Isoniazid Toxicity

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This article focuses on the acute and chronic isoniazid (isonicotinic acid hydrazide [INH] toxicity. Acute INH toxicity leads to central nervous system (CNS) toxicity, including seizures, whereas chronic INH toxicity results in hepatotoxicity.

Since 1952, INH has been used as a front-line antimicrobial for tuberculosis (TB). ^{[1, 2]} INH is commonly used for prophylaxis of patients with a recently converted Mantoux tuberculin skin test (TST) with purified protein derivative (PPD) or in conjunction with other medications for the treatment of active TB infection.

A typical regimen for tuberculosis includes INH, rifampin, pyrazinamide, and ethambutol or streptomycin. Treatment lasts for 6 months for active TB, assuming responsiveness to antimicrobial therapy. Although the exact mechanism of activity is unknown, INH is believed to act by interfering with the mycobacterial cell wall synthesis.

Acute INH overdose predominantly involves the brain and may cause prolonged seizures, anion gap metabolic acidosis, and coma. Note the following:

INH hepatotoxicity is a common complication of antituberculosis therapy, ranging in severity from asymptomatic elevation of serum transaminases to hepatic failure necessitating liver transplantation. This toxicity is not caused by high plasma INH levels but appears to represent an idiosyncratic response. ^[3]

INH hepatotoxicity presents a difficult management problem, for several reasons, including the following:

Guidelines for the diagnosis, treatment, control, and prevention of tuberculosis, including the medications used, have been established by the American Thoracic Society (ATS), the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA). ^[4] Awareness of INH poisoning may prevent severe morbidity and mortality.

A list of guidelines for TB from the CDC by topic is available at http://www.cdc.gov/tb/publications/guidelines/. The World Health Organization also has TB guidelines at http://www.who.int/publications/guidelines/tuberculosis/en/ and http://www.ncbi.nlm.nih.gov/books/NBK138748/.

Acute isoniazid (INH) overdose results in decreased pyridoxal-5′-phosphate levels, decreased gamma-aminobutyric acid (GABA) synthesis, increased cerebral excitability, and seizures. The presumed mechanism of INH-induced seizure involves a decrease in the availability of GABA, which is the major inhibitory neurotransmitter in the central nervous system (CNS), as well as a relative increase in the amounts of glutamate, the primary excitatory neurotransmitter. INH metabolites directly inhibit pyridoxine phosphokinase. This enzyme converts pyridoxine (vitamin B-6) to its active form, pyridoxal-5′-phosphate, a key cofactor in the production of GABA. This functional depletion of pyridoxine causes a disruption of glutamate and GABA homeostasis and leads to an excessive excitatory milieu in the brain.

Chronic INH hepatotoxicity results in the induction of hepatocyte apoptosis, with associated disruption of mitochondrial membrane potential and DNA strand breaks. ^[5] The most likely biochemical mechanism is that the metabolism of INH produces reactive metabolites that bind and damage cellular macromolecules in the liver. INH is mostly acetylated via the liver and the subsequent product, acetylisoniazid, and further (1) eliminated by the kidney; (2) oxidized to hydroxylamine, a toxic metabolite; (3) hydrolyzed into hydrazine, also toxic; or (4) further hydrolyzed to another toxic compound, acetylhydrazine. Patients who are slow acetylators may be at higher risk for hepatotoxicity. ^{[6, 7, 8, 9]}

The mild elevation of transaminases seen in as many as 20% of patients who are treated during the first 2 months of therapy may reflect direct toxicity from hydrazine metabolites, which can covalently bind to cellular macromolecules, including DNA. The more severe form of hepatitis, seen in up to 1% of adults who are treated, may be a consequence of the production of more reactive species by the CYP-450 enzyme system.

Although the most common presentation of INH hepatotoxicity is hepatocellular damage, patients occasionally may present with true drug hypersensitivity characterized by skin rash, fever, and eosinophilia.

Acute central nervous system (CNS) toxicity typically occurs in isoniazid (INH) overdose, but it may also be found with therapeutic use if administered in conjunction with rifampin, ethanol, barbiturates, and other CYP-450 inducers.

A number of risk factors for the development of severe INH hepatotoxicity have been identified.

Genetic predisposition is an important factor, but no clinical test for this predisposition is currently available. ^{[10, 11, 12]} Age is an important risk factor, presumably reflecting aging-related changes in hepatic metabolism. Female sex increases both the risk of developing INH hepatitis and the risk of death once hepatitis develops. Animal studies suggest that low levels of certain antioxidants such as glutathione which are associated with poor nutrition increase the risk for hepatotoxicity. However, human studies to support these findings are lacking.

Patients taking carbamazepine, phenobarbital, or rifampin, or those who abuse alcohol while taking INH have a higher risk for hepatotoxicity. ^{[13, 14, 15]} Ethionamide and para-aminosalicylic acid may exacerbate the toxicity of INH by interfering with its acetylation. High plasma levels of INH do not increase the risk of hepatoxicity. Conversely, neither administering lower INH doses nor monitoring plasma levels during therapy helps to decrease the rate of hepatotoxicity.

In a study of genetic predisposition to hepatotoxicity induced by anti-tuberculosis (TB) drugs that investigated the association between INH hepatitis and polymorphisms in genes for 7 drug-metabolizing enzymes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, NAT2, UGT1A1, and UGT1A3) in 67 patients with INH hepatitis and 159 control subjects, Kim et al identified a significant association between INH hepatitis and 2 mutations in NAT2 (-9796T>A in the promoter and R197Q) but found no association between the disorder and mutations in the other 6 genes. ^[16]

The rise in INH toxicity correlates with the rise in TB. During the late 1980s, the resurgence of TB in the United States caused the highest number of reported cases of INH exposures. Contributing factors include the following:

Acute toxicity

From 2009 to 2014, there were 1373 cases of isoniazid (INH) overdose reported by the American Association of Poison Control Centers’ National Data Collection System. Of these cases, 558 (40.6%) occurred in patients younger than 20 years, and 219 (16%) occurred in children younger than 5 years. In the past 6 years, 94 cases were reported as having a major effect, with two reported fatalities associated with INH. ^{[17, 18, 19, 20, 21, 22]}

Chronic toxicity

The frequency of INH hepatotoxicity depends on the threshold for making the diagnosis.

Approximately 10%-20% of adult patients receiving INH show elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to about 1-3 times the upper limit of normal during the first two months of therapy. These elevations typically normalize within 3-6 weeks after discontinuance of the drug. However, most patients who continue taking INH normalize the transaminase levels within several months, with no apparent adverse effects from continuing the drug.

A comprehensive study of 13,838 INH-treated patients published by the US Public Health Service (USPHS) in 1978 found that about 10% of patients with mild transaminase elevations (1-2% of all adults treated) progress to severe hepatitis and liver failure unless the drug is discontinued. ^[12] Death occurred in 8 patients (0.06%). When INH is given together with other drugs for active TB, the incidence of severe hepatotoxicity is greater.

Subsequent retrospective studies suggested a much lower incidence of toxicity, provided that patients were monitored according to the current guidelines. On average, hepatotoxicity occurs in 9.2 of 1000 patients taking INH for antituberculosis therapy. ^[23]

Rates within different countries reflect the frequency of INH use and tend to be highest in countries that have both sufficient public health resources to treat TB and large populations of patients infected with TB. Many of these persons are coinfected with the human immunodeficiency virus (HIV). Patients who are coinfected are at a particularly high risk for hepatitis, because both antituberculosis therapy and antiviral therapy may produce hepatotoxicity.

Patients of all ages may experience either chronic or acute INH hepatotoxicity. However, susceptibility to INH-induced hepatitis and subsequent death appears to increase dramatically with advancing age.

According to the USPHS study of 13,838 INH-treated patients reported by Kopanoff et al in 1978, hepatitis was uncommon in patients younger than 20 years and occurred in 0.3% of patients aged 20-34 years, 1.2% of patients aged 35-49 years, and 2.3% of patients aged 50-64 years. ^[12] Although subsequent studies have reported lower rates of hepatotoxicity, age remains an important risk factor for INH hepatotoxicity.

A study of a 7-year experience with INH hepatotoxicity in a public health TB clinic reported 4.40 events per 1000 for patients aged 25-34 years, 8.54 per 1000 for patients aged 35-49 years, and 20.83 per 1000 for those aged 50 years or older. ^[24]

INH hepatotoxicity may be more common in females than in males, especially the more severe forms of hepatitis leading to liver failure and death; however, not all studies have shown this finding. In a review of all possible INH-associated hepatitis fatalities from 1969 to 1989 in which the sex of the patient was identified, 111 cases (69%) occurred in females. In a study of 41 patients in New York City who were hospitalized at least overnight for INH toxicity, 27 (82%) were female. ^[25]

Women in the immediate postpartum period appear to be commonly affected. However, this may be because women are more likely to have their TB infection diagnosed during pregnancy, with treatment delayed until after childbirth.

Racial differences in the susceptibility to INH hepatotoxicity are relatively small, and no studies have shown any substantial race-based predilection for this condition.

The rate of acetylation of INH in the liver is race-dependent, with 60% of black patients and white patients being slow acetylators, compared with 10%-20% of Asians. Whereas slow acetylators appear to be more prone to INH-induced hepatitis and neuropathy with long-term use, it is unclear whether the rate of acetylation affects acute toxicity.

A 1975 study of more than 14,000 persons who were treated with INH found that hepatitis developed in 1.1% (55/5190) of white patients, 0.6% (36/6140) of black patients, and 0.9% (23/2608) of Asians, although follow-up was incomplete. Because fewer Asians (34%) than white (52%) or black (59%) patients dropped out of this study, the data suggest that the risk is lowest in Asians. Black females appeared to be at particularly high risk. However, a subsequent study by Yee and coworkers found a significantly elevated risk in Asians. ^[26]

Endemic cases of INH toxicity have been reported in persons who have emigrated from Southeast Asia because of their increased risk of TB and greater likelihood of undergoing INH therapy. Inuits and American Indians are also at an increased risk for TB and thus for INH toxicity.

In a review of possible INH-associated hepatitis fatalities identified between 1969 and 1989, a total of 38% occurred in black patients, 40% in non-Hispanic white patients, 15% in Hispanics, 4% in Native Americans, and 1% in Asians.

In adults, acute ingestion of as little as 1.5 g of isoniazid (INH) can lead to mild toxicity. ^[27] Acute ingestion of over 20 mg/kg can cause convulsions. Patients who ingest 80-150 mg/kg develop severe central nervous system (CNS) symptoms. ^[28] Ingestion of 6-10 g may be fatal, and ingestion of 15 g is usually fatal if not appropriately treated. Reported deaths from acute INH toxicity are rare.

The overall mortality for INH toxicity has been estimated to be as high as 20%. With current methods of supportive care, which include liver transplantation, mortality may now be lower. From 1972 to 1988, an estimated 152 fatalities were caused by INH-related hepatitis. A 2006 literature review estimated that hepatotoxicity occurred in 9.2 of every 1000 patients taking INH as anti-tuberculosis (TB) therapy, with a case-fatality rate of 4.7%. ^[23]

Survival rates depend on the severity of the hepatitis and on how early it is detected. If drug therapy is discontinued promptly when a 5-fold or greater transaminase elevation occurs (or a 3-fold or greater elevation with symptoms), mortality should be negligible. If INH is continued after this point or after symptoms develop, mortality due to hepatic failure may exceed 50% unless liver transplantation is performed. Patients who survive usually recover completely, without residual liver damage.

When hepatic failure occurs, prognosis depends on early identification and correction of complications (eg, aspiration pneumonia, hypotension, and cardiopulmonary arrest). Advanced age, underlying seizure disorder, severe metabolic acidosis, and decreased renal function are associated with a poor prognosis. Serum eosinophilia may be associated with a favorable outcome in patients with INH-induced hepatotoxicity.

All patients who receive isoniazid (INH) therapy should be counseled about the risk of severe hepatitis and the harmful effects of overdose. Warn all patients started on INH that the medication should be taken only as prescribed, and urge them to immediately report any symptoms suggestive of hepatitis, including nausea, fatigue, jaundice, and abdominal distress.

Advise patients to avoid heavy use of alcohol or acetaminophen and to maintain good nutrition.

Parents of pediatric patients should be instructed not to try to make up for any missed INH doses. Patients should be instructed to place INH pill bottle out of reach of young children to avoid accidental overdose.

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Joseph L D’Orazio, MD, FAAEM Director, Division of Medical Toxicology, Director, Medical Toxicology Fellowship Program, Department of Emergency Medicine, Einstein Medical Center; Consulting Staff in Medical Toxicology, Department of Pediatrics, Division of Emergency Medicine, Children’s Hospital of Philadelphia

Joseph L D’Orazio, MD, FAAEM is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology

Disclosure: Nothing to disclose.

Michael A Hayoun, MD, MPhil Resident Physician, Department of Emergency Medicine, Einstein Healthcare Network

Michael A Hayoun, MD, MPhil is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, American Medical Association, Emergency Medicine Residents’ Association

Disclosure: Nothing to disclose.

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Richard A Weisiger, MD, PhD Emeritus 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, American Society for Clinical Investigation

Disclosure: Nothing to disclose.

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.

Isoniazid Toxicity

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