Assessing the Risk of Toxicity
Principles Guiding the Diagnostic Approach.
Most APAP exposures result in no toxicity, and the overall mortality rate after acute APAP ingestion is less than 0.5%.299 However, APAP is now the leading cause of acute hepatic failure in the United States and much of the developed world.176 To maintain the seemingly divergent goals of avoiding the enormous cost of over-treatment while minimizing patient risk, clinicians must understand the basis for and sensitivity of current toxicity screening methods. A discussion of the diagnostic approach follows.
When considering risk determination, it is useful to separate different categories of APAP exposure. There is an extensive body of experience and literature on acute overdose in typical circumstances, permitting a more systematic approach with demonstrated efficacy. For issues related to repeated supratherapeutic APAP dosing, uncertain circumstances, new APAP formulations, and many other permutations, there is an important conceptual framework for decision-making but little in the way of validated strategies. For these challenges, the central concepts and one approach are presented here, with the understanding that the challenges continue to evolve and that more than one approach may have validity.
The ideal model for determining risk after APAP overdose would assess the individual’s metabolic enzyme activity (CYP2E1, UDP-glucuronosyl transferase, and sulfotransferase activity), the amount and rate of NAPQI formation, the availability of hepatic GSH, and the balance of NAPQI formation and hepatic GSH turnover. At present, none of these measures is available to clinicians.
Plasma GSH concentration can be measured or approximated using the plasma γ-glutamyl transferase (GGT) concentration but have an uncertain relationship to hepatic GSH availability.283,302
Protein adducts indicate intracellular binding of NAPQI to hepatocyte proteins78,147,247,339 and can be determined experimentally, but have been inadequately studied to be useful in risk assessment or the assignment of causality of hepatic failure. After over-exposure to APAP, NAPQI is not immediately bound to GSH and is released within the cell to bind with the cysteine components on proteins. One of these protein-APAP adducts is 3-(cysteinyl-S-yl)-APAP, for which there is a research assay. However, hepatic toxicity from APAP requires not only protein binding, and therefore protein adducts, but an inflammatory cascade to produce cell necrosis.38 Therefore, protein adducts are signs of NAPQI binding, but not necessarily of toxicity. Animals exposed to APAP overdose develop elevated concentrations of serum protein adducts. However, those who are rescued with NAC have protein adducts within the liver, but little is spilled into the blood because hepatic cellular necrosis does not occur.34,133,149
In humans with therapeutic dosing of APAP, protein adducts are usually detected in small quantities in the blood (< 0.5 nmol/mL), likely from intrahepatic protein binding followed by hepatic cellular turnover. However, concentrations of up to 1.0 nmol/mL have also been detected in patients with therapeutic dosing.133 In humans after overdose, protein adducts are released into the serum and largely parallel the aminotransferases in their time-course. Peak concentrations are detected in 2 to 3 days and decrease with an elimination half-life of 1.7 days. Protein adducts remain detectable for up to 2 weeks.146 A protein adduct concentration above 1.0 nmol/mL has been suggested as being consistent with an acute APAP overdose, but this recommendation will require further validation.133
Other hepatic cellular components may be detected in serum during APAP toxicity and are being analyzed as biomarkers of hepatotoxicity. miRNA are small, noncoding RNA that regulate cell proteins by repressing mRNA.310 miRNA-122 is the most abundant hepatic microRNA and is specific to the liver.310 In human studies, miRNA-122 increases prior to other markers, such as ALT, and may be actively released from hepatocytes prior to cell lysis.309 [miRNA-122] correlates with peak ALT10 and peak INR.10 In patients with acute APAP overdose whose initial ALT is normal and in patients who are treated within 8 hours, [miRNA-122] is higher in those who develop hepatic injury,10 suggesting that it may be useful in differentiating low risk patients from high risk patients earlier than other markers.
Another biomarker, HMGB-1, is passively released by hepatocytes during necrosis. HMGB-1 is elevated in patients with APAP hepatotoxicity but not in those without hepatotoxicity and correlates with both peak ALT and INR. An acetylated form of HMGB-1 is secreted as an inflammatory mediator by macrophages and monocytes and increases only in patients with APAP toxicity who later either meet transplant criteria (King’s College Criteria), die, or receive a hepatic transplant. This biomarker requires further study, but has promise as an earlier marker for more intensive treatment or for transplant.11
Risk Determination Following Acute Overdose.
Determining risk in a patient with acute overdose consists of determining the initial risk based on dosing history and then potentially further risk stratifying with serum [APAP].
Acute overdose usually is considered a single ingestion, although many patients actually overdose incrementally over a brief period of time. For purposes of this discussion, an acute overdose is arbitrarily defined as one in which the entire ingestion occurs within a single 8-hour period.75 Doses of 7.5 g in an adult or 150 mg/kg in a child are widely disseminated as the lowest acute dose capable of causing toxicity.244 These standards are likely quite conservative but have stood the test of time as sensitive markers and have been corroborated with some data in humans.335,357 However, it is more likely that doses of at least 12 g in an adult or 200 mg/kg in a child are necessary to cause hepatotoxicity in most patients.214,335
The adult standard may be considered less controversial than that for children because massive ingestions, unreliable histories, and factors that might predispose to toxicity occur primarily in adults, justifying continued use of 7.5 g as a screening amount to avoid missing serious toxicity. In patients younger than 6 years of age, with unintentional ingestions, use of a higher 200-mg/kg cutoff has been suggested52,214,315 and is likely appropriate but has been incompletely studied.
The dose history should be used in the assessment of risk only if there is reliable corroboration or direct evidence of validity. Although the amount ingested by history roughly correlates with risk of toxicity and an [APAP] over the treatment line,21,335,357 historic information is not sufficiently reliable in all patients to exclude significant ingestion, particularly in patients with the intent of self-harm or drug abuse.357 In fact, suicidal patients with ingestions who do not confirm an ingestion of APAP may have a measurable concentration in 1.4% to 8.4% of cases14,194 and a concentration over the treatment line in up to 0.2% to 2.2%.14,194 Therefore, when the history suggests possible risk, the patient should be further assessed an [APAP].
Interpretation of [APAP] after acute exposures is based on adaptation of the Rumack-Matthew nomogram (Fig. 35–2).259 The original nomogram was based on the observation that untreated patients who subsequently developed AST or ALT concentrations above 1000 IU/L could be separated from those who did not on the basis of their initial [APAP]. A nomogram was constructed that plotted the initial concentration versus time since ingestion, and a discriminatory line was drawn to separate patients who developed hepatotoxicity from those who did not. The initial discriminatory line stretched from [APAP] of 300 µg/mL at 4 hours to 50 µg/mL at 12 hours but was lowered to between 200 µg/mL at 4 hours and 50 µg/mL at 12 hours after evaluation of additional patients.259 The half-life of APAP was not a factor in the development of the nomogram, and the slope of the treatment line is based on empirical clinical data and does not reflect any discriminatory APAP half-life or APAP kinetics.259 The nomogram is designed and validated using a single value obtained at or greater than 4 hours after ingestion to allow for complete APAP absorption. Although patients who develop hepatotoxicity may have APAP half-lives greater than 4 hours,246,292 plotting multiple points on the nomogram or using an APAP half-life to determine risk has not been adequately studied and has significant limitations.165,301 The nomogram was later extrapolated to 24 hours using the same slope of the original nomogram line.259
Rumack-Matthew nomogram (reconstructed) for determining the risk of APAP induced hepatoxicity after a single acute ingestion. Serum concentrations above the treatment line on the nomogram indicate the need for N-acetylcysteine therapy.
It is important to realize that the line was based on aminotransferase concentration elevation rather than on hepatic failure or death, and it was chosen to be very sensitive, with little regard to specificity. Without antidotal therapy, only 60% of those with an initial [APAP] above this original line will develop hepatotoxicity as defined by aminotransferase concentrations above 1000 IU/L, but the risk of hepatotoxicity is not the same for all such patients. Elevated aminotransferase concentration develops in virtually all untreated patients with [APAP] far above the line, and serious hepatic dysfunction occurs frequently; the incidence of hepatotoxicity among untreated people with [APAP] immediately above the line is very low, and the risk of hepatic failure or death is far less.243,293
The line used in the United States runs parallel to the original but was arbitrarily lowered by 25% to add even greater sensitivity.259,262 The lower line, subsequently referred to as the treatment line or 150-line, starts at a concentration of 150 μg/mL at 4 hours following ingestion; declines with a 4 hour half-life, and ends at 4.7 µg/mL 24 hours following the overdose. The treatment line is one of the most sensitive screening tools used in medicine. The incidence of nomogram failures in the United States using this line is only 1% to 3% (depending on time to treatment).259 These infrequent “failures” may result from inaccurate ingestion histories, or may include patients with currently undefined risk factors for toxicity, including unique GSH handling or CYP enzyme activities.204,259
In September 2012, the United Kingdom adopted a single nomogram line starting at 100 µg/mL at 4 hours (“100-line”) for all acute APAP ingestions.109 This single 100-line replaced a two-tiered treatment protocol that treated low risk patients if either [APAP] exceeded the “200-line” and high risk patients if their [APAP] exceeded the “100-line”.333 The change was motivated by concern with regard to a small number of patients with [APAP] between the 100- and 200-lines who developed hepatic toxicity19,43,79,259,297,333 and a desire to simplify the treatment protocol. Why a 100-line was chosen by the UK Medicines and Healthcare Regulatory Agency and not a 150-line is not clear and has been questioned by several authors.109,204
Based on these observations and more than 25 years of use, the 150-line should be considered adequate in nearly all cases and is reliable when rigorously followed. When using the APAP nomogram, it is essential to precisely define the time window during which APAP exposure occurred and, if the time is unknown, to use the earliest possible time as the time of ingestion. Using this approach, patients with [APAP] below the treatment line, even if only slightly so, do not require further evaluation or treatment for acute APAP overdose. This also applies to most patients with factors that may predispose them to APAP-induced hepatotoxicity. There appears to be adequate experience with acute APAP overdose in the settings of potentially predisposing factors such as chronic heavy ethanol use, chronic medication with CYP-inducing xenobiotics, and inadequate nutrition to recommend that no special approach is required in such cases. Further study is needed to determine if rare events, such as acute APAP ingestion in the setting of chronic isoniazid (INH) use,93,220,353 may uniquely predispose patients to toxicity and require alteration of this approach.
The goal should be to determine [APAP] at the earliest point at which it will be meaningful in decision-making. Therefore, measurement of [APAP] 4 hours after ingestion or as soon as possible thereafter is used to confirm the patient’s risk of toxicity and, thus, the need to initiate NAC. No established guidelines are available for the use of determinations made less than 4 hours after ingestion, and because of variability in absorption, such values have less predictive value. Although it is optimal to start NAC therapy as soon as possible after confirmation of risk, NAC is nearly 100% effective if started prior to 6 to 8 hours after ingestion.293,299 This allows clinicians some leeway to wait for the laboratory results before starting therapy in patients in whom the history of ingestion suggests that the 4h [APAP] will fall below the treatment line. However, it should be noted that delaying NAC therapy longer than 6 to 8 hours after ingestion may increase the patient’s risk. If there is any concern about the availability of an [APAP] before this time, then treatment with NAC should be initiated. In such cases, [APAP] still should be determined as soon as possible. The results, when they become available, should be interpreted according to the treatment line on the APAP nomogram and NAC either continued or discontinued on the basis of this result. In the unusual circumstance in which no determination of [APAP] can ever be obtained, evidence of possible risk by history alone is sufficient to initiate and complete a course of NAC therapy post ingestion.
Early Measurement of [APAP].
Measurement of [APAP] between 1 and 4 hours after ingestion may be helpful only to exclude ingestion of APAP. If [APAP] is undetectable in this time frame, significant APAP overdose can likely be excluded. However, an [APAP] that is detectable between 1 and 4 hours cannot be definitively interpreted and, unless undetectable, mandates repeat testing at 4 hours.
Determination of Risk When the Acetaminophen Nomogram Is Not Applicable
Risk Determination When Time of Ingestion Is Unknown.
With careful questioning of the patient, family, and others, it is almost always possible to establish a time window during which the APAP ingestion must have occurred. The earliest possible time of ingestion (“worst-case scenario”) is used for risk-determination purposes. If this time window cannot be established or is so broad that it encompasses a span of more than 24 hours, then the following approach is suggested. Determine both [APAP] and AST concentrations. If the AST concentration is elevated, regardless of [APAP], treat the patient with NAC. If the time of ingestion is completely unknown and [APAP] is detectable, it is prudent to assume that the patient is at risk and to initiate treatment with NAC. If [APAP] is undetectable and the AST concentration is normal, there is little evidence that subsequent consequential hepatic injury is possible291 and NAC is unnecessary.
Risk Assessment Following Extended-Release Acetaminophen.
Extended-release formulations of APAP exist in the United States, Australia, New Zealand, and other countries worldwide. The pills available in the United States consists of a 325 mg immediate-release APAP dose and an additional 325 mg dose designed for delayed dissolution.76 The pills found in Australia and New Zealand (all three have identical contents) consist of a 665 mg bilayer tablet with 206 mg in the immediate release form and 459 mg in a sustained-release gel matrix.112,113 Both products result in the immediate release of APAP with delayed release of an additional dose. Pharmacokinetic analysis of the US product reveals that the majority of APAP is absorbed within 4 hours,85,327 the peak [APAP] is within 4 hours,58,85,312 and a small number of patients may have an initial [APAP] below the treatment line, but then have a subsequent [APAP] above the treatment line (“nomogram crossing”).58,327“Nomogram crossing” has been described with the Australian and New Zealand products as well.112 This “nomogram crossing” is not unique to the extended-release products and occurs in up to 10% of acute ingestions of immediate-release APAP.46 There is little evidence that nomogram crossing effects outcome76 and no evidence that an alternate approach to extended-release products should be used. In a 9 year review of 2596 extended-release APAP overdoses in the United States, one death was reported from acute overdose and there was no increased risk over immediate-release APAP.76 In Australia and New Zealand, five cases of overdose have been described. Three patients had an [APAP] over the treatment line at 4 hours or later, were treated with NAC and did not develop hepatotoxicity.112 One patient ingested 79 g of extended-release APAP, developed a double-hump [APAP] and a peak [APAP] of about 470 µg/mL at 10 to 15 hours, was treated with early NAC and developed mild aminotransferase elevations.113 The final patient had an [APAP] that was just below the treatment line at 4 hours, just above the line at 6 hours, was treated with NAC, and also did not develop hepatotoxicity.112,113 Certainly, a single [APAP] can reliably be plotted on the treatment nomogram after ingestion of the US APAP extended-release ingestion. Whether an alternative approach will be necessary for the Australian and New Zealand products, or any other new formulation, will require additional study.
Acute Overdose of Intravenous Acetaminophen.
Several intravenous APAP and prodrug APAP products exist worldwide and the US Food and Drug Administration (FDA) approved an intravenous APAP product in 2010 (intravenous APAP, 1 g in 100 mL).115 Experience with intravenous APAP overdoses is limited, but 23 intravenous APAP overdoses have been described, as well as one case of hepatic toxicity with coagulopathy.22,115,224 Errors commonly occur in young children and include 10-fold dosing errors, confusion between mg and mL, and incorrect route (oral product given intravenously).23,115
The approach described here is likely conservative and unstudied and is based on limited information including a well-documented case in which a dose of 90 mg/kg intravenously produced a 6h [APAP] of 38 µg/mL with hepatic toxicity and coagulopathy.22 This approach is reasonable based on current data, but should be modified as more information emerges. If a single dose error occurs that is in excess of 60 mg/kg, then immediate treatment with NAC is recommended.22,115 If a single dose is given but the exact dose is unknown, then an [APAP] should be drawn and plotted on the nomogram using a new, lower line starting at 50 µg/mL at 4 hours and decreasing with a 4 hour half-life. If the concentration is above this “50-line,” then treatment with NAC is indicated.22 There are few data on which to base a treatment decision prior to 4 hours if the dose is unknown. However, in this circumstance, there is likely no harm in waiting for a 4 hour [APAP] prior to initiating therapy. Finally, patients receiving multiple supratherapeutic doses of intravenous APAP should be treated with NAC if there is evidence of hepatic toxicity (eg, elevated aminotransferase concentrations or evidence of hepatic failure) or if there is evidence of APAP accumulation (eg, [APAP] is above therapeutic concentrations that are expected for the last dose).115
Risk Determination Following Repeated Supratherapeutic Ingestions (or Chronic Overdose).
No well-established guidelines are available for determining risk after chronic exposure to APAP. Conceptually, several factors must be considered before assessing and determining an individual’s risk of toxicity. It has been well established that therapeutic dosing of APAP is safe; however, some risk factors may put individual patients at risk for toxicity at supratherapeutic doses.
The chronic ingestion of “maximal therapeutic” doses (4 g/day) in normal adults without special circumstances appears to be safe. Several randomized, controlled trials have used maximal therapeutic doses of APAP (4 g/day) in thousands of patients over periods from 4 weeks to 2 years with no reported increase in adverse events or hepatic injury. A transient increase in aminotransferases of one to three times normal, but rarely up to 10 times normal is detected in some patients taking therapeutic doses,2,338 but these abnormalities resolve spontaneously despite continued use and have not led to hepatic dysfunction.172,338 Finally, several studies have evaluated abstaining chronic alcoholics administered APAP 4 g/day for up to 10 days with no evidence of hepatic damage, although elevations in aminotransferases were detected in both APAP and control groups.72,173
In 2009, an FDA advisory committee recommended to the FDA to decrease the daily dose of APAP to 3250 mg/day and in 2011 McNeil Pharmaceuticals limited its recommended daily dose for the 500 mg tablet to 3000 mg/day. This recommendation and the change in dosing was neither evidence based nor based on any safety data. The recommended daily dose for the 325 mg tablet and 650 mg extended-relief tablet remains at 3900 mg/day. The FDA did not mandate this reduction of daily dosing.170
Although therapeutic dosing appears to be safe, repeated supratherapeutic ingestions (RSTIs) may lead to toxicity. Given the amount of APAP use, the incidence of serious APAP toxicity after repeated doses is small, and hepatotoxicity appears to occur only after massive dosing188 or prolonged excessive dosing. The risk of hepatotoxicity is likely proportional to both the total amount of APAP ingested and the duration of the exposure; however, exact cutoffs for safe dosing are difficult to determine and are likely subject to factors related to the individual.
Although short-term prospective studies of supratherapeutic dosing (6–8 g/day) have not identified alterations in APAP kinetics or hepatotoxicity,105 several series and case reports have identified patients with hepatotoxicity who retrospectively report therapeutic or slightly supratherapeutic doses. Retrospective dosage reporting is prone to significant errors and issues in which those giving the history may be unable or unwilling to report or estimate ingestions accurately. Cases describing hepatic toxicity after in-hospital therapeutic doses exist, but are exceedingly rare, involve unusual risk factors, and demonstrate multifactorial hepatic injury.55,61 Furthermore, because APAP is commonly used in patients with chronic heavy ethanol use and viral infections, it is unclear in which cases APAP was causative, contributory, or unrelated to hepatotoxicity.
Conceptually, the groups that are at “high risk” for hepatotoxicity after RSTI of APAP have either potentially increased activity of CYP2E1 and therefore proportionally increased NAPQI formation or have decreased GSH stores and turnover rate. Many reported cases of APAP toxicity from RSTI involve patients who have factor(s) that influence their GSH supply or turnover, NAPQI production, or both, including infants with febrile illness who have received excessive dosing, chronic heavy ethanol users, and patients chronically taking CYP-inducing medications. The interplay of NAPQI and GSH may also be an important factor. For example, malnutrition is theorized to increase the risk of APAP toxicity342; however, both CYP2E1 activity59 and GSH supply163 are decreased in malnourished patients, and their relative impact on risk is unknown.
When there is concern about risk of toxicity after RSTI dosing, several approaches are suggested. The goal should be to select patients at risk based on dosing history and other risk factors and to then use limited laboratory testing to determine the need for NAC. A logical screening laboratory evaluation consists of determination of [APAP] and AST concentrations, with additional testing as indicated by these results and other clinical features. The objective is to identify the two conditions that warrant NAC therapy—remaining APAP yet to be metabolized and potentially serious hepatic injury.
Role of History and Physical Examination in Repeated Supratherapeutic Ingestions.
The first consideration when evaluating a patient with a history of repeated supratherapeutic APAP dosing is the presence or absence of signs or symptoms of hepatotoxicity. Regardless of risk factors or dosing history, such findings should prompt treatment with NAC and laboratory evaluation. This is particularly important because most reported cases of serious toxicity after repeated dosing are symptomatic for more than 24 hours before diagnosis, and earlier treatment may improve outcome.
In asymptomatic patients, a reasonable approach is to perform laboratory evaluation for those who have ingested more than 200 mg/kg/day (or 10 g/day, whichever is less) in a 24 hours period or more than 150 mg/kg/day (or 6 g/day, whichever is less) in a 48 hours period.72,75,196 In children younger than 6 years of age, laboratory evaluation should be performed if the reported ingestion is more than 100 mg/kg/day during a 72 hours period or longer.
Several factors or characteristics place patients at higher risk for chronic APAP toxicity. High-risk factors that have been theorized include chronic heavy ethanol use; chronic ingestion of INH; febrile illnesses in infants and young children; and malnutrition, AIDS, or anorexia. In some cases, animal or basic science studies show evidence of increased risk, and in most cases, there have been multiple anecdotal reports of toxicity at therapeutic or slightly supratherapeutic doses. Whether these patients require a lower threshold for laboratory screening is unknown.
Role of Laboratory Evaluation in Repeated Supratherapeutic Ingestions.
After a patient is determined to be at risk, an [APAP] and [AST] should be determined. These should be interpreted using the concept that a patient may be at risk of hepatotoxicity if there is evidence of hepatic injury (elevation of AST) or there remains enough APAP to produce further hepatic damage.
Using the strategy described here, patients with elevated [AST] are considered at risk, regardless of [APAP]. An [APAP] is useful in patients with normal [AST] as a tool to determine only whether sufficient APAP remains to lead to subsequent NAPQI formation and delayed hepatotoxicity. In many cases, [AST] is normal and [APAP] is below 10 µg/mL, obviating the need for NAC. If the [AST] is normal, then the patient should be considered at risk if [APAP] is 10 µg/mL or above. Higher thresholds for non-treatment, such as APAP below 30 µg/mL or AST twice as high as normal, have been suggested, but have not been studied and their sensitivity is unknown.
Patients who develop highly elevated [AST] after chronic APAP overdose should be treated and further evaluated with laboratory tests to assess hepatotoxicity and prognosis (creatinine, PT, INR, pH, phosphate, and lactate). Initial elevations of INR or creatinine may be markers of poor prognosis in APAP RSTI.4
The measurement of APAP protein adducts in urine has been described and theoretically could quantify NAPQI production in the liver. It has been suggested that adduct concentrations may identify APAP-induced hepatotoxicity in undifferentiated patients with elevated [AST]; however, adducts are elevated after both therapeutic and RSTI APAP ingestions and a clear defining value has not been determined.133 In addition, the test remains largely unavailable and has been insufficiently studied.78,149,218 Several other biomarkers, including miRNA-122 and acetylated HMGB-1, have been tested in acute overdoses, but their utility in RSTI is unclear.
Patients who are identified as at risk, with either an elevated [AST] or an elevated [APAP], should be treated with NAC.
Risk Determination Following Acetaminophen Exposure in Children
Serious hepatotoxicity or death after acute APAP overdose is extremely rare in children.261,315 Predominant theories5 for resistance to toxicity include a relative hepatoprotection in children because of increased sulfation capacity207 or differences in the characteristics of children poisonings, including smaller ingested doses, overestimation of liquid doses, and unique formulations (pediatric elixirs that contain propylene glycol may result in decreased toxicity due to inhibition of CYP2E1).158,317 This has led some to suggest higher screening values and a higher nomogram line for children.35 However, no significant change in NAPQI production has been demonstrated in children, and a more liberal approach to children’s acute APAP ingestions has been inadequately studied and is not recommended. After repeated supratherapeutic APAP dosing, there is no evidence that children are relatively protected. Hepatic injury after therapeutic APAP is likely exceedingly rare in children.179 However, infants and children with acute febrile illnesses comprise one of the few groups in which toxicity after repeated excessive dosing is well described.246 Common sources of dosing errors include substitution of adult for pediatric preparations; overzealous dosing by amount or frequency in attempts to maximize effect, and failure to read the label and dose carefully.8,246 Age younger than 2 years is an independent risk factor for development of toxicity.156 These rare cases of toxicity in febrile children with repeated supratherapeutic dosing may simply reflect that these children constitute the most common setting for pediatric APAP use and that children are at greater relative risk for excessive dosing because of their size. Although logically one can argue that inflammatory oxidant stress and short-term fasting during febrile infectious illnesses affect oxidative drug metabolism and decrease GSH supply, these relationships are complex and not well defined. Of the reported cases of repeated supratherapeutic APAP dosing in children with hepatic injury, the cause was likely an isolated infectious illness in some, APAP in others, and a combination of the two in still others.
Risk Determination Following Acetaminophen Exposure in Pregnancy
The initial risk of toxicity in a pregnant woman is similar to that of a nonpregnant patient with a few exceptions. Little evidence suggests that any alteration of the treatment line is necessary. In fact, there are no reported cases of fetal or maternal toxicity in women with [APAP] below the treatment line203 or in those treated with NAC within 10 hours of an acute ingestion.255 However, there is controversy in assessing the risk of fetal toxicity after the mother has been determined to be at risk. To better understand the issues, a review of maternal–fetal physiology and pharmacokinetics related to APAP and NAC is necessary.
APAP is capable of crossing the human placenta,188,223,256 and APAP may be present in concentrations similar to maternal serum concentrations within hours after ingestion.223,256 Fetal metabolism of APAP probably is inefficient but is not completely understood. Fetal sulfation and oxidative metabolism of APAP are slower than in adults, and glucuronidation is undetectable until 23 weeks of gestation.257 CYP enzymes that are capable of oxidizing APAP are present in the fetus as early as 18 weeks gestation.257 However, the activity of these enzymes is less than 10% that of adult enzymes at 18 weeks gestation and increases to only 20% activity at 23 weeks.257 How the opposing forces of decreased overall metabolism of APAP and decreased NAPQI formation impact fetal risk is unclear.
The mechanism of fetal risk in women with APAP toxicity remains controversial. The degree of fetal toxicity that is attributable to fetal metabolism of APAP or to maternal illness is unclear. In clinical case series, the majority of pregnant women who overdose on APAP have uneventful pregnancies.203,255 Pregnant women who develop APAP toxicity in the first trimester have an increased risk of spontaneous abortion,255 fetal demise is described in the second trimester,318 and those who develop APAP toxicity in the third trimester have a potential risk of fetal hepatotoxicity because of fetal metabolism. However, reports of third-trimester fetal hepatotoxicity are rare203,255 and are only associated with severe maternal toxicity.255,331 The factors associated with poor fetal outcome after a large APAP overdose are delayed treatment with NAC and young gestational age.
The decision to treat a pregnant woman with NAC requires consideration of what is known about the efficacy and beneficial effects as well as the adverse events of NAC for both the fetus and the mother. Every indication suggests that NAC is both safe and effective in treating the mother,255 but there are inadequate data to evaluate efficacy in the fetus, although fetal outcome has generally been excellent after maternal treatment with NAC.255 Given that NAC has been safely used in many pregnancies203,255 and fetal mortality is linked to delays to treatment, NAC should be initiated in pregnant women who meet the same criteria as nonpregnant patients. The necessary length of NAC therapy is difficult to determine. The 20 hour intravenous protocol probably is the most commonly recommended NAC protocol used for pregnant women worldwide; however, there is a paucity of published experience supporting NAC treatment courses shorter than the oral 72 hour protocol (Chap. 31).203,255
Ethanol and Risk Determination
The effects of ethanol on APAP toxicity are complex and are best described by clearly separating experimental animal data from actual human overdose experience, acute ethanol use from chronic heavy ethanol use or alcoholism, and single from repeated supratherapeutic APAP dosing. Ethanol use itself is difficult to define and many studies used different definitions. For the purpose of this section, the term chronic heavy ethanol use is defined as a person who ingests a mean of greater than two to three standard ethanol-containing drinks per day.276 Moderate ethanol use is defined as a mean of one to two standard ethanol-containing beverages per day. The term alcoholic will be used to define people whom either self-define as alcoholics or are identified as an alcoholic by the CAGE questionnaire, the Michigan Alcohol Screening Test, or similar screen.77,171,173
Although not entirely consistent, both animal and human data suggest that acute ethanol coingestion with APAP may be hepatoprotective. Ethanol coingestion decreases NAPQI formation presumably by inhibiting CYP2E1 in both humans321,322 and animals.271,322 In large retrospective evaluations of overdoses, acute ethanol ingestion independently decreases the risk of severe hepatotoxicity in chronic heavy ethanol users276 and in nonchronic heavy ethanol users,293 but did not significantly decrease the risk of hepatotoxicity (ALT > 1000 IU/L) in a smaller prospective study.336
However, chronic ethanol administration increases the risk of hepatotoxicity from APAP dosing in animals.325,356 This may be a consequence of increased NAPQI formation due to induction of CYP2E1 metabolism once the ethanol is metabolized319 or decreased mitochondrial GSH supply or regeneration.356
After acute APAP overdose, chronic heavy alcohol users who have not coingested ethanol may be at a slightly increased risk; however, this elevated risk appears to be of little clinical importance given the sensitivity of the treatment line.298 There is no credible evidence that chronic heavy alcohol use should alter the approach after an acute APAP overdose using the treatment line. In fact, the treatment line was developed with clinical data that included chronic heavy ethanol users.246,262 Given the paucity of data linking chronic heavy ethanol use to nomogram failures, it appears that the treatment line is adequately sensitive for screening after an acute APAP overdose, regardless of the patient’s history of chronic heavy ethanol use.
The relationship between chronic heavy ethanol use and chronic APAP use is complex. Hepatotoxicity has been sporadically reported in patients with chronic heavy ethanol use after repeated supratherapeutic APAP dosing. Complicating these reports are the clinical challenges of obtaining accurate histories in chronic heavy ethanol users, failure to exclude non-APAP causes of hepatotoxicity, and other factors. Alcoholics are at higher risk of both using supratherapeutic doses of APAP and using combinations of multiple APAP-containing products.283 In contrast, prospective evidence demonstrates minimal risk of hepatotoxicity in alcoholic patients who ingest therapeutic doses of APAP.17,132,171,173 In prospective trials of ingestion of 4 g/day of APAP or placebo in chronic moderate to heavy ethanol users for up to 10 days, no clinically relevant increases in AST versus placebo have been identified.17,77,132,171,173 However, it should be noted that, in studies involving persons who abuse alcohol, mild AST elevations (< 120 IU/L) were noted in 40% of both study and controls, and more significant increases (> 120 IU/L, or three times normal) were noted in 4% to 6% of participants.171,173 In addition, in all studies, a small group of patients developed significant increases in aminotransferases, but most were unchanged. Patients who develop elevated aminotransferases after therapeutic dosing who are then rechallenged with additional APAP develop similar [AST] increases,132 implying that individual factors are likely more important than the chronic heavy ethanol use itself.
CYP Inducers and Risk Determination
Inducers of the CYP enzymes have long been theorized to increase the risk of toxicity from APAP because of a proportionally increased production of NAPQI. It is now clear that APAP is metabolized to NAPQI largely by CYP2E1130,198 and that only induction of this specific enzyme is likely to increase the risk of hepatotoxicity.
Although ethanol and INH are known inducers of CYP2E1, there is no evidence that the clinical approach to these patients should be altered. Similarly, several other medications, including phenytoin, carbamazepine, and phenobarbital, are theorized to increase APAP toxicity because of nonspecific CYP induction activity. None of these anticonvulsants induces CYP2E1, although there is some evidence that they increase NAPQI formation in cultured human hepatocyte and animal models, possibly through inhibition of glucuronidation.87,211 However, clinical experience suggests that there is no need to change the approach to these patients.
Assessing Actual Toxicity: Critical Components of the Diagnostic Approach
The [APAP] should be measured in patients with acute APAP overdose and no evident hepatotoxicity, but no other initial laboratory assessment is required. AST concentration should be measured in patients who are considered to be at risk for APAP toxicity according to the nomogram or history (in the case of repeated supratherapeutic dosing) or in those suspected of already having mild hepatotoxicity by history and physical examination.
Unless evidence of serious hepatotoxicity is present, [AST] is a sufficient indication of hepatic conditions, and no additional testing is initially needed. Death of hepatocytes, resulting in release of measurable hepatic enzymes, precedes all cases of serious hepatic dysfunction. Mild renal toxicity may rarely occur without hepatotoxicity40; however, at least minimal elevation of [AST] generally precedes evidence of clinically significant nephrotoxicity.3,51 Exceptions are rare,40,161 and routine screening of renal function in the absence of elevated [AST] is probably unnecessary.
APAP overdose may lead to minor prolongation of PT even without causing hepatotoxicity.343 This most commonly occurs between 4 and 24 hours following ingestion and may be a result of NAPQI-related inhibition of vitamin K–dependent γ-carboxylation of factors II, VII, IX, and X.316,343 These minor prolongations (resulting PT usually is less than twice control) are rarely clinically relevant, are not evidence of hepatotoxicity, and should not be used as prognostic factors or indications for NAC treatment. In fact, treatment with NAC may also prolong PT150,167 by interfering with the PT assay, by reversing an APAP/NAPQI effect,316 or by direct NAC effects.316
Ongoing Monitoring and Testing.
If no initial elevation of [AST] is noted, then repeated determination of [AST] alone—without other biochemical testing—is sufficient to exclude the development of hepatotoxicity. [AST] should be determined at the end of the protocol (eg, at 21 hours if using the standard intravenous protocol) or every 24 hours if using a longer protocol. If an elevated [AST] is noted, then PT and INR and creatinine should be measured and repeated every 24 hours or more frequently if clinically indicated. Results of other hepatic tests, such as GGT, alkaline phosphatase, lactate dehydrogenase, and bilirubin, which are useful when determining the cause of hepatic abnormalities, will be abnormal in cases of serious APAP-induced hepatotoxicity but provide little additional useful information if the cause is certain (Chap. 23).
If evidence of hepatic failure is noted, then careful monitoring of blood glucose, pH, PT, INR, creatinine, lactate, and phosphate concentrations are important in assessing extrahepatic organ toxicity and are vital in assessing hepatic function and the patient’s potential need for hepatic transplant (see Assessing Prognosis). In addition, meticulous bedside evaluation is necessary to determine and document vital signs, neurologic status, and evidence of bleeding. Many additional tests may be useful in the setting of hepatic failure based on clinical condition and local protocols. Testing for other rare APAP-associated conditions by electrocardiography, lipase determination, or other studies should be performed on a case-by-case basis only.