Isoniazid Hepatotoxicity Workup

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

Approach Considerations

No correlation exists between serum isoniazid (isonicotinic acid hydrazide [INH]) levels and severity of acute intoxication. Serum INH levels are not readily available in most hospitals and do not help in the initial management of isoniazid toxicity.

Laboratory studies generally are not helpful in diagnosis of acute INH toxicity but may identify complications. Laboratory abnormalities observed with INH therapy include the following:

  • Elevated liver enzyme levels
  • Granulocytopenia or agranulocytosis
  • Eosinophilia
  • Thrombocytopenia
  • Anemia
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Laboratory Studies

Serum transaminases

levels of serum transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) should be determined. Patients with pretreatment AST levels above the upper limit of normal are predisposed to hepatotoxicity.

If transaminase values are elevated less than 3-fold in a patient who is asymptomatic, cautious continued administration of INH is permissible. However, additional testing to exclude other causes of hepatitis is usually indicated. If transaminase levels are elevated more than 3-fold, it is usually necessary to discontinue INH and any other potentially hepatotoxic drugs.

Viral serologies

Hepatitis A may be excluded by a negative test result for anti-HAV (hepatitis A virus) immunoglobulin M (IgM). Hepatitis C is excluded by a negative result for anti-HCV (hepatitis C virus) antibody; however, this test occasionally may remain negative for several weeks after the onset of hepatitis C. Hepatitis B may be excluded by a negative result for either hepatitis B surface antigen (HBsAg) or antibody to hepatitis B core antigen (anti-HBc). Testing for viral DNA or RNA also may be used, but it is more expensive.

Toxicology

Potential hepatotoxins other than INH must be excluded. In patients with a compatible history, blood or urine levels of other potential hepatotoxins (eg, acetaminophen and ethanol) may be useful.

Prothrombin time/international normalized ratio

The international normalized ratio (INR) usually is normal in early and mild cases. Significant elevation of the INR that does not respond to parenteral vitamin K is a grave sign that should prompt hospitalization and consultation with a transplant hepatologist.

Serum iron

High transferrin saturations associated with high ferritin levels suggest hemochromatosis, which often presents with transaminase abnormalities. However, ferritin is an acute-phase reactant that often is elevated in other types of hepatitis. Thus, the presence of high ferritin levels does not suggest hemochromatosis unless the iron saturation also is high. Genetic testing for hemochromatosis may be useful in these patients.

Serum ceruloplasmin

In younger persons, efforts must be made exclude Wilson disease, especially if any neuropsychiatric components exist.

Additional tests

Additional laboratory studies may be performed to assess for the following:

  • Elevated aspirin and acetaminophen levels in patients with intentional exposure
  • Urine toxicologic screen, if suicide is suspected
  • Pregnancy, if indicated
  • Leukocytosis (complete blood count [CBC])
  • Lactic acidosis
  • Hyperglycemia
  • Ketonuria
  • Glycosuria
  • Ketonemia
  • Hypokalemia
  • Transient elevation of liver enzymes
  • Myoglobinuria
  • Cerebrospinal fluid (CSF) pleocytosis
  • Ketonemia
  • Positive disseminated intravascular coagulation (DIC) panel
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Other Studies

Abdominal imaging is not normally required and should only be considered in patients with symptoms suggesting biliary disease or to exclude biliary obstruction if the alkaline phosphatase level is elevated more than the transaminase levels are. Imaging may show hepatomegaly, but splenomegaly and ascites typically are absent. Computed tomography (CT) of the head, with and without intravenous (IV) contrast, is recommended in patients with seizures of questionable etiology.

Electrocardiography (ECG) is recommended in patients with a suspected history of tricyclic antidepressant toxicity, which can reveal QRS prolongation.

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Histologic Findings

Liver biopsy is rarely indicated for evaluation of acute hepatitis, because the histologic features typically are nonspecific. Liver histology closely resembles that of acute viral hepatitis and includes ballooning degeneration, sinusoidal acidophilic bodies, and focal necrosis occasionally accompanied by slight cholestasis. Necrosis is more extensive in cases that are more severe. Inflammatory infiltrates with lymphocytes and plasma cells are common, whereas eosinophilic infiltrates are rarely seen.

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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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