA, Mitch WE, Alcoholism, nonprescription drugs and hepatotoxicity. The risk from unknown acetaminophen ingestion. J Gastroenterol 76:530-3, 1981.
16. Schiodt FV, Rochling FA, et al, Acetaminophen toxicity in an urban county hospital. New Eng J Med 337:1112-7, 1997.
17. Johnston SC, Pelletier LL Jr, Enhanced hepatotoxicity of acetaminophen in the alcoholic patient. Two case reports and a review of the literature. Medicine 76:185-91, 1997.
To request a printed copy of this article, please contact/Shahrokh Bagheri, DMD, MD, Department of Surgery, Division of Oral and Maxillofacial Surgery, Emory University School of Medicine, 1365B Clifton Road, NE, Atlanta, GA 30322.
Figure 1. Overview of acetaminophen metabolism.
Table 1. Commonly Encountered Acetaminophen-Containing Preparations
Anexia: Hydrocodone/acetaminophen
Capital with codeine: Codeine/acetaminophen
Darvocet: Propoxphene/acetaminophen
Fioricet with Codeine: Codeine/caffeine/acetaminophen
Lorcet: Hydrocodone/acetaminophen
Lortab: Hydrocodone/acetaminophen
Percocet: Oxycodone/acetaminophen
Tylenol #3: Codeine/acetaminophen
Tylox: Oxycodone/acetaminophen
Vicodin: Hydrocodone/acetaminophen
Wygesic: Propoxyphene/acetaminophen
Zydone: Hydrocodone/acetaminophen
