ATT induced liver injury

liver injury due to anti tubercular drugs

1. ATT INDUCED LIVER INJURY

2. 2 " … he who aspires to treat correctly of human regimen must first acquire knowledge and discernment of the nature of man in general – knowledge of its primary constituents and discernment of the components by which it is controlled. … though they are made from the same materials, no two are alike …” Hippocrates 460-377 B.C. The Father of Medicine

3. INTRODUCTION Idiosyncratic DILI – imp. cause of morbidity & mortality following drugs taken in therapeutic doses. Vastly unrecognised and under reported. Reported estimates range from 1:10,000 cases to 1:100,000 cases Common drugs causing DILI appear geographical Most common cause of aborted drug development or withdrawl of drug

4. INTRODUCTION DILI is a leading cause of ALF in Western world, with paracetamol being commonest followed by antimicrobials. In India ATT is commonest cause of drug induced ALF in adults and children contributing to 5.7–22% of all cases of ALF Kumar R et al. ATT induced ALF: magnitude, profile, prognosis, and predictors of outcome. Hepatology . 2010;51 Devarbhavi H . DILI with hypersensitivity features has a better outcome: a single-center experience of 39 children and adolescents. Hepatology . 2011;54 Devarbhavi H, Fulminant hepatic failure: cause, course and predictors of outcome. Ind J Gastroenterol . 2005; 24

5. DEFINITION DILI :Drug-induced liver injury - a clinical diagnosis of exclusion. Elevation of transaminases (either AST and/or ALT) or bilirubin or alkaline phosphatase (SAP) >2 ULN (upper limit of normal) Elevation of ALT or AST > 5 ULN without symptoms. Elevation of SAP > 2 ULN or Bilirubin > 2 ULN with any elevation in AST or ALT. Elevation of AST or ALT < 5 ULN with symptoms

6. OTHER TERMS !!!!!

7. NATURAL HISTORY AND PROGNOSIS Mortality principally depend on degree of hepatocelluler injury 10% mortality for agents causing severe hepatitis or toxic steatosis (especially those who require hospitalization) Prognosis is worse whenever jaundice accompanies hepatocelluler injury Agents that cause cholestatic injury rarely , if ever , produce acute fatalities

8. IM IMMUNOALLERGIC (HYPERSENSITIVITY)

9. INTRINSIC AND IDIOSYNCRATIC DILI INTRINSIC DILI ? Dose dependent hepatotoxicity Latent period – short IDIOSYNCRATIC DILI ? Most common Dose independent /genetically determined Unpredictable Latent period – long (months) ATT induced hepatotoxicity comes under idiosyncratic type

10. METABOLIC IDIOSYNCRASY : Pathways of drug metabolism favours drug accumulation or formation of toxic metabolites Alterations in ATP transporters which actively pumps drug metabolites out of hepatocytes IMMUNOALLERGIC : Hypersensitivity response Repeated exposure results in exaggerated and unhelpful tissue based or systemic injurious inflammatory response Less understood mechanism

11. Tujios, S. & Fontana, R. J. (2011) Mechanisms of drug-induced liver injury: from bedside to bench Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2011.22 RISK FACTORS

12. Young adults DILI and AGE High drug consumption Old Children Exceptions: Reye’s syndrome with aspirin and Reye-like syndrome with valproate > > Susceptibility (e.g., isoniazid)

13. (Same in females and males before 50 ) DILI and gender S Agro, Hepatology 2002;36:451 Incidence of DILI: 2.6-fold higher in females than males in persons aged 50 years or more

14. CIRRHOSIS Does not change the incidence of DILI but worsens it outcome ( The same degree of liver injury, which is well tolerated in a normal subject, can trigger liver failure, complications and death in patients with an already impaired liver function) DILI IN CIRRHOSIS

15. PATTERNS OF DRUG-INDUCED LIVER INJURY Based on R value : (ALT/ULN) / (ALP/ULN) PATTERNS ALT SAP R VALUE HEPATOCELLULAR >3ULN >5 CHOLESTATIC >2ULN <2 MIXED >3ULN >2ULN >2 < 5

16. 17 DILI “ tolerators ” – Most people exposed to a new drug show no injury

17. 18 DILI “adaptors” – Some show transient injury, but adapt

18. 19 DILI “ susceptibles ” – Few fail to adapt and show serious injury

19. CHARACTERISTIC CLINICAL SIGNATURE Pattern of abnormal liver panel (hepatitis, cholestasis or mixed) Duration of latency to symptomatic presentation Presence or absence of immune -mediated hypersensitivity Response to drug withdrawal.

20. 21 TIP OF THE ICEBERG Death or Tx Acute Liver Failure Serious DILI – Threatening Detectable DILI – but Not Serious Patient Adaptation to New Agent Exposure Patients/People Tolerate Exposure Without Effects

21. HEPATOTOXIC ATT DRUGS 1 st line 2 nd line Isoniazid Ethionamide Rifampin PAS Pyrazinamide Flouroquinolones

22. LIVER FRIENDLY ATT DRUGS

23. INH -ISONIAZID

24. ISONIAZID METABOLISM Genetic polymorphisms in NAT2 1)Fast acetylators 2)Slow acetylators 3)Intermediate acetylators Fast acetylators :>90% of drug excreted as acetyl isoniazid Slow acetylators: 67% as acetyl isoniazid and a greater percentage excreted unchanged into urine Who are at high risk for toxicity? SLOW acetylators – as they have greater cumulative accumulation Fast Acetylators : clears MAH more rapidly

25. MECHANISMS BY WHICH TOXICITY OCCURS.. Reactive metabolites of MAH – Free radical generation-toxic to tissues Metabolic idiosyncratic mechanisms also play a role. Homozygous CYP450 2E1 –makes ACETYL HYDRAZINE bind directly to liver macromolecules Within weeks to months

26. RIFAMPICIN AND HEPATOTOXICITY Metabolised in the liver - active deacetylated metabolite- which is mainly excreted in bile Undergoes entero - hepatic circulation Rifampicin is an effective liver enzyme-inducer Promotes the upregulation of hepatic cytochrome P450 enzymes (such as CYP2C9 and CYP3A4 ) Increases the rate of metabolism of many other drugs that are cleared by the liver through these enzymes. As a consequence, rifampicin can cause a range of adverse reactions when taken concurrently with other drugs

27. RIFAMPICIN Mechanism of hepatotoxicity Combination with INH and pyrazinamide – higher toxicity Conjugated hyperbilirubinemia 1)inhibits major bile salt exporter pump 2) Can be dose dependent Hepatocellular injury – rarely –hypersensitivity reactions

28. PYRAZINAMIDE METABOLISM Longer half life - 10 hours In alcoholics/pre existing liver disease –half life is extended >15 hours

29. MECHANISM OF HEPATOTOXICITY Both dose dependent and idiosyncratic hepatotoxicity. Doses 40 to 50 mg/kg commonly caused hepatotoxicity Alters nicotinamide acetyl dehydrogenase levels in rat liver which might result in generation of free radical species. Patients who previously had hepatotoxic reactions with isoniazid have had more severe reactions with rifampin and pyrazinamide Hypersensitivity reactions with eosinophilia and liver injury or granulomatous hepatitis Allopurinol combination – inhibits xanthine oxidase

30. MODES OF PRESENTATION Hepatic adaptation Asymptomatic ,transient elevations in ALT Drug induced hepatitis Similar to viral hepatitis with prodromal symptoms(fever, nausea, vomiting, lethargy, coagulopathy) NAFLD Nausea, vomiting, abdominal pain Granulomatous hepatitis Presents as hypersensitivity reactions Fever , myalgias , rash ,lymphadenopathy ,hepatosplenomegaly Cholestasis Asymptomatic ,reversible increase in SAP levels Acute Liver Failure

31. INVESTIGATIONS TO RULE OUT OTHER CAUSES

32. CAREFUL PRE - TREATMENT SCREENING Age >35 years (22% to 33% >35 years vs 8% to 17% in <35 years) Children : younger than 5 years, use of pyrazinamide , extrapulmonary TB Sex : women increased risk Cofactors : Alcohol , Obesity, diabetes Abnormal baseline testing Acetylator status : slow acetylators Malnutrition/hypoalbuminemia HLA-DQB1*0201 – Independent risk factor Gene polymorphisms at loci of genes coding for P4502E1 Presence of rifampicin in a multidrug - increased risk HIV, HbsAg , HCV

33. CAUSALITY ASSESSMENT TOOLS Roussel Uclaf Causality Assessment Method (RUCAM) Maria and Victorino (M and V) DILIN (Drug-Induced Liver Injury Network)

34. Approach to DILI – ACG GUIDELINES

35. ABNORMAL LIVER ENZYMES AT BASELINE

36. ABNORMAL ENZYMES DURING TREATMENT

37. ATS GUIDELINES DURING TREATMENT-ACTIVE TB INFECTION

38. MANAGEMENT Once a diagnosis of DILI is suspected, the offending drug(s) is/are discontinued Intensive supportive care and transfer to advanced centers for consideration of transplantation with advanced disease Rechallenge is routine with first line anti tuberculous agents. Rechallenge with drugs that produced immunoallergic manifestations such as skin rashes, fever, lymphadenopathy or eosinophilia is fraught with a potential risk of a severe reaction with a shorter latency period.

39. ANY DRUGS USEFUL ? N-acetylcysteine (NAC) Silymarin Antioxidants S- adenosinemethionine Ursodeoxycholic acid -In patients with cholestasis Cholestyramine -interrupts the enterohepatic cycle minimizing the liver injury Corticosteroids too may be attempted – cholestasis- particularly those associated with features of hypersensitivity such as skin rashes, and fever. In recent studies in subjects older than 70 years, NAC showed minimal to no elevation in liver transaminases in patients exposed to TB drugs and simultaneously given oral NAC

40. RE- CHALLENGE IN ACTIVE TB- ATS GUIDELINES

41. British Thoracic Guidelines

42. COMPARISON OF BTS AND ATS GUIDELINES BTS– Isoniazid should be initiated ATS – Rifampicin to be initiated A comparative study conducted with 327 patients Conclusion : No significant major differences between both guidelines but ATS was perceived to be easier to follow

43. REINTRODUCTION Sequential: ATS, BTS Sequential without Pyrazinamide safer 1 Simultaneous: WHO, IUALTD Sequential for 2 nd re-challenge if DILI recurs Tahaoglu K et al. Int J Tuberc Lung Dis. 2001;5:65–69.

44. REINTRODUCTION of ATDs 11-24% develop recurrent DILI after reintroduction, sequential or simultaneous

45. ATT IN PATIENTS WITH LIVER DISEASE End Stage Liver Disease a risk factor for TB TB 14x commoner in Liver Cirrhosis Pulm TB Mixed ascites Intestinal TB Genitourinary TB Dhiman RK, Saraswat VA. J CLINEXPHEPATOL2012;2:260–270

46. ATT IN PATIENTS WITH LIVER DISEASE PROBLEMS WITH ATT Diagnosis of TB difficult Frequency of hepatotoxicity higher In LC, CHB, CHC, ALD Severity greater Common cause for ACLF Monitoring difficult Fluctuating LFT due to LD Dhiman RK, Saraswat VA. J CLINEXPHEPATOL2012;2:260–270

47. PROPOSED REGIMENS IN CIRRHOSIS CTP ≤ 7: 2-hepatotoxic drugs regimens HRE for 9 months SHRE for 2 months followed by HR for 6 months RZE for 6-9 months CTP 8-10: 1-hepatotoxic drug regimen SHE for 2 months followed by HE for 10 months CTP  11: No hepatotoxic drugs EMB+Oflox+CS + Capreo / Strepto for 18–24 months Treatment of Tuberculosis: Guidelines. 4th ed. WHO/HTM/TB/2009.420; Dhiman RK, Saraswat VA. J CLINEXPHEPATOL2012;2:260–270

48. PREVENTION OF DRUG-INDUCED LIVER INJURY Idiosyncratic :Difficult to predict Assess risk factors : risk factors such as old age, comorbid diseases, HIV status, daily dose of drug >50 mg, or poly pharmacy. Patient education : development of new symptoms such as nausea, vomiting, anorexia, dark urine or jaundice The suspected drug should be stopped at the slightest suspicion of DILI, in order to prevent progressive liver damage

49. PRECAUTIONS AND PATIENT EDUCATION Look for baseline risk factors – Appropriate pt selection presence of established cirrhosis, known or latent concomitant liver disease: EtOH , HBV, HCV, HIV, etc. deranged LFT; concomitant drug therapy with hepatotoxic drugs or known inducers of CYP4502E1; Record baseline LFT, prescribe ATT as per body-weight,

50. PRECAUTIONS AND PATIENT EDUCATION Patient education and staff education compliance monitoring Warning symptoms of hepatotoxicity advise them to stop all ATD and contact doctor for ‘alarm symptoms no alcohol; no other drugs without consulting doctor

51. PATIENT MONITORING Close clinical monitoring with symptoms more effective in reducing hepatotoxicity Monitoring with LFT: Routine LFT monitoring on therapy, q 2 wk at least for 1 st 8-12 weeks, in those with deranged baseline tests or risk factors eg . pre-existent LD. No advantage in those without these factors.

52. CONCLUSION Educate patients 2. Always consider possibility of DILI 3. Immediately withdraw all suspected drugs in severe cases Difficult to avoid, predict and diagnose Avoid most mishaps, Liver Transplant