Isoniazid Hepatotoxicity Treatment & Management

  • Author: Richard A Weisiger, MD, PhD; Chief Editor: Julian Katz, MD   more...
 
Updated: May 23, 2012
 

Approach Considerations

Medical care for isoniazid (isonicotinic acid hydrazide [INH]) hepatotoxicity is essentially supportive. Discontinue isoniazid and any other potentially toxic drug, and closely monitor the patient.

Hospitalize persons who are more severely affected (eg, with significant elevation of the prothrombin time [PT]) for monitoring and potential liver transplantation; early hospitalization in a suitable institution carries less risk and permits more time to evaluate the patient for transplantation. Care of such patients is identical to that for other causes of fulminant hepatitis.

Admit patients to the intensive care unit (ICU) if they are lethargic, comatose, or severely acidotic or are experiencing refractory seizures. Transfer patients after stabilization of vital signs if ICU facilities or the services of a medical toxicologist are warranted but unavailable.

Consider INH toxicity in patients with unexplained new onset, recurrent, or intractable seizure. Prescribe only a 1-month supply of INH at a time to prevent the availability of a large amount. If seizure is refractory to standard anticonvulsant therapy, consider acute INH toxicity, and administer pyridoxine.

No activity restrictions are necessary unless the PT is elevated. Activity often is limited by fatigue.

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Supportive and Pharmacologic Therapy

Therapy for INH hepatotoxicity is mostly supportive and includes attention to the ABCs (airway, breathing, and circulation). Provide oxygen and continuous cardiac and pulse oximetry monitoring. Obtain intravenous (IV) access. If the patient shows no signs of toxicity 4 hours following an ingestion of less than 20 mg/kg, expectant management is sufficient. Treatment of patients with evidence of toxicity involves managing immediate life threats, administering pyridoxine, and supportive care.

If acute neurotoxicity (seizure, coma) occurs, administer pyridoxine immediately. Benzodiazepines and barbiturates can be used to potentiate the anticonvulsant effect of pyridoxine or as first-line therapy if pyridoxine is not yet available.[4] Use phenytoin with caution, because INH inhibits the metabolism of phenytoin. Ipecac syrup is contraindicated in patients with acute INH neurotoxicity, because it may increase the risk of aspiration secondary to seizure.

The availability of pyridoxine may be an issue. Because pyridoxine has few other emergency indications, individual hospitals may not have enough of it on hand to manage critically intoxicated patients. For example, a survey of 130 US institutions (in which 80% responded) found that at least 33% of the responding institutions were inadequately equipped with pyridoxine to treat acute INH toxicity.[32] Therefore, establishment of a network of resources from which hospitals can obtain adequate quantities rapidly should be considered.

Hospitals in urban areas with increased incidence of tuberculosis should have at least 5 g of pyridoxine available in the emergency department (ED). The wholesale cost for a 3-g vial of pyridoxine is approximately US $4, and it has a shelf life of 24 months. An argument can be made for a larger supply. Management of a single severely intoxicated patient may require 20 g of pyridoxine, which suggests that this amount should be readily available if tuberculosis is common among the patient population.

Once the airway is secured, consider gastric lavage. Next, administer activated charcoal in a dose 10 times the amount of INH ingested, or in a dose of 50 g if the amount of INH ingested is unknown. Lavage and activated charcoal may not be effective if administered more than 1-2 hours after an acute ingestion.

Control of seizures generally will correct metabolic acidosis. Administration of sodium bicarbonate may be beneficial in severe cases.

Although INH is dialyzable, dialysis is usually unnecessary if adequate doses of anticonvulsants and pyridoxine are administered. Hemodialysis may be indicated if the patient fails to improve with standard therapy.

Patients with clinically significant INH-associated hepatitis and progressive hepatic failure may be successfully treated with liver transplantation. INH is second only to acetaminophen among drugs resulting in hepatotoxicity severe enough to warrant liver transplantation.

Monitor all patients until transaminase levels normalize. Patients with minor transaminase elevations who continue to take INH require frequent monitoring (as much as twice weekly). Patients who have stopped using INH because of transaminase elevations should generally avoid subsequent use of the drug.

Reintroduction of INH does not always produce hepatitis, which suggests that environmental factors (eg, other medications, illness, and malnutrition) also may be important in some patients.

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Prevention

The incidence of severe hepatitis and death may be reduced by applying the following measures:

  • Avoid prophylactic use of INH in older persons (eg, >35 y), unless the potential benefit clearly outweighs the risk; treatment of tuberculin reactors is more strongly indicated in immunosuppressed persons and in those with a recent exposure history
  • Obtain a baseline alanine aminotransferase (ALT) level before starting INH when prior liver disease is suspected
  • Instruct patients to report possible adverse effects of INH hepatotoxicity immediately; interview patient regularly (eg, monthly) for adverse effects, or monitor transaminase levels monthly
  • For any transaminase elevation above 5 times the normal value (>3 times the normal value in the presence of symptoms), stop INH immediately; for lesser elevations, increase the frequency of monitoring
  • Where possible, avoid simultaneous administration of drugs that induce the cytochrome P-450 system (eg, phenobarbital and rifampin)
  • Avoid simultaneous use of other potentially hepatotoxic drugs (eg, pyrazinamide and protease inhibitors for HIV) unless the benefit of using them exceeds the risk of developing hepatitis
  • Instruct patients to avoid heavy consumption of ethanol while on INH
  • Because of the reduced threshold for liver damage, advise patients to avoid taking acetaminophen in a dosage higher than 3 g/day

Animal studies suggest that certain antioxidants may reduce the risk of INH hepatitis; these include silymarin, vitamin E, N- acetylcysteine, and melatonin. Although it is not known whether these results apply to humans, correcting nutritional deficiencies before starting INH may be warranted.

Routine monitoring of ALT is not required in healthy young persons treated for latent tuberculosis, provided that they are instructed to immediately report any symptoms that suggest toxicity. However, the American Thoracic Society (ATS) recommends monitoring of transaminases for patients who have a history of long-term alcohol use, who take concomitant hepatotoxic drugs, who have known liver disease, or who are or recently were pregnant.[33] Some experts also recommend monitoring for those older than 35 years.

Routine monitoring of aspartate aminotransferase (AST) levels among patients undergoing INH prophylaxis may detect early cases of hepatotoxicity.

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Consultations

Patients with serum transaminase elevations exceeding 3 times the normal level should be evaluated by a hepatologist or gastroenterologist to ensure that all possible causes of hepatitis are carefully considered. Consultation also should be obtained for those with lesser elevations that do not resolve within 2-3 months.

For patients with elevated PT, hospitalization and evaluation for possible liver transplantation are warranted.

Discuss the patient’s treatment with a regional poison control center or consult with a medical toxicologist.

Obtain a psychiatric consultation in all cases of intentional overdose before discharge from hospital. Consider neuropsychiatric evaluation for possible dementia.

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Contributor Information and Disclosures
Author

Richard A Weisiger, MD, PhD  Director, GI and Liver Faculty Practice, Professor, Department of Internal Medicine, University of California, San Francisco, School of Medicine

Richard A Weisiger, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases and American Society for Clinical Investigation

Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD  Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Additional Contributors

John G Benitez, MD, MPH, FACMT, FAACT, FACPM, FAAEM, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

John G Benitez, MD, MPH, FACMT, FAACT, FACPM, FAAEM, is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society

Disclosure: Nothing to disclose.

Douglas M Heuman, MD, FACP, FACG, AGAF Chief of GI, Hepatology, and Nutrition at North Shore University Hospital/Long Island Jewish Medical Center; Professor, Department of Medicine, Hofstra North Shore-LIJ School of Medicine

Douglas M Heuman, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, and American Gastroenterological Association

Disclosure: Novartis Grant/research funds Other; Bayer Grant/research funds Other; Otsuka Grant/research funds None; Bristol Myers Squibb Grant/research funds Other; Scynexis None None; Salix Grant/research funds Other; MannKind Other

David C Lee, MD Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Terence David Lewis, MBBS, FRACP, FRCPC, FACP Program Director, Internal Medicine Residency, & Assistant Chairman, Associate Professor, Department of Internal Medicine, Division of Gastroenterology, Loma Linda University Medical Center

Terence David Lewis, MBBS, FRACP, FRCPC, FACP is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Medical Association, California Medical Association, Royal College of Physicians and Surgeons of Canada, and Sigma Xi

Disclosure: Nothing to disclose.

C Crawford Mechem, MD, MS, FACEP Associate Professor, Department of Emergency Medicine, University of Pennsylvania School of Medicine; Emergency Medical Services Medical Director, Philadelphia Fire Department

C Crawford Mechem, MD, MS, FACEP is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Binita R Shah, MD, FAAP Professor of Clinical Pediatrics and Emergency Medicine, SUNY Health Sciences Center at Brooklyn; Director of Pediatric Emergency Medicine, Departments of Emergency Medicine and Pediatrics, Kings County Hospital Center

Binita R Shah, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

David Tran, MD Attending Physician, Department of Emergency Medicine, North Shore-LIJ Plainview Hospital

David Tran, MD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians

Disclosure: Nothing to disclose.

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center

Disclosure: Merck Salary Employment

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

William T Zempsky, MD Associate Director, Assistant Professor, Department of Pediatrics, Division of Pediatric Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center

William T Zempsky, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

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Metabolism of isoniazid.
Risk of developing overt hepatitis (%) versus age (y). Risks are much greater for older persons. Data are from a series of 13,838 patients on prophylactic isoniazid therapy reported by Kopanoff and coworkers (1978).
Risk of developing overt hepatitis versus duration of therapy. Most hepatitis presents early in the course of therapy.
Isoniazid metabolism.
Gamma-aminobutyric acid (GABA) synthesis.
 
 
 
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