What are the causes and risk factors of Isoniazid (INH) toxicity?

From the Guidelines

Isoniazid toxicity primarily occurs due to excessive dosing, prolonged treatment, or individual susceptibility factors, and the main risk factors include genetic variations, advanced age, malnutrition, pre-existing liver disease, and concurrent use of other hepatotoxic medications. The causes of isoniazid toxicity can be multifactorial, involving a combination of patient-related factors, treatment-related factors, and environmental factors. Some of the key risk factors for isoniazid toxicity include:

• Genetic variations in N-acetyltransferase 2 (NAT2) enzyme, which can lead to slow acetylation and drug accumulation in approximately 50% of Caucasians and African Americans 1
• Advanced age, which increases the risk of toxicity due to decreased drug metabolism and clearance
• Malnutrition, particularly vitamin B6 (pyridoxine) deficiency, which can heighten susceptibility as pyridoxine is depleted by isoniazid
• Pre-existing liver disease, including hepatitis, cirrhosis, or alcohol use disorder, which can significantly increase toxicity risk as isoniazid is metabolized in the liver
• Concurrent use of other hepatotoxic medications like acetaminophen, rifampin, or alcohol consumption, which can compound liver damage
• Pregnancy and the immediate postpartum period, which are associated with higher hepatotoxicity risk To prevent toxicity, pyridoxine supplementation (25-50 mg daily) is recommended for high-risk patients, particularly those with malnutrition, diabetes, HIV, alcoholism, pregnancy, or seizure disorders. Regular liver function monitoring is essential, especially during the first three months of treatment when most hepatotoxicity occurs 1. Patients should be educated about symptoms of toxicity, including nausea, vomiting, abdominal pain, jaundice, and neurological symptoms like peripheral neuropathy. It is also important to note that the risk of isoniazid toxicity can be reduced by careful monthly monitoring and stopping of medication if symptoms occur 1. In addition, routine measurements of hepatic and renal function and platelet count are not necessary during treatment unless patients have baseline abnormalities or are at increased risk of hepatotoxicity 1.

From the FDA Drug Label

The risk of developing hepatitis is age related Approximate case rates by age are: less than 1 per 1,000 for persons under 20 years of age, 3 per 1,000 for persons in the 20-34 year age group, 12 per 1,000 for persons in the 35-49 year age group, 23 per 1,000 for persons in the 50-64 year age group, and 8 per 1,000 for persons over 65 years of age. The risk of hepatitis is increased with daily consumption of alcohol Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease and injection drug use. A recent report suggests an increased risk of fatal hepatitis associated with isoniazid among women, particularly black and Hispanic women The risk may also be increased during the post partum period. Use of isoniazid should be carefully monitored in the following: Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + isoniazid hepatitis.Patients with active chronic liver disease or severe renal dysfunction.Age > 35.Concurrent use of any chronically administered medication.History of previous discontinuation of isoniazid. Existence of peripheral neuropathy or conditions predisposing to neuropathy.Pregnancy.Injection drug use.Women belonging to minority groups, particularly in the post-partum period. HIV seropositive patients

The causes and risk factors of Isoniazid (INH) toxicity include:

• Age: The risk of developing hepatitis is age-related, with increasing risk for persons over 35 years of age 2
• Alcohol consumption: Daily consumption of alcohol increases the risk of hepatitis 2 2
• Chronic liver disease: Patients with active chronic liver disease are at increased risk of hepatitis 2
• Injection drug use: Injection drug use is associated with an increased risk of hepatitis 2 2
• Pregnancy and post-partum period: The risk of fatal hepatitis may be increased during the post-partum period, particularly among women, especially black and Hispanic women 2 2
• Concurrent use of other medications: The use of any chronically administered medication may increase the risk of hepatitis 2
• History of previous discontinuation of isoniazid: A history of previous discontinuation of isoniazid may increase the risk of hepatitis 2
• Existence of peripheral neuropathy or conditions predisposing to neuropathy: Patients with peripheral neuropathy or conditions predisposing to neuropathy should be carefully monitored 2
• HIV seropositive patients: HIV seropositive patients should be carefully monitored 2

From the Research

Causes and Risk Factors of Isoniazid (INH) Toxicity

• Isoniazid (INH) therapy has been associated with severe liver injury, including hepatotoxicity and liver transplantation 3
• The risk of INH-associated liver injury is idiosyncratic and can occur in patients of any age, with or without putative predictors for liver injury 3
• Risk factors for INH toxicity include:
  • High age 4, 5
  • Malnutrition 5
  • High alcohol consumption 4, 5
  • Economic hardship 4
  • Chronic liver disease 4
  • Previous viral hepatitis 4
  • Intravenous drug use (IDU) 4
• Comorbidities, such as human immunodeficiency virus (HIV) infection, may increase the risk of INH-associated adverse events, but some studies suggest that HIV infection may actually decrease the odds of developing INH-associated adverse events 4
• Polypharmacy and concomitant use of other medications may also increase the risk of INH toxicity due to drug interactions 5

Hepatotoxicity and Liver Injury

• INH has been shown to cause severe liver injury, including hepatotoxicity and liver transplantation 3, 6, 7
• The risk of hepatotoxicity is higher with INH than with other anti-tuberculosis drugs, such as rifampicin and pyrazinamide 6
• Liver function should be monitored regularly in patients receiving INH therapy to prevent serious hepatotoxicity 3, 5

Other Adverse Reactions

• INH can also cause other adverse reactions, including:
  • Peripheral neuritis 5
  • Gastric reactions 5
  • Allergic reactions, including fever or rash 5
  • Ocular toxicity (with ethambutol) 5