It is 6 AM and your shift is winding down. The last patient you are about to see is a 20-year-old man with a complaint of tooth pain. On your walk to his room you start to daydream about enjoying a little sunlight after working 6 nights in a row when you notice your patient is carrying an industrial sized bottle of acetaminophen from which he you just saw him pop five pills.
Through a quick interview you find out the pills are 500 mg tablets and he has taken multiple doses of between three and five pills sporadically over the past day to control his pain. Even a rough estimate tells you this is potentially a toxic dose. To make it worse, a straightforward Rumack-Matthew nomogram slam-dunk is impossible now because of the staggered dosing he took. You have no good way of risk stratifying this patient so you choose an aggressive approach. You plan to, give charcoal for pills still hanging out in the proximal gut, and start N-acetylcysteine. You also consider whole bowel irrigation but recall that even extended release acetaminophen is absorbed from the gut pretty quickly rendering this method not useful. As you put your plan into motion, the question of how high his actual risk for hepatic injury could be continues to nag at you.
Acetaminophen poisoning is one of the most commonly fatal ingestions in the United States whether alone or in combination with other substances. Toxicity is mediated by N-acetyl-p-benzoquinone imine (NAPQI), which is a product of CYP-450 enzyme activity on acetaminophen. It also possesses a cute little name for such a lethal toxin.
Source: Emmet et al., 2014.Metabolism of acetaminophen through CYP 450 enzyme action leads to formation of N-acetyl-p-benzoquinone imine (NAPQI). This toxin, in turn, is metabolized is a process that involves glutathione.6
Luckily, there is an effective antidote that has relatively little risk compared to its benefit: N-acetylcysteine (NAC). This agent helps replete the stores of glutathione in the liver that can detoxify NAPQI and it is the reason the Rumack-Matthew nomogram calculation is clinically useful. As helpful as having the nomogram is, this method has its limitations. It can only be used for acute ingestions with a known time of occurrence. If toxicity occurs in the setting of chronic ingestions, then the nomogram is not reliable. Chronic poisoning may occur in the geriatric population or in the setting of staggered doses (as with our patient).
It is for these more unpredictable cases that the acetaminophen-aminotransferase multiplication product was conceived. Also known as the paracetamol-aminotransferase multiplication product, or APAP X AT for short, it is a simple calculation that can be done at bedside and helps place the patient is a low- or high- risk group for developing hepatotoxicity. Recall that normally alanine aminotransferase (ALT) is in the 50-60 IU/L range and aspartate aminotransferase (AST) is in the 30-40 UI/L range. Patients with acetaminophen levels above 150 mg/L are at risk for toxicity per the Rumack-Matthew nomogram, and treatment is recommended for any patients above this level.
Keeping in mind that: 1) The Rumack-Matthew nomogram uses units of mcg/mL for acetaminophen concentration, and 2) mathematically, 1 mcg/mL is equivalent to 1 mg/L, the formula looks like this
(X mg/L) x (Y IU/L)
It is based upon the principles that as the APAP is metabolized the AT will rise and that the multiplication product of these values will be high at any given point if toxicity is likely. The calculation must be from simultaneously measured values from a single sample. It does not depend on one discrete ingestion and can also be used when the ingestion time is unknown. If you are wondering why AT level alone is not used, data has not shown this practice useful in predicting toxicity.5 In addition, the authors ultimately used whichever aminotransferase was available.
The original study was a secondary analysis of the Canadian Acetaminophen Overdose Study (CAOS) that included 94 patients who developed hepatotoxicity and met criteria pre-specified by the investigators. In order to allow comparison to the Rumack-Matthew nomogram, the authors included only single acute ingestions with APAP and AT concentrations taken at least 4 hours after ingestion. Subjects had varying lengths of time from ingestion as depicted by the graph below.4
Source: Sivilotti et al., 2010. Note the varying lengths of time from ingestion for subjects.4
Hepatotoxicity is defined as a peak aminotransferase (either AST or ALT) level of 1000 IU/L. The higher of the two aminotransferases was used for calculations, and patients were grouped by the predicted time post-ingestion based on two consecutive measurements of aminotransferase (AT) spanning 1000 IU/L. N-acetylcysteine was initiated in these subjects at a median time of 15.5 hours post-ingestion.
All but one subject had APAP X AT values above 1500 mg/L x IU/L (the study expresses it in SI units as 10000 μmol/L x IU/L2). Subjects who developed hepatotoxicity earlier exhibited higher values earlier on. Earlier hepatotoxicity was also associated with longer half-life values for acetaminophen, leading to higher APAP values when these were re-measured. A slower decrease of APAP X AT values (likely due to poor metabolism by a damaged liver) was a poor prognostic sign. These findings describing hepatotoxicity were supported by a later study looking at rise of aminotransferase and international normalized ratio (INR). Finally, the authors examined the relationship between the APAP X AT and the peak INR within the first 12 hours of therapy. The graph depicting these values shows a rough equivalency between elevated INR and consistently elevated APAP X AT from first measurement to 12 hours later even with therapy. (See graph with explanation below.)
Source: Sivilotti et al., 2010.4
One of the authors of the original study attempted an external validation study through a retrospective analysis. They included patients with APAP overdose who presented to two inner city hospitals in the United Kingdom between 2005 and 2013 who had their AST or ALT measured. Three mutually exclusive categories were reached by consensus: Acute (an ingestion that occurred over <1 hour), delayed (more than 24 hours elapsed between ingestion and presentation), and staggered (ingestion of more than 75 mg/kg/day with therapeutic intent). Primary and secondary outcomes were hepatotoxicity defined as ALT >1000 IU/L and INR >2, respectively. Mainly, the authors wanted to test the diagnostic accuracy of the 1500 mg/L x IU/L mark established in the derivation study and an upper cutoff of 10000 mg/L x IU/L in determining likelihood of hepatotoxicity. They also attempted to describe the variation in APAP X AT values over time in subjects with hepatotoxicity with more than one APAP concentration recorded. In a secondary analysis, they input a low value (5 mg/L) for APAP if it was undetectable to see which values would be associated with hepatotoxicity
There were 2,703 acute single ingestions. Eighteen (0.74%) had a multiplication product greater than 10000 mg/L x IU/L. Eight of these developed hepatotoxicity yielding a sensitivity of 80% and a specificity of 99.6%. In the intermediate group with multiplication products between 1500 and 10000, only 2 of 216 (~1%) developed hepatotoxicity. Keep in mind two things while reading through these figures. First, it is better to over-treat than under-treat patients with acetaminophen toxicity. Therefore, high sensitivity is more important than high specificity and even a test with low specificity (meaning more false positives and more people being treated) is acceptable so as to miss as few cases as possible. Second, these numbers are pretty small and may, understandably, draw more scrutiny than they provide confidence.
The study presents data in a number of ways that can be confusing, especially when certain raw numbers are missing. In order to simplify the presentation of their data, it is adapted into two tables below. The most important idea to take away from these tables is that predictive values for the extremes (especially a multiplication product >10000 mg/mL x IU/L) correlate with better likelihood ratios and negative predictive values. For the second table (drawn from the secondary analysis) note that they replaced an arbitrary value of 5 mg/L for any undetectable or unmeasured APAP value, the LR+ for the intermediate group increased to 21.
Accuracy for hepatotoxicity for all subjects presenting <24 hrs after acute ingestion
|Multiplication Product||Sensitivity (95% CI)||Specificity (95% CI)||Likelihood Ratio (95% CI)
In Study table
Calculated from sensitivity and specificity
Calculated from sensitivity and specificity
*Some values were either not present in the text, could not be calculated, or were not clinically applicable.
Statistical Outcomes for Hepatotoxicity in Differing Groups
|Single Acute (8-24 hrs)||Delayed (>24 hrs)||Staggered|
|LR+ (CI)||LR- (CI)||LR+ (CI)||LR – (CI)|
|1500-10000||*||*||1||5.75 (1.63-20.3)||0.75 (0.47-1.20)|
|>10000||Sensitivity 88.8% (50.1-99.4%), Specificity 100% (99.8-100%)||*||*||*||0.29 (0.09-0.92)|
Adapted from Wong et al., 2015. Where values were not provided by the text, calculations were made using online software.7,8
*Some values were either not present in the text, could not be calculated, or were not clinically applicable.
Though not shown in the table above, the authors also discussed cases related to supratherapeutic ingestions. The term is not explicitly defined, but can be applied to the patient in our case. Of the 202 presenting subjects, only 8 had detectable APAP levels (seven with APAP X AT level <1500 mg/mL x IU/L and one with a level >10000 mg/mL x IU/L). All received NAC and the one patient with a product >10000 had resolution of elevated ALT after treatment .
A subsequent study confirmed that a multiplication product >10000 mg/mL x IU/L was predictive of acute liver injury in subjects exposed to acute and staggered ingestions of extended-release formulations of acetaminophen (LR 27, sensitivity 100%, specificity 97% when APAP X AT >10,000).
Although the number of subjects who developed hepatotoxicity in the validation study was small, they were taken from a large pool. This study shows how the APAP X AT can be useful without having to determine acuity or chronicity of ingestion. The clinically important weakness in this validation study is that within 8 hours of an acute single ingestion, a value >10000 mg/mL x IU/L is not as dependable in predicting hepatotoxicity as a value taken after 8 hours. They suggest a value taken greater than 12 hours after would supplement the 8 hour value and would be better for increasing sensitivity. This makes it less useful in decision-making about which patient should receive NAC with this tool because NAC is most effective when given within 8 hours of ingestion. However, keep in mind that most patients in the study received treatment with NAC based on Rumack-Matthew Nomogram, so the APAP X AT woud be a risk stratification tool in this context, rather than a tool to decide whether to use antidote. We will discuss this further in the next section.
SO WHAT DO WE DO?
So how do we put this APAP X AT multiplication product to practical use? The creators of this tool agree it is not meant to replace the Rumack-Matthew nomogram. The nomogram remains useful in acute, single overdoses with a known time of ingestion, and it was used to start NAC in subjects meeting its criteria in the studies discussed here. The authors frame the multiplication product as a tool at 8-12 hours after ingestion to help predict those who are likely to develop hepatotoxicity despite treatment and require escalation of care (i.e., prolonged NAC, ICU, transplant, etc.).6 Furthermore, many cases of acetaminophen ingestion do not have a known time of ingestion or are not single discrete ingestions. The usefulness of the multiplication product in real-world situations may be estimated by the study methods – the vast majority of the subjects were receiving NAC. This means the cutoffs were derived from patients being treated as we would treat them in our ED, giving a method for risk-stratifying patients with massive overdoses or ingestions that do not fit the nomogram. The authors of the validation study acknowledge that more work is needed to fine-tune the cutoff points. A finding that is heartening is that despite the large number of ingestions in some of these studies, only a very small population developed liver toxicity. However, this is also a major limitation of these studies. Only 7.4% and 0.9% of subjects developed liver toxicity in the original study and validation study, respectively. The small number of people with the target condition reaffirms that NAC is a very effective antidote, but it also makes these results less generalizable because the disease prevalence was so low.
Other shortcomings of these studies include uncertainty about how baseline liver disease (i.e. transaminitis) may interfere with a calculation of the multiplication product. Late presentations can also be misleading due to possibly undetectable concentrations of acetaminophen. If this is the case, especially in the setting of elevated liver enzymes, you should probably worry rather than think of a multiplication product of zero as reassuring. The lack of refinement with the cutoff points also poses a challenge. While the high-risk group (>10000 mg/mL x IU/L) seems like an easy patient for whom to get a critical care consult, the intermediate risk group is still a head-scratcher. On the other hand, patients who fall into the low risk group seem like they will undergo initial NAC treatment uneventfully. For instance, most patients in a retrospective analysis had mild reactions (nausea/vomiting). Those with more serious symptoms (rash, hypotension, bronchospasm) were able to complete their treatment after modifications to treatment such as slowing infusion rates and addition of antihistamines. All patients placed on NAC were able to complete their treatment. That is encouraging news when we are risk stratifying. It should be noted about these studies is that in the authors acknowledge financial support from a manufacturer of n-acetylcysteine. This does not necessarily imply bias, but it is something to keep in mind as you read through these studies.
So, is this something you can use in your regular practice right now? Yes, but probably only in a specific subset of patients. It is most clearly useful as a way to risk-stratify patients that were previously outside the scope of the Rumack-Matthew nomogram. Whereas beforehand, this group was “treat, watch, and wait”, now there is a calculation from your initial lab values that can suggest a need to intensify care in patients with a higher risk for developing severe toxicity. Remember that this was developed in patients being treat with NAC already so the decision to treat or not is outside this tool’s ability to determine. However, it can help guide how to proceed and can be useful when discussing appropriate disposition with our colleagues in Internal Medicine and Critical Care.
This post could not have been possible without the help of the usual Staten Island peer review/editing/writing staff: Drs. Ian de Souza, Eden Kim, and Kyle Kelson. Together we would like to thank our faculty Toxicologist, Dr. Sage Weiner, whose valuable input was instrumental in the writing of this post.
 Mowry JB, Spyker DA, Brooks DE, Zimmerman A, Schauben JL. 2015 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 33rd Annual Report. Clin Toxicol (Phila). 2016 Dec;54(10):924-1109. doi: 10.1080/15563650.2016.1245421. PubMed PMID: 28004588.
 Emmett M. Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid): A Tale of Two Cycles, One an ATP-Depleting Futile Cycle and the Other a Useful Cycle. Clinical Journal of the American Society of Nephrology : CJASN. 2014;9(1):191-200. doi:10.2215/CJN.07730713.
 Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975 Jun;55(6):871-6. PubMed PMID: 1134886.
 Sivilotti ML, Green TJ, Langmann C, Yarema M, Juurlink D, Johnson D. Multiplying the serum aminotransferase by the acetaminophen concentration to predict toxicity following overdose. Clin Toxicol (Phila). 2010 Oct;48(8):793-9. doi: 10.3109/15563650.2010.523829. Epub 2010 Oct 8. PubMed PMID: 20932103.
 Green TJ, et al. When do the aminotransferases rise after acute acetaminophen overdose? Clin Toxicol. Submitted for publication.
 Wong A, Sivilotti ML, Dargan PI, Wood DM, Greene SL. External validation of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose. Clin Toxicol (Phila). 2015;53(8):807-14. doi: 10.3109/15563650.2015.1066507. Epub 2015 Jul 15.
 Wong A, Sivilotti MLA, Graudins A. Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose. Clin Toxicol (Phila). 2017 Jun;55(5):346-351. doi: 10.1080/15563650.2017.1290253. Epub 2017 Feb 15. PubMed PMID: 28421844.
 Zyoud SH, Awang R, Syed Sulaiman SA, Sweileh WM, Al-Jabi SW. Incidence of adverse drug reactions induced by N-acetylcysteine in patients with acetaminophen overdose. Hum Exp Toxicol. 2010 Mar;29(3):153-60. doi: 10.1177/0960327109359642. Epub 2010 Jan 13.
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