Guideline for the Management of

Anti-Tuberculosis Therapy
Induced Liver Injury
(Version 2.0)

Revision History
Guideline Author:
Guideline Sponsor:
Date of Approval:
Approved by:
Date of CSC Ratification:
Review Date:
Related Policies / Topic /
Driver
Version No
1.0

Baljit Ahitan, Dr Martin Dedicoat.

Respiratory Directorate
June2013
Respiratory and ID directorates
June 2015

Date of Issue Author

Baljit Ahitan, Dr Martin Dedicoat,

Clinical Director:

Signed

Reason for Issue

New guideline

NameDR E G Smith
Date18.07.2013

Paper Copies of this Document

If you are reading a printed copy of this document you should check the Trusts Guideline website
to ensure that you are using the most current version.

Overview/Introduction

This guideline has been developed to standardise the prescribing and monitoring of the
reintroduction of anti-tuberculosis (ATT) medication in adult patients diagnosed with drug
induced liver injury (DILI) and in patients with baseline liver enzyme abnormalities..

Flow Chart

Available within body of guideline

Objectives of the Guideline

Aim:
1. To ensure safe and appropriate prescribing of ATT in patients diagnosed with DILI as an
adverse effect.
2. To ensure all patients prescribed the re-introduction regimen are monitored appropriately.

Body of Guideline

Modest elevations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT)

are not uncommon in the pre-treatment liver function tests (LFTs) of TB patients, or
immediately after the introduction of therapy (see flow chart 1 for management).
Before starting ATT always check baseline LFTs and hepatitis B&C serology. If the patient
has an abnormal baseline ALT, AST or bilirubin level, treatment need not be withheld but will
require repeat LFT monitoring during ATT. Also, patients with risk factors for DILI should be
monitored by repeat liver function testing throughout ATT. These risk factors include:
1.
2.
3.
4.
5.
6.
7.

Hepatitis B or C infection
Heavy alcohol use
Malnutrition or low serum albumin at baseline
Cirrhosis or any other chronic liver disease
Other concurrent potentially hepatotoxic medications
Elderly
During pregnancy or up to 3 months post partum

During ATT, DILI should be suspected in any patient that vomits, develops itching, develops
jaundice or feels unwell after starting treatment. In these cases LFTs should be checked.
Flowchart 2 below details how patients on treatment who develop elevated AST, ALT or
bilirubin levels should be managed:

FLOW CHART 1. Liver enzymes abnormal at baseline

AST/ ALT or bilirubin raised at baseline

Assess reasons for raised enzymes and modify if

possible. E.g. alcohol excess, hepatitis B/C, other
medication.

ALT/AST<3x upper limit of normal (ULN)

Start standard TB treatment
Check ALT/AST in one week

ALT/AST<3x upper limit of normal (ULN)

Continue TB treatment
Check ALT/AST in one week

ALT/AST > 3 x ULN or raised bilirubin

Consider admitting patient
Start liver friendly regimen
AND seek advice from TB consultants

ALT/AST > 3x upper limit of normal (ULN)

Stop TB treatment
Consider admitting patient
If the patient is well and has non infectious
TB all treatment can be stopped
If the patient has infectious TB or is unwell
start a liver friendly regimen (see table 2
below)

FLOW CHART 2. Liver enzymes become abnormal on treatment.

AST /ALT or bilirubin levels raised.

ALT/AST /
bilirubin< 2x
ULN

ALT/AST/ >
2x ULN
(<3xULN)

Repeat LFTs
after 2
weeks
Or sooner if
becomes
unwell

Monitor LFTs
weekly for 2
weeks, then
2 weekly
until
normalisation

If levels
decrease,
repeat LFTs
as per
patient
symptoms

If levels
increase
above twice
normal value

ALT/AST> 3x
ULN with
patient
symptoms OR
bilirubin level
rises > twice
normal value

ALT/AST> 5x
ULN
regardless of
symptoms

STOP ALL
MEDICATION

Consider
reintroduction
regimen when
LFTs < twice
normal value1

1. If the patient is well and has non infectious TB all medication can be stopped. If the patient is
unwell or has infectious TB admit them and start treatment with a liver friendly regimen as
outlined below.

Points for consideration:

a) If the patient is not unwell and the form of TB is non- infectious no treatment need be
given until LFTs return to normal.
b) If the patient is clinically unwell/smear positive discuss prescribing alternative drug
therapy with ID/respiratory specialist. Amikacin, moxifloxacin and ethambutol should
be considered unless clinical/bacteriological evidence of resistance(see table 2).
Other non-hepatotoxic medication may be considered. Alternative regimens should
again be on the advice of ID/respiratory specialist.
c) Once LFTs have normalised (or at least less than twice normal value), original
medication can be reintroduced as per the regimen in table 1 below. If no further
reaction the above alternative medication can be discontinued.

Table 1. Medication Re-introduction Regimen

Day
1M
2T
3W
4T
5F
S
S
6M
7T
8W
9T
10F
S
S
11M
12T
13W

Isoniazid dose
100mg
200mg
300mg
300mg
300mg
300mg
300mg
300mg
300mg
300mg
300mg
300mg
300mg
300mg
300mg
300mg
300mg

Rifampicin dose

Pyrazinamide dose

Check LFT
X

150mg
150mg
150mg
150mg
300mg
450mg / 600mg1
450mg / 600mg
450mg / 600mg
450mg / 600mg
450mg / 600mg
450mg / 600mg
450mg / 600mg
450mg / 600mg
450mg / 600mg

X
250mg
500mg
1g
1g
1g
1.5g/2g2
1.5g/2g
1.5g/2g

X
X
X
X

1. <50Kg body weight = 450mg rifampicin, >50Kg body weight = 600mg rifamipcin
2. <50Kg body weight = 1.5g pyrazinamide, >50Kg body weight = 2g pyrazinamide
3. If the patient is well and non infectious start full dose ethambutol on day 13, if the
patient is infectious or unwell start moxifloxacin 400mg daily, ethambutol 15mg/Kg
daily (maximum 1.2g daily) and either amikacin or streptomycin 15mg/Kg daily
(maximum 1g daily) immediately.
4. In patients who are well reintroduction can be managed as an outpatient in
conjunction with the TB nursing team. In this case where it is not possible to check
the LFT e.g. over a weekend doses should be left the same and not escalated or new
medication introduced see table for inpatients omit days marked S (Saturday /
Sunday)
Table 2 Liver friendly ATT regimen

Medication
Ethambutol

Dose
15 mg/Kg
(max1.2g)

Frequency
Daily

Moxifloxacin
Amikacin

400mg
15 mg/Kg (max 1g)

Daily
Daily

Notes
Caution in renal
disease seek
expert advice
Caution in renal
disease seek
expert advice

Reason for Development of the Guideline

The guideline assists all staff involved in the management of DILI in patients with
tuberculosis (TB). It details the re-introduction of the ATT medication as well as the
monitoring regime.

Methodology

The draft guideline was written in consultation with Dr Martin Dedicoat (Consultant ID
Medicine) and Dr Heinke Kunst (Consultant - Respiratory Medicine). It was further refined
following consultation with all Respiratory and ID consultants, TB clinical nurse specialists,
Christine Gunner (Medicines Information Manager) and Dr Grace Smith (Consultant
Microbiologist/Chair Birmingham TB Network).

Implementation

This clinical guideline will be circulated to the appropriate clinical areas. An electronic
version will be available on the Trust internet site for access at all times.

Monitoring

Adherence to the guideline will be monitored by respiratory/ID, pharmacy and nursing staff.
The guideline will be subject to audit.

Application of the Guideline

Clinicians, pharmacy and nursing staff will benefit from the guideline as it will provide clear
advice on the re-introduction and monitoring of ATT in TB patients diagnosed with DILI as an
adverse effect within the trust. The guideline is only to be used by staff working in the
infectious disease and respiratory department who are competent in the care of patients with
TB and are working as part of a multidiscipline team.
10 References
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4. An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy. Am J Respir
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5. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung
Dis 2001;5(1):65-69
6. Anti-tuberculosis medication and the liver: dangers and recommendations in
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7. Liver injury during antituberculosis treatment: an 11-year study. Tuberc Lung Dis
1996;77:335-340
8. Hepatoxic Reaction to Antituberculous Drugs:Adjustments to Therapeutic Regimen.
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9. Safety of 3 Different Reintroduction Regimens of Antituberculosis Drugs after
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12. NICE clinical guideline 117 Tuberculosis March 2011