ATT induced liver injury is very common with anti tubercular drugs as tuberculosis is one of the most common infection in india. Management of att liver injury is very important in medicine and is elaborated here.

1. ATT INDUCED HEPATITIS
Dr Harpreet Kaur
MD Medicne
GMC PATIALA

2. Five “first line” anti tubercular drugs :
1.Isoniazid (H)
2.Rifampicin (R)
3.Pyrazinamide (Z)
4.Ethambutol (E)
5.Streptomycin (S)

3. 2nd Line Anti Tubercular Drugs
Flouroquinolones: Ofloxacin, Levofloxacin, Moxifloxacin ,
Ciprofloxacin
INJECTABLE : Kanamycin , Amikacin, Capreomycin
OTHERS: Ethionamide, Prothionamide , Cycloserine/
Teriziodone, PAS

4. ANTI TB REGIME
 The RNTCP adopted thrice weekly regimen for treatment
of drug sensitive TB until now
 The program has now introduced daily regimen for
treatment of Drug sensitive TB among PLHIV and pediatric
TB patients in the entire country and for all TB patients in
104 Districts initially
 The daily regimen will be gradually scaled up to the entire
country

5.  The Principle of treatment with daily regimen is to
administer daily fixed dose combinations of First line ATT
in appropriate weight bands
(Drug) (Adult Daily Dose mg/kg)
 Isoniazid 5
 Rifampicin 10
 Ethambutol 15
 Streptomycin 15
 Pyrazinamide 25

6. CATEGORY TYPE OF PATIENT REGIMEN
NEW 1.New sputum smear
+ve
2.New sputum smear –
ve
3.New extra pul. TB
2 HRZE
+
4 HRE
Previosuly treated 1.Sputum smear +ve
Relapse
2.Sputum smear +ve
Failure
3.Sputum +ve
Treatment after
Default
4.Others
2 HRZES
+
1 HRZE
+
5 HRE

7. HEPATOTOXIC DRUGS
 Isonaizid
 Rifampicin
 Pyrazinamide
 Rifabutin
 Ethionamide/ Prothionamide
 Para amino salicylic acid

8. Hepatic safe Drugs
 Streptomycin (amg )
 Ethambutol
 Flouroquinolones : levofloxacin , moxifloxacin , ofloxacin
 Cycloserine

9. ATT DILI
 Derangement in liver function while the patient is on ATT,
provided other causes of deranged LFTs are ruled out,
classified as ATT DILI.
 Drug-induced liver injury (DILI) is ultimately a clinical
diagnosisof exclusion
 Must rule out :
1. Excessive alcohol consumption
2. Hepatitis A or E (esp. in India )
3. Hepatitis B or C if not done at baseline
4. Other hepatotoxic drugs

10.  In India , ATT is the leading cause of DILI and DIALF.
 Usually, Occurs within three months but can occur anytime
during the treatment course and even after the drug is
stopped
 Rechallenge with the suspected offending agent with more
than twofold serum alanine aminotransferase (ALT)
elevation, and discontinuation leading to a fall in
ALT, is the strongest confirmation of the diagnosis.

11. MECHANISM
(i) Idiosyncratic damage : Most Common
(ii) Dose-dependent toxicity;
(iii) Induction of hepatic enzymes;
(iv) Drug-induced acute hepatitis;
(v) Allergic reactions
(vi) Drug induce autoimmune like hepatitis

12. ISONIAZID
 Onset generally within week to months
 Approximately 60 % of the hepatotoxicity indcidence
occurred between first 3 months of the treatment
 Manifestations can occur as late as 14 months

13.  Severity increases with age higher mortality in those older
than 50 years
 Pregnant women and those in first three months post
partum are at higher risk
 Women are at higher risk of more severe injury from
Isoniazid related hepatitis due to increased CYP3A4
activity

14. Mechanism of isoniazid hepatotoxicity
A/W
 Reactive metabolite
 Immunoallergic injury
 Mitochondrial injury
 Impaired liver cell regeneration as hydralazine derivatives
inhibit histone deacetylase

16.  Slow acetylators are more prone to isoniazid induced
hepatotoxicity
 Genotype CYP2E1 c1/c1 have higher production of
hepatotoxins
 The pattern of liver enzyme elevations is usually
hepatocellular with marked increases in ALT levels (>10
times ULN) and minimal increases in alkaline phosphatase
values (usually <2 times ULN).

17. H/P resembles that of viral hepatitis –hepatocyte necrosis,
ballooning degeneration and inflammatory infilitrates.

18. RIFAMPICIN
 Rifampicin induced Hepatotoxity occurs earlier compared
to Isoniazid
 Incidence 0.6-0.7 %
 Elevation in bilirubin and ALP is characteristic with
Rifampicin
 H/P patchy cellular abnormality and periportal
inflammation

19. mechanism
 May cause conjugated hyper bilirubinemia by inhibiting
major bile salt exporter pump
 Asymptomatic elevation in bilirubin may result from dose
dependent competition with bilirubin for clearance at
sinusoidal membrane or from impeded secretion at
canalicular level
 Rifampicin may rarely cause hepatocellular injury due to
hyper sentivity reaction which is more common in large
intermittent dose

20. RIFAMPICIN AND ISONIAZID
Rifampicin and Isoniazid have additive effect
Rifampicin enhances conversion of INH to reactive metabolites by
microsomal p450 enzyme induction

21. pyrazinamide
 Most hepatotoxic
 Incidence 15%
 Half life 10 hours
 Increased to 15 hrs in pre existing hepatic disease
 The onset of injury due to pyrazinamide is generally after
4 to 8 weeks and occasionally becomes apparent only
after the pyrazinamide is stopped.

22.  Mechanism of injury : dose dependant
Idiosyncratic hepatotoxicity
 It alters nicotinamide acetyl dehydrogenase levels in liver
resulting in generation of free radical species

23.  The pattern of liver enzyme elevations is typically
hepatocellular and the clinical syndrome resembles acute
viral hepatitis, much like isoniazid hepatotoxicity.
 Liver biopsy demonstrates changes typical of acute
hepatitis with portal and lobular inflammation,
hepatocellular necrosis ,variable degrees of cholestasis or
granulomatous hepatitis

24. CONCEPT OF ADAPTATION
 Unique phenomenon seen with ATT its tolerance to the
drugs k/a adaptation
 Phenomenon when there is asymptomatic deranged LFTs
which resolves on its own while the patient is continued
on drugs
 Seen in 20% patients on ATT
 Awareness of adaptation is important in management of
TB to prevent inadvertent discontinuation of first line ATT.

25. RISK FACTORS FOR DILI
 Hepatitis B , C , HIV
 Alcohol abuse
 Malnutrition / serum albumin < 3.5 gm/dl at base line
 Chronic liver disease
 Abnormal LFTs at baseline
 Concurrent hepatotoxic drugs
 Age > 35 yrs
 Pregnancy or 3 months postpartum

26.  Acetylator status – slow acetylators – higher risk of
hepatotoxicity and more severe DILI
 Absence of HLA –DQA1*0102 and
 Presence of HLA-DQB1*0201
 polymorphisms present in genes coding for
Cytochrome p450 2E1 and Glutathione S transferase
 Extensive TB disease
 Liver transplant cases with TB

27. Clinical features
Jaundice
Nausea and vomiting
Anorexia
Malaise
Right upper quadrant pain
fever is noted in 10% and rash in 5% of patients.
Coagulopathy, hypoglycaemia ,mental status changes signify
life-threatening hepatic dysfunction

28. Clinical spectrum
 Clinical syndromes observed in patients with drug induced
hepatotoxicity :
 Abnormal liver function tests in asymptomatic patients
 Acute viral hepatitis-like presentation
 Acute (fulminant) hepatic failure
 Subacute hepatic failure
 Cholestatic hepatitis, obstructive jaundice, chronic cholestasis
 Liver disease with signs of hypersensitivity
 Auto-immune hepatitis-like injury
 Cirrhosis

29. MANAGEMENT

30. HOW OFTEN TO CHECK LFTs
Baseline LFTs to be done in all patients to be started on ATT(ATS/BTS)
Situaion Recommendation
1.LFT normal at baseline and no
risk factor for DILI
1.LFT at baseline , repeat if
clinically indicated
2. LFT normal at baseline with risk
factor or LFT abnormal at baseline
2.Repeat every 2 to 4 weeks
3.LFT normal at baseline but
become abnormal after starting ATT
3.Repeat LFT weekly for 2 weeks
then
2 weekly until normalisation

31. WHEN TO STOP ATT
1.Liver enzymes normal at baseline :
AST/ALT >= 5 x ULN , in the absence of symptoms or
hyperbilirubinemia ( ATS )
OR
AST /ALT >= 3 x ULN , in the presence of symptoms or
hyperbilirubinemia ( ATS )
2. If liver enzymes are abnormal at baseline
stop first line ATT if
AST/ALT >= 3 x ULN , even if there are no sypmptoms or
hyperbilirubinema ( ATS )

32. ALTERNATIVE THERAPY
1.When patient is well and non infectious
no treatment until the LFTs return to normal
2.Patient clinically unwell or smear Positive
alternative drug therapy may be prescribed

33. A combination of:
 one Aminoglycoside (Streptomycin 15 mg /kg IM)
 one Fluoroquinolone (levofloxaxin / ofloxocin/ moxifloxocin)
 Ethambutol (15 mg/Kg PO OD )
LFTs to be monitored weekly until normalisation or until enzymes <= 2 x
ULN

34. REINTRODUCTION
 Once LFTs have normalised or are atleast less than twice
normal value, original medication can be reintroduced
 If there is no further reaction the alternative medication
can be withdrawn.

35. THREE ARMS
ATS
BTS
WHO

36.  Three re-introduction regime
1.ATS regimen
 to restart when ALT <= 2 x ULN,
 start with rifampicin (full dose) +/- EMB
 Check ALT after 3-7 days
 (if ALT normal) after 3 to 7 days INH ( full dose)
 check ALT after every 3 to 7 days
 (If ALT normal ) consider PZA rechallenge after 3 -7 days
 if DILI reoccurs stop last drug added
(PZA should NOT be reintrointroduced if there is h/o severe or prolonged
DILI )

37.  INH dose titration at a dose of 100 mg /day DAY 1
monitor LFT daily
 Maximum dosage DAY 4
monitor LFT daily
 R at dosage of 150 mg /day DAY 8
monitor LFT daily
 Maximum dosage DAY 11
monitor LFT daily
 Z at 500 mg/day DAY 15
monitor LFT daily
 Maximum dosage DAY 18
 if DILI reoccurs stop last drug added
BTS

38. WHO REGIMEN
Restart when LFT normalise

39.  no statistical difference noticed in the recurrence rate of DILI
between the three regimens
 However , it is recommended that ATT should be introduced
sequentially because it helps identifying the culprit drug and
continuing the rest first line drugs.

40.  PZA is the most hepatotoxic drug so caution should be
executed when introducing it
 Avoid PZA when there is H/O severe DILI

41. WHEN NOT TO RECHALLANGE
 Rechallange is not recommended for those who have had
fulminant hepatitis.

42. MONTIOR LFTs
AST/ALT >= 5 ULN ( in absence of s/s)
or
AST/ALT >= 3 ULN (in presence of Jaundice or s/s )
STOP IST LINE ATT
Pt.clinically well or non infectious Pt. unwell / infectious
no alternative treatment streptomycin, FQ , EMB
BASELINE LFTS

43. Repeat LFT every week
Liver ezymes <= 2 ULN and Bil < 2mg/dl *UpToDate
Re Start ATT sequentially
( ATS / BTS regimen )
If DILI recurs Stop the last offending drug and put the
patient on alternate regimen by omitting the offending drug

44. ALTERNATE REGIMEN FOR OMITTED DRUG
(table 1)
DRUG OMITTED INTENSIVE PHASE TOTAL DURATION
Rifampicin Isoniazid
FQs 2M
Ethambutol
Streptomycin
Isoniazid
FQ 16M
Ethambutol
18 months
Isoniazid RIF
FQ 2M
Ethambutol
Streptomycin
RIF
FQ 10M
Ethambutol
12 months
Pyrazinamide RIF
INH 9M
Ethambutol
9 months

45. ATT in CLD
 Tuberculosis is 15 times more common in people with CLD
 Management of TB is complicated since three of the first
line drugs are hepatotoxic.
 Treatment regimen depends on child pugh status .

46. Management depends on Child status of
cirrhosis
CHILD PUGH
STATUS
PRINCIPLE TREATMENT DURATION
A Standard ATT 2 HRZE ,4 HRE
Or
HRE 9 months
(PZA omitted )
6 months
9 months
B PZA should be
omitted
Option 1 : two
hepatotoxic drugs:
HRE for 9 months
Option 2 : one
Hepatoxic Drug :
inh+emb+streptom
ycin for 2 M
Inh + emb for 10 M
C NO Hepatoxic Drug Streptomycin
Ethambutol
FQ
18 – 24 months

47.  Initially Weekly monitoring of LFTs in CLD patient on ATT is
required
 Cut off for stopping ATT in CLD :
Hepatotoxic drugs should be stopped
if a rising trend of ALT /AST on two consecutive testing
or
Any rise in bilirubin

48.  Hepatotoxic ATT should be restarted only after serum
bilirubin and transaminases return to normal.
 It is preferable to restart these drugs in a sequential
fashion with rifampicin first followed by INH and lastly
PZA which may be avoided altogether.

49. TAKE HOME MESSAGE
 patients with risk factors of DILI or those with abnormal LFTs
should be monitored timely throughout ATT
 DILI is a diagnoses of exclusion , before diagnosing a patient
with DILI other common causes of deranged LFTs must be ruled
out (esp. hepatitis)
 patient and the family members must be EDUCATED about the
potential side effects and symptoms of ATT induced
hepatotoxicity . Patients should be told to consult their
doctor immediately if they develop any such symptoms.

50.  First line ATT should be reintroduced sequentially .
 Extra cautious while reintroducing PYRAZINAMIDE ,which
is the most hepatotoxic drug , should be avoided when
there is H/O severe or prolonged DILI.

51. Thank you