Isoniazid Toxicity

What is Isoniazid Toxicity?

Isoniazid, often referred to as INH, is a strong antibiotic used to treat tuberculosis (TB), a serious lung infection. However, treatment with INH can come with risks of toxicity, which can be sudden (acute) or long-term (chronic).

Acute toxicity can cause neurological symptoms, in particular, seizures. Ingesting even as little as 2 grams of INH could make a patient prone to acute toxicity. Patients with certain risk factors and long-term use of INH could develop chronic toxicity, showing as damage to the liver (hepatotoxicity) and damage to the peripheral nerves (peripheral neuropathy).

There are two known conditions of liver damage from INH:

1. A mild type, not causing any symptoms, and only showing up as a temporary increase in liver enzyme levels in blood tests
2. A severe acute liver disease which can be deadly

The nerve damage can be because of a lack of vitamin B6 (also known as pyridoxine), although this is not very common.

What Causes Isoniazid Toxicity?

Isoniazid, often abbreviated as INH, is a highly effective drug that fights against the bacteria causing tuberculosis (TB), by blocking its ability to build cell walls. This medicine has been successfully used for TB treatment and prevention since the 1950s, helping to significantly reduce TB-related illness and death.

The suggested dose for adults ranges from 300 mg daily to 900 mg once or twice a week. However, because bacteria can quickly adapt and become resistant to medicines, INH is usually used alongside other antibiotics for TB treatment. Some commonly paired drugs include rifampin, pyrazinamide, streptomycin, or ethambutol, to help fight the bacteria from different angles.

INH might cause some mild side effects like stomach discomfort, fever, and skin rash. Taking it in high doses could potentially lead to peripheral neuropathy, a kind of nerve damage that affects the hands and feet. However, this can be prevented by taking it with vitamin B6 (also known as pyridoxine).

Some conditions can increase the risk of liver damage while on INH treatment, such as older age, alcohol use, taking other medications that affect the body’s cleansing system, prior or ongoing liver disease like viral hepatitis, previous intolerance to INH, being female, illicit injection drug use, and certain inherited traits such as slow acetylation status.

Risk Factors and Frequency for Isoniazid Toxicity

Acute toxicity, particularly from INH (a drug often used to treat tuberculosis), isn’t commonly seen in America. A report found that there were only 54 cases of INH toxicity in 2020. Many of these cases were accidents, such as children unknowingly ingesting the drug.

• Between 15 and 20 percent of people who take INH have a temporary rise in their liver enzymes which doesn’t cause symptoms.
• In 0.5 to 1 percent of people, INH prompts acute liver damage, causing yellowing of the skin and eyes (jaundice).
• The chance of getting life-threatening liver inflammation (hepatitis) from INH is about 0.05 to 1 percent.
• While mild liver toxicity from INH doesn’t depend on how quickly your body breaks down the drug, the risk of acute hepatitis might.
• Peripheral neuropathy, a condition that results in weakness, numbness and pain, happens in about 1.1 percent of the general population taking INH and around 6.5 percent of aged patients taking the drug.

Signs and Symptoms of Isoniazid Toxicity

Acute toxicity from certain substances can result in changes in mental state, seizures, and in some cases, persistent seizures known as status epilepticus. Issues that can develop over time include brain damage due to a lack of oxygen and dementia. The start of liver toxicity caused by INH, a form of medication, can be gradual, showing up anywhere between 2 weeks to 6 months. Adults around the age of 35 are most commonly affected, particularly those over 50 years. Other factors that make a person more likely to experience liver toxicity include long term use of high doses of medication, combining multiple drugs for treating tuberculosis, like rifampin, and malnutrition. The symptoms of liver toxicity are similar to those of viral hepatitis, with early signs including:

• Nausea
• Lost appetite
• Fatigue
• Abdominal discomfort
• Pain in the upper right side of the abdomen
• General flu-like symptoms
• Dark-colored urine
• Yellowing of skin and eyes, also known as jaundice

Nerve-related symptoms, often felt as numbness, tingling, or a burning sensation, typically occur in both the hands and feet and can slowly spread towards the upper body. Serious symptoms, like lack of coordination or involuntary eye movements, are rarely seen. Those with optic neuritis, a condition that inflames the nerves in the eyes, may experience reduced vision, eye pain, and issues with color perception. They may also notice central blind spots and a loss of vision on the outer sides of their visual field.

Testing for Isoniazid Toxicity

If your doctor suspects you may have a serious response to a medication or illness, they may conduct several lab tests. These tests could include an examination of your blood’s contents, the level of basic chemicals in your body, your liver function, a specific protein called creatinine kinase, as well as the amount of lactate and pH level in your blood. There’s also a test for INH serum concentrations, but it’s not always available and your treatment won’t be delayed waiting for it.

Severe reactions to certain medications and illnesses can trigger seizures, a condition known as metabolic acidosis (when your body’s fluids contain too much acid), and coma. High lactate levels usually accompany metabolic acidosis, likely due to your muscles contracting unusually due to seizures. This reaction can be connected to high INH serum concentrations, but your treatment won’t be delayed waiting for these test results.

Chronic exposure to toxic substrates can affect your liver, specifically increasing the levels of alanine aminotransferase and aspartate aminotransferase, enzymes that usually indicate liver damage if found in high levels in your blood. In some severe instances, around 10% of cases, it can progress to acute liver failure, leading to problems with blood clotting, fluid accumulation in the belly (ascites), swelling (edema), and a decline in brain function (encephalopathy).

Treatment with INH (a medication used for tuberculosis) can cause your body to produce antinuclear antibodies (ANA), which usually signal that the body’s immune system is attacking its own cells. They can be present during acute liver injury phase but usually in very low amounts. These antibodies can also show up in a condition called autoimmune hepatitis, so if you don’t have joint pain and an unusually high level of globulin (a type of protein in the blood), it could suggest your liver damage came from INH. That being said, recent findings have detected antibodies to INH in patients taking it, but it isn’t entirely clear whether their presence directly ties into liver injury.

Treatment Options for Isoniazid Toxicity

When dealing with acute toxicity, the primary focus is ensuring the patient’s airway remains clear. If the patient gets to the hospital in time, activated charcoal may be used, which can absorb harmful substances that have been ingested. If seizures occur, medicines called benzodiazepines can be used to manage them. Pyridoxine is given to help restore GABA stores, a neurotransmitter in the brain that helps send messages. This can improve seizure and coma symptoms rapidly. For larger ingestions or cases where there is not enough pyridoxine, a process known as extracorporeal removal might be considered. This is a procedure that helps the body remove harmful substances.

During the first few weeks of taking INH (Isoniazid, a medication used to prevent and treat tuberculosis), some patients might see an increase in their serum aminotransferase levels. This is an enzyme that helps the liver work effectively. However, in most cases, this increase is self-limiting, meaning it should resolve on its own over time. But if the patient shows symptoms of hepatitis, which includes loss of appetite, nausea, a yellowing of the skin and eyes (jaundice), and fatigue, or if the aminotransferase levels keep rising, the use of INH should be discontinued immediately.

The exact increase of aminotransferase levels at which INH should be stopped is not clear. However, generally, if the total bilirubin (a substance produced by the liver) is more than 3 mg/dL and liver enzymes are over five times the normal limit, INH should be stopped. If these levels are less than that, treatment can continue, but liver enzymes should be checked again in three days to ensure they are not worsening. It is important if there are increasing symptoms of hepatitis or the liver enzymes keep worsening, the medication should be stopped, or the patient should be closely monitored.

Once the liver enzymes come back to normal levels, the medication that may harm liver can be restarted one at a time and with careful monitoring, including INH if the therapy indication is strong and if severe hepatotoxicity (liver damage due to chemicals like INH) was not a problem before the treatment.

Many public health programs who diagnose a TB infection via a skin or blood test recommend INH treatment as prevention. Usually, liver enzyme monitoring is conducted every month, especially in patients with an existing liver disease, or those aged 50 years and above, as they are at a higher risk for developing liver damage due to INH. Although no specific therapies are available for liver damage caused by INH, some studies show that using corticosteroids and N-acetylcysteine (an antioxidant that can help reduce inflammation and promote healing) early in the treatment process may help. However, in rare and severe cases of liver damage caused by INH, an emergency liver transplant may be required. The side effect of peripheral neuropathy (nerve damage that causes weakness, numbness and pain) can be prevented and treated by giving pyridoxine daily along with INH.

What else can Isoniazid Toxicity be?

If someone has been poisoned by acute INH, it’s usually characterized by seizures and a condition called status epilepticus. But, it might be something else entirely, such as:

• An undiscovered disorder causing seizures
• A metabolic disorder
• Bleeding within the brain, known as intracranial hemorrhage
• A traumatic brain injury
• Withdrawal from alcohol
• Withdrawal from drugs that make you sleep or feel less anxious (like benzodiazepines, baclofen, barbiturates)
• A reaction to sympathomimetic drugs
• Exposure to hydrazine, a toxic chemical present in rocket fuel
• Accidentally eating gyromitrin mushrooms, which are toxic

There are also a number of factors that could be the root cause if someone has been poisoned by chronic INH. These could include:

• Diseases and conditions that cause jaundice (yellowing of the skin), such as:
  • Hemolytic jaundice caused by rapid red blood cell breakdown
  • Obstructive jaundice, caused by a blockage in your bile ducts
  • The effects of other drugs that damage the liver, like certain types of anti-inflammatory drugs, antiviral drugs for HIV, or statins
  • Viral hepatitis
• Diseases that lead to peripheral neuropathy (nerve damage), such as:
  • Alcoholic neuropathy, from heavy drinking over a long period of time
  • Diabetic neuropathy, which is nerve damage due to high blood sugar levels
• Causes of optic neuritis (inflammation of the optic nerve), such as:
  • Exposure to ethambutol, a drug used to treat tuberculosis which can cause eye damage
  • An autoimmune disease like lupus
  • Multiple sclerosis, a disease of the nervous system
  • Serious infections

What to expect with Isoniazid Toxicity

The outlook for INH toxicity is typically good. In the instance of sudden or ‘acute’ toxicity, providing a quick treatment with a vitamin called pyridoxine helps to clear symptoms such as seizures, coma, and metabolic acidosis – a serious condition that occurs when the body produces too much acid or the kidneys aren’t removing enough acid from the body.

With chronic (long-term) toxicity, patients usually fully recover from peripheral neuropathy (damage to the peripheral nerves, which transmit signals between the body and the brain), optic neuritis (an inflammation of the optic nerve that can cause vision loss), and other damage to the central nervous system, (CNS, consisting of the brain and spinal cord) when vitamin pyridoxine is added to their treatment. However, in some people, a residual (remaining) sensory neuropathy, a form of nerve damage that causes various symptoms such as pain, tingling, or numbness, may persist.

Possible Complications When Diagnosed with Isoniazid Toxicity

Some possible complications from INH toxicity could involve liver failure, coma, damage to peripheral nerves, inflammation of the optic nerve, brain disorders, and even death.

Possible Complications:

• Liver failure
• Coma
• Damage to peripheral nerves
• Inflammation of the optic nerve
• Brain disorders
• Death

Preventing Isoniazid Toxicity

The patient should be guided on how to correctly take INH (a type of medication). It’s crucial the instructions given are clear about the amount to take and how often to take it. This is to prevent any accidental cases of taking too much, especially in children.