ATT Induced Liver Injury Dr. Zubair Sarkar JR2,Deptt. of Medicine J.N.M.C.H. , Aligarh Muslim University
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- 1. ATT Induced Liver Injury Dr. Zubair Sarkar JR2,Deptt. of Medicine J.N.M.C.H. , Aligarh Muslim University
- 2. Introduction Tuberculosis is one of the deadliest communicable diseases WHO(2013) : 9 million developed TB with mortality of 1.5 million MDRTB (3.5% of new and 20.5% of previously treated cases) and XDR-TB (9%of MDR-TB) are rampant 1.1 million (13%) of 9 million were HIV seropositive
- 3. The liver (metabolic factory of the body) is central to the metabolism of all foreign substance including anti-tuberculosis drugs. Drug-induced liver injury (DILI) : common, often unrecognized cause of liver damage in treatment of tuberculosis
- 4. Isoniazid, rifampicin and pyrazinamide are essential components (First Line Drugs) of the treatment of tuberculosis and all the three drugs have hepatotoxic potential Several second line drugs (including ethionamide , prothionamide , few flouro-quinolones and PAS) are potentially hepatotoxic.
- 5. Many ART drugs including zidovudine , didanosine , ritonavir , indinavir , nevirapine and efavirenz are hepatotoxic. Use of ATT and ART together in HIV-TB co-infected increases risk of DILI Treatment of latent TB infection contributes to the pool of anti TB DILI
- 6. Mechanisms of drug toxicity Direct toxicity (Dose dependent) Idiosyncratic damage Induction of hepatic enzymes Allergic reactions
- 7. Direct toxicity : Acute/subacute Dose related : increases with escalation of dosages Free radicals mediated necrosis Usually no extra-hepatic manifestations.
- 8. Idiosyncratic Reaction : Most types of DILI. Include metabolic or hypersensitivity reactions. Largely independent of dose May occur anytime post exposure. Result from genetic or acquired variations in drug biotransformation pathway
- 9. Induction of hepatic enzymes : Alter plasma drug levels Enhance hepatotoxicity of other drugs Associated with extra hepatic adverse drug reactions
- 10. Allergic reaction : Reactive metabolite mediated Manifests with fever , lymphadenopathy, rash and severe hepatocyte injury
- 11. Specific patterns of hepatic damage : I. Disruption of intracellular calcium homeostasis II. Cholestatic damage III. Interruption of transport pumps and loss of villous processes IV. Reactions involving cytochrome P-450 system
- 12. V. Activation of apoptotic pathways and programmed cell death VI. Inhibition of mitochondrial function
- 13. Anti-tuberculosis drugs and hepatotoxicity Isoniazid (INH) : Not well-understood. Delayed onset : weeks to months 60% incidence in first 3 months No hepatotoxicity on re-challenge
- 14. Isoniazid is associated with : Reactive metabolite Immuno-allergic injury : HLA-DQB1*0201 Mitochondrial injury
- 15. Acetyl-isoniazid, the principal metabolite of isoniazid, is converted to mono-acetyl hydrazine. The microsomal p-450 enzymes convert mono-acetyl hydrazine to other compounds resulting in hepatotoxicity.
- 16. Histopathology : resembles viral hepatitis showing hepatocyte necrosis, ballooning degeneration and inflammatory infiltrates. Absence of symptoms associated with hypersensitivity : rash, fever, arthralgia and eosinophilia.
- 17. Rifampicin (RIF) : Occurs earlier Produces a patchy cellular abnormality with marked peri-portal inflammation.
- 18. Mechanisms include: 1) Conjugated hyperbilirubinemia caused by: RIF inhibiting the major bile salt exporter pump. Dose-dependent competition with bilirubin for clearance at sinusoidal membrane. Impeded canalicular secretion
- 19. 2) Hypersensitivity reaction Rare More common with large, intermittent doses. Hypersensitivity reactions in combination with renal dysfunction, hemolytic anemia, or flulike syndrome
- 20. Pyrazinamide (PZA) : Most hepatotoxic. Half life of 10 hours : can increase to 15 hours in pre-existing liver disease Exhibits both dose dependent and idiosyncratic hepatotoxicity. Free radical generation.
- 21. There may be shared mechanisms of injury for INH and PZA : some similarity in molecular structure. Patients with previous hepatotoxic reactions with INH : more severe reactions with RIF and PZA combination. May induce hypersensitivity reactions with eosinophilia and liver injury, or a granulomatous hepatitis.
- 22. Isoniazid + Rifampicin : Due to the additive effect or synergistic effect The toxicity is due to direct toxic effect of drugs or is a hypersensitivity phenomenon.
- 23. Increased risk is attributed to the interaction between the metabolism of INH and rifampicin Rifampicin enhances conversion of INH to acetylated metabolites by microsomal p450 enzyme induction.
- 24. Factors implicated in development of Anti TB DILI Ethnic and Racial variation : More common in India (11.5% risk) compared to western countries (4.5% risk) Age : >50 years Male Genetic : Absence of HLA DQA1*0102 and Presence of HLA-DQB1*0201 are independent risk factors for DILI
- 26. Alcoholism and underlying CLD : Both predispose to the development of DILI Infections : Hepatitis B : independent risk factor Hepatitis C HIV
- 27. Malnutrition : Poor nutritional status and Decreased serum albumin levels (3 times UNL* and total bilirubin >2 times UNL after excluding other potential causes *upper normal limit
- 38. As per ATS/CDC/IDSA guidelines: In patients receiving anti-TB treatment for active TB disease : ALT level >5 times of UNL or >3 times of UNL in the presence of nausea, vomiting, jaundice , abdominal pain or fatigue in the absence of laboratory evidence of acute viral hepatitis
- 39. Other criteria for diagnosis of anti-TB DILI : i. AST and /or ALT >5 times UNL ii. Total serum bilirubin rise of 1.5mg/dl and iii. Any increase in pre-treatment levels of AST and/or ALT together with anorexia, nausea, vomiting and jaundice
- 40. WHO Classification : GRADE ALT levels I 51 to 125 IU/L or 1.25 to 2.5 times normal II 126 to 250 IU/L or 2.6 to 5.0 times normal III 251 to 500 IU/L or 5.1 to 10.0 times normal IV >500 IU/L or >10.0 times normal or >250 IU/L if accompanied by symptoms
- 41. Score for Diagnosis Roussel Uclaf Causality Assessment Method (RUCAM) score Clinical, biochemical, serological and radiological features of liver injury Validated, standardized tool to assess the probability of drug relatedness for liver injury.
- 42. Total range : -9 to +14 Highly probable : >8 Probable : 6 8 Possible : 3 5 Unlikely : 1 2 Excluded : 5 : Hepatocellular 25 : Mixed 5 times or >3 times in presence of symptoms i.e. jaundice.
- 49. Question 2 : What drugs to be given after stopping first line ATT? Ethambutol + Hepatosafe flouroquinolone (Levofloxacin/Moxifloxacin/Ofloxacin/Cipr ofloxacin) + Aminoglycoside (Streptomycin) Supportive management for hepatic dysfunction
- 50. Question 3 : When to restart first line anti TB drugs? ATS : When ALT levels are
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