Att induced heapatotoxicity and it's side effect profile

Antitubercular drug induced hepatotoxicity

1. Att induced hepatotoxicity Dr Pavan Reddy D.M Gastroenterology 1 st year Registrar

2. ABBREVATION ATS American Thoracic Society BTS British Thoracic Society ERS European Respiratory Society IUALTD International Union Against Tuberculosis and Lung Disease's  DILI Drug Induced Liver Injury DIH Drug Induced Hepatotoxicity ATT Anti Tubercular Therapy

3. Incidence Adverse drug reaction (ADR) - 3.6% of all admissions. 17% of all in-patients develop ADR with 0.5 % mortality. DILI accounts for 7% of ADR 5- 20 % persistent elevation for more than 6 months 10% death / transplant Bouvy , J. C et al (2015). Epidemiology of adverse drug reactions in Europe: a review of recent observational studies. Drug Safety 38, 437–453.

4. Question? Which of the following are true except ? A) Most common cause of drug induced acute liver failure in india is paracetmol . B) Degree of liver enzymes correlate with severity if liver disease. C) Clinical jaundice is predictor of mortality. D) Cholestatic pattern of DILI can be prolonged even on stopping of offending drug.

5. Devarbhavi H et al. Single- center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol. 2010 Nov;105(11):2396–404 Consecutive patients with DILI from 1997 to 2008 from a tertiary care hospital in South India DILI (n) = 313

6. Types of adr Type A, or intrinsic, adverse drug reactions Dose-related, predictable toxic effects of medications , accounts for most drug-induced ALF Acute liver failure resulting from acetaminophen overdose Type B or idiosyncratic adverse drug reactions Immunological / hyper sensitivity Allergic, presenting with fever, rash, eosinophilia, and rapidly recurring on rechallenge Non immunological/ metabolic idiosyncracy Non allergic classic example INH Not related to dose Variable delay or latency period Associated with drug, patient, and environmental risk factors Difficult to predict Iasella CJ, Johnson HJ, Dunn MA. Adverse Drug Reactions. Clin Liver Dis. 2017 Feb;21(1):73–87

7. No specific tests to confirm the diagnosis of DILI A temporal relationship with respect to medication exposure Time of DILI onset - time of the first qualifying laboratory tests/clinical symptom Course of the reaction - fall by at least 50% from the peak value Presence of risk factors. The dose (defined daily dose or cumulative dose) of a drug may be important. Use RUCAM worksheet for assessing the probability of drug implicating in DILI. https://livertox.nih.gov/livertoxrucamv5.pdf Roussel Uclaf Causality Assessment Method (RUCAM), Maria and Victorino clinical diagnostic scale Clin Pharmacol Ther . 2011 Jun 1;89(6):806–15. causality assessment

8. Types of dili Hepatic adaptation Drug induced hepatocellular injury Granulomatous hepatitis Cholestatic injury

9. Patterns of liver injury

10. Case 1 28 years female case of sputum positive pulmonary tuberculosis was started on first line ATT as per DOTS daily regime with 4 drug HRZE . Base line LFT normal Pt was discharged. On follow up after 4 week Asymptomatic LFT T.B 1.4 / AST 160 / ALT 139/ ALP 70 Q) what is the next line of management ?

11. HEPATIC ADAPTATION Mild , Non Progressive , injury to hepatocyte mitochondria or membranes No inflammation on biopsy. LFT remain Normal .

12. This asymptomatic elevation of transaminases is well documented 20 % prevalence 1, 2 ,3 5-20 % of these progress to have transaminases of more than 5 ULN 4 Probable mechanism : Immunosuppressive cytokine on t cells that inhibit progression of immune reaction to any drug 5. Lack of recurrence of ATT hepatoxicity upon reintroduction suggest possibility of metabolic adaptation. 6 1.BTS Chemotherapy and management of tuberculosis in UK1998. Thorax 1998; 53: 536–48. 2. ATS Treatment of tuberculosis. Am. J. Respir. Crit. Care Med. 2003; 167: 603–62. 3. Ormerod LP et al. Hepatotoxicity of antituberculosis drugs. Thorax 1996; 51: 111–13. 4. Yamamoto T,et al. Elevated serum aminotransferase induced by isonizid in relation to isoniazid acetylator phenotype. Hepatology 1986; 6: 295–8 5.Zimmerman HJ, et al Management of drug-induced liver disease. Curr . Gastroenterol. Rep. 2001; 3: 38–48 6. Danielides IC,et al. Hepatitis on high dose isoniazid: reintroduction of the drug in severe tuberculous meningitis. Am. J. Gastrol . 1983; 78: 378–80.

13. Aware of hepatic adaptation Lack of awareness of this clinical entity lead to unnecessary interruption of first line ATT Which leads to increase duration of treatment, emergence of drug resistance.

14. Case 1 follow up Transaminases elevation < 5 ULN Asymptomatic So continued on first line ATT Follow up LFT T.Bil 1.2 / AST 45 / ALT 38 . She completed ATT 6 months with out any further events This asymptomatic mild elevation of transaminases is hepatic adaptation and not DILI Hence no need to stop hepatotoxic drugs

15. 2.Drug induced hepatocellular injury Transaminase threshold level for clinicopathologically significant DIH is cannot be determined For example pt on phenytoin may have transaminases up to 3 times ULN and liver biopsies don’t reveal any significant pathology Mtx may have histologic evidence of liver injury with out any elevation of transaminase. Usually poor correlation between degree of ALT elevation and the severity of the liver disease Histology a more accurate indicator of liver injury. S Verma, N Kaplowitz Gut 2009;58:1555–1564. doi:10.1136/gut.2008.163675 Abboud G, Kaplowitz N. Drug-induced liver injury. Drug Safety 2007;30:277–94

16. Hy’s law ‘Presence of clinical jaundice is a strong predictor of mortality’ Modified Hy’s law Serum ALT or AST >3 × ULN Serum total bilirubin elevated to >2 × ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase) No other reason can be found to explain the combination of increased aminotransferases and bilirubin, such as viral hepatitis A, B, C, or other preexisting or acute liver disease When these criteria are met there is 1 in 10 mortality risk of DILI

17. Granulomatous hepatitis Hypersensitivity reaction to drugs Drugs implicated are allopurinol, quinidine, sulphonamides, and pyrazinamide. Fever, myalgia, rash, lymphadenopathy, hepatospleenomeagly and even vasculitis.

18. cholestasis The cholestatic pattern can be due to canalicular cholestasis or ductular injury. Canalicular cholestasis Inhibition of bilirubin or the bile-salt transport ( eg , cyclosporine or oestrogen metabolite); This is referred to as ‘‘bland’’ cholestasis because histologically there is virtual absence of inflammation or necrosis. Ductular injury Some degree of cholangiocyte injury Presentation can mimic biliary obstruction or the course can be more indolent with jaundice and pruritus. The resolution of cholestatic injury is a lengthier process compared to the hepatitis form, maybe because in contrast with the hepatocytes, the cholangiocytes regenerate more slowly.

19. Hepatotoxic att drugs INH Rifampicin +

20. Up to 12 % of pt on INH have transaminitis and majority are self limited and asymptomatic Age most important risk factor for INH hepatotoxicity Age Hepatoxicity < 20 yrs Rare 20- 34 yrs 0.3 % 35-49 yrs 1.2 % > 50 rs 2.3 % Bailey WC et al. The effect of isoniazid on transaminase levels Ann Intern Med 1974;81:200-202 Tostmann et antitubercular drug-induced hepatoxicity: concise up-to-date review J Gastoenterol Hepatol 2008; 23:192-202

21. Slow acetylators has More hepatotoxicity Higher peak ALT than fast acetylators With rechallenge frequently have transaminases 3 times ULN Most of the hepatotoxic evident with in the 1 st month unlike days to weeks of onset as seen with hypersensitivity reactions ATS Treatment of tuberculosis. Am. J. Respir. Crit. Care Med. 2003; 167: 603–62.

22. Rifampicin Mecahnism Cholestatic injury : Inhibit BSEP( major bile salt exporter protein) Usually insidious Hepatocellular injury: Rare Idio syncratic Hypersensitivity reaction Fever, anorexia, nausea, vomiting, malaise. With intermittent and high doses can have flu like symptoms, haemolytic anemia and renal failure Lft : Conjugated bilirubin, mildly elevated ALT Rifampicin most commonly participates in ATT DIH by potentiating hepatotoxicity of other ATT drugs

23. Pyrazinamide Mechanism Historically considered to be the most hepatotoxic drugs where high dose 40-70mg/kg was used Data on current recommended lower doses 15-25mg/kg is not known Toxicity is rare when used < 35mg/kg ( 52 ref from wjg att in cirrhosis challenges and option) Both dose dependent( common ) and idiosyncratic. T ½ 10 hrs increases to 15 hr with underlying disease. Metabolites pyrazinoic acid and 5 –OH pyrazinamide are responsible for hepatoxicity. Occasionally hypersensitivity reaction with eosinophilia and liver injury or granulomatous hepatitis.

24. Latency With INH most of the hepatotoxic evident with in the 1 st month unlike days to weeks of onset as seen with hypersensitivity reactions When pyrazinamide was added can occur upto 3 rd month transaminase activity which occurs Late ( usually after one month ) has been attributed to pyrazinamide-induced hepatotoxicity Early increase in transaminases ( usually within first 15 days ) has been attributed to rifampicin and isoniazid-induced hepatotoxicity . In a retrospective study from a large TB centre in UK More than 50 % of cases occurred in first 2 weeks and 87% with in first 2 months Unlike classical hypersensitivity INH rechallenge dosent always elicit rapid recuurence of hepatotoxicity

25. Incidence of att induced hepatitis Incidence Author Study 16% Sharma SK et al. Am. J. Respir. Crit. Care Med. 2002 10.5% Deepak et al Gastroenterol Hepatol . 2005 9.48% Saha et al J Prim Care Community Health. 2016 4.38 % Westren studies , meta analysis Steele Ma et al. A meta-analysis. Chest. 1991Feb;99(2):465–71

26. Definitions of att induced dili WHO Grading Grade Type Level x ULN Grade 1 Mild < 2.5 Grade 2 Mild 2.5 -5 Grade 3 Moderate 5-10 Grade 4 Severe >10 ATT DILI diagnostic criteria Transaminases 5 ULN If symptomatic X 3 ULN Others consider and increase Tot bil 2.5 mg/dl ( other 1.5mg/dl)

27. Question? Regarding hepatotoxicity of anti-tubercular therapy (ATT) the following are TRUE: 1. Rechallenge with isoniazid is contraindicated if patient has history of isoniazid induced hepatotoxicity. 2. Isoniazid induced transaminitis is self limited and asymptomatic in majority of patients. 3. Isolated conjugated hyperbilirubinemia is seen with rifampicin. 4. Pyrazinamide mainly causes idiosyncratic hepatotoxicity. 5. Inactive carriers of hepatitis B do not have increased risk of ATT induced hepatotoxicity.

28. Case 2 37 years old gentleman Mr.G was recently admitted and diagnosed to have HIV infection clinical stage 4 and disseminated tuberculosis. He was started on daily weight based anti-tubercular drugs(ATT) Baseline LFT showed 1.2/0.8/42/24/128/ 6/2.8/ 21 days after initiation of ATT, he presented to the casualty with 3 days history of yellowish discoloration of eyes and urine associated with right upper quadrant abdominal pain. On examination, he was conscious, oriented and afebrile. Pulse rate 108/min , BP 120/70 mm of Hg, RR 16/minute Icteric and systemic examination – hepatomegaly 3 cm non tender.

29. AGE > 35 Years X 4 times risk of TB DILI 1 Meta analyis by Steele et al found all age groups are at risk of DILI. 2 ATT DILI contributes 8.7% of pediatric cases 3 with substantial mortality 50% with 4 drug ATT and 80 % ATT DILI ALF against 67 % reported in adults 4 Singla R, et al. Indian J Med Res. 2010;132:81–6 Steele MA,et al. A meta-analysis. Chest. 1991;99:465–71 Devarbhavi H et al. Hepatology. 2011;54:1344–50 Kumar R, et. Hepatology. 2010;51:1665–74 Risk factors

30. gender Men outnumber DILI than women However female gender is a positive predictor of more severe liver disease including death. Devarbhavi H,et al. Single- center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol. 2010;105:2396–404.

31. Organ involvement / extent of TB disease Cavitory disease, multibacillary TB and extrapulmonary organ involvement have been incriminated as positive predictors for DILI Cirrhotics more likely to have extra pulmonary TB Parthasarathy R, et al. Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide . Tubercle. 1986;67:99–108. Sharma SK,et al. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med. 2002;166:916–9. Siagal et al.high prevalence and profile of tuberculosis in cirrhosis Gastroenterol 1998; 114:A38 .

32. MALNUTRITION Albumin < 3.5g/dl : X 3 fold increase Weight loss  weight loss of 2 kg or more developing within 4 weeks during TB treatment is highly significant independent risk factor for DILI Sharma SK,et al. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med. 2002;166:916–9. Warmelink I,et al. Weight loss during tuberculosis treatment is an important risk factor for drug-induced hepatotoxicity. Br J Nutr . 2011;105:400–8

33. Dosing regimes DO DOSING SCHEDULES MATTER ? No difference in daily when compared with intermittent. McNAB BD et al. Twice weekly isoniazid and rifampin treatment of latent tuberculosis infection in Canadian plains Aborigines.   Am J Respir Crit Care Med. 2000 Sep 1;162(3):989-93 . Chang KC, et al Standard anti-tuberculosis treatment and hepatotoxicity: do dosing schedules matter? Eur Respir J 2007 Feb 1;29(2):347-51.

34. Associated diseases ACUTE HEPATITIS: Wait till acute hepatitis resolve If on ATT, stop immediately In the interim period continue non hepatotoxic drugs.

35. Acute viral hepatitis Differentiation between hepatic virus reactivation and ATT hepatotoxicity is yet to be determined. Acute viral hepatitis a real confounding factor in ATT induced hepatotoxicity. Wang JY, et al. Risk factors of hepatitis during anti-tuberculous treatment and implications of hepatitis virus load J. Infect. 2011 Jun 1;62(6):448-55 . Ungo J.R et al. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus.  Am J Respir Crit Care Med. 1998;157:1871–1876 In a study by Sharma SK,et al found that in 200 pts who developed acute hepatitis on ATT, 25 ( 12.5%) had acute viral hepatitis , of these 25pts, 14(56%) developed Hepatitis E.

36. With acute viral hepatitis, compared with patients with DIH, had Later onset of hepatitis, Greater elevations in hepatic transaminase levels, and A longer time for normalization of liver function test results. Sarada P, Sharma SK et al Role of acute viral hepatits as a confounding factor in antitubercular treatment induced hepatotoxicity Indian J Med Res 2009; 129: 64-67 Sharma SK,et al Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment–induced hepatotoxicity Clinical Infectious Diseases. 2010 Mar 15;50(6):833-9

37. CHRONIC HBV Significant risk factor for ATT DILI Later onset hepatotoxicity Increased mortality More severe injury histologically HbeAg positive ATT hepatoxicity more when compared with negative HbeAg (RR 11.38 CI5.49-23.59 p < 0.001)

38. Hcv More frequent HIV + HCV  x 14.4 times. ATT reintroduction is generally safe DAA reduces ATT DILI DAA Allows safe reintroduction who previously developed hepatoxicity

39. HIV HIV  x 4 times risk for ATT induced hepatitis HIV + HCV  x 14.4 times.

40. Question? Which if the following statements are true? With underlying cirrhosis Tb pts have high likely hood false negative TST. In tb peritonitis even with underlying cirrhosis ascitic fluid total protein and saag retain their diagnostic abilities. LDH is a useful screening tool in Tb peritonitis with underlying cirrhosis. Sensitivity of ADA drops to 30 % with underlying cirrhosis

41. Tuberculin skin test higher likelihood for false negative not a reliable test in detecting latent Tb. Tb abdomen paucibacillary ADA sensitivity drops 30% Çelikbilek M, et alThe effect of hepatotropic virus (HBV-HCV) infections on tuberculin skin test in patients with cirrhosis. Turk J Gastroenterol 2012; 23: 234-238 Hillebrand DJ, Runyon BA et al. Ascitic fluid adenosine deaminase insensitivity in detecting tuberculous peritonitis in the United States. Hepatology 1996; 24: 1408-1412 Sanai FM, Bzeizi KI. Systematic review: tuberculous peritonitis presenting features, diagnostic strategies and treatment. Aliment Pharmacol Ther 2005; 22: Riquelme A, et al . Value of adenosine deaminase (ADA) in ascitic fluid for the diagnosis of tuberculous peritonitis: a meta-analysis. J Clin Gastroenterol 2006; 40: 705-710

42. Parameter Tb peritonitis T.B peritonitis+ cirrhosis Only cirrhotic ascites without infection Tot Protein >2.5 gm/dl 100 % 70% 0% Ldh >90 U/L 100 % 84 % 0% SAAG >1.1gm/dl 52% 96% Shakil AO et al. Diagnostic features of tuberculous peritonitis in the absence and presence of chronic liver disease: a case control study. Am J Med. 1996 Feb;100(2):179-85

43. Cirrhosis Treatment of TB in cirrhosis is challenging The presence of pre existing liver injury increases the likelihood of DIH Outcomes are worse Monitoring is confounded due to underlying liver disease and fluctuating LFT Derranged LFT caused by TB may improve with ATT.

44. Interaction of factors to produce hepatotoxicity in cirrhosis

45. Options in cirrhosis CTP NO. HEPATOTOXIC DRUGS HEPATOTOXIC DRUGS REGIMENS DURATION (MONTHS) A 2 R+H ±Z (H+R+Z+E) 2 (H+R+E) 4 (HRE) 9 6- With Z 9 Without Z B 1 R/H Avoid Z ( H+E+Lfx+S ) 2  ( H+E+Lfx ) 10 (R+ Lfx + E) 2 +( R+Lfx+E ) 10 9-12 C E+Lfx+Cs+Cm /Km 18–24 1.Treatment of Tuberculosis: Guidelines. 4th ed. WHO/HTM/TB/ 2009.420 . 2. Kumar N, Sarin SK.et al Antitubercular therapy in patients with cirrhosis: challenges and options. World Journal of Gastroenterology: WJG. 2014 May 21;20(19):5760.

46. Case 2 37 years old gentleman Mr.G was recently admitted and diagnosed to have HIV infection clinical stage 4 and disseminated tuberculosis. He was started on daily weight based anti-tubercular drugs(ATT) Baseline LFT showed 1.2/0.8/42/24/128/ 6/ 2.8/ 21 days after initiation of ATT, he presented to the casualty with 3 days history of yellowish discoloration of eyes and urine associated with right upper quadrant abdominal pain. On examination, he was conscious, oriented and afebrile. Pulse rate 108/min , BP 120/70 mm of Hg, RR 16/minute Icteric and systemic examination – hepatomegaly 3 cm non tender.

47. Repeat LFT showed 4.8 / 190/ 188/ 145/ 6.3/ 2.8 CASE OF ATT INDUCED DILI WITH RISK FACTORS SEVERITY GRADE 2 MILD. Q) what could have been done ?

48. Predictive scoring system Risk factors for DILI Score HIV infection 3 Chronic liver disease 4 Daily treatment Regimen 2 Female gender 2 Hypoalbuminemia (S.albumin < 3.5 g/dl) 2 Disseminated disease 2 Score of >5 will predict DILI Sensitivity 74% Specificity 67% Mani SS et al. Predictors, outcome, profile of anti-tubercular drug induced hepatitis–A prospective nested case-control study in a South Indian tertiary hospital. International Journal of Infectious Diseases. 2016 Apr 1;45:398-9.

49. Need for close monitoring J Gastroenterol Hepatol (2005) 20, 1745–1752 DOI: 10.1111/j.1440-1746.2005.04048.x Subhash agal et al in their study significant reduction in morbidity and mortality when LFT was monitored at regular intervals Group A – Patients with DILI who were periodically followed up Group B – patients who are treated elsewhere and presented with DILI

50. Baseline LFT Normal No risk factors No need to monitor unless symptomatic Baseline LFT Abnormal Risk factors + Weekly for 2 Weeks 2 Weekly for 2 Months Normal ↑ transaminases Normal ↑ transaminases 5 x ULN ↑ transaminases 2-5 x ULN ↑ transaminases < 2 ULN 2 Weekly for 2 Months Stop hepatotoxic drugs Weekly for 2 Weeks 2 Weekly till level reaches normal MONITORING ATT HEPATOTOCICITY BTS PROTOCOL

51. ATT – INCREASE TRANSAMINASES HEAPATIC ADAPATION Vs DILI STOP HEPATOTOXIC DRUGS Attempt to continue 3 non hepato toxic drugs FQ + ETHM+ AG MONITOR LFT 1.Return of transaminases and bilirubin to base line 2. ↓ to < 2 X ULN RECHALLANGE

52. Which of the following statements are true? A) The success of reintroduction of all the three ATT drugs ie ., H, R, Z is less than 50 % B) Severe the first of DIH high the risk of recurrence with reintroduction. C) Reintroduction of all drugs at full doses on the same day increases risk of recurrent DILI D) Pre treatment albumin predicts recurrence of DILI

53. Rechallenge following DILI The successful reintroduction of anti-TB drugs H,R,Z without recurrence of DIH is about 90% . 11-24 % of pts re exposure to the same drug regimen leads to recurrence of DILI The severity of the first episode of DILI did not affect the risk of recurrence of DILI Pre treatment serum albumin level is an important predictor of a second recurrence of DILI. Singh J, Garg PK,et al. Hepatotoxicity due to anti-tuberculosis therapy: clinical profile and reintroduction of therapy . J Clin Gastroenterol1996; 22:211–214 . Tahaoglu K, Atac¸et al. The management of anti-tuberculosis drug induced hepatotoxicity. Int J Tuberc Lung Dis 2001; 5: 65–69. Agal S, Baijal R, et al. Monitoring and management of anti-tuberculosis drug induced hepatotoxicity. J Gastroenterol Hepatol 2005; 20:1745–1752 . Sharma SK,et al. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment–induced hepatotoxicity. Clinical Infectious Diseases. 2010 Mar 15;50(6):833-9 .

54. Day 8 R 75 mg/day Day 4 H max 300 mg Day 11 R max Day 15 Z 500 mg Day 15 Z max Day 8 H max Day 1 H 50 mg/day Day 1 R max Day 18 Z max ATS BTS ERS WHO IUALTD Day 1 All drugs full dose

55. Sharma SK,et al in their study ‘Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment–induced hepatotoxicity.’ A total of 175 patients with a diagnosis of ATT DILI were randomized to receive 1 of 3 arms [All 3 drugs at same time Vs ATS vs BTS]. Clinical Infectious Diseases. 2010 Mar 15;50(6):833-9

56. MILD ICTERIC HEPATITIS With No Risk Factors With Clinical Risk Factors Start HRZ full dose at a time R  H  Z at full doses SEVERE ICTERIC HEPATITIS INH/ RIF Would advise rechallenge at escalating doses Pyrazinamide rechallenge may be avoided

57. Need of further research Urgent need to develop and validation of clinical prediction score for ATT induced hepatotoxicity Further studies needed to understand the safety of the currently used lower doses of pyrazinamide in cirrhosis.

58. Take home messages Identify the risk factor before starting ATT Monitoring is the key - ‘ prevention is better than cure’ Don’t hold first line drugs just because you have fear. As first line drugs have significant impact in management of TB. Always rule out other causes especially acute viral hepatitis before labelling ATT induced hepatitis as culprit.