This document discusses hepatotoxicity caused by antitubercular drugs (ATDs). It notes that isoniazid, rifampicin, and pyrazinamide, which form the core of TB treatment, can all cause liver damage. Risk factors for ATD-induced hepatotoxicity include age over 35, childhood, male sex, cavitary/extra-pulmonary TB, malnutrition, alcohol use, hepatitis B/C infection, HIV coinfection, and genetic factors. The document explores the metabolic pathways and risks associated with each of the three main ATDs. It provides guidelines for managing hepatotoxicity from the ATS, RNTCP, Kabra-Seth, and BTS.

1. ANTITUBERCULAR DRUGS
AND HEPATOTOXICITY

2. • The DOTS therapy forms the cornerstone of the management of TB.
• Isoniazid, Rifampicin and Pyrazinamide form essential components of
the Anti-Tuberculosis management, and all three drugs have
hepatotoxic potential.

3. • Incidence of ATD induced hepatitis in adults is between 2-20%
• Incidence of ATDH in children varied between 1 to 10%, accounts for 30 %
of DILI.
• A Study conducted by Indumathi et al, published IJP , March 2019 revealed
ATDH incidence at 2.3% in children.

4. RISK FACTORS FOR ATD INDUCED HEPATOTOXICITY
• Age over 35 years
• Children
• Sex- Incidence more in men, severity more in women
• Organ involvement: Cavitary TB, EPTB, Multibacillary TB. In child, more in TB
meningitis.
• Malnutrition and low albumin levels (3 fold increased )
• Alcohol consumption
• Hepatitis B- 4 fold increased risk in carriers than non carriers
• Hepatitis C- Combined chemo and ATD increases ATDH risk 5 fold
• HIV coinfection
• Genetic polymorphism – NAT2, CYP2E1, glutathione-S-transferase
• HLA- HLA DQB1*0201 , HLADQA1*0102 ( odd’s ratio, 1.9 and 4.0 respectively)

5. ISONIAZID
• Poorly understood, metabolic idiosyncrasy postulated as predominant
• Hydralazine (more ) and hydralazine metabolites ie acetylisoniazid and acetylhydralazine are
culprit molecules

6. NAT2 AND INH
• NAT2- Involved in 3 steps of INH biotransformation
• Levels of INH is dependant on acetylation status of the patient ie fast,
intermediate or slow acetylators
• Acetylation status depends on NAT2 phenotype, differs in ethnic groups
• Earlier observations: Rapid acetylators more at risk, Increased production of
AcHz
• Current :Slow acetylators have increased cumulative exposure to INH and
AcHz. Increased INH > increased Hz production and free INH mediated liver
injury(immune- mediated)

7. P450 IN INH METABOLISM AND HEPATOTOXICITY
• CYP450 subgroup CYP2E1 c1/c1 phenotype (wild type) independent risk
factor for INH hepatotoxicity
• Associated with high CYP2E1 activity increased production of
hepatotoxins
• Risk 2 times in CYP2E1 c1/c1 phenotype
• Risk 7 times when concomitant slow acetylator status

8. GLUTATHIONE-S-TRANSFERASE AND INH
• GSTs detoxify toxic molecules produced by oxidation of Hz and AcHz
• GSTM1 null phenotype (Asians) and GSTT1 null phenotype
(Caucasians) – decreased enzyme activity  toxic metabolite-induced
liver damage

9. RIFAMPICIN
• Known to potentiate hepatotoxic actions of other ATD
• Binds to hepatocyte PXR (xeno sensing pregnane X receptor) and induces metabolic
enzyme pathways of CYP 450 molecules (CYP3A4)
Increased metabolism of INH and more production of toxic metabolites
• Induces INH hydrolases, resulting in increased formation of hydralazine especially in
slow acetylators
• Interferes with bilirubin uptake and results in conjugated jaundice without hepatocyte
damage
• Inhibits bile salt exporter pump, hence preventing excretion of bile

10. PYRAZINAMIDE
• Deamidated to pyrazinoic acid, then oxidised to 5-OH pyrazinoic acid by
Xanthine Oxidase.
• May have both dose-dependant hepatotoxicity and metabolic idiosyncrasy
• High doses of pyrazinamide used initially (40-50 mg/kg) was found to have
more hepatotoxic effect
• t1/2 is longer than INH or rifampicin (10hrs), further prolonged in
concomitant liver disease (15 hrs) or usage of xanthine oxidase inhibitors
• Murine models show induction of CYP450 pathways and NAD level
alterations which may lead to free radical production

11. INTERVENTIONS DURING HEPATOTOXICITY
• If ALT> 5 times ULN or > 3 times ULN with nausea, vomiting , jaundice or
unexplained fatigue, all hepatotoxic drugs should be stopped
• Viral markers should be investigated
• If indicated, unless specific cause identified, physicians should consider 3
drug therapy with low hepatotoxic potential

12. RECHALLENGE GUIDELINES: ATS
1. After ALT < 2 times ULN, rechallenge with Rifampicin +/-
Ethambutol
2. After 3-5 days consider INH if ALT normal
3. If symptoms recur/ ALT increase- stop last drug added.
4. Consider withholding pyrazinamide with t/t extended to 9 m in c/o
severe or prolonged hepatotoxicity

13. RNTCP UPDATED PEDIATRIC TB GUIDELINES 2019
• If ALT and/or AST> 5 times ULN in asymptomatics/ ALT/AST >3 times
ULN with nausea, vomiting , jaundice
OR
• Serum Total Bilirubin > 1.5 mg/dl
• Stop all hepatotoxic drugs- H, R, Z
• Other causes especially viral hepatitis excluded
• If child seriously ill, low hepatotoxic regime- Streptomycin, Ethambutol and
Levofloxacin
• After symptoms subside and ALT/ AST< 2 times ULN, rechallenge with full
dose primary drugs.
• R started first(full dose). Rest added sequentially in 3-4 day intervals with
LFT monitoring

14. KABRA-SETH RECOMMENDATIONS
• H,R,Z stopped in case of hepatotoxicity
• Streptomycin, Ethambutol and flouroquinolones continued in serious TB patients
with LFT monitoring
• When ALT < 2 times ULN, Rifampicin introduced first at half dose( 5mg/kg/day)
with Streptomycin and ethambutol. Gradually increased to 10 mg/kg/day in 1
week
• INH added next in half dose, increased to full dose in 1 week
• Pyrazinamide not added unless child has TBM or miliary TB. Reintroduced at half
dose and then increased.

15. BTS GUIDELINES
• Rechallenge with INH Rifampicin Pyrazinamide
• Rechallenge initiated with low dose drugs and dose increased
gradually over 1 week to full dosage.
 Multiple drug trials like Sreenivas trial and Tahoghlu trial conducted
to test rechallenge regimens, no statistically significant differences.