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Estimated risk of hepatotoxicity after an acute acetaminophenoverdose in alcoholics

Fahad M. Ali*, Edward W. Boyer, Steven B. BirdDivision of Medical Toxicology, Department of Emergency Medicine, University of Massachusetts Medical School, 55 Lake Avenue North,

Worcester, MA 01655, USA

Received 16 October 2006; received in revised form 1 November 2007; accepted 5 November 2007

Abstract

CTEDPRO

A published logistic regression model based on the Canadian Acetaminophen Overdose Study registry was used to calculate the risk ofhepatotoxicity after an acute acetaminophen overdose and to estimate a treatment threshold line for alcoholic patients who did not co-ingestalcohol (i.e., abstinent alcoholics) on the RumackeMatthew nomogram. The risk of hepatotoxicity in nonalcoholic and abstinent alcoholicpatients was calculated at the acetaminophen concentration of 150 mg/ml at 4 h (37.5 mg/ml at 12 h) treatment threshold line. This corre-sponds to the ‘‘possible risk’’ line on the RumackeMatthew nomogram and represents a 1.6% risk of hepatotoxicity for nonalcoholic pa-tients at or below this line. At or below this same 150 mg/ml at 4-h line, abstinent alcoholic patients have a hepatotoxicity risk of 10.7%. Therisk of hepatotoxicity in abstinent alcoholics’ equivalent to that of nonalcoholics (i.e., 1.6%) occurs at a lower acetaminophen concentra-tions treatment threshold line, that is, 104 mg/ml at 4 h (26 mg/ml at 12 h). Because of difficulties plotting this new line on the familiarRumackeMatthew semilogarithmic scale, a line connecting 100 mg/ml at 4 h (25 mg/ml at 12 h) is proposed. This line equates toa 1.1% risk of hepatotoxicity in abstinent alcoholic patients. The analysis supports the observation that based on the published model; ab-stinent alcoholics might have a greater risk of hepatotoxicity after an acute acetaminophen overdose. This proposed new risk line can beused in hypothesis generation for future clinical studies in this alcohol related problem. � 2008 Elsevier Inc. All rights reserved.

Keywords: Acetaminophen; Alcoholism; Hepatotoxicity; Overdose; Poisoning; Theoretical models

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Introduction

The RumackeMatthew nomogram is an important clin-ical decision-making tool used by physicians and poisoncontrol centers when managing patients presenting withan acute acetaminophen overdose. The nomogram is usedto discern which acetaminophen-poisoned patients are atsufficient risk to require treatment with N-acetylcysteine(NAC), but does not incorporate patient-specific risk factorssuch as history of alcoholism (Rumack, 2002). A lowerthreshold for treatment of acetaminophen poisoning hasbeen advocated in chronic alcoholics based originally onanimal studies, but no human studies have addressed the is-sue of the treatment threshold after an acute acetaminophenoverdose in alcoholic patients (Buckley & Srinivasan,2002).

The practice of using a lower plasma acetaminophenconcentration threshold for the treatment of acetaminophen

ALC5918_proof � 13-

* Corresponding author. Tel.: þ1-508-421-1401; fax: þ1-508-421-

1490.

E-mail address: fahadalimd@hotmail.com (F.M. Ali).

0741-8329/08/$ e see front matter � 2008 Elsevier Inc. All rights reserved.

doi: 10.1016/j.alcohol.2007.11.005

68697071

poisoning, after an acute overdose in ‘‘high-risk groups’’such as chronic alcoholism patients, is based on anecdotalcase reports and small case series (Dargan & Jones, 2002;Reid & Hazell, 2003). There is no consensus on the useof these lower threshold treatment ‘‘safety lines’’ whenmaking treatment decisions in patients with potentially in-creased risk of hepatotoxicity after an acetaminophen over-dose (Reid & Hazell, 2003).

Arguments about the possibility of increased hepatotox-icity risk after an acetaminophen overdose in chronic alco-holics should be differentiated from acute acetaminophenoverdose with alcohol coingestion. There is evidence fromboth animal and human studies that acute alcohol coinges-tion inhibits the toxic metabolic activation of acetamino-phen in the liver. This protective effect can decreases therisk of development of hepatotoxicity after an acetamino-phen overdose, even in cases with preexisting chronic alco-holism (Dargan & Jones, 2002; Prescott, 2000; Tredger,1985). Furthermore, the possibility of increased hepatotox-icity after an acetaminophen overdose in chronic alcoholicsshould not be confused with the possibility of increased riskof liver injury in long-term alcoholics at repeated maximum

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therapeutic daily doses of acetaminophen (i.e., 4 g/day). Inthe latter case, there is evidence from human studies thatthis was not associated with evidence of liver injury whenthe maximum therapeutic dose was administered for 2 con-secutive days (Kuffner et al., 2001).

Factors that have been suggested to increase the risk ofhepatotoxicity after an acetaminophen overdose include:patients who are chronic alcohol abusers; patients on drugsthat induce microsomal enzymes; patients with underlyinghepatic impairment; patients likely to have glutathionedepletion from recent severe fasting, acute illness with pro-longed vomiting or dehydration; anorexia nervosa, bulimia,or conditions that could lead to malnourishment (e.g., ma-lignancy); and AIDS (Reid & Hazell, 2003). Various bio-chemical mechanisms, as described elsewhere, have beenpostulated to explain case observations of increased riskof hepatotoxicity in this subset of patients. Furthermore,this is still an area of ongoing debate. (Lauterburg & Velez,1988; Prescott, 2000; Reid & Hazell, 2003).

Some international authorities (e.g., the New ZealandNational Poisons Center) currently recommend that a lowertreatment line of 100 mg/ml (660 mmol/l) at 4 h postinges-tion on the RumackeMatthew nomogram be used asthreshold for treatment of all patients that might have in-creased risk of hepatotoxicity after an acetaminophen over-dose (Reid & Hazell, 2003). The basis of placing this‘‘high-risk’’ line at 100 mg/ml at 4 h was developed by sim-ply dividing the acetaminophen concentration of the con-ventional UK treatment line of 200 mg/ml at 4 h by two,without prospective or retrospective derivation or valida-tion. This recommendation was subsequently incorporatedinto the national guidelines in the UK in 1995 (Routledgeet al., 1998).

A recently published logistic regression model to esti-mate the risk of hepatotoxicity after an acute acetamino-phen overdose, based on the Canadian AcetaminophenOverdose Study registry, supports the observation that

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Calculate the risk-of-hepatotoxicity for non-alcoholic (no ethanol co-ingestion) patients “a

below” the possible-risk line on theacetaminophen nomogram

Locate an equivalent risk-of-hepatotoxicity linealcoholic (no ethanol co-ingestion) patients on

acetaminophen nomogram

Find an approximately-equivalent line foralcoholic (no ethanol co-ingestion) patients th

easily plots on the existing acetaminophennomogram

Fig. 1. Schematic representati

F

alcoholic patients who overdosed on acetaminophen anddid not acutely coingest ethanol with the overdose (‘‘absti-nent alcoholics’’ or ‘‘dry alcoholics’’), might carry a greaterrisk of developing hepatotoxicity (defined as peak amino-transferase level of 1,000 IU/l or greater at 24 h or longer)than nonalcoholic patients (Bond, 2005; Sivilotti et al.,2005b).

The purpose of this analysis was to use this publishedmodel to estimate a treatment threshold line for abstinentalcoholic patients on the familiar RumackeMatthew nomo-gram. This estimated treatment threshold line can be usedas an aid in hypothesis generation for future clinical trialsthat examines if serum acetaminophen levels should be cau-tiously interpreted in alcoholic patients after an acute acet-aminophen overdose.

EDPROMaterials and methods

The estimated risk of hepatotoxicity after an acute acet-aminophen overdose in abstinent alcoholic and nonalcoholicpatients based on a timed, postpeak serum acetaminophenconcentration and the time of initiation of NAC therapywas calculated using the published logistic regression model(Sivilotti et al., 2005a, 2005b).

The schematic steps of the solution are presented inFig. 1. Numeric computation of the model was done onMATLAB� (Version R2007a; The MathWorks, Inc., NatickMA, USA).

Results

The risk of hepatotoxicity in nonalcoholic and abstinentalcoholic patients after an acute acetaminophen overdosewas calculated at the 150 mg/ml at 4 h (37.5 mg/ml at12 h) line. This corresponds to the possible hepatotoxicityline on the RumackeMatthew nomogram and represents

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t or

for the

at

150 µg/mL at 4 hours line

104 µg/mL at 4 hours line

100 µg/mL at 4 hours line

on of the solution steps.

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a 1.6% risk of hepatotoxicity at or below this line for non-alcoholic patients. At or below this same 150 mg/ml at 4-hline, abstinent alcoholics have a higher risk of hepatotoxic-ity (10.7%). The risk of hepatotoxicity, equivalent to that ofnonalcoholics (i.e., 1.6%) in abstinent alcoholics occurs atthe lower acetaminophen concentrations line of 104 mg/mlat 4 h (26 mg/ml at 12 h). Because of difficulties plottingthis new line on the familiar RumackeMatthew semiloga-rithmic scale, a line connecting 100 mg/ml at 4 h (25 mg/mlat 12 h) is proposed. This later line equates to a 1.1% risk ofhepatotoxicity in abstinent alcoholics.

The risk of hepatotoxicity equivalency concept is tabu-lated in Table 1 and illustrated in Figs. 2 and 3. The newproposed possible risk line for abstinent alcoholics on theRumackeMatthew nomogram is presented in Fig. 4.

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Discussion

The management of an acute acetaminophen overdose inalcoholic patients is controversial. When it comes to treat-ing patients with a history of chronic alcoholism and pre-senting with an acute acetaminophen overdose, someauthorities recommend using a lower treatment decisionline, whereas others do not (Buckley & Srinivasan, 2002;Cheung et al., 1994; Dargan & Jones, 2002; Lauterburg &Velez, 1988; Prescott, 2000; Reid & Hazell, 2003; Rout-ledge et al., 1998; Seeff et al., 1986). Cheung et al. (1994)reported a 21-year-old female with a history of chronic al-cohol ingestion who overdosed on acetaminophen. This pa-tient had a serum acetaminophen level of 151 mg/ml at 3 hpostingestion and 124 mg/ml at 4 h postingestion. The pa-tient was not treated with NAC and subsequently developedfulminant hepatic failure (Cheung et al., 1994). The U.S.Food and Drug Administration in 1998 mandated that the

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Table 1

Probability of hepatotoxicity after an acute acetaminophen overdose at or below

therapy

Treatment

time (h)

Probability of hepatotoxicity

[APAP]

mg/ml

100 mg/ml at 4 h line

[APAP]

mg/ml

104 mg/ml at 4 h line

Not

alcoholic,

no ethanol

Alcoholic,

no ethanol

Not

alcoholic,

no ethanol

Alcoholi

no ethan

4 100.0 0.0 0.0 104.0 0.0 0.0

5 84.1 0.0 0.0 87.5 0.0 0.0

6 70.7 0.0 0.0 73.5 0.0 0.0

7 59.5 0.0 0.5 61.8 0.0 0.6

8 50.0 0.1 1.0 52.0 0.1 1.4

9 42.0 0.1 1.1 43.7 0.1 1.6

10 35.4 0.1 1.1 36.8 0.1 1.6

11 29.7 0.1 1.1 30.9 0.1 1.6

12 25.0 0.1 1.1 26.0 0.1 1.6

13 21.0 0.1 1.1 21.9 0.1 1.6

. . . . . . .24 3.1 0.1 1.1 3.3 0.1 1.6

[APAP] 5 Post peak serum acetaminophen concentration.

EDPROOF

public be warned of the risk of acetaminophen with chronicalcohol use (FDA, 1998).

Physicians and poison control centers use the RumackeMatthew nomogram as an aid in determining whether totreat an acetaminophen overdose patient with NAC. Tothe best of our knowledge, a possible risk line for the Ru-mackeMatthew nomogram in cases of an acute acetamino-phen overdose with a history of chronic alcohol use has notbeen determined. This analysis can be used to examine fur-ther if serum acetaminophen concentrations should be cau-tiously interpreted in abstinent alcoholic patients withacetaminophen overdose, and if a more conservative ap-proach to the management of these patients should be con-sidered. The debate on the use of ‘‘high-risk groups’’ ora ‘‘safety line’’ when making treatment decisions on alco-holic patients can only be put to rest after prospective clin-ical studies have been done.

The proposition is that the 100 mg/ml at 4 h risk line forabstinent alcoholic patients represents a comparable thresh-old of hepatotoxicity risk in an acute acetaminophen over-dose, to the 150 mg/ml at 4-h line in nonalcoholic patients.Others have already used this same published model and es-timated the risk of hepatotoxicity to be 8%, in abstinentalcoholic patients, after an acute acetaminophen overdoseat or below the 150 mg/ml at 4-h line (Bond, 2005). The hy-pothesis is that treating an abstinent alcoholic patient afteran acute acetaminophen overdose whose postpeak serumacetaminophen is located at or above the new proposed100 mg/ml at 4-h line, is analogous to treating a nonalco-holic patient whose serum acetaminophen concentration islocated at or above the 150 mg/ml at 4-h line. The premisepresented herein will benefit from validation using existingpoison control databases, if abstinent alcoholic patients’data can be identified, as this could also lead to futurerefinements of the model.

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different risk lines on the acetaminophen nomogram with acetylcysteine

[APAP]

mg/ml

150 mg/ml at 4 h line

[APAP]

mg/ml

200 mg/ml at 4 h line

c,

ol

Not

alcoholic,

no ethanol

Alcoholic,

no ethanol

Not

alcoholic,

no ethanol

Alcoholic,

no ethanol

150.0 0.0 0.0 200.0 0.0 0.0

126.1 0.0 0.0 168.2 0.0 0.0

106.1 0.0 0.0 141.4 0.0 0.0

89.2 0.3 2.9 118.9 0.7 6.0

75.0 0.8 6.5 100.0 2.1 12.7

63.1 1.3 9.0 84.1 3.3 17.3

53.0 1.5 10.3 70.7 4.2 20.2

44.6 1.6 10.7 59.5 4.8 22.0

37.5 1.6 10.7 50.0 5.0 22.8

31.5 1.6 10.7 42.0 5.1 22.9

. . . . . .4.7 1.6 10.7 6.3 5.1 22.9

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0.1 0.11.6

5.1

1.1 1.6

10.7

22.9

0.0

5.0

10.0

15.0

20.0

25.0

100 Line 104 Line 150 Line 200 LineRisk lines in µg/mL at 4 hours

Pro

bab

ility o

f h

ep

ato

to

xicity (%

)

Not Alcoholic & No EthanolAlcoholic & No Ethanol

Fig. 2. Probability of hepatotoxicity at or below different risk lines after an acute acetaminophen overdose.

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The issue of risk-benefit from treating a larger subset ofpatients with NAC by lowering the treatment threshold war-rants mention. Most authorities believe that NAC is a rela-tively safe antidote and provides an excellent risk-benefitprofiledespecially when given early after overdosedandthus should be given when there is any doubt about the needfor treatment in high-risk patients (Reid & Hazell, 2003). Inaddition, the risk of NAC administration (particularly ana-phylactoid reactions) depends primarily on its rate of ad-ministration (Prescott et al.,� 1998). On the other hand,some authors caution that the kinetics of NAC could be al-tered in patients with alcoholic liver disease, thus resulting

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04

1

510

50100150

2000

5

10

15

20

25

Time

Serum

Acetam

inophen (µg/mL)

Pro

bab

ility o

f H

ep

ato

to

xicity (%

)

Not Alcoholic & No EthanolAlcoholic & No Ethanol

N

100 Line

150 Line

200 Line

Fig. 3. Risk of hepatotoxicity after an acute acetaminophen overdose, with tre

EDPRin higher plasma concentration and a higher rate of adverse

drug reaction (Dargan & Jones, 2002).Central to the estimation of the new proposed possible risk

line for abstinent alcoholics is the ability to calculate the riskof hepatotoxicity after an acute acetaminophen overdose inabstinent alcoholic and nonalcoholic patients. This risk ofhepatotoxicity is calculated from a published model thatwas derived from a study population of 1,270 patients, 210of whom were alcoholics and 77 of whom were abstinent al-coholics (i.e., had no ethanol coingestion) (Sivilotti et al.,2005b). The estimated risks of hepatotoxicity presentedherein must be viewed within the limitations of the

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812

1620

24

to N-A

cetylcysteine Therapy (hours)

i

Abstinent Alcoholics Hepatotoxicity

on-Alcoholics Hepatotoxicity

atment with N-acetylcysteine in dry alcoholic and nonalcoholic patients.

383384385386387388389390391392393394395396397398399400401402403404405406407

T

0 4 8 12 16 20 241

5

10

50

100

150

200

300

400

Time post Ingestion (hours)

Seru

m A

cetam

in

op

hen

(µ

g/m

L)

Probable Risk Line

Possible Risk Line

Possible Risk Line in Abstinent Alcoholics

Fig. 4. RumackeMatthew acetaminophen nomogram with the proposed

possible-risk 100 mg/ml at 4-h line and 25 mg/ml at 12-h line, for dry alco-

holic patients after an acute acetaminophen overdose.

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UNCORRECunderlying model (Sivilotti, 2004; Sivilotti et al., 2005a,

2005b). For instance, it is important to recognize that the as-sumptions underlying this model are approximations and thecalculated risk of hepatotoxicity is an estimate. In addition,there were only 77 abstinent alcoholics in the data set, thisconstituted 37% of the alcoholic study patients (i.e., 77/210) and 6% of the total study patients (i.e., 77/1,270). Thisstudy population characteristic could be relevant when con-sidering the estimated risk of hepatotoxicity for abstinent al-coholics based on the logistic function, as it approaches the1% boundary threshold (i.e., possible risk line).

When comparing the results of hepatotoxicity risk innonalcoholic patients at the possible-risk 150 mg/ml at 4-hline (i.e., 1.6%) with the published National MulticenterStudy, Smilkstein et al. (1988) reported a hepatotoxicityrisk of 1.4% for all patients that had a serum acetaminophenlevel below the possible risk line of 150 mg/ml at 4 h, andwere treated with NAC within 8 h of an overdose (Smilk-stein et al., 1988). Rumack (2002) reported a risk of hepa-totoxicity for all patients below the possible risk line of1.08% when treated within 10 h of ingestion, 2.84% whentreated from 10 to 16 h of ingestion and 3.16% when treatedfrom 16 to 24 h of ingestion (Rumack, 2002, 2004).

Direct comparisons of the estimated risks of hepatotox-icity from the published Canadian Acetaminophen Over-dose Study registry logistic regression model and the

ALC5918_proof � 13-2

EDPROOF

National Multicenter Study data are challenging (Sivilottiet al., 2005b; Smilkstein et al., 1988). This is because thepublished outcome data from the National MulticenterStudy used (1) distinct stratification for the initial serumacetaminophen level (e.g., below the possible risk line, be-tween the possible risk and the probable risk lines, etc.), (2)the time of initiating NAC therapy was divided into discreteintervals (i.e., 4e10 h, 10e16 h, and 16e24 h), and (3) didnot stratify patients into those with and without a history ofchronic alcoholism and presence or absence of ethanol co-ingestion (Rumack, 2002, 2004; Smilkstein et al., 1988).Accurate reporting of hepatotoxicity for different risk strataof patients between distinct risk lines is difficult for thosepatients who present for treatment many hours after anoverdose. In contrast, Sivilotti et al. used their previouslypublished pharmacokinetically derived mathematical model(i.e., ‘‘Psi’’ that combined serum acetaminophen concentra-tion and time to therapy in one unifying variable) to predictthe toxicity of acetaminophen after an overdose and treat-ment (Sivilotti, 2004; Sivilotti et al., 2005a, 2005b). In ad-dition, Sivilotti et al. used patients’ risk state modifiers (i.e.,alcoholism and ethanol coingestion) in their hepatotoxicityprediction logistic regression model (Sivilotti et al., 2005b).

Lastly, no universally recognized or used definition ofchronic alcoholism is readily available. The World HealthOrganization states that ‘‘alcoholic’’ is generally taken torefer to chronic continual drinking or periodic consumptionof alcohol, which is characterized by impaired control overdrinking, frequent episodes of intoxication, and preoccupa-tion with alcohol and the use of alcohol despite adverseconsequences (WHO, 2005). The above subjective charac-terization makes it difficult to discern with certainty thisrisk-modifier in patients, especially when retrospective re-views of published toxicology literature or poison controldatabases are undertaken.

Conclusions

Based on the published logistic regression model fromthe Canadian Acetaminophen Overdose Study data, the es-timated risk of hepatotoxicity after an acute acetaminophenoverdose in abstinent alcoholics might be greater than innonalcoholic patients. The hypothesis is that for abstinentalcoholics, a treatment threshold line of 100 mg/ml at 4 his comparable in risk of hepatotoxicity to the 150 mg/mlat 4-h line for nonalcoholic patients.

The results can serve as a starting point in hypothesisgeneration for future clinical studies. These studies can ex-amine if abstinent alcoholics do actually have a greater riskof hepatotoxicity after an acute acetaminophen overdose.

Uncited references

Prescott et al., 1986; Tredger et al., 1985.

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