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Home , Hepatotoxicity, Paracetamol poisoning

European Review for Medical and Pharmacological Sciences 2017; 21 (1 Suppl): 95-101 of and related fatalities

R. TITTARELLI1, M. PELLEGRINI2, M.G. SCARPELLINI3, E. MARINELLI1, V. BRUTI4, N.M. DI LUCA4, F.P. BUSARDÒ1, S. ZAAMI4

1Unit of Forensic (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy 2Drug Abuse and Doping Unit, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy 3Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy 4Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy

Abstract. – Paracetamol, also known as ac- intensity. Being the main prescribed for fe- etaminophen, is the most commonly used anti- eble pains, it can be used together with non-ste- pyretic and pain reliever and since 1955 it is avail- roidal analgesic also to treat pains of mo- able over-the-counter as a single formulation or in derate intensity. When pain persists or increases, combination with other substances and, as indi- cated by the World Health Organization, it can be paracetamol is used as an additional analgesic in used in all the three steps of pain intensity. Parac- combination with weak (e.g. tramadol) or strong etamol is one of the most common caus- (e.g., morphine, fentanyl) opioids. Moreover, it is a es of worldwide. While paracetamol is drug of choice in patients, in whom administration described as relatively nontoxic when adminis- of non-steroidal anti-inflammatory drugs is con- tered in therapeutic doses, it is known to cause traindicated, such as in the case of gastric ulcers, toxicity when taken in a single or repeated high dose, or after chronic ingestion. Repeated supra- hypersensitivity to , impairments in blood therapeutic misuse, non-intentional misuse, and , in pregnant women, nursing mothers intentional ingestion may all result in hepatic tox- and children with elevated body temperature asso- icity, the main cause of acute failure (ALF) in ciated to a disease (fever related to illness)2. the United States and Europe. Since paracetamol Although many side effects following drug use is responsible for nearly half of the cases in the had been registered since the approved use in the US of acute and remains the leading 50s, its hepatotoxicity was not significantly recog- cause of , continued aware- ness promotion, education and research should nized until 1980. Cases of fatal drug-related hepa- be constantly undertaken. totoxicity dubbed “therapeutic misadventures” and We herein review the literature on parac- the association of with al- etamol toxicity with particular attention to as- cohol were firstly reported during the mid 1980s3. pects of liver damage and related fatalities. While paracetamol is described as relatively Key Words: nontoxic when administered in therapeutic dos- Paracetamol, Hepatotoxicity, Fatalities, Liver toxicity. es4, it is known to cause toxicity when taken in a single or repeated high dose, or after chronic ingestion. Introduction The usual dosing of immediate-release oral preparations in adults is 325-650 mg every 4-6 Paracetamol, also known as acetaminophen hours or 1 g every 4-6 hours as necessary, without (IUPAC name: N-(4-hydroxyphenyl)ethanamide), exceeding 4 g per day5. Conversely, in children, is the most commonly used antipyretic and pain the recommended dose is 10-15 mg/kg every 4-6 reliever and since 1955 has been available over- hours up to a maximum daily dose of 50-75 mg/ the-counter as a single formulation or in combi- kg6. Adverse events typically associated with par- nation with other substances1. acetamol intoxication are represented by acute As indicated by the World Health Organization liver failure (ALF), centrilobular hepatic , this drug can be used in all the three steps of pain renal tubular necrosis and hypoglycaemic coma6,7.

Corresponding Author: Francesco P. Busardò, MD, MSc, DipFMS; e-mail: [email protected] 95 R. Tittarelli, M. Pellegrini, M.G. Scarpellini, E. Marinelli, V. Bruti, N.M. di Luca, F.P. Busardò, S. Zaami

According to recent information provided Materials and Methods by the American National Data System (NPDS), paracetamol is one of the 25 drugs asso- The selection of appropriate scientific articles ciated with the largest number of fatalities, either was performed through the following research alone or in combination with other medications8. engines: Cochrane Central, EMBASE, Medline, Paracetamol overdoses are the leading cause of Science Direct, Scopus, Web of Science, up to acute poisoning in the United States and represent November 2016 using the following keywords: about 39%9,10 of all cases of acute hepatic injury. “paracetamol”, “adult”, “paediatric”, “hepatotox- Furthermore, paracetamol is still the almost ex- icity”, “fatalities”, “side effects” and “liver tox- clusive cause of liver transplantation related to an icity”. The sources initially found were screened acute , with an average of one case to exclude papers not suitable for the purpose of per six million inhabitants per year in European the review and duplicate sources. Papers were se- countries such a France, Greece, Ireland, Italy, the lected independently by three co-authors and in- Netherlands, Portugal and the UK11. This seems cluded if selected at least by two of them. to be about eight times less than the numbers re- ported in the US. Paracetamol Mechanism of Action Large differences exist among European coun- Paracetamol is used worldwide for its analge- tries, with a six-times higher risk in Ireland and a sic and antipyretic actions. It has a spectrum of two-fold higher risk in the UK compared with the action similar to that of non-steroidal anti-inflam- average of the other countries. matory drugs (NSAIDs) and particularly resem- Several paracetamol overdoses are closely re- bles the cyclooxygenase type 2 (COX-2) selective lated to suicide attempts, but also unintentional or inhibitors. Paracetamol is on average a weaker cumulative overdosing can occur, usually caused analgesic than NSAIDs or COX-2 selective inhib- by a misuse of the drug, even when therapeutic itors, but it is often preferred because of its bet- doses are administered. Many cases of paraceta- ter gastric tolerance. Despite the similarities to mol poisoning are also due to the use of paraceta- NSAIDs, the mode of action of paracetamol has mol combination products such as acetylsalicylic been not completely clarified, but it is now gener- acid, codeine, oxycodone, propoxyphene, caf- ally accepted that it inhibits cyclooxygenase type feine, dextromethorphan, , and de- 1 (COX-1) and COX-2 through by the congestants12. peroxidase function of these isoenzymes15. This Moreover, there are several factors that may results in the inhibition of phenoxyl radical for- contribute to an increased risk of hepatotoxicity mation from a critical tyrosine residue, essential related to the administration of paracetamol at for the activity of COX-1 and COX-2 and pros- therapeutic dose i.e. abuse, , taglandin (PG) synthesis16. Paracetamol shows underlying or pre-existing liver disorders and selectivity for inhibition of the synthesis of PGs concomitant ingestion of other potentially hepa- and related factors, when low levels of arachidon- totoxic drugs13. ic acid and peroxides are available. Conversely, Identification of paracetamol overdose is criti- the drug shows little activity at substantial lev- cal, since significant morbidity and mortality may els of arachidonic acid and peroxides. The result be prevented with early diagnosis and subsequent is that paracetamol does not suppress the severe therapy. Many intoxicated subjects have only inflammation of rheumatoid arthritis and acute minimal and non-specific symptoms which can gout, but it inhibits the lesser inflammation re- be mistaken for viral prodrome. These symptoms sulting from e.g. the extraction of teeth16. Unlike include malaise, with or without , both non-selective NSAIDs and selective COX-2 and abdominal pains. inhibitors, paracetamol inhibits other peroxidase Poor prognostic signs include multi-organ fail- including myeloperoxidase. Inhibition ure, which may involve cerebral oedema, renal of myeloperoxidase involves the paracetamol ox- failure, profound and lactic acido- idation and the concomitant decreased formation sis, any signs of which should prompt an immedi- of halogenating oxidants (e.g. hypochlorous acid, ate liver transplant evaluation14. hypobromous acid) that may be associated with Recent studies on paracetamol hepatotoxicity multiple inflammatory including ath- eventually leading to fatalities together with the erosclerosis and rheumatic diseases. Therefore, studies describing other side effects are here re- according to this mechanism, the development viewed. of these diseases is slowed down. As in the case

96 Hepatotoxicity of paracetamol and related fatalities of NSAIDs, the analgesic effect of paracetamol of NAPQI in excessive quantities together with its is reduced by the inhibitors of many endogenous ability to bind the sulfhydryl groups on neurotransmitter systems including serotonergic, and lysine residues of the mitochon- opioid, and cannabinoid systems17. drial also results in decreasing the mi- tochondrial respiration, an increase of oxidative Hepatotoxicity of Paracetamol and stress and in mitochondrial dysfunction with ATP Related Fatalities stores depletion14,19. After the administration of an oral dose, pa- Another hepatotoxicity mechanism involves racetamol is rapidly absorbed by the intestine, the formation of peroxynitrite, a toxic free radical because of its weak acidity and lipid-solubility. produced in the mitochondria, from a superoxi- Then, an amount between 50 and 60% is conver- de and reaction; by causing oxidative ted to its main and pharmacologically inactive injuries, it is responsible for the DNA fragmenta- glucuronidated and sulfated conjugates elimina- tion and is directly connected to the cessation of ted in urine. ATP synthesis19,21. In liver microsomes, a small percentage of pa- Therefore, the massive presence of NAPQI racetamol (5-10%) is converted by cytochrome causes mitochondrial GSH depletion, the forma- P450 isoforms (CYP2E1, CYP2A6) into a reacti- tion of proteins adducts, with severe damages to ve metabolite, N-acetyl-para-benzo-quinone imi- mitochondrial functions and the arrest of ATP ne (NAPQI), that is primarily related to paraceta- production. All these modifications lead to a ho- mol hepatotoxicity14. About 2% of paracetamol is meostasis alteration, an increase in the permeabi- excreted in urine unchanged18 (Figure 1). lity of the with a consequent cel- The cellular damages caused by NAPQI are di- lular swelling, karyolysis, vacuolization and the rectly related to the dose of paracetamol consumed. loss of cellular elements (as alanine aminotransfe- In the case of non-toxic consumption, NAPQI is rase, ALT), which represent one of the biochemi- rapidly conjugated by hepatic , throu- cal evidence of hepatocytes necrosis19,22. gh glucuronidation and sulfonation reactions, to Repeated supratherapeutic misuse, non-inten- form mercaptate and cysteine complexes, that are tional misuse, and intentional ingestion may all eliminated with urine. Differently, if paraceta- result in hepatic toxicity. mol is ingested at hepatotoxic doses, the majority Paracetamol hepatotoxicity is the main cause of of the drug is metabolized by CYP2E1 pathway (ALF) in the United States and resulting in glutathione depletion, by activation Europe, with more than 300,000 admissions to the of GST-S-, and with the build-up of hospital each year in the US alone. About 42% ca- NAPQI at toxic concentrations19,20. The presence ses of ALF are attributable to paracetamol overdo-

Figure 1. Paracetamol metabolism.

97 R. Tittarelli, M. Pellegrini, M.G. Scarpellini, E. Marinelli, V. Bruti, N.M. di Luca, F.P. Busardò, S. Zaami ses23,24, while about 63% paracetamol-related liver Unintentional overdose with paracetamol in toxicity cases are caused by unintentional harmful children is relatively common, primarily because dosage induced by containing parace- the drug is used worldwide in paediatrics. tamol in combination, primarily those of opioids Young children can unintentionally suffer pa- used for the treatment of chronic pain25. racetamol overdose in two ways: firstly, by taking In the last two decades, several fatalities have an unsupervised single large dose; secondly as a been registered in the USA, Europe and Australia result of chronic exposure over one or more days in adults and children. Low rates of hepatotoxi- to excessive doses31. city were registered in Asian patients with para- For example, in 2008, the National Poison Centre cetamol overdose. Mortality and morbidity were in Dunedin New Zealand fielded 806 calls regard- non-existent despite high doses of paracetamol ing paracetamol poisoning in children, with similar ingestion and delayed hospitalization26. results reported in the USA32. A recent study in the In fatal cases, in which paracetamol induced United Kingdom noted that most of the prescriptions fulminant hepatic failure, the most frequent cau- for this drug in children is off-label and overdosing ses of death are cerebral oedema or , in the was relatively frequent in young children33. While early phase, and multiorgan failure later. the hepatotoxic effects of the drug have been well In patients who develop fulminant hepatic fai- recognized in cases of acute overdose and chronic lure or who are otherwise expected to die from supratherapeutic doses, the toxic effects are rarely liver failure, the mainstay of management is li- documented in cases where therapeutic guidelines ver transplantation27. The mortality rate from pa- are followed, e.g. an 8-month-old boy underwent a racetamol overdose increases two days after the cleft palate repair and placement of bilateral myrin- ingestion, reaches a maximum on day four, and gotomy tubes. He received paracetamol for routine then gradually decreases. Metabolic is postoperative and was tolerating the most important single indicator of probable liquids and discharged home on postoperative day mortality and the need for transplantation28. 1. On day 3, the child was profoundly lethargic with In a study carried out on twenty-one parace- multiple episodes of emesis and was taken to the tamol users who died without undergoing liver emergency department, after 4 days his metabolic transplantation29, significant cerebral oedema was acidosis, and acute started to regress, and present in thirteen individuals and absent in ei- he was discharged without any surgical intervention ght. The patients without cerebral oedema had a on day 1534. lower arterial pH on admission, a shorter interval Although children can be more exposed to between overdose and death than patients with an overdose of paracetamol, toxic exposures are cerebral oedema. The cause of death in patients rare in neonates, however they may occur via the without cerebral oedema was predominantly car- placenta, resulting from intentional ingestion of diovascular collapse with rapidly progressive re- overdoses of paracetamol by mothers in the hours sistant and/or cardiac arrest. preceding delivery35, or by oral36 or intravenous Although, most paracetamol fatalities have dosing errors in the order of 10 times the therapeu- been related to hepatic failure due to massive cen- tic dose, or finally due to orally repeated doses37. trilobular necrosis associated with renal tubular Recently a case of a 26-day-old male admitted to necrosis, in recent years a number of cases have emergency with intestinal bleeding, shock signs, been reported pointing to a role played by heart slight liver enlargement, , metabolic toxicity, as highlighted in cases of myocarditis acidosis, hypoglycemia, increased serum amino- and fatalities with relatively unimportant concur- activity and hyperbilirubinemia after rent liver damage or time patterns which were in- receiving oral paracetamol (10 mg/kg/dose every consistent with death by liver toxicity30. 4 hours) for three consecutive days, has been de- Finally, a fatal case of paracetamol consump- scribed38. It is important to highlight that parace- tion with liver and renal damage has been repor- tamol pharmacokinetics and pharmacodynamics ted, and it highlights an atypical isolated skin in neonates and infants differ substantially from eruption with significant phenomena of epider- those in older children and adults. Despite the re- molysis, rhabdomyolysis, disseminated intrava- duced rates of metabolism of the P450 CYP2E1 scular coagulation and myocardial ischemia. All and the increased ability to synthesize these delayed the correct diagnosis and rose the glutathione which provides greater resistance question of reviewing the known spectrum of the after overdose, it is possible to produce hepato- adverse side effects of paracetamol7. toxic metabolites (N-acetyl-p-benzoquinone) that

98 Hepatotoxicity of paracetamol and related fatalities cause hepatocellular damage, if glutathione sour- risk of paracetamol-induced nephrotoxicity. Al- ces are depleted. Paracetamol clearance is redu- though the data are limited, it is reasonable to as- ced and the half-life of elimination is prolonged. sume that patients with a nephrotoxicity risk may Therefore, a particular dosing regimen should be be similar to those at risk for hepatotoxicity, i.e. followed due to the toxicity risk of cumulative do- patients with depleted glutathione due to starva- ses. This report highlights the risk of severe hepa- tion, , or alcoholism42. totoxicity in neonates taking paracetamol multi- Some studies suggest that paracetamol has an ple doses for more than two to three days. adverse cardiovascular safety profile43 and becau- As reported by Doyon12, paracetamol is com- se this substance has been shown to inhibit COX- monly sold combined with antihistamines, de- 2, it has the potential to increase blood pressure congestants, dextromethorphan, , and/or and promote thrombosis. aspirin in over-the-counter (OTC) preparations. Since traditional non-steroidal anti-inflamma- Furthermore, there are combinations with opioids tory drugs have been associated with an increa- or with butalbital/caffeine in preparations to be sed risk of acute cardiovascular events, current dispensed after medical prescription. guidelines recommend acetaminophen as the In its annual report, the American Association first-line analgesic of choice on the assumption of Poison Control Centers reported that paraceta- of its greater cardiovascular safety. However, 33 mol combination products were involved in 48% of patients with coronary artery disease included paracetamol-associated fatalities39. The most har- in a randomized, double-blind, placebo-control- mful combination products which cause the majo- led, crossover study, received acetaminophen (1 rity of deaths are paracetamol/opioid. Conversely, g) on top of standard cardiovascular therapy for the combination product most involved in suicides 2 weeks. This study demonstrated for the first is paracetamol/diphenhydramine. Fatal overdoses time that paracetamol induces a significant in- involving paracetamol combination products re- crease in ambulatory blood pressure in patients ported to US poison centres are on the rise. After with coronary artery disease. Thus, the use of the examination of 337 deaths resulting from in- paracetamol should be evaluated as rigorously as gestion of paracetamol combination products re- traditional non-steroidal anti-inflammatory dru- ported to US poison centres, it emerged that the gs and cyclooxygenase-2 inhibitors, particularly ingredient responsible for death was paracetamol in patients at increased cardiovascular risk44. itself and not the combination products.

Other Side Effects of Paracetamol Conclusions Paracetamol-induced liver necrosis has been stu- died extensively, but the extrahepatic manifestations Paracetamol ingestion and subsequent hepato- of paracetamol toxicity are currently not well descri- toxicity is a critical problem that continues to pla- bed in the literature. Renal insufficiency occurs in gue individuals across the world. Due to its low approximately 1-2% paracetamol users following cost and easy access, paracetamol is an ubiqui- overdose18. Limited data in a retrospective case se- tous analgesic and anti-pyretic drug available off ries of pediatric patients with paracetamol poisoning the counter and in prescription-only suggests that associated nephrotoxicity may be more formulations19. common in children and adolescents40. Because of soaring cases of hepatotoxicity rela- The pathophysiology of renal toxicity in para- ted to abuse/misuse of paracetamol, the US Food cetamol poisoning has been attributed to cyto- and Drug Administration (FDA) in 2009 asked chrome P450 although other mechanisms have for the elimination of drugs containing paraceta- been elucidated, including the role of prostaglan- mol-related products (FDA 2009). Subsequently, in din synthetase and N-deacetylase enzymes. Para- 2011, the US FDA established that all medications doxically, glutathione is considered an important containing paracetamol in combination should not element in the detoxification of paracetamol and exceed 325 mg of paracetamol per tablet24,25. its metabolites; however, its conjugates have been Thus, since January 2014, after the ratification implicated in the formation of nephrotoxic com- of the FDA’s decision, more than half of pharma- pounds41. When significant paracetamol-induced ceutical manufacturers voluntarily limited the hepatotoxicity occurs, a renal injury is also com- amount of paracetamol, in paracetamol related monly seen. Several case reports have attempted products, to no more than 325 mg for each tablet6. to define patients characterized by an increased However, some combination drug medications

99 R. Tittarelli, M. Pellegrini, M.G. Scarpellini, E. Marinelli, V. Bruti, N.M. di Luca, F.P. Busardò, S. Zaami containing more than 325 mg of paracetamol are 7) De Giorgio F, Lodise M, Chiarotti M, d’Aloja E, Car- still commercially available45. US FDA has decla- bone A, Valerio L. Possible fatal acetaminophen red that it is crucial that the packages have labels intoxication with atypical clinical presentation. J with information about the risk of liver damage Forensic Sci 2013; 58: 1397-1400. Mowry JB, Spyker DA, Brooks DE, McMillan N, caused by the overuse of the drug; moreover it is 8) Schauben JL. 2014 Annual Report of the American essential to use only its international name and Association of Poison Control Centers’ National not the two different names of the same drug (pa- Poison Data System (NPDS): 32nd Annual Report. racetamol or acetaminophen) because it could Clin Toxicol 2015; 53: 962-1147. mislead the patients; in fact, if not properly in- 9) Nourjah P, Ahmad SR, Karwoski C, Willy M. Esti- formed, the unaware patient can ingest the same mates of acetaminophen (Paracetomal)-associat- substance under different names15. ed overdoses in the United States. Pharmacoepi- Nevertheless, today in the US the number of pa- demiol Drug Saf 2006; 15: 398-405. 10) Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, racetamol overdose related deaths, intentional or Davern TJ, Han SH, McCashland TM, Shakil AO, Hay unintentional, is still very high, averaging about 500 JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, victims per year; for this reason, a new legislation Lee WM, U.S. Acute Liver Failure Study Group. informing more clearly about the administration of Results of a prospective study of acute liver fail- paracetamol, packaging and selling and its combi- ure at 17 tertiary care centers in the United States. nation with other drugs, especially with opioid anal- Ann Intern Med 2002; 137: 947-954. gesics, is currently highly needed46,47. The most dra- 11) Gulmez SE, Larrey D, Pageaux GP, Bernuau J, Bissoli F, Horsmans Y, Thorburn D, McCormick PA, Stricker stic proposal suggested by FDA is the withdrawal of B, Toussi M, Lignot-Maleyran S, Micon S, Hamoud all complex drugs, both available over the counter F, Lassalle R, Jové J, Blin P, Moore N. Liver trans- (OTC) and by prescription, because as the various plant associated with paracetamol overdose: re- studies indicate, they are responsible to a great de- sults from the seven-country SALT study. Br J Clin gree for acute paracetamol poisoning. Pharmacol 2015; 80: 599-606. Since paracetamol is responsible for nearly half 12) Doyon S, Klein-Schwartz W, Lee S, Beuhler MC. the cases in the US of acute liver failure and re- Fatalities involving acetaminophen combina- tion products reported to United States poison mains the leading cause of liver transplantation, centers. 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