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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

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Anti TBhepatotoxicity

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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

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ALT AST

L = liver

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Relative pattern of HepaticEnzyme Elevation vs. type

of hepatic lesion

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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

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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

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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)

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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)

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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)

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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

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(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?

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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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