- Email: [email protected]
The Headache of Acetaminophen Overdose: Getting the NAC
Accepted Manuscript The Headache of Acetaminophen Overdose – Getting the NAC Norman L. Sussman, MD, Christopher H. Remien, PhD
PII: DOI: Reference:
S1542-3565(16)31235-6 10.1016/j.cgh.2016.12.011 YJCGH 55035
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 19 December 2016 Please cite this article as: Sussman NL, Remien CH, The Headache of Acetaminophen Overdose – Getting the NAC, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2016.12.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
The Headache of Acetaminophen Overdose – Getting the NAC Norman L. Sussman, MD and Christopher H. Remien, PhD
RI PT
Norman L. Sussman, MD Baylor College of Medicine 6620 Main Street, #1425
SC
Houston, TX 77030
e-mail: [email protected]
M AN U
Phone: 832-355-1400
Conflict of Interest: Collaboration with some of the authors on other topics related to acute liver failure, and I was an external reviewed on the ALFSG NIH grant
TE D
renewal. No financial conflicts or conflicts related to AcetaSTAT.
Christopher H. Remien, PhD University of Idaho
EP
300 Brink Hall, P.O. Box 441103
AC C
Moscow, ID 83844-1103 Phone: 208-885-5901 [email protected]
Conflict of Interest: Collaboration with some of the authors on acetaminophen toxicity. No financial conflicts or conflicts related to AcetaSTAT.
ACCEPTED MANUSCRIPT
Acetaminophen (APAP) overdose is a relatively common reason for emergency
RI PT
department (ED) visits in the United States, accounting for about 50 cases per 1,000 ED visits in 2012(1). While most cases of APAP result in relatively modest liver
injury, the most severe cases lead to acute liver failure (ALF); APAP overdose is the most common cause of ALF in many countries, and accounts for over 40% of ALF
SC
cases in the United States(2).
M AN U
As with most emergencies, early diagnosis is the key to effective treatment in ALF. Patients with ALF are critically ill, and timely therapeutic decisions may make the difference between life and death. In APAP-induced ALF, early diagnosis allows for timely administration of the antidote (N-acetylcysteine, NAC). Early treatment is
TE D
associated with markedly diminished liver injury and early discharge from the hospital while delayed treatment may result in an expensive, complicated hospital course with eventual recovery in the best cases, and liver transplantation or death
EP
in the worst cases. Non-APAP cases of ALF must be identified early and triaged for potential liver transplant while APAP cases must be stratified by risk. Low risk
AC C
cases can be managed locally, but severe cases require assessment by a transplant center.
The current tools for timely diagnoses of APAP-induced liver injury are inadequate; patients are frequently identified only after significant liver injury. We rely on history and/or the combination of markedly elevated serum ALT, AST, and INR with a moderately elevated bilirubin. APAP cases include patients who give a precise
ACCEPTED MANUSCRIPT
overdose history, patients who give an inaccurate history or deny ingestion, and patients with altered mentation who are unable to provide any meaningful history. The serum APAP level by itself is rarely helpful, and may be frankly misleading. The
RI PT
short serum half-life means that APAP has often cleared from the circulation by the time liver injury is apparent(3). Furthermore, patients with ALF of any etiology frequently take one or more doses of APAP in an effort to relieve symptoms,
SC
resulting in a detectable serum APAP level. We need a test that distinguishes APAP toxicity from both inconsequential serum APAP levels and from other causes of
M AN U
acute liver injury. The APAP adduct assay appears to be just such a test. APAP toxicity is a multi-step process that includes the generation of a toxic metabolite (N-acetyl-p-benzoquinone imine, NAPQI) via cytochrome P450 enzymes. NAPQI binds avidly to cysteine, which is usually in plentiful supply in hepatocytes in
TE D
the form of the tripeptide glutathione. Once glutathione is depleted, NAPQI binds to cysteine residues in cellular proteins to form APAP-protein adducts that are
EP
released into the circulation during hepatocyte lysis. Thus, the presence of APAP adducts in serum is highly specific to APAP-related liver injury.
AC C
The potential utility of APAP adducts as a specific biomarker of APAP toxicity was demonstrated by Davern et al. over 10 years ago(4). In that paper, adducts were 100% sensitive and 100% specific for APAP toxicity. The finding, although important, could not be used in clinical practice because of the detection method – APAP adducts were measured by high-pressure liquid chromatography with electrochemical detection (HPLC-EC). This technique requires sophisticated equipment and trained personnel that are not readily available in most clinical
ACCEPTED MANUSCRIPT
laboratories. Even if available, the time required to get a result diminishes its clinical utility – we need a result in minutes rather than hours or days.
RI PT
In some sense, we have been waiting over a decade for the paper by James et al. in this issue of CGH(ref). The exciting update is the availability of a point-of-care test for APAP adducts. The new test, AcetaSTAT, is simple and fast with 100%
sensitivity, 82.6% specificity, 89.2% positive predictive value, and 100% negative
SC
predictive value. These are impressive results that offer a new level of precision in
M AN U
assessing causality and making therapeutic decisions in patients with ALF. A rapid APAP adduct test will allow ED staff to immediately distinguish between APAP and non-APAP causes of acute liver injury. Cases of ALF in the absence of adducts should be referred or transferred immediately for liver transplant
TE D
evaluation. Cases of APAP overdose with early or trivial injury will nearly always recover with timely NAC; these patients can be treated locally. More serious cases also require immediate NAC, but recovery in these cases is less certain. Evaluation
EP
at a liver transplant center is still advisable in these cases even though transplantation may prove unnecessary if the patient recovers, or may be denied for
AC C
various reasons.
The availability of a point-of-care APAP adduct assay highlights a weakness in the management algorithm – the lack of a good predictive tool to stratify patients into low-risk and high-risk cases as described above. Several predictive schemas such as the King’s College Criteria(5, 6), Classification and Regression Tree (CART) models(7), and the Model of APAP-induced Liver Damage (MALD)(8, 9) have been
ACCEPTED MANUSCRIPT
described, but need work. If we are able to match the sensitivity and specificity of AcetaSTAT with an equally accurate predictive model, we will have achieved a new level of sophistication in managing ALF. James et al. deserve praise for their
RI PT
accomplishments in first identifying APAP adducts as an important biomarker, and then converting their finding to a practical tool. We look forward to FDA approval of their test, and we must get to work on improving predictive algorithms so that they
SC
match the quality of adduct assays.
M AN U
References
AC C
EP
TE D
1. Major JM, Zhou EH, Wong HL, Trinidad JP, Pham TM, Mehta H, Ding Y, et al. Trends in rates of acetaminophen-related adverse events in the United States. Pharmacoepidemiol Drug Saf 2016;25:590-598. 2. Lee WM, Squires RH, Jr., Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: Summary of a workshop. Hepatology 2008;47:1401-1415. 3. James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, et al. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos 2009;37:17791784. 4. Davern TJ, 2nd, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ, Lalani E, et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 2006;130:687-694. 5. Singanayagam A, Bernal W. Update on acute liver failure. Curr Opin Crit Care 2015;21:134-141. 6. McPhail MJ, Farne H, Senvar N, Wendon JA, Bernal W. Ability of King's College Criteria and Model for End-Stage Liver Disease Scores to Predict Mortality of Patients With Acute Liver Failure: A Meta-analysis. Clin Gastroenterol Hepatol 2016;14:516-525 e515; quiz e543-e545. 7. Speiser JL, Lee WM, Karvellas CJ, Group USALFS. Predicting outcome on admission and post-admission for acetaminophen-induced acute liver failure using classification and regression tree models. PLoS One 2015;10:e0122929. 8. Remien CH, Adler FR, Waddoups L, Box TD, Sussman NL. Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: early discrimination between survival and death. Hepatology 2012;56:727-734. 9. Remien CH, Sussman NL, Adler FR. Mathematical modelling of chronic acetaminophen metabolism and liver injury. Math Med Biol 2013.
PII: DOI: Reference:
S1542-3565(16)31235-6 10.1016/j.cgh.2016.12.011 YJCGH 55035
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 19 December 2016 Please cite this article as: Sussman NL, Remien CH, The Headache of Acetaminophen Overdose – Getting the NAC, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2016.12.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
The Headache of Acetaminophen Overdose – Getting the NAC Norman L. Sussman, MD and Christopher H. Remien, PhD
RI PT
Norman L. Sussman, MD Baylor College of Medicine 6620 Main Street, #1425
SC
Houston, TX 77030
e-mail: [email protected]
M AN U
Phone: 832-355-1400
Conflict of Interest: Collaboration with some of the authors on other topics related to acute liver failure, and I was an external reviewed on the ALFSG NIH grant
TE D
renewal. No financial conflicts or conflicts related to AcetaSTAT.
Christopher H. Remien, PhD University of Idaho
EP
300 Brink Hall, P.O. Box 441103
AC C
Moscow, ID 83844-1103 Phone: 208-885-5901 [email protected]
Conflict of Interest: Collaboration with some of the authors on acetaminophen toxicity. No financial conflicts or conflicts related to AcetaSTAT.
ACCEPTED MANUSCRIPT
Acetaminophen (APAP) overdose is a relatively common reason for emergency
RI PT
department (ED) visits in the United States, accounting for about 50 cases per 1,000 ED visits in 2012(1). While most cases of APAP result in relatively modest liver
injury, the most severe cases lead to acute liver failure (ALF); APAP overdose is the most common cause of ALF in many countries, and accounts for over 40% of ALF
SC
cases in the United States(2).
M AN U
As with most emergencies, early diagnosis is the key to effective treatment in ALF. Patients with ALF are critically ill, and timely therapeutic decisions may make the difference between life and death. In APAP-induced ALF, early diagnosis allows for timely administration of the antidote (N-acetylcysteine, NAC). Early treatment is
TE D
associated with markedly diminished liver injury and early discharge from the hospital while delayed treatment may result in an expensive, complicated hospital course with eventual recovery in the best cases, and liver transplantation or death
EP
in the worst cases. Non-APAP cases of ALF must be identified early and triaged for potential liver transplant while APAP cases must be stratified by risk. Low risk
AC C
cases can be managed locally, but severe cases require assessment by a transplant center.
The current tools for timely diagnoses of APAP-induced liver injury are inadequate; patients are frequently identified only after significant liver injury. We rely on history and/or the combination of markedly elevated serum ALT, AST, and INR with a moderately elevated bilirubin. APAP cases include patients who give a precise
ACCEPTED MANUSCRIPT
overdose history, patients who give an inaccurate history or deny ingestion, and patients with altered mentation who are unable to provide any meaningful history. The serum APAP level by itself is rarely helpful, and may be frankly misleading. The
RI PT
short serum half-life means that APAP has often cleared from the circulation by the time liver injury is apparent(3). Furthermore, patients with ALF of any etiology frequently take one or more doses of APAP in an effort to relieve symptoms,
SC
resulting in a detectable serum APAP level. We need a test that distinguishes APAP toxicity from both inconsequential serum APAP levels and from other causes of
M AN U
acute liver injury. The APAP adduct assay appears to be just such a test. APAP toxicity is a multi-step process that includes the generation of a toxic metabolite (N-acetyl-p-benzoquinone imine, NAPQI) via cytochrome P450 enzymes. NAPQI binds avidly to cysteine, which is usually in plentiful supply in hepatocytes in
TE D
the form of the tripeptide glutathione. Once glutathione is depleted, NAPQI binds to cysteine residues in cellular proteins to form APAP-protein adducts that are
EP
released into the circulation during hepatocyte lysis. Thus, the presence of APAP adducts in serum is highly specific to APAP-related liver injury.
AC C
The potential utility of APAP adducts as a specific biomarker of APAP toxicity was demonstrated by Davern et al. over 10 years ago(4). In that paper, adducts were 100% sensitive and 100% specific for APAP toxicity. The finding, although important, could not be used in clinical practice because of the detection method – APAP adducts were measured by high-pressure liquid chromatography with electrochemical detection (HPLC-EC). This technique requires sophisticated equipment and trained personnel that are not readily available in most clinical
ACCEPTED MANUSCRIPT
laboratories. Even if available, the time required to get a result diminishes its clinical utility – we need a result in minutes rather than hours or days.
RI PT
In some sense, we have been waiting over a decade for the paper by James et al. in this issue of CGH(ref). The exciting update is the availability of a point-of-care test for APAP adducts. The new test, AcetaSTAT, is simple and fast with 100%
sensitivity, 82.6% specificity, 89.2% positive predictive value, and 100% negative
SC
predictive value. These are impressive results that offer a new level of precision in
M AN U
assessing causality and making therapeutic decisions in patients with ALF. A rapid APAP adduct test will allow ED staff to immediately distinguish between APAP and non-APAP causes of acute liver injury. Cases of ALF in the absence of adducts should be referred or transferred immediately for liver transplant
TE D
evaluation. Cases of APAP overdose with early or trivial injury will nearly always recover with timely NAC; these patients can be treated locally. More serious cases also require immediate NAC, but recovery in these cases is less certain. Evaluation
EP
at a liver transplant center is still advisable in these cases even though transplantation may prove unnecessary if the patient recovers, or may be denied for
AC C
various reasons.
The availability of a point-of-care APAP adduct assay highlights a weakness in the management algorithm – the lack of a good predictive tool to stratify patients into low-risk and high-risk cases as described above. Several predictive schemas such as the King’s College Criteria(5, 6), Classification and Regression Tree (CART) models(7), and the Model of APAP-induced Liver Damage (MALD)(8, 9) have been
ACCEPTED MANUSCRIPT
described, but need work. If we are able to match the sensitivity and specificity of AcetaSTAT with an equally accurate predictive model, we will have achieved a new level of sophistication in managing ALF. James et al. deserve praise for their
RI PT
accomplishments in first identifying APAP adducts as an important biomarker, and then converting their finding to a practical tool. We look forward to FDA approval of their test, and we must get to work on improving predictive algorithms so that they
SC
match the quality of adduct assays.
M AN U
References
AC C
EP
TE D
1. Major JM, Zhou EH, Wong HL, Trinidad JP, Pham TM, Mehta H, Ding Y, et al. Trends in rates of acetaminophen-related adverse events in the United States. Pharmacoepidemiol Drug Saf 2016;25:590-598. 2. Lee WM, Squires RH, Jr., Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: Summary of a workshop. Hepatology 2008;47:1401-1415. 3. James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, et al. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos 2009;37:17791784. 4. Davern TJ, 2nd, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ, Lalani E, et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 2006;130:687-694. 5. Singanayagam A, Bernal W. Update on acute liver failure. Curr Opin Crit Care 2015;21:134-141. 6. McPhail MJ, Farne H, Senvar N, Wendon JA, Bernal W. Ability of King's College Criteria and Model for End-Stage Liver Disease Scores to Predict Mortality of Patients With Acute Liver Failure: A Meta-analysis. Clin Gastroenterol Hepatol 2016;14:516-525 e515; quiz e543-e545. 7. Speiser JL, Lee WM, Karvellas CJ, Group USALFS. Predicting outcome on admission and post-admission for acetaminophen-induced acute liver failure using classification and regression tree models. PLoS One 2015;10:e0122929. 8. Remien CH, Adler FR, Waddoups L, Box TD, Sussman NL. Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: early discrimination between survival and death. Hepatology 2012;56:727-734. 9. Remien CH, Sussman NL, Adler FR. Mathematical modelling of chronic acetaminophen metabolism and liver injury. Math Med Biol 2013.