Tylenol Acetaminophen Liver Toxicity by Jeffrey Dach MD

Posted on March 25, 2016

Tylenol Acetaminophen
Liver Toxicity
by Jeffrey Dach MD
Rebecca is a 46 year old CEO of a large manufacturing company and arrives in my office with a chief complaint of low back pain for which she takes Extra Strength Tylenol for the past 4 years ( Acetaminophen – Three 500mg tablets three times daily) for a daily dosage of 4500 mg Acetaminophen).  Left image: courtesy of WakeMed Pharmacy.
I explained to Rebecca that Tylenol consumption is the main cause of Liver failure requiring liver transplantation in the  United States and Great Britain.  Liver damage is additive by combining  alcohol consumption with Tylenol.  So far, Rebecca has been lucky, and has not suffered liver damage as an adverse side effect of Tylenol. Left Image Courtesy of wikimedia commons.
I explained to Rebecca that her Liver converts the Acetaminophen into a toxic metabolite called N-acetyl-p-benzoquinonimine (NAPQI).   This NAPQI depletes the liver cells of glutathione, our most important intracellular anti-oxidant.
According to Dr Jack Hinson in a 2010 report, this loss of glutathione in the liver cells leads to initiation of mitochondrial damage with inability to synthesize ATP, our main source of cellular energy.  Loss of ATP causes massive hepatic necrosis (liver cell death).(4)

Left Image: FDA Warning for Acetaminophen.
Antidote to Tylenol Poisoning is NAC
Restoring glutathione levels with NAC (N-acetyl cysteine) is the antidote to Tylenol induced liver damage.  Dr David Brownstein also recommends (ALA) Alpha Lipoic Acid and Vitamin c to protect the liver from acetaminophen toxicity. (10)  Dr Brownstein also advises against using Tylenol in infants after vaccination, or in infants with fever.(10)  Left Image Tylenol label courtesy of WIkimedia Commons.
Ineffective for Low Back Pain
A recent report by Dr Gustavo Machado in 2015 BMJ ,concluded: ” Paracetamol (acetaminophen) is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis.”(12)
Alternatives to Tylenol
There are many safer alternatives to Tylenol (Acetaminophen) for reduction of musculoskeletal inflammation and pain relief.   Botanicals such as Boswellia, Curcumin, and Berberine are all good alternatives.
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Links and References
Acetaminophen toxicity
1) http://www.cnn.com/2014/01/15/health/fda-acetaminophen-dosage/
FDA: Acetaminophen doses over 325 mg might lead to liver damage  By Holly Yan, CNN
2) Acetaminophen toxicity mitochondrial damage hepatocytes J Biol Chem1991 Burcham  J Biol Chem. 1991 Mar 15;266(8):5049-54.
Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes. Burcham PC1, Harman AW.     1Department of Pharmacology, Queen Elizabeth II Medical Centre, University of Western Australia, Nedlands.
Exposure of isolated mouse hepatocytes to a toxic concentration of acetaminophen (5 mM) resulted in damage to the mitochondrial respiratory apparatus. The nature of this damage was investigated by measuring respiration stimulated by site-specific substrates in digitonin-permeabilized hepatocytes after acetaminophen exposure. Respiration stimulated by succinate at energy-coupling site 2 was most sensitive to inhibition and was decreased by 47% after 1 h. Respiration supported by NADH-linked substrates (site 1) was also decreased but to a lesser extent, while there was no decrease in the rate of ascorbate + N,N,N’,N’-tetramethyl-p-phenylenediamine (TMPD)-supported respiration (site 3). The loss of mitochondrial respiratory function was accompanied by a decrease in ATP levels and ATP/ADP ratios in the cytosolic compartment and was preceded by a loss of reduced glutathione in both the cytosol and mitochondria. All these effects occurred well before the loss of cell membrane integrity. The putative toxic metabolite of acetaminophen, N-acetyl-p-benzoquinonimine (NAPQI), produced a similar pattern of respiratory dysfunction in isolated hepatic mitochondria. Respiration stimulated by succinate- and NADH-linked substrates was very sensitive to 50 microM NAPQI, while ascorbate + TMPD-supported respiration was unaffected. The interaction between NAPQI and the respiratory chain was further investigated using submitochondrial particles. Succinate dehydrogenase (associated with respiratory complex II) was found to be very sensitive to NAPQI, while NADH dehydrogenase (respiratory complex I) was inhibited to a lesser extent. Our results indicate that a loss of the ability to utilize succinate- and NADH-linked substrates due to attack of the respiratory chain by NAPQI causes a disruption of energy homeostasis in acetaminophen hepatotoxicity.
2005
3) http://www.journal-of-hepatology.eu/article/S0168-8278%2804%2900429-5/fulltext?mobileUi=0
Masubuchi, Yasuhiro, Chieko Suda, and Toshiharu Horie. “Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice.” Journal of hepatology 42.1 (2005): 110-116.
toxicity has been shown to be initiated by cytochrome P450 metabolism to N-acetyl-p-benzoquinone imine (NAPQI) [[1], [2]]. The high reactivity of NAPQI with sulfhydryl groups results in depleting glutathione in hepatocytes, followed by covalent binding to intracellular proteins
Mitochondrial permeability transition (MPT) is recently focused as a mechanism for drug-induced hepatocyte injury [[16], [17], [18]]. The MPT represents an abrupt increase in permeability of the mitochondrial inner membrane to allow solutes with a molecular weight less than 1500 [19]. The MPT is promoted by the accumulation of excessive Ca2+ and stimulated by various compounds and conditions. It leads to dissipation of membrane potential (Δψ), uncoupling of oxidative phosphorylation, loss of pre-accumulated Ca2+, and expansion of the matrix volume. MPT causes both apoptotic and necrotic cell death.
2010
4) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836803/?tag=stupide-21
Hinson, Jack A., Dean W. Roberts, and Laura P. James. “Mechanisms of acetaminophen-induced liver necrosis.” Adverse Drug Reactions. Springer Berlin Heidelberg, 2010. 369-405.
the hepatotoxicity of acetaminophen appears to occur by a complex mechanistic sequence (Fig. 3). These events include:
(1) CYP metabolism to the reactive metabolite NAPQI which depletes glutathione by a conjugation reaction and covalently binds to proteins;
(2) loss of glutathione causing an increased oxidative stress response (decreased detoxification of reactive oxygen and nitrogen species);
(3) increased oxidative stress, possibly associated with alterations in calcium metabolism, initiation of signal transduction responses and mitochondrial permeability transition;
(4) mitochondrial permeability transition occurring with an even larger increase in oxidative stress, loss of mitochondrial membrane potential, and loss of the ability of the mitochondria to synthesize ATP; and
(5) loss of ATP which causes necrosis.
Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today.
each week approximately 50 million adults in the United States take acetaminophen-containing products.
Reaction of NAPQI with glutathione occurs by conjugation to form 3-glutathion-S-yl-acetaminophen and by reduction to acetaminophen
reactive metabolite of acetaminophen was identified to be N-acetyl-p-benzoquinone imine (NAPQI). It was found to be formed by cytochrome P-450 (CYP) by a direct two electron oxidation of acetaminophen
In initial work describing the importance of hepatic glutathione in acetaminophen-induced hepatotoxicity in mice, Mitchell et al. (1973a, b) showed that administration of cysteine prevented hepatotoxicity. This finding led to the development of N-acetyl-cysteine (available as Mucomyst®) as the preferred antidote
N-acetylcysteine inhibits acetaminophen toxicity has been postulated to be increased detoxification of NAPQI by a direct conjugation or through increased glutathione synthesis
NAC antidote to acetamenophen live toxicity
2008 full pdf
5) Algren, D. Adam. “Review of N-acetylcysteine for the treatment of acetaminophen (paracetamol) toxicity in pediatrics.” Second Meeting of the Subcommittee of the Expert Committee on the Selection and Use of Essential Medicines. Vol. 29. 2008.
2015
6) http://www.ncbi.nlm.nih.gov/pubmed/25537186
Arch Toxicol. 2015 Feb;89(2):193-9. doi: 10.1007/s00204-014-1432-2. Epub 2014 Dec 24.  Acetaminophen hepatotoxicity: an updated review.
Lancaster EM1, Hiatt JR, Zarrinpar A.
As the most common cause of acute liver failure (ALF) in the USA and UK, acetaminophen-induced hepatotoxicity remains a significant public health concern and common indication for emergent liver transplantation. This problem is largely attributable to acetaminophen combination products frequently prescribed by physicians and other healthcare professionals, with unintentional and chronic overdose accounting for over 50 % of cases of acetaminophen-related ALF. Treatment with N-acetylcysteine can effectively reduce progression to ALF if given early after an acute overdose; however, liver transplantation is the only routinely used life-saving therapy once ALF has developed. With the rapid course of acetaminophen-related ALF and limited supply of donor livers, early and accurate diagnosis of patients that will require transplantation for survival is crucial. Efforts in developing novel treatments for acetaminophen-induced ALF are directed toward bridging patients to recovery. These include auxiliary, artificial, and bioartificial support systems. This review outlines the most recent developments in diagnosis and management of acetaminophen-induced ALF.
7) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652821/
Chen, Yu-Guang, et al. “Risk of Acute Kidney Injury and Long-Term Outcome in Patients With Acetaminophen Intoxication: A Nationwide Population-Based Retrospective Cohort Study.” Medicine 94.46 (2015).
8) diagram of biochemical pathways
https://www.pharmgkb.org/pathway/PA166117881
Acetaminophen Pathway (toxic doses), Pharmacokinetics
2012
9) http://tbiomed.biomedcentral.com/articles/10.1186/1742-4682-9-55
Ben-Shachar, Rotem, et al. “The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model.” Theoretical Biology and Medical Modelling 9.1 (2012): 55.
Acetaminophen overdoses, either accidental or intentional, are the leading cause of acute liver failure in the United States, accounting for 56,000 emergency room visits per year. The standard treatment for overdose is N-acetyl-cysteine (NAC), which is given to stimulate the production of glutathione.
10)  Just Say No To Acetaminophen
Also, it is best to support the liver with the proper supplements when using acetaminophen. This can include taking vitamin C (3-6,000mg/day), N-acetyl cysteine (300-600mg/day), and alpha lipoic acid (3-600mg/day).
11)  Roberts, Emmert, et al. “Paracetamol: not as safe as we thought? A systematic literature review of observational studies.” Annals of the rheumatic diseases (2015): annrheumdis-2014.
12) Machado, Gustavo C., et al. “Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials.” bmj 350 (2015): h1225.
conclusion: Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines.
13) New FDA Steps Aimed at Cutting Risks from Acetaminophen
Sandra Kweder, M.D., deputy director of FDA’s Office of New Drugs, says the agency’s most recent action is aimed at making pain medications containing acetaminophen safer for patients to use.
“Overdoses from prescription products containing acetaminophen account for nearly half of all cases of acetaminophen-related liver failure in the U.S., many of which result in liver transplant or death,” says Kweder.
Most of the cases of severe liver injury occurred in patients who
took more than the prescribed dose of an acetaminophen-containing product in a 24-hour period took more than one acetaminophen-containing product at the same time drank alcohol while taking the drug
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