12. Major adverse drug reaction of Isoniazid
O a. Nephrotoxicity
O b. Hepatotoxicity
Ο Ο Ο Ο
c. Neuromuscular paralysis
d. Ototoxicity
Answers
Isoniazid (INH) remains a mainstay for the treatment of tuberculosis despite the fact that it can cause liver failure. Previous mechanistic hypotheses have classified this type of drug‐induced liver injury (DILI) as ‘metabolic idiosyncrasy’ which was thought not to involve an immune response and was mainly due to the bioactivation of the acetylhydrazine metabolite. However, more recent studies support an alternative hypothesis, specifically, that INH itself is directly bioactivated to a reactive metabolite, which in some patients leads to an immune response and liver injury. Furthermore, there appear to be two phenotypes of INH‐induced liver injury. Most cases involve mild liver injury, which resolves with immune tolerance, while other cases appear to have a more severe phenotype that is associated with the production of anti‐drug/anti‐CYP P450 antibodies and can progress to liver failure.
Keywords: biomarker, hepatotoxicity, immune mediated, reactive metabolite, tolerance
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Clinical characteristics of isoniazid‐induced liver injury
Due to its high efficacy, isoniazid (INH) remains the drug of choice for treatment of latent tuberculosis (TB) despite the fact that it can cause liver failure 1. Although drug‐induced liver injury (DILI) caused by different drugs is somewhat different, the clinical characteristics of INH‐induced liver injury are fairly typical for idiosyncratic DILI and include malaise, fatigue, nausea and vomiting 2, 3. The duration of therapy before manifestation of jaundice can vary between 1–25 weeks with an average of 12 weeks 2, 3. Fever affects on average 20% of the patients and eosinophilia is present in up to 15% of the affected individuals 2, 4. In most cases, liver injury is asymptomatic and is only detected by measuring markers of hepatocyte injury such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This is especially true for mild cases of liver injury, which occur in up to 20% of patients treated with the drug 5. However, in most patients, liver function returns to normal despite continued treatment with the drug, a phenomenon referred to as ‘adaptation’ by hepatologists 6. Severe liver injury is seen in up to 1% of the patients 2, 4. Elevations in ALT and AST can start as early as 1 week and sometimes as late as 9 months after starting treatment with INH. However, in more than half of the patients an ALT increase occurs between 1–6 months 2, 3, 5. The abrupt increase in ALT that leads to liver failure is idiosyncratic in nature and is not clearly related to the duration of treatment, the dose of the drug, fever or eosinophil count 2. When liver injury is identified, the first line of treatment is to stop the drug and monitor the patient for recovery. In most cases patients recover. However, rechallenge of patients with more severe liver injury can result in a rapid onset of symptoms (within hours) and is contraindicated 2, 3. Histological characteristics of severe INH‐induced liver injury include hepatocellular injury with multilobular necrosis and a mononuclear cell infiltrate, which is generally indistinguishable from viral hepatitis 2. Steatosis is unusual in INH‐induced liver injury. However, during active TB treatment, when INH is given in combination with other agents such as ethambutol, pyrazinamide and rifampicin (RMP), there have been reported cases of steatosis and cholestatic liver injury 7, 8, 9. Prolonged treatment with INH can also lead to a lupus‐like autoimmune reaction with the presence of antinuclear antibodies 2, 10, which occurs in up to 20% of the patients 4.
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Reactive metabolites proposed to be responsible for INH‐induced liver injury
INH is a hydrazide that is readily oxidized 11. Three metabolites have been proposed to be responsible for INH‐induced liver injury, acetyl hydrazine (AcHz), hydrazine (Hz) and more recently a metabolite resulting from the bioactivation of INH itself 12.
Experiments implicating AcHz and Hz as hepatotoxic species were performed several decades ago, mostly in rats where the acute liver injury correlated with covalent binding of AcHz and with blood levels of Hz 12. At the time, the parent drug (INH) was not thought to contribute to liver injury because its administration did not produce severe liver injury. However, these experiments utilized ring‐labelled acetylisoniazid (AcINH) 5. This conclusion was not warranted because the drug that was administered was not INH. It was AcINH in which the hydrazine is blocked. If hydrolysis led to AcHz and isonicotinic acid, no covalent binding of the pyridine ring would occur. In addition, the characteristics of the liver toxicity in these studies were different from that in humans. In particular, it was an acute rather than a delayed onset idiosyncratic liver injury. Furthermore, the metabolism in humans may be different from that in rats. However, the conclusion that direct bioactivation of INH does not occur has persisted.
Answer:
Hepatotoxicity
Explanation:
The common prodromal symptoms of hepatitis are anorexia, nausea, vomiting, fatigue, malaise and weakness. Mild hepatic dysfunction, evidenced by mild and transient elevation of serum transaminase levels occurs in 10 to 20 percent of patients taking isoniazid.