This document discusses drug-induced liver injury (DILI) caused by anti-tuberculosis (ATT) drugs. It notes that ATT drugs, particularly isoniazid, rifampin, and pyrazinamide, are common causes of DILI. Isoniazid metabolism varies depending on acetylator status, and its toxicity may be due to reactive metabolites. Rifampin induces liver enzymes and its toxicity is often seen in combination with other ATT drugs. Pyrazinamide toxicity depends on dose and can cause fatty liver. Presentations of ATT-induced DILI range from asymptomatic elevations in enzymes to acute liver failure. Careful screening and monitoring of patients on ATT is needed to prevent DILI

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. TYPES OF DILI
INTRINSIC IDIOSYNCRATIC
METABOLIC
IMIMMUNOALLERGIC
(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

12. 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

13. 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)

14. (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

15. 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

16. 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

17. 17
DILI
“tolerators” – Most people exposed to a new drug show no injury
Time Course of Liver Tests
"tolerator" - M47 - Gilbert's syndrome
0.1
1.0
10.0
100.0
-60
0
60
120
180
240
300
360
420
480
540
600
660
720
780
840
900
960
1020
1080
1140
1200
1260
1320
1380
1440
1500
1560
1620
1680
1740
1800
1860
1920
1980
2040
2100
Days Since Exposed to Drug
TestValues,(xULN)
ALTx
ASTx
ALPx
TBLx
start drug stop drug

18. 18
DILI
“adaptors” – Some show transient injury, but adapt
Time Course of Liver Tests
"adaptor" - M63 - transaminase rises only
0.1
1.0
10.0
100.0
-60
0
60
120
180
240
300
360
420
480
540
600
660
720
780
840
900
960
1020
1080
1140
1200
1260
1320
1380
1440
1500
1560
1620
1680
1740
1800
1860
1920
1980
2040
2100
Days Since Exposed to Drug
TestValues,xULN
ALTx
ASTx
ALPx
TBLx
start drug stop drug

19. 19
DILI
“susceptibles” – Few fail to adapt and show serious injury
Time Course of Abnormalities
Patient xxx F44, "susceptible"
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
-15
0
15
30
45
60
75
90
105
120
Study Day
Log(10)ofxULN
ALT
AST
ALP
GGT
TBL
start Drug stop Drug
------------hospitalized-----------------
ULN
10xULN
100xULN

20. 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.

21. 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

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

24. LIVER FRIENDLY ATT DRUGS

25. INH -ISONIAZID

26. 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

27. 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

28. 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

29. 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

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

31. 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

32. 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

33. INVESTIGATIONS TO
RULE OUT OTHER
CAUSES

34. 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

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

36. Approach to DILI –
ACG GUIDELINES

37. ABNORMAL LIVER ENZYMES AT BASELINE

40. 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.

41. 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

42. RE- CHALLENGE IN ACTIVE TB- ATS GUIDELINES

44. 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

45. REINTRODUCTION
• Sequential: ATS, BTS
• Sequential without Pyrazinamide safer1
• Simultaneous: WHO, IUALTD
• Sequential for 2nd re-challenge if DILI recurs
Tahaoglu K et al. Int J Tuberc Lung Dis. 2001;5:65–69.

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

47. 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

48. 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

49. 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

51. 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

52. 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,

53. 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

54. 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 1st 8-12 weeks, in those with
• deranged baseline tests or
• risk factors eg. pre-existent LD.
• No advantage in those without these factors.

55. CONCLUSION
1. 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