ATT Induced Liver

Injury

Dr. Zubair Sarkar

JR2,Deptt. of Medicine
J.N.M.C.H. ,
Aligarh Muslim University
Introduction
 Tuberculosis is one of the deadliest
communicable diseases
 WHO(2013) : 9 million developed TB
with mortality of 1.5 million
 MDR–TB (3.5% of new and 20.5% of
previously treated cases) and XDR-TB
(9%of MDR-TB) are rampant
 1.1 million (13%) of 9 million were HIV
seropositive
 The liver (“metabolic factory” of the body)
is central to the metabolism of all foreign
substance including anti-tuberculosis
drugs.

 Drug-induced liver injury (DILI) :

 common,
 often unrecognized cause of liver
damage in treatment of tuberculosis
 Isoniazid, rifampicin and pyrazinamide
are essential components (First Line
Drugs) of the treatment of tuberculosis
and all the three drugs have
hepatotoxic potential

 Several second line drugs (including

ethionamide , prothionamide , few
flouro-quinolones and PAS) are
potentially hepatotoxic.
 Many ART drugs including zidovudine ,
didanosine , ritonavir , indinavir ,
nevirapine and efavirenz are
hepatotoxic.

 Use of ATT and ART together in HIV-TB

co-infected increases risk of DILI

 Treatment of latent TB infection

contributes to the pool of anti TB DILI
Mechanisms of drug toxicity
 Direct toxicity (Dose dependent)
 Idiosyncratic damage
 Induction of hepatic enzymes
 Allergic reactions
 Direct toxicity :
 Acute/subacute
 Dose related : increases with escalation
of dosages
 Free radicals mediated necrosis
 Usually no extra-hepatic manifestations.
 Idiosyncratic Reaction :
 Most types of DILI.
 Include
 metabolic or
 hypersensitivity reactions.
 Largely independent of dose
 May occur anytime post exposure.

 Result from genetic or acquired variations

in drug biotransformation pathway
 Induction of hepatic enzymes :
 Alter plasma drug levels
 Enhance hepatotoxicity of other drugs
 Associated with extra hepatic adverse
drug reactions
 Allergic reaction :
 Reactive metabolite mediated
 Manifests with fever , lymphadenopathy,
rash and severe hepatocyte injury
 Specific patterns of hepatic damage :

I. Disruption of intracellular calcium

homeostasis
II. Cholestatic damage
III. Interruption of transport pumps and loss
of villous processes
IV. Reactions involving cytochrome P-450
system
V. Activation of apoptotic pathways and
programmed cell death
VI. Inhibition of mitochondrial function
Anti-tuberculosis drugs and
hepatotoxicity

 Isoniazid (INH) :
 Not well-understood.
 Delayed onset : weeks to months
 60% incidence in first 3 months
 No hepatotoxicity on re-challenge
 Isoniazidis associated with :
 Reactive metabolite
 Immuno-allergic injury : HLA-DQB1*0201
 Mitochondrial injury
 Acetyl-isoniazid, the principal metabolite
of isoniazid, is converted to mono-acetyl
hydrazine.

 The
microsomal p-450 enzymes convert
mono-acetyl hydrazine to other
compounds resulting in hepatotoxicity.
 Histopathology : resembles viral hepatitis
showing
 hepatocyte necrosis,
 ballooning degeneration and
 inflammatory infiltrates.

 Absence of symptoms associated with

hypersensitivity : rash, fever, arthralgia
and eosinophilia.
 Rifampicin (RIF) :
 Occurs earlier
 Produces a patchy cellular abnormality
with marked peri-portal inflammation.
 Mechanisms include: –
1) Conjugated hyperbilirubinemia caused
by:
 RIF inhibiting the major bile salt exporter
pump.
 Dose-dependent competition with
bilirubin for clearance at sinusoidal
membrane.
 Impeded canalicular secretion
2) Hypersensitivity reaction –
 Rare
 More common with large, intermittent
doses.
 Hypersensitivity reactions in combination
with renal dysfunction, hemolytic
anemia, or “flulike syndrome”
 Pyrazinamide (PZA) :
 Most hepatotoxic.
 Half life of 10 hours : can increase to 15
hours in pre-existing liver disease
 Exhibits both dose dependent and
idiosyncratic hepatotoxicity.
 Free radical generation.
 There may be shared mechanisms of
injury for INH and PZA : some similarity in
molecular structure.

 Patients with previous hepatotoxic

reactions with INH : more severe
reactions with RIF and PZA combination.

 May induce hypersensitivity reactions

with eosinophilia and liver injury, or a
granulomatous hepatitis.
 Isoniazid + Rifampicin :

 Due to the additive effect or synergistic

effect

 The toxicity is due to direct toxic effect

of drugs or is a hypersensitivity
phenomenon.
 Increased risk is attributed to the
interaction between the metabolism of
INH and rifampicin

 Rifampicin enhances conversion of INH

to acetylated metabolites by microsomal
p450 enzyme induction.
Factors implicated in
development of Anti –TB DILI
 Ethnic and Racial variation :
More common in India (11.5% risk)
compared to western countries (4.5% risk)

 Age : >50 years

<35 years
 Gender :
Female > Male

 Genetic :
 Absence of HLA –DQA1*0102 and
 Presence of HLA-DQB1*0201
are independent risk factors for DILI
Alcoholism and underlying CLD :
Both predispose to the development of DILI

 Infections :
 Hepatitis B : independent risk factor
 Hepatitis C
 HIV
 Malnutrition :
 Poor nutritional status and
 Decreased serum albumin levels (<3.5
g/dl)

 Types of tuberculosis :
 Extensive cavitary form of pulmonary TB
 TB meningitis
 Acetylator phenotype :
 Highly debated : slow vs. fast acetylators
 Previous suggestion : rapid acetylators are
more prone to DILI because of larger
amount of acetyl-isoniazid
 New concept :
 Products of hydrolysis are critical toxic
metabolites which is greater in slow
acetylators
 Rifampicin induces isoniazid hydrolase
forming isonicotinic acid and hydrazine
 Drug metabolising enzymes :
 N-acetyl transferase 2 (NAT2) : slow
NAT2 genotype (East Asians)
 Cytochrome p450 2E1 : CY2E1 Rsal/Pstl
polymorphism ( Chinese Koreans and
East Asians)
 Glutathione S-transferase M1/T1 :
GSTM1 null genotype (Chinese and East
Asians)

 Recent prospective trial showed no risk in

north indian population in association with
Clinical Presentation
 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 and/or disease in other
organs
 Auto-immune hepatitis-like injury
 Cirrhosis
 Primary hepatic neoplasms
Clinical Syndromes of DILI
 Hepatic adaptation:
 Physiologic adaptive response to certain
drugs e.g. rifampicin.
 Asymptomatic transient rise in ALT & non
progressive liver injury.
 No inflammation.
 Acute hepatitis or hepatocellular injury:
 Asymptomatic or prodrome (fever,
constitutional symptoms, nausea,
vomiting , lethargy).
 Markedly elevated transaminases
 Jaundice
 Coagulopathy – delayed 24-36 hours
later.
 Granulomatous hepatitis:
 Hypersensitivity reaction e.g. PZA.
 Fever, lethargy ,rash, lymphadenopathy,
vasculitis.
 Raised trasaminases.
Diagnosis
 Hepatic Adaptation vs. true DILI :
 Exposure to certain drugs may cause
physiological adaptive response :
asymptomatic transient rise of ALT
 Rarely results in inflammation or cell
death
 20% patients on 4 drug regimen
 Definitions :

 Hy’s Law for hepatocellular DILI:

ALT level >3 times UNL* and total bilirubin

>2 times UNL after excluding other
potential causes

*upper normal limit

 As per ATS/CDC/IDSA guidelines:
In patients receiving anti-TB treatment for
active TB disease :
 ALT level >5 times of UNL or
 >3 times of UNL in the presence of
nausea, vomiting, jaundice , abdominal
pain or fatigue
in the absence of laboratory evidence of
acute viral hepatitis
  Other criteria for diagnosis of anti-TB DILI
:
i. AST and /or ALT >5 times UNL
ii. Total serum bilirubin rise of 1.5mg/dl and
iii. Any increase in pre-treatment levels of
AST and/or ALT together with anorexia,
nausea, vomiting and jaundice
 WHO Classification :
GRADE ALT levels

I 51 to 125 IU/L or
1.25 to 2.5 times normal
II 126 to 250 IU/L or
2.6 to 5.0 times normal
III 251 to 500 IU/L or
5.1 to 10.0 times normal
IV >500 IU/L or
>10.0 times normal or
>250 IU/L if accompanied by
symptoms
Score for Diagnosis
 Roussel Uclaf Causality Assessment
Method (RUCAM) score
 Clinical, biochemical, serological and
radiological features of liver injury
 Validated, standardized tool to assess the
probability of drug – relatedness for liver
injury.
 Total range : -9 to +14
 Highly probable : >8
 Probable : 6 – 8
 Possible : 3 – 5
 Unlikely : 1 – 2
 Excluded : <0
R Ratio
 For differentiating hepatocellular, mixed or
cholestatic jaundice
 R = (ALT/ ALT UNL) / (ALP/ ALP UNL)
 R ratio :
>5 : Hepatocellular
2–5 : Mixed
<2 : Cholestatic
Management of anti –TB DILI
 No consensus guidelines yet

 Guidelines published by ATS/BTS/WHO

/CDC/ IDSA form the basis for
management
 Baseline :
Serum transaminases, bilirubin, ALP,
creatinine and platelet count should be
obtained for all patients starting treatment
for TB
 Monitoring of liver function recommended
in :
 Chronic liver disease
 Chronic use of alcohol
 HIV positive on HAART
 Pregnant and upto 3 months postpartum
females
 Concomitant treatment with other
medication
 Chronic medical conditions
Frequency of monitoring :
Serum transaminases and bilirubin is to be
measured every 2 to 4 weeks for first 2 to 3
months and then as necessary
Management cont….
 Question 1:
When to stop anti – TB drugs?

 Most authorities suggest ALT levels > 5

times or >3 times in presence of
symptoms i.e. jaundice.
 Question 2 :
What drugs to be given after stopping first
line ATT?

 Ethambutol + Hepatosafe flouroquinolone

(Levofloxacin/Moxifloxacin/Ofloxacin/Cipr
ofloxacin) + Aminoglycoside
(Streptomycin)

 Supportive management for hepatic

dysfunction
Question 3 :
When to restart first line anti –TB drugs?

 ATS : When ALT levels are <2 times

normal (<80 IU/L)

 BTS/WHO : ALT within normal limits

Question 4 :
How to re-introduce first line drugs?
 ATS :

Rifampicin in full dose

Isoniazid in full dose after 3-7 days if LFT is

normal

Monitor ALT 3-7 days after re-challenge

Pyrazinamide After 7 days if LFT remains

normal

If DILI occurs stop the last offending drug

 BTS :
Isoniazid : Dose titration 2-3 days(50mg to 300mg/day)
Daily monitoring of LFT

Rifampicin : Dose titration 2-3 days (75mg to

600mg/day)
Daily monitoring of LFT

Pyrazinamide : Dose titration 2-3days(250mg to

2000mg/day)
Daily monitoring of LFT

Stop offending drug

 WHO :
Start all drugs in full dosage
Monitor LFT

Stop if DILI occurs again

Give Ethambutol and Streptomycin

Reintroduce one by one