Paracetamol hepatotoxicity

Paracetamol hepatotoxicity is injury to the liver resulting from excessive use of the analgesic drug paracetamol (called acetaminophen in the United States). It is the most common cause of acute liver failure in the United States and the United Kingdom.

Damage to the liver, or hepatotoxicity, results not from paracetamol itself, but from one of its metabolites, "N"-acetyl-"p"-benzoquinoneimine (NAPQI). NAPQI depletes the liver's natural antioxidant glutathione and directly damages cells, leading to liver failure. Risk factors for paracetamol hepatotoxicity include excessive alcohol intake and the use of certain drugs such as isoniazid.

Many individuals with paracetamol hepatotoxicity may have no symptoms at all. Others may have nonspecific complaints such as vague abdominal pain and nausea. With progressive disease, signs of liver failure may develop; these include low blood sugar, low blood pH, easy bleeding, and hepatic encephalopathy. Some will spontaneously resolve, although rare untreated cases may result in death.

Treatment is aimed at removing the paracetamol from the body and replacing glutathione. These can often be achieved with the use of activated charcoal and acetylcysteine, respectively. Efforts to prevent paracetamol overdose include limiting individual sales of the drug and combining paracetamol with methionine, which can be converted into glutathione in the liver.

Epidemiology

Paracetamol is contained in many preparations, available as both over-the-counter and as prescription-only medications. Because of the wide availability of paracetamol, there is a large potential for overdose and toxicity. [cite journal | author = Sheen C, Dillon J, Bateman D, Simpson K, Macdonald T | title = Paracetamol toxicity: epidemiology, prevention and costs to the health-care system | journal = QJM | volume = 95 | issue = 9 | pages = 609–19 | year = 2002 | pmid = 12205339 | url=http://qjmed.oxfordjournals.org/cgi/content/full/95/9/609 | doi = 10.1093/qjmed/95.9.609] Without timely treatment, overdose can lead to liver failure and death within days; paracetamol toxicity is, by far, the most common cause of acute liver failure in both the United States and the United Kingdom.cite journal |author=Larson AM, Polson J, Fontana RJ, "et al" |title=Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study |journal=Hepatology |volume=42 |issue=6 |pages=1364–72 |year=2005 |pmid=16317692 |doi=10.1002/hep.20948] [cite journal |author=Ryder SD, Beckingham IJ |title=ABC of diseases of liver, pancreas, and biliary system. Other causes of parenchymal liver disease |journal=BMJ |volume=322 |issue=7281 |pages=290–92 |year=2001 |pmid=11157536 |doi=10.1136/bmj.322.7281.290 [11157536 Free full text] ] Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance, accounting for more than 100,000 calls, as well as 56,000 emergency room visits, 2,600 hospitalizations, and 458 deaths due to acute liver failure per year.cite journal |author=Lee WM |title=Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure |journal=Hepatology |volume=40 |issue=1 |pages=6–9 |year=2004 |month=July |pmid=15239078 |doi=10.1002/hep.20293 |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/109086434/PDFSTART] A study of cases of acute liver failure between November 2000 and October 2004 by the Centers for Disease Control and Prevention (US) found that paracetamol was the cause of 41% of all cases in adults, and 25% of cases in children.cite journal |author=Bower WA, Johns M, Margolis HS, Williams IT, Bell BP |title=Population-based surveillance for acute liver failure |journal=Am. J. Gastroenterol. |volume=102 |issue=11 |pages=2459–63 |year=2007 |month=November |pmid=17608778 |doi=10.1111/j.1572-0241.2007.01388.x |url=http://www.blackwell-synergy.com/doi/abs/10.1111/j.1572-0241.2007.01388.x]

Mechanism

Paracetamol is mostly converted to inactive compounds via Phase II metabolism by conjugation with sulfate and glucuronide, with a small portion being oxidized via the cytochrome P450 enzyme system. Cytochromes nowrap|P450 2E1 (CYP2E1) and 3A4 (CYP3A4) convert paracetamol to a highly-reactive intermediary metabolite, "N"-acetyl-"p"-benzoquinoneimine (NAPQI).cite journal |author=Richardson, JA |title=Management of acetaminophen and ibuprofen toxicoses in dogs and cats |journal=J Vet Emerg Crit Care |volume=10 |issue= |pages=285–291 |year=2000 |month=July-September |pmid= |doi= |url=http://www.aspca.org/site/DocServer/veccs_july00.pdf?docID=132] cite journal |author=Rumbeiha WK, Lin YS, Oehme FW |title=Comparison of N-acetylcysteine and methylene blue, alone or in combination, for treatment of acetaminophen toxicosis in cats |journal=Am. J. Vet. Res. |volume=56 |issue=11 |pages=1529–33 |year=1995 |month=November |pmid=8585668 |doi= |url=] Sellon, R.K. Acetaminophen. In: Peterson ME, Talcott PA, eds. Small Animal Toxicology. Toronto: WB Saunders, 2001: 388–395.]

Under normal conditions, NAPQI is detoxified by conjugation with glutathione. In cases of paracetamol toxicity, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. As a result, hepatocellular supplies of glutathione become exhausted and NAPQI is free to react with cellular membrane molecules, resulting in widespread hepatocyte damage and death, leading to acute hepatic necrosis. In animal studies, hepatic glutathione must be depleted to less than 70% of normal levels before hepatotoxicity occurs.

Risk factors

Toxic dose

The toxic dose of paracetamol is highly variable. In adults, single doses above 10 grams or 200 mg/kg of bodyweight, whichever is lower, have a reasonable likelihood of causing toxicity.cite journal | author=Dart RC, Erdman AR, Olson KR, Christianson G, Manoguerra AS, Chyka PA, Caravati EM, Wax PM, Keyes DC, Woolf AD, Scharman EJ, Booze LL, Troutman WG; American Association of Poison Control Centers | title=Acetaminophen poisoning: an evidence-based consensus guideline for out-of- hospital management | journal=Clin Toxicol (Phila) | year=2006 | pages=1–18 | volume=44 | issue=1 | pmid= 16496488] cite journal |author=Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA |title=Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres |journal=Med. J. Aust. |volume=188 |issue=5 |pages=296–301 |year=2008 |month=March |pmid=18312195 |doi= |url=http://www.mja.com.au/public/issues/188_05_030308/dal10916_fm.html] Toxicity can also occur when multiple smaller doses within 24 hours exceeds these levels. In children acute doses above 200 mg/kg could potentially cause toxicity.cite journal | author = Tenenbein M | title = Acetaminophen: the 150 mg/kg myth | journal = J Toxicol Clin Toxicol | volume = 42 | issue = 2 | pages = 145–48 | year = 2004 | pmid = 15214618] However, acute paracetamol overdose in children rarely causes illness or death, and it is very uncommon for them to have levels that require treatment, with chronic supratherapeutic doses being the major cause of toxicity in children.

Since paracetamol is often included in combination with other drugs, it is important to include all sources of paracetamol when checking a person's dose for toxicity. In addition to being sold by itself, paracetamol may be included in the formulations of various analgesics and cold/flu remedies as a way to increase the pain-relieving properties of the medication, and sometimes in combination with opioids such as hydrocodone to deter people from using it recreationally or becoming addicted to the opioid substance. In fact, the human toll of paracetamol, in terms of both fatal overdoses and chronic liver toxicity, likely far exceeds the damage caused by the opioids themselves.cite book | author = Brecher, Edward M | title = Consumers Union Report on Licit and Illicit Drugs | year = 1972 |location = Boston |publisher = Little, Brown | isbn = 0316153400] page number

igns and symptoms

In general, damage occurs in hepatocytes as they metabolize the paracetamol. Rarely, acute renal failure also may occur. This is usually caused by either hepatorenal syndrome or Multiple organ dysfunction syndrome. Acute renal failure may also be the primary clinical manifestation of toxicity. In these cases, it has been suggested that the toxic metabolite is produced more in the kidneys than in the liver.cite journal | author = Boutis K, Shannon M | title = Nephrotoxicity after acute severe acetaminophen poisoning in adolescents | journal = J Toxicol Clin Toxicol | volume = 39 | issue = 5 | pages = 441–5 | year = 2001 | pmid = 11545233 | doi = 10.1081/CLT-100105413]

The severity of paracetamol toxicity varies depending on the dose and the appropriate treatment. In some cases, massive hepatic necrosis leads to fulminant hepatic failure with complications of bleeding, hypoglycemia, renal failure, hepatic encephalopathy, cerebral edema, sepsis, multiple organ failure, and death within days. In many cases, the hepatic necrosis may run its course, hepatic function may return, and the patient may survive with liver function returning to normal in a few weeks. [cite journal |author=Linden CH, Rumack BH |title=Acetaminophen overdose |journal=Emerg. Med. Clin. North Am. |volume=2 |issue=1 |pages=103–19 |year=1984 |month=February |pmid=6394298 |doi= |url=]

Diagnosis

Evidence of liver toxicity may develop in one to four days, although, in severe cases, it may be evident in 12 hours. Right-upper-quadrant tenderness may be present. Laboratory studies may show evidence of massive hepatic necrosis with elevated AST, ALT, bilirubin, and prolonged coagulation times (in particular, elevated prothrombin time). After paracetamol overdose, when AST and ALT exceed 1000 IU/L, paracetamol-induced hepatotoxicity can be diagnosed. However, the AST and ALT levels can exceed 10,000 IU/L. In general, the AST is somewhat higher than the ALT in paracetamol-induced hepatotoxicity.

A drug nomogram was developed in 1975, which estimated the risk of toxicity based on the serum concentration of paracetamol at a given number of hours after ingestion.cite journal | author = Rumack B, Matthew H | title = Acetaminophen poisoning and toxicity | journal = Pediatrics | volume = 55 | issue = 6 | pages = 871–76 | year = 1975 | pmid = 1134886] To determine the risk of potential hepatotoxicity, the paracetamol level is traced along the standard nomogram. A paracetamol level drawn in the first four hours after ingestion may underestimate the amount in the system because paracetamol may still be in the process of being absorbed from the gastrointestinal tract. Delay of the initial draw for the paracetamol level to account for this is not recommended, since the history in these cases is often poor and a toxic level at any time is a reason to give the antidote.

Treatment

Initial measures

The initial treatment for uncomplicated paracetamol overdose, similar to most other overdoses, is gastrointestinal decontamination. In addition, the antidote acetylcysteine plays an important role. Paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this time. Absorption may be somewhat slowed when it is ingested with food. There is considerable room for physician judgement regarding gastrointestinal decontamination; activated charcoal administration is the most commonly-used procedure; however, gastric lavage may also be considered if the amount ingested is potentially life-threatening and the procedure can be performed within 60 minutes of ingestion.cite journal | author=Vale JA, Kulig K; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists | title=Position paper: gastric lavage | journal=J Toxicol Clin Toxicol | year=2004 | pages=933–43 | volume=42 | issue=7 | pmid=15641639 | doi=10.1081/CLT-200045006] Syrup of ipecac has no role in paracetamol overdose because the vomiting it induces delays the effective administration of activated charcoal and oral acetylcysteine.

Activated charcoal adsorbs paracetamol, reducing its gastrointestinal absorption. Administering activated charcoal also poses less risk of aspiration than gastric lavage. Previous to this method, there was reluctance to give activated charcoal in paracetamol overdose, because of concern that it may also absorb acetylcysteine. Studies have shown that no more than 39% of an oral acetylcysteine is absorbed when they are administered together.cite journal | author = Ekins B, Ford D, Thompson M, Bridges R, Rollins D, Jenkins R | title = The effect of activated charcoal on N-acetylcysteine absorption in normal subjects | journal = Am J Emerg Med | volume = 5 | issue = 6 | pages = 483–87 | year = 1987 | pmid = 3663288 | doi = 10.1016/0735-6757(87)90166-5] Other studies have shown that activated charcoal seems to be beneficial to the clinical outcome. It appears that the most benefit from activated charcoal is gained if it is given within two hours of ingestion.cite journal | author=Buckley NA, Whyte IM, O'Connell DL, Dawson AH. | title=Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose | journal=J Toxicol Clin Toxicol | year=1999 | pages=753–57 | volume=37 | issue=6 | pmid=10584587 | doi=10.1081/CLT-100102452] However, administering activated charcoal later than this can be considered in patients that may have delayed gastric emptying due to co-ingested drugs or following ingestion of sustained- or delayed-release paracetamol preparations. Activated charcoal should also be administered if co-ingested drugs warrant decontamination. There are conflicting recommendationscite journal | author = Spiller H, Krenzelok E, Grande G, Safir E, Diamond J | title = A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose | journal = Ann Emerg Med | volume = 23 | issue = 3 | pages = 519–23 | year = 1994 | pmid = 8135427 | doi = 10.1016/S0196-0644(94)70071-0] regarding whether to change the dosing of oral acetylcysteine after the administration of activated charcoal, and even whether the dosing of acetylcysteine needs to be altered at all.

Acetylcysteine

Acetylcysteine (also called "N"-acetylcysteine or NAC) works to reduce paracetamol toxicity by supplying sulfhydryl groups (mainly in the form of glutathione, of which it is a precursor) to react with the toxic NAPQI metabolite so that it does not damage cells and can be safely excreted. Additionally, methionine has been recommended in some cases,cite journal |author=Mant TG, Tempowski JH, Volans GN, Talbot JC |title=Adverse reactions to acetylcysteine and effects of overdose |journal=Br Med J (Clin Res Ed) |volume=289 |issue=6439 |pages=217–9 |year=1984 |month=July |pmid=6234965 |pmc=1442311 |doi= |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1442311&blobtype=pdf] although studies show that N-acetylcysteine is a more effective antidote to paracetamol overdose.cite journal |author=Alsalim W, Fadel M |title=Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Oral methionine compared with intravenous n-acetyl cysteine for paracetamol overdose |journal=Emerg Med J |volume=20 |issue=4 |pages=366–7 |year=2003 |month=July |pmid=12835357 |pmc=1726135 |doi= |url=http://emj.bmj.com/cgi/pmidlookup?view=long&pmid=12835357]

If the patient presents less than eight hours after paracetamol overdose, then acetylcysteine significantly reduces the risk of serious hepatotoxicity. If NAC is started more than 8 hours after ingestion, there is a sharp decline in its effectiveness because the cascade of toxic events in the liver has already begun, and the risk of acute hepatic necrosis and death increases dramatically. Although acetylcysteine is most effective if given early, it still has beneficial effects if given as late as 48 hours after ingestion.cite journal | author = Keays R, Harrison P, Wendon J, Forbes A, Gove C, Alexander G, Williams R | title = Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial | journal = BMJ | volume = 303 | issue = 6809 | pages = 1026–9 | year = 1991 | pmid = 1954453] In clinical practice, if the patient presents more than eight hours after the paracetamol overdose, then activated charcoal is probably not useful, and acetylcysteine is started immediately. In earlier presentations, the doctor can give charcoal as soon as the patient arrives, start giving acetylcysteine, and wait for the paracetamol level from the laboratory.

In United States practice, intravenous (IV) and oral administration are considered to be equally effective. However, IV is the only recommended route in Australasian and British practice. Oral acetylcysteine is given as a 140 mg/kg loading dose followed by 70 mg/kg every four hours for 17 more doses. [cite journal |author=Woo OF, Mueller PD, Olson KR, Anderson IB, Kim SY |title=Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose |journal=Ann Emerg Med |volume=35 |issue=4 |pages=363–8 |year=2000 |month=April |pmid=10736123 |doi= |url=] Oral acetylcysteine may be poorly tolerated due to its unpleasant taste, odor, and its tendency to cause nausea and vomiting. It can be diluted to a 5% solution, from its marketed 10% or 20% solutions, to improve palatability. Where oral acetylcysteine is required, the inhalation formulation of acetylcysteine (Mucomyst) is often given orally. The respiratory formulation can also be diluted and filter sterilized by a hospital pharmacist for IV use; however this is an uncommon practice. If repeat doses of charcoal are indicated because of another ingested drug, then subsequent doses of charcoal and acetylcysteine should be staggered every two hours.

Intravenous acetylcysteine (Parvolex/Acetadote) is used as a continuous intravenous infusion over 20 hours (total dose 300 mg/kg). Recommended administration involves infusion of a 150 mg/kg loading dose over 15 to 60 minutes, followed by a 50 mg/kg infusion over four hours; the last 100 mg/kg are infused over the remaining 16 hours of the protocol. Intravenous acetylcysteine has the advantage of shortening hospital stay, increasing both doctor and patient convenience, and allowing administration of activated charcoal to reduce absorption of both the paracetamol and any co-ingested drugs without concerns about interference with oral acetylcysteine.cite journal | author = Buckley N, Whyte I, O'Connell D, Dawson A | title = Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning? | journal = J Toxicol Clin Toxicol | volume = 37 | issue = 6 | pages = 759–67 | year = 1999 | pmid= 10584588 | doi = 10.1081/CLT-100102453]

Baseline laboratory studies include bilirubin, AST, ALT, and prothrombin time (with INR). Studies are repeated at least daily. Once it has been determined that a potentially-toxic overdose has occurred, acetylcysteine is continued for the entire regimen, even after the paracetamol level becomes undetectable in the blood. If hepatic failure develops, acetylcysteine should be continued beyond the standard doses until hepatic function improves or until the patient has a liver transplant.

Prognosis

The mortality rate from paracetamol overdose increases two days after the ingestion, reaches a maximum on day four, and then gradually decreases. Patients with a poor prognosis are usually identified for likely liver transplantation. Acidemia is the most important single indicator of probable mortality and the need for transplantation. A mortality rate of 95% without transplant was reported in patients who had a documented pH less than 7.30. Other indicators of poor prognosis include renal insufficiency, grade 3 or worse hepatic encephalopathy, a markedly elevated prothrombin time, or a rise in prothrombin time from day three to day four. One study has shown that a factor V level less than 10% of normal indicated a poor prognosis (91% mortality), whereas a ratio of factor VIII to factor V of less than 30 indicated a good prognosis (100% survival).cite journal |author=Pereira LM, Langley PG, Hayllar KM, Tredger JM, Williams R |title=Coagulation factor V and VIII/V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: relation to other prognostic indicators |journal=Gut |volume=33 |issue=1 |pages=98–102 |year=1992 |pmid=1740285 | doi = 10.1136/gut.33.1.98 PMC|1373872]

Prevention

Besides preventing an overdose, one way to prevent liver damage may be the use of Paradote. Paradote is a combination tablet containing 100 mg methionine and 500 mg paracetamol. Methionine is included in order to ensure that sufficient levels of glutathione in the liver are maintained in order to minimize the liver damage caused if a paracetamol overdose is taken.

Other attempts at minimizing paracetamol's adverse effects include limiting the quantity of the drug sold. In the UK, sales of over-the-counter paracetamol are restricted to packs of 32 tablets in pharmacies, and 16 tablets in non-pharmacy outlets. [ [http://www.hants.gov.uk/regulatory/tradingstandards/medicines.html Limits on Sale in UK] ] Up to 100 tablets may be sold in a single transaction, except in pharmacies, where only 32 may be sold, with more being sold at a pharmacist's discretion. In Ireland, the limits are 24 and 12 tablets, respectively. In Australia, paracetamol tablets are available at supermarkets in small-pack sizes, whereas, with children's formulations, pack sizes greater than 48 tablets and suppositories are restricted to pharmacies.Fact|date=June 2008

References

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