A case series of three patients presenting with isoniazid induced toxicity and N-acetyl transferase 2 gene mutation: A management conundrum for programmatic therapy of tuberculosis in India

Indian J Tuberc. 2020 Jul;67(3):407-410. doi: 10.1016/j.ijtb.2020.01.005. Epub 2020 Jan 20.

Abstract

Isoniazid is an essential drug in the management of tuberculosis but there is a high degree of variation in the Indian population's capacity to acetylate or inactivate isoniazid to the inactive metabolite acetyl isoniazid, and they can be distinctly characterized phenotypically as being either slow or rapid inactivators (the concentration of the enzyme being higher in rapid inactivators). Several mutations in the N-acetyl transference 2 (NAT2) gene account for majority of the slow acetylator genotypes in the human population (NAT2*5A, NAT2*5B, and NAT2*6A). Such individuals are at a greater risk of drug-induced adverse reactions due to reduced drug elimination, compared to those possessing the wild type allele. Here we discuss two cases of Isoniazid induced peripheral neuropathy and one case of Isoniazid induced hepatotoxicity confirmed as having heterozygous or homozygous NAT2 gene mutation. In all 3 cases, the presence of NAT2 gene mutation was associated with the adverse events and the adverse events subsided on stopping or reducing the dose of isoniazid. However, due to lack of guideline-based management of adverse events occurring due to isoniazid, the drug was either abruptly stopped or dosage lowered based only on clinical expertise, which could potentially lead to further resistance to Mycobacterium tuberculosis (as occurred in one of our cases). Further studies of the relationship between NAT2 genotypes, isoniazid concentrations and adverse drug events are required to make genotyping a helpful tool for optimizing isoniazid's therapeutic response and minimizing adverse drug reactions, particularly in countries with a high burden of tuberculosis.

Keywords: Hepatotoxicity; Isoniazid toxicity; NAT2 polymorphism; Peripheral neuropathy.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Antitubercular Agents / adverse effects*
  • Arylamine N-Acetyltransferase / genetics*
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / genetics*
  • Deprescriptions
  • Humans
  • India
  • Isoniazid / adverse effects*
  • Male
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / genetics*
  • Pharmacogenomic Testing
  • Tuberculosis, Multidrug-Resistant / drug therapy
  • Tuberculosis, Pulmonary / drug therapy*
  • Young Adult

Substances

  • Antitubercular Agents
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • Isoniazid