Hepatotoxicity Associated With Acetaminophen Usage in Patients Receiving Multiple Drug Therapy for Tuberculosis

doi:10.1378/chest.105.2.408

Chest

Volume 105, Issue 2, February 1994, Pages 408-411

https://doi.org/10.1378/chest.105.2.408 Get rights and content

We report three patients who experienced hepatotoxic reactions in association with acetaminophen ingestion while undergoing treatment for active tuberculosis with isoniazid, rifampin, and other agents. All were young adult women. One patient intentionally took a large amount of acetaminophen and had typical signs and symptoms of acetaminophen overdosage; another took acetaminophen in combination form for a minor upper respiratory illness. She experienced no symptoms. The remaining patient took acetaminophen to ameliorate the symptoms of fever and malaise that were subsequently attributed to tuberculosis. She had the rapid onset of signs and symptoms of isoniazid hepatotoxicity. The patterns of liver function abnormalities were similar: each patient experienced pronounced serum elevations of hepatocellular enzymes with at most only modest rises in those of bilirubin. All antituberculous drugs were withheld until symptoms resolved and laboratory values became normal; then treatment for tuberculosis was resumed without isoniazid and was successfully completed in all three patients. These cases plus similar reports in the literature suggest that isoniazid or rifampin, or both, may potentiate the hepatotoxicity of acetaminophen, perhaps by induction of cytochrome P450 isozymes that oxidize acetaminophen to its toxic metabolites.

Section snippets

Case 1

A woman born in 1960, had been receiving treatment for drug-resistant tuberculosis with isoniazid, rifampin, pyrazinamide, and streptomycin since her immigration from the Philippines in December 1990. In May 1991, she was hospitalized 24 h after ingesting 15 to 20 tablets of acetaminophen (300 mg acetaminophen per tablet); an ingestion of 4.5 to 6.0 g of acetaminophen. She complained of abdominal pain.

On physical examination, the liver was palpable 2 cm below the right costal margin. Admission

Comments

In this report, we described three patients being treated for active tuberculosis who experienced hepatotoxicity in temporal association with the ingestion of acetaminophen. The circumstances were disparate. One patient (patient 1) intentionally took a relatively large amount of acetaminophen; another (patient 2) took acetaminophen in combination form for a minor upper respiratory illness; the remaining one (patient 3) took it in order to ameliorate the symptoms of fever and malaise that were

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Concomitant use of medications that induce the CYP system, such as anticonvulsants (eg, phenobarbital, phenytoin, and carbamazepine) and antituberculosis agents (eg, isoniazid and rifampicin), may predispose to APAP hepatotoxicity by increased production of NAPQI by way of the oxidative pathway.15,36,37 Severe APAP hepatotoxicity associated with the concurrent use of these medications has been anecdotally reported, although there are no compelling data that this occurs at a therapeutic dose.36,37 Phenytoin is primarily metabolized by CYP3A4 and not CYP2E1 and as such there is an insignificant amount of APAP metabolite being produced.
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Acetaminophen toxicity is a major health problem in the United States today because of its contribution to the development of acute liver failure, coupled with the ubiquity of the drug in the US formulary. While significant progress has been achieved since 2000 in better defining mechanisms of toxicity in experimental models, our understanding of factors that are important to the development of toxicity in the clinical setting is poor. Very little research has attempted to translate new understandings of the mechanism of toxicity to the clinical setting. In addition, the treatment of acetaminophen overdose has not significantly changed since recognition of the role of metabolism and glutathione depletion to the development of toxicity in the 1970s. The chapter reviews the history of acetaminophen, our understanding of its human pharmacology and toxicity, and current approaches and challenges in the recognition and treatment of toxicity in various clinical settings.
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Tuberculosis remains a health problem in developed countries like the United States. Except for ethambutol, all the other first-line antitubercular drugs have the potential to result in hepatotoxicity and, after acetaminophen, isoniazid remains the second most common cause of drug-induced acute liver failure in the United States. The incidence of hepatotoxicity varies from <1% with monotherapy to 2–4% with multidrug regimen and is dependent on many host and genetic factors. Though the drug-induced liver injury is clearly idiosyncratic, underlying mechanisms nonetheless remain speculative. Hepatotoxicity generally develops within the first 2 months of initiation of therapy and results in an acute hepatitis that is usually reversible upon drug discontinuation, although in presence of jaundice mortality can be as high as 10%. Rarely, antitubercular therapy can result in acute liver failure that carries a dismal prognosis in the absence of liver transplantation. Criteria for discontinuation of drugs are well established and it is essential that these be adhered to as ongoing use of antitubercular drugs in the face of abnormal liver function tests can increase the severity of liver injury. In those with preexisting chronic liver disease, first-line drugs must be used with extreme caution and if possible are best avoided. In patients > 35 years of age on isoniazid monotherapy, or in those with underlying liver disease and/or using a multidrug regimen irrespective of age, monitoring of alanine aminotransferase levels is recommended. Therefore, the decision to initiate antitubercular drugs must be made after carefully weighing the pros and cons, and needs to be closely supervised. There also remains an urgent need to develop new and safer drugs for the treatment of tuberculosis.
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There are evidences that rifampin elevates the levels of P450 and cytochrome b5 and the activities of cytochrome c reductase and substrate-metabolizing enzymes both in liver and small intestine (Huang et al., 1996). Some patients experienced hepatotoxic reactions after using acetaminophen while underwent treatment for active tuberculosis with rifampin, isoniazid, and other agents (Nolan et al., 1994). Human pregnane X receptor (PXR) is involved in regulation of acetaminophen-induced toxicity through CYP3A4 mediated hepatic metabolism of acetaminophen in the presence of PXR ligands, thus, some PXR activators, such as rifampin may induce acetaminophen’s toxicity (Cheng et al., 2009).
This study examined the effects and possible mechanisms of rifampin against acetaminophen-induced hepatotoxicity in mice. Rifampin significantly enhanced the biotransformation of acetaminophen, evidenced by the increase in p-aminophenol formation in rifampin-treated microsomes and the increase in plasma clearance rate of acetaminophen. Pretreatment with rifampin significantly decreased serum alanine transaminase (ALT) activities, aspartate transaminase (AST) activities and prevented severe liver necrosis following acetaminophen overdose. The contents and activities of microsomal drug-metabolizing enzyme were less affected in rifampin-pretreated mice in comparison to the animals treated with acetaminophen alone. Rifampin was capable of increasing glutathione (GSH) level and GSH reductase activity and reducing GSH depletion and the decrease in GSH reductase activity by acetaminophen in mice. In addition, it was found that the microsomal Ca²⁺-ATPase activity was not directly related to acetaminophen toxic species generated in the P450 enzyme system in vitro. These findings suggest that rifampin has species-specific effects on the liver against acetaminophen-induced hepatotoxicity in mice, which increase the level of GSH by promoting GSH regeneration.
Covalent functionalization of graphene oxide with l-lysine for highly sensitive and selective simultaneous electrochemical detection of rifampicin and acetaminophen
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: Manuscript received April 16; revision accepted May 27.

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Chest

Clinical InvestigationsInfectionsHepatotoxicity Associated With Acetaminophen Usage in Patients Receiving Multiple Drug Therapy for Tuberculosis

Section snippets

Case 1

Comments

Chest

Arch Biochem Biophys

Biochem Pharmacol

Isoniazid-associated hepatitis: report of an outbreak

Am Rev Respir Dis

Isoniazid-related hepatitis: a US Public Health Service cooperative surveillance study

Am Rev Respir Dis

Stop isoniazid prophylaxis

Ann Intern Med

Isoniazid for the tuberculin reactor: take it or leave it

Am Rev Respir Dis

The age threshold for isoniazid chemoprophylaxis

JAMA

Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment

Arch Intern Med

Severe acetaminophen toxicity in a patient receiving isoniazid

Ann Intern Med

Acetaminophen, isoniazid, and hepatic toxicity

Ann Intern Med

Clinical Investigations
Infections
Hepatotoxicity Associated With Acetaminophen Usage in Patients Receiving Multiple Drug Therapy for Tuberculosis