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Isoniazid Toxicity
Introduction
Isoniazid (INH) is a potent bactericidal tuberculosis (TB) antibiotic. Treatment with INH therapy has a risk of toxicity, which is acute or chronic. Acute toxicity manifests as neurological symptoms, specifically seizures. Consumption of as little as 2 g of INH can predispose a patient to acute toxicity. Patients with certain risk factors and prolonged use can develop chronic toxicity, presenting as hepatotoxicity and peripheral neuropathy.
Two known syndromes of hepatotoxicity are recognized:
- Mild type manifesting as transient and asymptomatic elevation in serum aminotransferase levels
- Severe acute hepatitis that is fatal [1]
Peripheral neuropathy is secondary to vitamin B6 (pyridoxine) deficiency, though the prevalence is relatively low.
Etiology
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Etiology
Isoniazid is a potent antimycobacterial agent that inhibits TB cell wall synthesis and is used in therapeutic and prophylactic regimens. Introduced in 1954, INH has contributed to the treatment of TB, resulting in a significant decline in TB-related morbidity and mortality. The recommended dose of INH in adults is 300 mg (5 mg/kg) daily to 900 mg (15 mg/kg) once or twice weekly. Due to the rapid development of microorganism resistance, treatment regimens include other antibacterial agents. Most of the regimens have INH alone or with other agents, including rifampin, pyrazinamide, streptomycin, or ethambutol. Common side effects include gastrointestinal upset, fever, and rash. High doses of INH can cause peripheral neuropathy, preventable with concurrent administration of pyridoxine (vitamin B6).
Hepatotoxicity development increases with other contributing risk factors such as increased age, alcohol consumption, concurrent use of medications that induce cytochrome P oxidative enzymes, prior or concurrent liver disease like viral hepatitis, previous INH intolerance, female sex, injection drug use, and genetic causes like slow acetylation status.[2][3]
Epidemiology
Acute toxicity is rarely reported in the United States. According to the report from the American Association of Poison Control Centers based on the National Poison Data System, only 54 cases of INH toxicity were reported in 2020, with the majority being unintentional, such as in the case of exploratory ingestions in children.[4] Transient asymptomatic liver enzyme elevation due to INH is seen in 15% to 20% of recipients. INH-induced, clinically apparent, acute liver injury with jaundice is seen in 0.5% to 1% of recipients, and the risk of fatal hepatitis is about 0.05% to 1%. While the occurrence of mild hepatotoxicity is not related to acetylation status, the occurrence of acute hepatitis can depend on it.[5] The incidence of peripheral neuropathy is 1.1% in the general population and around 6.5% in older patients.
Pathophysiology
A functional pyridoxine deficiency causes INH toxicity. This occurs via 2 different mechanisms. In normal physiology, pyridoxine is metabolized to an active form, pyridoxal-5'-phosphate, an important cofactor in several biotransformation reactions. INH metabolites can inhibit the enzyme pyridoxine phosphokinase, which converts pyridoxine to its active form. INH also directly combines with pyridoxal phosphate, forming an inactive hydrazone. This complex is renally excreted.[6] Increasing doses of INH also lead to increased urinary excretion of pyridoxine. This functional depletion is similar to that which occurs in gyromitrin mushroom poisoning and poisoning from rocket fuel (hydrazine).
Acute toxicity manifests due to the depletion of gamma-aminobutyric acid (GABA) neurotransmitters. Functional depletion of pyridoxine leads to the inhibition of glutamic acid decarboxylase, which converts glutamate to GABA.[7] Hepatic injury is thought to occur through 2 mechanisms. The first is an immunologic process. The more common mechanism involves INH metabolites hydrazine, acetylhydrazine, and free radicals that are involved in the pathogenesis of INH-induced hepatitis. INH is metabolized via the N-acetyltransferase 2 gene (NAT2) to form the inactive N1-acetyl-N2-isonicotinohydrazide (AcINH), which is then hydrolyzed to form monoacetylhydrazine (AcHZ) and isonicotinic acid, INA. These metabolites are further acetylated to non-toxic metabolites and excreted in the urine. As NAT2 is the primary enzyme involved in the metabolism of INH, its deficiency can cause INH-related hepatotoxicity. This is particularly seen in slow acetylators due to the higher concentration of AcHZ.
The incidence of toxic hepatitis increases when INH is used with rifampin, pyrazinamide, or barbiturates, as these medications are inducers of the cytochrome P (CYP) enzyme system, resulting in increased production of toxic INH metabolites.[8][9][10] CYP2E1 likely plays a vital role.[3][11] INH causes peripheral neuropathy through the depletion of pyridoxine via the mechanisms mentioned above. Risk factors for the development of neuropathy include malnutrition, alcohol use, uremia or renal failure, and diabetes. Slow acetylators are also at higher risk. INH is also associated with optic neuritis, particularly in patients who are also metabolizing ethambutol and etanercept.[12][13][14]
Histopathology
Liver biopsy of INH hepatotoxicity reveals morphologic changes similar to viral hepatitis, such as bridging necrosis, increased numbers of eosinophils, and prominence of cholestasis.[15][16]
Toxicokinetics
Therapeutic doses of INH vary between 300 mg daily to 900 mg 2 to 3 times a week. When an oral dose of 300 mg is taken, it is rapidly absorbed with peak serum concentrations occurring within 2 hours, ranging between 3 to 5 μg/mL.[17][18] Delayed absorption leading to peak serum concentrations at 6 hours post-ingestion is also possible.[19]
INH is metabolized primarily via acrylamide NAT2 to acetyl isoniazid, which is renally excreted and metabolized further to hydrazine or acetyl hydrazine. These metabolites are further metabolized into reactive metabolites, leading to increased oxidative stress in the liver and hepatic damage. Between 75% to 95% of these metabolites are renally excreted within 24 hours of ingestion.
History and Physical
Acute toxicity presents as altered mental status, seizures, and sometimes status epilepticus.[20] Long-term complications include anoxic encephalopathy and dementia. The onset of INH-induced hepatotoxicity is insidious, ranging from 2 weeks to 6 months. Toxicity usually affects adults around 35 years, with the highest frequency among those over 50 years. Other risk factors include chronic supratherapeutic dosing and co-administration of other anti-tuberculous drugs, such as rifampin and malnutrition. The symptoms are similar to viral hepatitis, with prodromal symptoms of nausea, anorexia, fatigue, abdominal discomfort, right upper quadrant pain, generalized flu-like symptoms, dark urine, and jaundice.
Neuropathy symptoms are usually sensory and include numbness, tingling, and a burning sensation in all the extremities; they present in a stocking-glove distribution and progress proximally.[21] Central features like ataxia and nystagmus are rarely seen. Patients with optic neuritis will have decreased visual acuity, eye pain, and dyschromatopsia. Patients can also have central scotoma and bitemporal hemianopsia on visual field testing.[22]
Evaluation
Lab evaluation should include complete blood counts, a basic metabolic panel, a hepatic function panel, a creatinine kinase level, a lactate level, and arterial or venous blood gas. If available, INH serum concentrations can be considered, but this testing is not readily available, and care should not be delayed.
Acute toxicity manifests as seizures, metabolic acidosis, and coma. The metabolic acidosis is associated with elevated lactate, likely secondary to muscle contraction from seizure activity.[23] Acute toxicity is associated with INH serum concentrations greater than 10 μg/mL at 1 hour, 3.2 μg/mL at 2 hours, and 0.2 μg/mL at 6 hours.[24] Management should not be delayed waiting for serum INH concentrations. In chronic toxicity, the pattern of elevation of liver enzymes is consistent with a hepatocellular injury with marked alanine aminotransferase and aspartate aminotransferase elevations (greater than 10 times the upper limit of normal) and minimal alkaline phosphatase elevations. The injury is mostly self-limited except for 10% of the cases where it can progress to acute liver failure with clinical manifestations of coagulopathy, ascites, edema, and encephalopathy.[25]
INH therapy can induce the production of antinuclear antibodies (ANA). These can be present during the acute hepatic injury phase but usually in very low titers. As ANA can also be positive in autoimmune hepatitis, the absence of arthralgia and hyperglobulinemia can help differentiate it from INH-induced hepatotoxicity. Recently, antibodies to INH have been detected in INH recipients, but their presence is not fully linked to liver injury.
Treatment / Management
Acute toxicity is approached by strict airway management, activated charcoal if the patient presents early, seizure management with the use of benzodiazepines, and pyridoxine administration (this helps with the rapid restoration of GABA stores).[26] If the amount of INH ingested is known, pyridoxine should be given at a gram-for-gram equivalent dose. If the amount of INH is unknown, a 70 mg/kg dose up to a maximum of 5 g is recommended. A second dose can be given if a patient continues to have seizures. Rapid resolution of seizure and coma is expected with pyridoxine administration.[27] In patients presenting with renal failure, massive ingestions, or insufficient pyridoxine to treat a patient, extracorporeal removal is considered.[28](A1)
Elevated serum aminotransferase levels develop during the first few weeks of therapy and are termed mild INH hepatotoxicity. In most cases, such toxicity is self-limiting, and the adaptive response allows the continuation as long as patients remain asymptomatic without a progressive elevation in aminotransferase levels. However, INH should be immediately discontinued if hepatitis-related symptoms or progressive elevation in aminotransferase levels are present. The onset of any symptoms of hepatitis, such as anorexia, nausea, jaundice, and fatigue in a patient with abnormal liver biochemical tests, should prompt cessation of INH.
The exact level of aminotransferases at which INH should be discontinued is unclear; the general recommendation is that if the total bilirubin is greater than 3 mg/dL and liver enzymes are over 5 times the upper limit of normal, INH (including other anti-TB medications) should be discontinued. If the bilirubin is less than 3 mg/dL and liver enzymes are less than 5 times the upper limit of normal, therapy can be continued, but liver enzymes should be checked in 3 days.
If liver enzymes continue to worsen or patients develop symptoms of hepatitis, therapy should be discontinued, or close monitoring is recommended.[29] When the liver enzymes return to baseline (or less than twice normal), the potential hepatotoxic drugs can be restarted one at a time with careful monitoring. Rechallenge with INH may be done cautiously with serial monitoring of liver biochemical tests in patients with a strong indication for therapy and who have not had severe hepatoxicity.
Many public health programs require INH prevention after a positive tuberculin skin test or a blood test for diagnosing TB infection, including monthly liver enzyme monitoring. However, limited evidence of benefit exists for such practice. Monitoring liver biochemical tests on therapy is generally recommended in patients with chronic liver disease or in those who are 50 years or older, as these individuals are at a higher risk for developing hepatotoxicity.[3] Though no specific therapies are evident for INH-induced liver damage, results from some studies have shown a mortality benefit in using corticosteroids and N-acetylcysteine early in the course of liver injury. In rare instances, the hepatotoxicity from INH is very severe, prompting the need for an emergency liver transplant.[30] Peripheral neuropathy can be prevented and treated by prescribing pyridoxine daily with INH.(B3)
Differential Diagnosis
Seizures and status epilepticus mainly characterize the presentation of acute INH toxicity. The differential is broad and includes:
- Undiagnosed seizure disorder
- Metabolic disorder
- Intracranial hemorrhage
- Traumatic brain injury
- Ethanol withdrawal
- Sedative or hypnotic withdrawal (eg, benzodiazepines, baclofen, barbiturates)
- Sympathomimetic toxicity
- Hydrazine (eg, rocket fuel) toxicity
- Gyromitrin mushroom toxicity
The main differential diagnoses of chronic INH toxicity include the differentials for jaundice and peripheral neuropathy.
Jaundice
- Hemolytic jaundice
- Obstructive jaundice
- Other hepatotoxic drug toxicity: non-steroidal anti-inflammatory drugs, anti-virals for human immunodeficiency virus infection, statins
- Viral hepatitis
Peripheral Neuropathy
- Alcoholic neuropathy
- Diabetic neuropathy
Optic Neuritis
- Ethambutol toxicity
- Autoimmune disease (eg, lupus)
- Multiple sclerosis
- Infectious
Toxicity and Adverse Effect Management
Isoniazid has multiple drug-drug interactions that can either increase the risk of toxicity from INH or increase toxicity from other drugs. Many of these interactions arise from CYP450 enzyme inhibition, resulting in increased concentrations of respective substrates. These include CYP1A2, CYP2C9/CYP2C19, and CYP3A4.[31][32][33] A complex relationship with CYP2E1 is evident, with an initial inhibitory effect followed by activity induction. INH also possesses weak monoamine oxidase inhibitory activity.[34][35]
Described interactions include:
- Increased risk of hepatic necrosis due to rifampin, pyrazinamide, and ethanol
- Increased INR in the setting of warfarin use (CYP2C9/CYP2C19)
- Unknown effects after interaction with acetaminophen
- Increased serum concentration of phenytoin (CYP2C9/CYP2C19), carbamazepine (CYP3A4), and theophylline (CYP1A2)
- Increased serum INH after ingestion of food, antacids, and lactose
- Tyramine reaction following consumption of red wine or soft cheeses
- Worsened scombroid toxicity [36]
Prognosis
The prognosis for INH toxicity is generally positive. In acute toxicity, rapid treatment with pyridoxine leads to the resolution of seizures, coma, and metabolic acidosis.[37] In the setting of chronic toxicity, patients have complete recovery from peripheral neuropathy, optic neuritis, and other CNS toxicity when pyridoxine is supplemented. In some patients, residual sensory neuropathy may persist.[38][39]
Complications
Potential complications of INH toxicity include hepatic failure, coma, peripheral neuropathy, optic neuritis, encephalopathy, and death.
Consultations
If concern for acute INH toxicity is present, pyridoxine should be administered as soon as possible. Consultation with a medical toxicologist or the regional poison control center should be obtained to help manage the patient's condition.
Deterrence and Patient Education
The patient should be instructed on the proper dosing of INH. Instructions should be clear concerning the dose and frequency to avoid accidental overdose, especially in children.
Enhancing Healthcare Team Outcomes
With rising rates of TB, the prescription of INH has increased. Sometimes, INH toxicity occurs because of multiple or inadvertent dosing. INH toxicity is usually managed by an interprofessional team that consists of an emergency clinician, a nurse practitioner, a medical toxicologist, a certified specialist in poison information at a poison control center, a neurologist, and an internist.
In all cases of INH toxicity, the offending agent must first be discontinued. The treatment is pyridoxine for acute toxicity. If evidence of liver damage is seen, small case studies suggest the use of N-acetyl cysteine and corticosteroids. In rare cases, a liver transplant may be required. Today, peripheral neuropathy is rarely seen because most patients are prescribed pyridoxine at the initiation of INH therapy.[40][41]
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