Isoniazid Hepatotoxicity Clinical Presentation

Author: Richard A Weisiger, MD, PhD; Chief Editor: Julian Katz, MD more...

Updated: May 23, 2012

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History
Physical Examination
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History

Isoniazid (isonicotinic acid hydrazide [INH]) hepatitis typically develops within the first few months of therapy, but it may present later (see the image below). Symptoms may remain mild until after potentially lethal liver damage has occurred. Thus, patients taking isoniazid should be educated to look for signs of liver toxicity and to report them immediately if they occur.

Risk of developing overt hepatitis versus duration of therapy. Most hepatitis presents early in the course of therapy.

In acute INH toxicity, patients are usually symptomatic within 30-45 minutes. However, symptoms may be delayed up to 2 hours, when the peak serum level occurs. Potential symptoms include the following:

Nausea
Vomiting
Diarrhea
Irritability
Lethargy
Vague abdominal pain
Confusion
Dizziness
Light sensitivity

Symptoms typically precede jaundice and liver failure by only a few days. Constitutional symptoms include fatigue, anorexia, nausea, myalgia, and arthralgia. Symptoms due to liver failure include jaundice, dark urine, light-colored stools, bleeding diathesis, pruritus, confusion, and coma. Symptoms due to hepatic inflammation include right upper quadrant tenderness and gastrointestinal (GI) distress. Immediate cessation of INH and any other potentially hepatotoxic drugs is required.

Physical Examination

The physical findings associated with INH hepatotoxicity resemble those characteristic of other forms of acute hepatitis.

Jaundice, evidenced by yellowing of the skin, sclera, or mucous membranes, is present in more severe cases as a late manifestation. Right upper quadrant tenderness may be elicited. Hepatomegaly may be present, but splenomegaly and ascites usually are absent. Stigmata of chronic liver disease typically are absent unless prior liver disease exists. In advanced cases, patients may exhibit bleeding from the gingiva or ecchymoses or have other manifestations of coagulopathy.

Ingestion of isoniazid in excess of 200 mg/kg produces a characteristic clinical triad, as follows:

Refractory seizures that are unresponsive to standard anticonvulsants – Seizures may be observed after ingestion of less than 40 mg/kg and are typical after doses of 80-150 mg/kg; they may occur abruptly and are often generalized and tonic-clonic, but focal seizures have been described
Increased anion gap metabolic acidosis
Coma – Hepatic encephalopathy or coma may develop after onset of other symptoms of severe disease

Other signs of INH toxicity include the following:

Hypotension
Tachycardia
Hyperpyrexia
Stupor
Tremor
Choking spells
Slurred speech
Mydriasis
Urinary retention
Ataxia
Hyperreflexia
Areflexia
Nystagmus
Hemorrhage (in the setting of disseminated intravascular coagulation [DIC])
Cyanosis

Various adverse effects of long-term ingestion of INH have been identified. Peripheral neuritis is uncommon in healthy individuals but more common in persons with diabetes, those with alcoholism, and malnourished elderly individuals. An increased risk of hepatitis has been noted in patients who are concomitantly using carbamazepine, phenobarbital, or rifampin and in those who abuse alcohol.

INH is known to cause a positive antinuclear antibody (ANA) test result in 25% of patients and to cause clinically apparent drug-induced lupus, characterized by fever, rash, arthralgias, arthritis, and constitutional symptoms, in approximately 1% of patients.

In rare cases, INH causes mania, depression, obsessive-compulsive disorder, and psychosis, probably either by acting as a monoamine oxidase inhibitor (MAOI) or by depleting pyridoxine. Rarely, an MAOI tyramine syndrome may occur after the ingestion of tyramine-containing foods (eg, red wines or cheeses).

A hypersensitivity reaction is usually absent but may be observed in 2% of patients using INH. Signs and symptoms include fever, lymphadenopathy, and skin rashes.

Other adverse effects from long-term use include the following:

Fever, GI upset, oliguria, arthralgias, malaise
Optic neuritis
Paresthesias
Hepatic encephalopathy

Proceed to Differential Diagnoses

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