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Anti-tuberculosis treatment
induced hepatotoxicity
Shima hatamkhani,Pharm.D
Tehran University of Medical Sciences
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Case
M.S a 40 yrs old male
C.C : fever, productive cough since 2weeks before admission
2- 3 times haemoptysis 4 days ago
PMH: 20-30 kg weight loss during lastyear
PDH: crack
PHE: Decreased breath sounds
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3
Smear +TB
CXRDx:TB
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Rx
INH 300mg/d [5mg/kg/d]
RFM 600mg/d [10mg/kg/d]
EMB 1000mg/d [15mg/kg]
PZA 1500mg/d [25mg/kg]
VitB6 40/d
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Follow-up
8 days after starting anti-TB treatment:
- nausea and vomiting
- malaise
- yellow eyes
- abdominal pain
5
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Anti TBhepatotoxicity
6
day 1 8
ALT 30 211
AST 20 118
ALP 231 184
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Drug Induced Liver Injury
(DILI)
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Liver enzymesALT: liver specificAST: liver, heart, muscle, kidney
Variations of 45% during a single day
Higher normal values: in men, BMI
Lower normal values: children, elderly
High values severe liver damage
Normal: 0.6 0.8AST/ALT 1: severe liver damage, muscle damage
9
ALT AST
L = liver
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Relative pattern of HepaticEnzyme Elevation vs. type
of hepatic lesion
10
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Drug-induced liver injury (DILI)
Dimension of the problem:Accounts for:
7% of all adverse drug reactions 2% of jaundice in hospitals
30-50% of fulminant/acute liver failure
DILI more frequent than viral hepatitis in acute
liver failure
11
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Drug-induced liver injury (DILI)Clinical manifestations:
Asymptomatic (hepatic adaption) Constitutional symptoms e.g malaise, fatigue Nausea, vomiting, abdominal pain Fever
Rash J aundice Coagulopathy, Hypoalbuminemia
Grading (WHO)
Grade ALT
1 2.5x ULN
2 2.6 5x ULN
3 5 10x ULN
4 >10x ULN
12
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Suspected DILIEvaluation
Max score:14
Score
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Hepatotoxicityof
anti-TB
treatment
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DILIInjury to :
-hepatocytes
-billiary epithelial cells
-vasculature
Predictable
(Direct toxicity)
*dose-related
*higher attack rate
*Occur rapidly
*Hepatocyte necrosis
*Free radicals
Unpredictable
Idiosyncratic
(immunologically)
*independent of dose
*hepatocellular injury +/cholestasis
*recur within days - weeksafter re-exposure
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ISTC TB Training Modules2009ATT-Induced
Hepatotoxicity
Hepatotoxic reactions: ALT or AST > 5 times ULN or >3 times ULN + Sign and symptom
Transaminase age-dependent with INH Transaminase dose-dependent with PZA
Cholestasis ( bilirubin and ALP) with RIF (Mild transaminase elevation may not be clinically significant)
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Drug-induced Hepatotoxicity (DIH)
Pyrazinamide
dose dependent and idiosyncratic hepatotoxicity
rarely: hypersensitivity reaction, granulomatous hepatitis
The most toxic drug in anti-TB treatment
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Drug-induced liver injury (DILI)Isoniazid
Mortality rates: 0 0.3:1000
Symptomatic LFT (>5x ULN): 0.1%Asymptomatic LFT (>5x ULN): ~ 0.6%
DILI occurs within weeks - months (60% first 3 mo,80% first 6 mo)
(median onset of symptoms: 16 weeks)
Risk factors:
age, malnutrit ion, alcohol abuse, active viral hepatitis B, baselineincreased LFT, RFM, prior INH DILI
Second most toxic drug in anti-TB treatment
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mild INHhepatotoxicity
mildly serumaminotransferases
(usually
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Drug-induced liver injury (DILI)Rifampin
Main manifestation: cholestasis, hepatocellular injury due tohypersensitivity
Increased LFT (>2x ULN): up to 2.5% (TB patients)
Symptomatic hepatitis (INH + RFM): ~ 2.5%
DILI occurs dur ing fi rst month of treatment
The Third hepatotoxic drug in anti-TB treatment
Induces hepatic enzymes => drug interaction
(usually lowers the drug levels => weakens Rx)
20
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Drug-induced liver injury (DILI)Ethambutol
Liver friendly anti-TB drugs
Non hepatotoxic drug for anti-TB treatment
Streptomycin
Non hepatotoxic drug for anti-TB treatment
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Anti-TB induced
hepatotoxicity risk factors
Age > 35Y(5%)
Severe malnutrition /
hypoalbuminemia/BMI < 20 Weight loss
HBsAg+
Anti-HCV +
basal ALT
DM
FCZ
Daily alcohol consomption
concurrent use of otherhepatotoxic drugs
pre-existing liver disease
IDU
black and Hispanic women,
all postpartum women
misdiagnosis
HIV+ ???
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The risk of DILI increased in the presence of one or more
of these risk factors
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Review Case risk factors for DILI
M.S a 40 yrs old male
PMH: 20-30 kg weight loss during last year
PDH: crack
HIV,HBsAg,Anti-HCV :
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Follow-up Routine monitoring of LFTs: not recommened
Routine monitoring of serum transaminaselevels is suggested in patients with riskfactors
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Management of DILI in TB-Rx
Continue first-line treatment:Mild gastrointestinal complaintsLFT x3 ULN in symptomatic patients
If indicated:continue with at least three least toxic drugs (EMB, SM, FQ)
Evaluate patient for hepatitis A, B and C virus, biliary disease,alcohol, other potentially hepatotoxic drugs
25 American Thoracic Society, 2006
HIV, HBsAg ,Anti-HCV :
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Protective agentsagainst ATT-induced hepatotoxicity
Animal models (2000). Hemidesmus indicus
(2006). garlic
(2007). Curcuma longa
Ocimum sanctum Tinospora cordifolia , Zizyphus mauritiana in pigs (2007). tocopherol in rabbits
(2008). Tinospora cordifolia
Phyllanthus emblica (2009). thiopronin
(2010). Silibinin(silymarin) (2010). Cissus quadrangularis stem extract
(2010). alpha-lipoic acid and aminoguanidine
(2008,2010). Carotenoids (2010) VitC
Human models
(2008). Curcuma longa,Tinospora cordifolia
(2010). NAC
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INH (5 mg/kg) RIF (10 mg/kg)
PZA (25 mg/kg),ETB (15 mg/kg)
I (n=32)
(37% DILI)
INH (5 mg/kg)
RIF (10 mg/kg)PZA (25 mg/kg),
ETB (15 mg/kg)NAC 600 mg, PO,BID
II (n=28)(0% DILI)
European J ournal of Gastroenterology &Hepatology2010, 22:12351238
In: Pul.TB(2 +smear),naiiveATT,60Y
Out :Alcohol
viral hepatitisHemoptysisabnormal pretreatment LFTchronic disease (asthma, liver,kidney)hepatotoxic drugsliver TBmoribund stateHIV +
NAC(2wk) protects against ATT-induced treatment in an elderly population
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"Prevention ofhepatotoxicity due to anti tuberculosis treatment:a novel integrative approach
28 World J Gastroenterol , 2008
INH (5 mg/kg) RIF (10 mg/kg)
PZA (25 mg/kg),ETB (15 mg/kg)
I(DILI: 27/192)
INH (5 mg/kg)
RIF (10 mg/kg)PZA (25 mg/kg),
ETB (15 mg/kg)Curcuma longa(25%)
+Tinospora cordifolia(50%)
II(DILI: 2/316)
Measurement:ALT, AST, Bill
The (2mo) herbal formulation prevented hepatotoxicity significantly and improved thedisease outcome as well as patient compliance without any toxicity or side effects.
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Effect of different
doses of carotenoids in INH-RFM inducedhepatotoxicity in rats
29 TropGastroenterol,2008
INH (50 mg/kg)
RIF (50 mg/kg)Carotenoids(2.5 mg/kg /day)
I
INH (50 mg/kg)RIF (50 mg/kg)
Carotenoids(5 mg/kg /day)II
INH (50 mg/kg)
IRIF (50 mg/kg)Carotenoids(10 mg/kg /day)III
INH (50 mg/kg)
IRIF (50 mg/kg)
Carotenoids(20 mg/kg /day)IV
Measurement:ALT, AST
,Histology
(28d)a minimum dose with
maximum hepatoprotection(10 mg/kg / day) was
selected as the optimumdose in the present study.
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Effect of garlic on isoniazid and rifampicin-
induced hepatic injury in rats
30 World J Gastroenterol,2006
INH (50 mg/kg) RIF (50 mg/kg)
I
Measurement:ALT, AST,Bill,
histology(Lipid peroxidation,GSH)
(28d)Freshly prepared garlic homogenate protects againstINH+RIF-induced liver injury in experimental animal model.
INH (50 mg/kg)RIF (50 mg/kg)0.25 g/kg /d freshly p repared garlichomogenate
II
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INH 50mg/kg/dI (10rat)
INH 50mg/kg/dVitC 100mg/kg/dII (10rat)
INH 50mg/kg
VitC 1000mg/kg/dIII (10rat)
31
glutathione (GSH)superoxide dismutase (SOD)Malondialdehyde(MDA)glutathione peroxidase (GSH-px)vitamin C
measurement
(21days) INH + vitC oxidative stressantioxidant effect :high-dose vit C low dose vitC
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When to start again?(reintroduction)
32
day 1 8 10 12 16 20 21 24 28
Bili 0.5/0.2 0.5/0.3 0.2/0.1 - 0.2/0.1 0.2/0.1 - 0.6/0.2
ALT 30 211 236 152 133 92 94 74 30
AST 20 118 124 52 42 39 45 32 13
ALP 231 184 207 278 219 289 277 276 215
ALT / AST < 2 ULN reintroduce drugs
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Reintroduction in Iran (ETM 15mg/kg/d ) +RFM 150mg/d
(ETM 15mg/kg/d ) + RFM 10mg/kg/d
(ETM 15mg/kg/d ) +(RFM 10mg/kg/d) +INH 50 mg/d
(ETM 15mg/kg/d ) +(RFM 10mg/kg/d) +INH 100mg/d
(ETM 15mg/kg/d ) +(RFM 10mg/kg/d) +INH 200mg/d
(ETM 15mg/kg/d ) +(RFM 10mg/kg/d) + INH 5mg/kg/d
33
(3-7 d)
(7 d)
(4 d)
(3 d)
(7 d)
If no RFM tolerance start the same regimen with INH2 SHE/ 10 HE
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Reintroduction
Modification/Re-challenge after stop (American Thoracic Society, 2006)
After ALT is
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No differences
day 1 4 8 11 15 18
INH
RFM
PZA
ETM
Sharma,et.al , CID 2010
day 1 4 8 11 15 18
INH
RFM
PZA
ETM
da 1 4 8 11 15 18
INH
RFM
PZA
ETM
Arm I
Arm II
Arm III
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How were the anti TB drugs re-introduced?
36
day 21 26 31 15 18
INH
RFM
PZA
ETM
ETM :full- doseRFM: 150mg/d 600mg/dINH: 50 mg/d100mg/d200mg/d300mg/d
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Summary
Incidence of Hepatotoxicity (any) ranges between 2 - 33%
Mortality due to hepatotoxicity in ATT is very low
Most toxic TB drugs are: PZA> INH > RFM
Avoid unnecessary risk of hepatotoxicity and make diagnosis of TBas accurate as possible
Stop ATT if LFT >3-5x ULN
If LFT < 2x ULN Stepwise rechallenge of RFP, INH (and PZA)seems safe after
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