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Medical-Legal Pitfalls in Managing Acetaminophen Toxicity
By Frank LoVecchio, DO, MPH, FACEP, Co-Medical Director, Banner Poison and Drug Information Center; Vice Chairman, Research Director, Maricopa Medical Center, Phoenix, AZ
Case: A 40-year-old man with a history of hepatitis C and alcoholism presents to the ED with dental caries. A brief history and unremarkable physical examination is documented. The patient is discharged and fills his prescription for hydrocodone 5 mg/acetaminophen 500 mg (1-2 tablets every 4-6 hours as needed, #25). Two weeks later he dies of fulminant liver failure, and the family initiates litigation for your excessive acetaminophen prescription.
On January 13, 2011, the U.S. Food and Drug Administration (FDA) limited acetaminophen in prescription combination products, and now requires liver-toxicity warnings. The agency specifically capped the maximum at 325 mg in combination products in an attempt to reduce risk of liver toxicity.1 An advisory committee to the FDA hearings concerning acetaminophen and acetaminophen-induced hepatotoxicity in 2002 and 2009 concluded that much of the concern is not evidence-based and is debatable.2 Independently, The Medical Letter on Drugs and Therapeutics conducted an extensive review on acetaminophen toxicity in 2002; a second review in 2009 found no risk of hepatotoxicity if less than 4 g of acetaminophen is ingested daily.3
Acetaminophen is rapidly absorbed from the gastrointestinal tract, with a half-life of approximately 1.5-2.5 hours, although it can be slightly prolonged at supratherapeutic concentrations. In adults, 45%-55% of acetaminophen is glucuronidated, while 20%-30% is sulfonated. In pediatric patients, sulfation is the primary pathway, and glucuronidation is a trivial component; thus, toxicity is more difficult to attain. The remainder of acetaminophen is metabolized via the cytochrome P450 isoenzyme CYP2E1 to form a substance called N-acetyl-para-benzoquinone imine (NAPQI). Normally, the body's endogenous glutathione supplies are able to bind to and reduce NAPQI, resulting in renal excretion in the form of cysteine or mercaptopuric acid conjugates. In overdose, NAPQI production exceeds the body's endogenous glutathione supply, and hepatotoxicity can result.4,5
Risk Factors for Liver Failure
Acetaminophen's toxicity is due to the metabolism of NAPQI by the cytochrome P450 isoenzyme CYP2E1. Thus, any xenobiotic that induces the P450 isoenzyme CYP2E1 theoretically can increase the risk for acetaminophen-induced hepatotoxicity. The best studied agent for inducing CYP2E1 is ethanol. Chronic ethanol consumption leads to increased CYP2E1 activity and, theoretically, increases the risk of hepatotoxicity but, at least in the short term, exposure to acetaminophen is not substantiated.6 The co-ingestion of ethanol with acetaminophen may result in inhibition of the microsomal oxidation of acetaminophen, thereby providing some degree of protection from acetaminophen-induced hepatotoxicity during acute intoxication.6-7 The strongest risk factor for developing hepatotoxicity is the time from a toxic ingestion until the antidote, N-acetylcysteine, is administered. The risk of hepatotoxicity, if N-acetylcysteine is started within the first eight hours of the overdose, is exceedingly low, while the risk increases substantially with delays more than eight hours and longer.8
Acute acetaminophen toxicity traditionally has been divided into four stages, with the time of each stage being imprecise. The first stage, which occurs during the first 24 hours of overdose, results in gastrointestinal symptoms, or may be asymptomatic. The second stage, which occurs from 24-72 hours post-ingestion, is characterized by the initial development of hepatic failure. During the third phase, which can begin as early as 72 hours post-ingestion, the clinical symptoms depend on the degree of liver failure. Coma, encephalopathy, renal failure, coagulopathy, severe metabolic acidosis, and hypoglycemia can occur.9 At this stage, the patient either will improve or will continue to worsen until he or she either dies or receives a liver transplant. Stage IV is characterized by resolution of liver damage. Following stage III, the patient either will die or will recover (stage IV). Unlike other causes of hepatic injury (e.g., alcohol-induced cirrhosis), acetaminophen-induced liver injury is not associated with long-term liver damage, if recovery occurs.
Diagnosis and Treatment
The diagnosis of acetaminophen toxicity relies in history and laboratory studies. Given vague symptoms in the early stage of acetaminophen toxicity, along with patient's occasional inadvertent confusion of acetaminophen, ibuprofen, and salicylates, it is recommended that all known or suspected overdoses have an acetaminophen level drawn. Because acetaminophen is present in so many different pharmaceutical agents, it is not uncommon that a patient may inadvertently overdose on acetaminophen by consuming multiple acetaminophen-containing products, each at the recommended dosage.
The need for treatment depends on the history, the physical exam, and laboratory studies. If treatment is desired, the preferred antidote is N-acetylcysteine (NAC).10 Any detectable acetaminophen 24 hours or more after acute ingestion is an indication for treatment, as per the standard used in the United States, referred to as the Rumack-Matthew nomogram. Treatment with NAC is indicated when the acetaminophen concentration is above the line on the Rumack-Matthew nomogram.
Although FDA-approved dosing regimens are of fixed durations, virtually all experts tailor the duration of therapy to the patient's clinical condition. After the patient has received at least 21-24 hours of intravenous therapy, transaminases and prothrombin levels should be rechecked before discontinuing therapy. If the liver functions and prothrombin time are normal, and the patient is clinically well (neither vomiting nor complaining of abdominal pain), the NAC can be discontinued. Some institutions recommend checking a repeat acetaminophen level before discontinuing therapy, although this is not an evidence-based practice.
It is important to recall that the Rumack-Matthew nomogram was designed for a single acute ingestion when the phlebotomy occurs between 4 and 24 hours post-ingestion. Many times patients do not present following a single acute ingestion, but rather consume some pills, and a few hours later consume additional pills. In this case, in order to use the nomogram, the safest method is to assume all pills were ingested at the first time, and plot the level based on that time.
Not uncommonly, patients will present with an unknown time of ingestion. In these cases, an acetaminophen level, liver function tests, and a prothrombin time (PT) should be obtained. If there is no detectable acetaminophen, and the liver functions and PT are normal, no treatment for the acetaminophen ingestion is needed. If there is any detectable acetaminophen, or if there are elevated transaminases or PT, treatment with NAC is indicated. Chronic ingestions, in which the patients have taken supratherapeutic ingestions for several days, should be managed the same as when the time of ingestion is not known.
In 1994, McNeil Pharmaceuticals released an "extended-release formulation" of acetaminophen, marketed under the name Tylenol Extended Relief. The pharmacokinetic profile between the regular-release and the extended-relief formulation are similar; it appears both safe and reasonable to use a single four-hour acetaminophen concentration and determine treatment based on the Rumack-Matthew nomogram for either the regular-release or the extended-release acetaminophen products, although not all experts agree on this approach.
It is important to consider acetaminophen in the differential diagnosis of any patient with hepatic failure. Although many drugs can cause a toxin-induced hepatitis, there are few xenobiotics that can cause fulminant hepatic failure. Among these drugs are acetaminophen, amoxicillin-clavulanate, isoniazid, nitrofurantoin, iron, herbals (e.g., pennyroyal and chaparral), non-steroidal anti-inflammatory medications (especially diclofenac or sulindac), phenytoin, and the thiazolidinedione troglitazone. In addition, the recreational drugs cocaine and 3,4 methylenedioxymethamphetamine (MDMA or ecstasy), as well as carbon tetrachloride, white phosphorus, arsenic, thallium, and borates can cause acute hepatic failure. It should be noted that the cause of acute hepatic failure is dose-dependent in some of these agents (e.g., acetaminophen), yet is idiosyncratic with other agents (e.g., troglitazone). Furthermore, any drug that produces profound hypotension can result in hepatic failure from shock liver. In addition, many drugs, such as the HMG-CoA reductase inhibitors ("statins"), can cause a liver injury, but not fulminant hepatic failure.
Although a full review of all causes of hepatic failure is beyond the scope of this paper, the emergency physician should always consider infectious etiologies (e.g., hepatitis B, hepatitis C, Epstein-Barr virus, herpes simplex virus, and cytomegalovirus); other causes include vascular etiologies (e.g. Budd-Chiari syndrome, ischemic hepatitis, veno-occlusive disorders), as well as miscellaneous etiologies such as Wilson's disease, autoimmune hepatitis, fatty liver of pregnancy, heat stroke, and HELLP syndrome.
Although the history may be helpful in distinguishing the etiology of fulminant hepatic failure, several additional laboratory features might be helpful as well. Frequently, the aspartate aminotransferase (AST) rises faster and peaks sooner than the alanine aminotransferase (ALT). In addition, unlike some other etiologies of hepatic failure, there is synthetic dysfunction occurring as well, which results in a rise in the prothrombin time.
The greatest concern following acetaminophen ingestions is the potential to develop hepatotoxicity. The risk of hepatotoxicity is substantially increased when NAC therapy is begun more than 8-10 hours post-acute ingestion.11 The development of liver failure is characterized not only by the development of transaminitis, but also encephalopathy, acidosis, renal failure, coagulopathy, and hypoglycemia. The proximate cause of death in acetaminophen-induced hepatic failure is usually cerebral edema.
NAC should be continued until one of three major endpoints happens: clinical and laboratory improvement, the patient receives a liver transplant, or death.
Pregnancy: Acetaminophen readily crosses the placenta, which places the fetus at potential risk of hepatotoxicity.12 However, because NAPQI does not cross the placenta, the fetus itself must metabolize the acetaminophen in order for hepatotoxicity to occur. The fetus is able to start metabolizing acetaminophen into both toxic and non-toxic metabolites beginning at approximately 18 weeks gestational age.12 NAC does cross the placenta in both animal models and humans, and its use is indicated in pregnant women whose serum concentration is above the treatment line on the Rumack-Matthew nomogram. Fetal outcome appears to be worse with delays in commencing NAC.
Alcoholics: Chronic alcohol consumption results in depletion of hepatic glutathione, and upregulation of CYP2E1, the isoenzyme that metabolizes acetaminophen to NAPQI. As such, there is concern that chronic alcoholics may be more susceptible to acetaminophen-induced hepatotoxicity. Kuffner and colleagues examined the effects of administering 4 g of acetaminophen daily to alcoholics entering an alcohol-detox facility. These patients are hypothesized to be at the highest risk of hepatotoxicity, as at the time these patients enter a detox facility, they will likely have their lowest glutathione supplies, while being at maximal induction of CYP2E1. While at the maximal recommended daily dose, they failed to demonstrate any increased risk of hepatotoxicity, including in those patients with alcoholic hepatitis.13,14 However, chronic alcohol abuse is associated with worsened outcomes in acute acetaminophen poisoning.
Opiates: Watkins and colleagues attempted to determine if the co-administration of opiates along with acetaminophen resulted in increased hepatotoxicity. In their study, 147 patients were randomized to receive placebo, acetaminophen, morphine and acetaminophen, hydromorphone and acetaminophen, or oxycodone and acetaminophen. All patients who received acetaminophen received 4 g daily. In the placebo group, only one patient had a rise in the ALT twice the upper limit of normal. In contrast, more than 19% of participants in each of the four active treatment groups had an ALT five times the upper limit of normal. All three of the opioid/acetaminophen treatments frequently resulted in elevation of the ALT.15 There is some concern that the co-administration of opiates with acetaminophen may result in increased incidence of hepatotoxicity.
Pediatrics: It appears that the increased rate of sulfation, along with possibly an increased relative size of the liver, affords some hepato-protective effects to pediatric patients. In fact, many authors have suggested that 200 mg/kg should be the potentially hepatic-toxic dose in pediatrics, as compared with the lower dose for adults.16
In general, patients who have NAC started within 8 hours of the overdose will do well. Once hepatic injury occurs, the King's College Criteria can be used to help predict which patients may benefit from liver transplant. According to these criteria, patients should be considered for liver transplant if 24 hours after admission, the arterial pH is less than 7.25 after fluid resuscitation, or if there is a combination of a prothrombin time longer than 100 seconds, grade III or IV encephalopathy, and a serum creatinine higher than 3.4 mg/dL.17
Pitfalls in Management
There are several common scenarios in which mistakes in management commonly occur. Perhaps the most common source of error is failure to interpret the acetaminophen level in the context of the time ingested. A single acetaminophen level is not helpful without knowing the time of ingestion. Thus, it is critical to interpret the acetaminophen level based on the time of ingestion, and plot the concentration on the Rumack-Matthew nomogram. If the time of ingestion is not known, it is important that the patient be started on N-acetylcysteine if any acetaminophen is detected, or if there are abnormal liver function tests or prothrombin time.
A second common source of error is discontinuing the NAC at 21 hours, simply because the time course for therapy is over. If the patient is having rising liver function tests or persistent right upper-quadrant tenderness, then therapy with NAC should be continued until these are improving. Patients meeting criteria for transplantation should be referred when indicated.
A third common source of error for the EP is failure to exclude other ingestions. Simply because a patient admits to ingesting acetaminophen, other potentially life-threatening ingestions, including salicylates, need to be evaluated in all patients.
A fourth common source of error for the EP is failure to obtain appropriate psychiatry consult when indicated. If a patient is being admitted to the hospital, then the consultation can be done once the patient is admitted. If the initial acetaminophen level does not warrant therapy, and the patient is to be medically cleared from the ED, it is important to obtain a psychiatric consultation, if indicated. Finally, not documenting a clear medication history, and not counseling a patient on limiting total daily acetaminophen to no more than 4 g daily, is a source for error.
Acetaminophen overdose remains a common cause of hepatic failure. To ensure optimal care, the diagnosis must be made early and treatment should be started within 8 hours. With prompt treatment with NAC, the incidence of hepatic failure can be reduced. The new FDA regulations serve as a reminder for better documentation.
1. U.S. FDA. FDA drug safety communication: Prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure. Available at: www.fda.gov/drugs/drugsafety/ucm239821.htm. Accessed Jan. 31, 2011.
2. U.S. FDA. Docket No. FDA-2009-N-0138. Fed Reg. 2009;74:18731.
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12. Wang LH, et al. Pharmacokinetic studies of the disposition of acetaminophen in the sheep maternal-placental fetal unit. J Pharmacol Exp Ther. 1986;238:198-205.
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14. Kuffner EK, et al. Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: A randomized, double-blind, placebo-controlled trial. Arch Intern Med. 2001;161:2247-2252.
15. Watkins PB, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: A randomized controlled trial. JAMA. 2006;296:87-93.
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17. Anand AC, et al. Early indicators of prognosis in fulminant hepatic failure: An assessment of the King's criteria. J Hepatol. 1997;26:62-68.