Isoniazid Toxicity Clinical Presentation

Updated: Jul 14, 2016
  • Author: Joseph L D'Orazio, MD, FAAEM; Chief Editor: BS Anand, MD  more...
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Presentation

History

Acute toxicity

In an acute isoniazid (INH) overdose, patients are typically 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

When INH is taken daily at approved doses, INH hepatotoxicity typically develops within the first few months of therapy, but it may also present later. Symptoms may remain mild until after potentially lethal liver damage has occurred. Thus, patients taking INH should be educated to look for signs of liver toxicity and to report them immediately if they occur.

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 including anorexia, nausea, and vomiting. Immediate cessation of INH and any other potentially hepatotoxic drugs is required.

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Physical Examination

Acute toxicity

Ingestion of isoniazid (INH) 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 20 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. [28]
  • Increased anion gap metabolic acidosis (see the Anion Gap calculator): Lactemia (lactic acidemia) is most likely secondary to muscle activity associated with generalized clonic tonic seizure.
  • Coma: Hepatic encephalopathy or coma may develop after the onset of other symptoms of severe disease; coma may last for 24-36 hours and may persist despite resolution of seizures and acidemia.

Other signs of acute 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
  • Rhabdomyolysis

Chronic toxicity

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 ecchymoses, bleeding from the gingiva, or have other manifestations of coagulopathy.

Various adverse effects of long-term ingestion of INH have been identified. Peripheral neuropathy and optic neuritis is uncommon in healthy individuals, but it is 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, as well as 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 INH use include the following:

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