Review ArticleHepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management
Section snippets
Drug Related Factors
It is difficult to estimate the incidence of hepatotoxicity due to individual agents as majority of patients are on combination of medications throughout the course of anti-TB therapy. While isoniazid, rifampicin and pyrazinamide are known to cause hepatotoxicity, ethambutol and streptomycin are considered not to be hepatotoxic. Information related to hepatotoxicity from isoniazid (INH), rifampicin17 and pyrazinamide18, 19 are derived from observations made during monotherapy for latent TB or
Genetic Susceptibility
Anti-TB DILI remains unpredictable even when variables such as drug regimen and environmental factors are taken into account. Neither the drug related factors nor the concurrent risk factors adequately explain why, in the vast majority of cases, hepatotoxicity occurs during the early phase of anti-TB therapy. In addition, observations such as Asian males have double the rate of isoniazid hepatitis than white males and nearly 14 times that of black males11, 12 indicate that genetic
Pathophysiology: unifying hypothesis
Development of idiosyncratic DILI is an intricate process involving both concurrent as well as sequential events determining the direction of the pathways, degree of liver injury and its outcome (Figure 2). The key upstream events include drug specific pathways triggered by particular drugs or their metabolites. Increased formation of reactive metabolites generally as a result of phase I metabolism or failure of detoxification usually a function of phase II metabolism is likely to be an
Management
Despite the huge global burden of TB and decades of experience in the use of anti-TB medications, studies investigating DILI lack scientific rigor, consistent methodology and large enough scale to generate the evidence on which recommendations can be based upon. Therefore, approaches to prevent, monitor and manage hepatotoxicity have been based primarily on retrospective observational studies. Recommendations from the American Thoracic Society (ATS),17 the British Thoracic Society (BTS)99 and
Future developments
Anti-TB drug induced hepatotoxicity is a serious adverse effect and continues to be a problem worldwide. Efforts at prevention and/or early recognition of anti-TB DILI are severely hampered by limited understanding of its pathogenesis. Future investigations exploring the mechanisms underlying the pathogenesis of anti-TB DILI should be performed using human tissue and samples whenever possible, so that the novel findings can be translated readily into clinical applications. Clear and consistent
Conflicts of interest
All authors have none to declare.
References (116)
- et al.
Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic
Chest
(2005) - et al.
Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome
Hepatology
(1996) - et al.
Rifampin hepatotoxicity associated with treatment of latent tuberculosis infection
Am J Med Sci
(2009) - et al.
Toxic hepatitis with isoniazid and rifampin. A meta-analysis
Chest
(1991) - et al.
Mitochondrial oxidative stress and permeability transition in isoniazid and rifampicin induced liver injury in mice
J Hepatol
(2006) - et al.
Concordance of the toxicity of pharmaceuticals in humans and in animals
Regul Toxicol Pharmacol
(2000) - et al.
Idiosyncratic drug reactions: the reactive metabolite syndromes
Lancet
(2000) - et al.
Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis
Hepatology
(2002) - et al.
Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis
Hepatology
(2003) - et al.
Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine
Biochem Pharmacol
(2011)
Expression and induction by rifampicin of CAR- and PXR-regulated CYP2B and CYP3A in liver, kidney and airways of pig
Toxicology
The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR)
J Biol Chem
The human bile salt export pump: characterization of substrate specificity and identification of inhibitors
Gastroenterology
Absorption, metabolism and excretion of pyrazinamide in man
Tubercle
Liver injury during antituberculosis treatment: an 11-year study
Tuber Lung Dis
Effect of age and gender on the activity of human hepatic CYP3A
Biochem Pharmacol
The danger hypothesis–potential role in idiosyncratic drug reactions
Toxicology
Risk factors of hepatitis during anti-tuberculous treatment and implications of hepatitis virus load
J Infect
Genetic variants in antioxidant pathway: risk factors for hepatotoxicity in tuberculosis patients
Tuberculosis (Edinb)
Mitochondrial abnormalities – a link to idiosyncratic drug hepatotoxicity?
Toxicol Appl Pharmacol
Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury
J Hepatol
A novel mechanism for drug-induced liver failure: inhibition of histone acetylation by hydralazine derivatives
J Hepatol
Todralazine hepatotoxicity: a sting in the histone tail
J Hepatol
Global Tuberculosis Control: WHO Report 2011
Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis
Eur Respir J
Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States
Ann Intern Med
Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome
Hepatology
Antituberculosis therapy drug-induced liver injury and acute liver failure
Hepatology
Case definition and phenotype standardization in drug-induced liver injury
Clin Pharmacol Ther
Antituberculosis drug-induced hepatotoxicity: concise up-to-date review
J Gastroenterol Hepatol
Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis
Ann Intern Med
Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid
Ann Intern Med
Epidemiology and individual susceptibility to adverse drug reactions affecting the liver
Semin Liver Dis
Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study
Am Rev Respir Dis
Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial
Bull World Health Organ
Hepatotoxicity due to antituberculosis therapy. Clinical profile and reintroduction of therapy
J Clin Gastroenterol
Isoniazid-related fatal hepatitis
West J Med
An official ATS statement: hepatotoxicity of antituberculosis therapy
Am J Respir Crit Care Med
High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis
Eur Respir J
Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis
CMAJ
Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis
Gut
4 months of rifampin compared with 9 months of isoniazid for the management of latent tuberculosis infection: a meta-analysis and cost-effectiveness study that focuses on compliance and liver toxicity
Clin Infect Dis
Isoniazid- and rifampin-resistant tuberculosis in San Diego County, California, United States, 1993–2002
Int J Tuberc Lung Dis
Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic
J Am Med Assoc
Isoniazid-associated hepatitis deaths: a review of available information
Am Rev Respir Dis
Standard anti-tuberculosis treatment and hepatotoxicity: do dosing schedules matter?
Eur Respir J
CYP2E1 mediated isoniazid-induced hepatotoxicity in rats
Acta Pharmacol Sin
Studies on hydrazine hepatotoxicity. 1. Pathological findings
J Toxicol Environ Health
Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin
Am Rev Respir Dis
Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression
DNA Cell Biol
Cited by (337)
Characteristics, management, and outcome of tuberculosis after liver transplant: A case series and literature review
2024, Infectious Diseases NowA novel synergistic enzyme-antibiotic therapy with immobilization of mycobacteriophage Lysin B enzyme onto Rif@UiO-66 nanocomposite for enhanced inhaled anti-TB therapy; Nanoenzybiotics approach
2024, International Journal of Biological MacromoleculesInhibiting the oligomerization of mycobacterial DNA-directed RNA polymerase (RNAP) using natural compound via in-silico techniques
2024, Medicine in Novel Technology and DevicesHepatoprotective potential of Phyllanthus niruri and Andrographis paniculata in isoniazid-rifampicin induced hepatotoxicity in rats
2024, Indian Journal of Tuberculosis