Late presentation of acetaminophen hepatotoxicity

Black, Martin M.; Cornell, James; Rabin, Lionel; Shachter, Neal

doi:10.1007/bf01296760

Cited by 27 publications

(9 citation statements)

References 16 publications

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“…This generally is attributed to lactic acidosis and kidney failure. However, in some cases, the anion gap cannot be explained (30,31). These patients often have less severe toxicity and a history of chronic acetaminophen ingestion.…”

Section: Discussionmentioning

confidence: 99%

Increased Anion Gap Metabolic Acidosis as a Result of 5-Oxoproline (Pyroglutamic Acid)

Fenves

Kirkpatrick

Patel

et al. 2006

Clinical Journal of the American Society of Nephrology

102

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The endogenous organic acid metabolic acidoses that occur commonly in adults include lactic acidosis; ketoacidosis; acidosis that results from the ingestion of toxic substances such as methanol, ethylene glycol, or paraldehyde; and a component of the acidosis of kidney failure. Another rare but underdiagnosed cause of severe, high anion gap metabolic acidosis in adults is that due to accumulation of 5-oxoproline (pyroglutamic acid). Reported are four patients with this syndrome, and reviewed are 18 adult patients who were reported previously in the literature. Twenty-one patients had major exposure to acetaminophen (one only acute exposure). Eighteen (82%) of the 22 patients were women. Most of the patients were malnourished as a result of multiple medical comorbidities, and most had some degree of kidney dysfunction or overt failure. The chronic ingestion of acetaminophen, especially by malnourished women, may generate high anion gap metabolic acidosis. This undoubtedly is an underdiagnosed condition because measurements of serum and/or urinary 5-oxoproline levels are not readily available.

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Section: Discussionmentioning

confidence: 99%

Increased Anion Gap Metabolic Acidosis as a Result of 5-Oxoproline (Pyroglutamic Acid)

Fenves

Kirkpatrick

Patel

et al. 2006

Clinical Journal of the American Society of Nephrology

102

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“…Hypoprothrombinemia, hypoglycemia, visual hallucinations, metabolic acidosis and leucocytosis can also occur. The degree of hypoprothrombinemia is relatively modest (24,62).…”

Section: Acetaminophen Hepatotoxicity In Alc Oholic S Ubjectsmentioning

confidence: 99%

Update: the clinical importance of acetaminophen hepatotoxicity in non-alcoholic and alcoholic subjects

Tanaka¹,

Yamazaki²,

Misawa³

2000

J Clin Pharm Ther

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Acetaminophen (paracetamol) is one of the most commonly used over-the-counter medications. Taken in doses greater than 150 mg/kg/day (>10 g), it usually causes acute liver failure. The authors review mainly the management of acetaminophen toxicity in both users and nonusers of alcohol. Chronic alcoholics are a special subgroup, who risk serious toxicity when taking acetaminophen, even in therapeutic doses. The acetaminophen-alcohol interaction is complex, because acute and chronic ethanol have opposite effects. This review also considers physiological and clinical changes, as well as the diagnosis and treatment of acetaminophen poisoning.

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“…There have been many reports claiming that the hepatotoxicity of paracetamol (acetaminophen) is increased in chronic alcoholics, and that such individuals not only carry an increased risk of severe and fatal liver damage after acute overdosage [1–20], but that similar serious liver damage may also occur with ‘therapeutic’ use [5, 9, 10, 17, 18, 21–64]. In the original studies of the mechanisms of toxicity, paracetamol was found to cause liver damage through conversion by hepatic cytochrome P450 enzymes to a minor but toxic intermediate metabolite [65–68] and this was subsequently identified as N ‐acetyl‐ p ‐benzoquinoneimine [69, 70].…”

Section: Introductionmentioning

confidence: 99%

Paracetamol, alcohol and the liver

Prescott

2000

Brit J Clinical Pharma

197

106

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It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with`therapeutic intent' had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol± alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic.The paracetamol±alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short-lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol±ethanol interaction is not speci®c for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical.In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the ®rst few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insuf®cient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestioningly accepted this supposed interaction in man for so long with such scant regard for scienti®c objectivity.

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Late presentation of acetaminophen hepatotoxicity

Cited by 27 publications

References 16 publications

Increased Anion Gap Metabolic Acidosis as a Result of 5-Oxoproline (Pyroglutamic Acid)

Increased Anion Gap Metabolic Acidosis as a Result of 5-Oxoproline (Pyroglutamic Acid)

Update: the clinical importance of acetaminophen hepatotoxicity in non-alcoholic and alcoholic subjects

Paracetamol, alcohol and the liver

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