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.
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
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
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
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.
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
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
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.
