Two Cases of Unusual Recurrence of Anti-tuberculosis Drug Induced

Hepatotoxicity in Children
Heda Melinda N Nataprawira, Ahmad Hafidz
Department of Child Health Faculty of Medicine Universitas Padjadjaran,
Dr. Hasan Sadikin General Hospital, Bandung

Abstract
Background. New cases of TB are increasing and most of them are in developing
countries. Anti-tuberculosis drug induced hepatotoxicity (ADIH) is one of the adverse
effect which causes increase of liver transaminases, bilirubin, icterus, anorexia,
nausea, and vomiting. Eventhough ATS and BTS have published guidelines for ADIH,
however, there is no guidelines for treating ADIH in children. ADIH is not so
common in children. It requires stopping all the potential hepatotoxic antituberculosis
drugs with a systematic and regular monitoring of liver enzymes. Baseline liver
function assessment before starting therapy for tuberculosis and parent education by
the treating pediatrician for early identification of features of clinical hepatitis in their
children will be useful in the appropriate management of these cases. Objective. To
report under-five TB children, aged 18 months old girl and 48 months old boy whose
experience ADIH after two times of consecutive anti-tuberculosis treatment. Case.
Both cases are reccurence of ADIH and have received tuberculosis drug for
reintroduction for several months. Tuberculosis reintroduction consists of rifampicin
(RMP), isoniazid (INH). Laboratory finding found increased of total bilirubin and
liver function test. Hepatitis markers showed negative results. Conclusions. There is
no exact guideline for ADIH in children.

INTRODUCTION

Tuberculosis is a disease known for years. New cases of TB are increasing and
most of them are in developing countries. Demographic data shows that tuberculosis
in children is 8% from total tuberculosis cases. In 2013, Indonesia TB data predicted
that among 325,582 new and relapsed cases of TB 26,054 cases aged under 15 years.
Standard TB treatment for children consists of a 6–month course with isoniazid,
rifampicin, pyrazinamid. In a clinical setting, this regimen can cure more than 95% of
the patients with active TB caused by normally sensitive Mycobacterium tuberculosis.
However, actual cure rates are lower. Adverse effects disrupt therapy adherence,
which may cause treatment failure, relapse or drug resistance.
Isoniazid, rifampicin and pyrazinamide are potentially hepatotoxic drugs. They are
metabolised in the liver, making this organ vulnerable for injury. The terms
hepatotoxicity, hepatitis, liver damage and liver injury are used interchangeably in the
literature, but for purposes of this review the term ADIH has been adopted and
indicates any significant deviation from normal in liver function tests (LFT) or
clinical signs that indicate liver dysfunction in the presence of antituberculosis
treatment.
Antituberculosis drug-induced hepatotoxicity (ADIH) is a serious adverse effect
that can be fatal if therapy is not interrupted in time, ADIH occurs in 2–28% of the
tuberculosis patients; the variation is large due to different definitions of
hepatotoxicity and differences between the populations studied. Several studies makes
a guideline for ADIH based on American Thoracic Society or British Thoracic
Society. Reccurence of ADIH after initial reintroduction therapy are uncommon in
report. The goal of this study was to evaluate management of reccurence anti-TB
drugs induced hepatotoxicity in Hasan Sadikin’s general hospital.
Regarding to this issue, the management of reccurence anti-TB drugs induced
hepatotoxicity, we report two difficult cases in Hasan Sadikin’s general hospital are 48
months-old-boy and 18 months-old-girl.

CASE REPORT

Patient 1

A 48 month-old-boy was presented in pediatric clinic with chief complaint developed

jaundice, malaise, nausea and vomiting. He was on the 7 th months commencement of
full dose reintroduction anti-tuberculosis drugs, after history of ADIH. We were
stopped anti-tuberculosis drug, and performed liver function tests revealed elevated
transaminase levels and elevated total bilirubin levels. His hepatitis A IgM antibody
level was negative and hepatitis B surface antigen test was also negative. Another
diagnostic method is ultrasonography of the liver was showed within normal
appearance.

History of illness previously diagnosed viral encephalitis and lung tuberculosis. The
child completed her intensive phase of 3-drug anti-tuberculosis therapy with no
adverse effects. However, 3 weeks into her continuation phase with isoniazid and
rifampicin, she diagnosed with ADIH. The child was put on hold for anti-tuberculosis
treatment. His liver enzymes repeated after 2 weeks and found normalized. He was re-
started on rifampicin and isoniazid as follows in modified ADIH guideline. Isoniazid
and rifampicin were in the full doses and planned for another 9 months therapy for
lung tuberculosis after anti-tuberculosis drug induced hepatotoxicity.

At present, after 2 weeks stopped anti-tuberculosis drugs, the liver enzymes were
again measured for evaluation and within normal limits. However, we are considering
to stop anti-tuberculosis treatment for this patient, the child in good clinical condition,
gain his weight and well nourished, we are considering to stop anti-tuberculosis
treatment for this patient.

Patient 2

An 18-months-old-girl was admitted to our pediatric clinic with complaints of nausea

and vomiting, with no jaundice. The child was diagnosed as unusual recurrence
ADIH. Previous histories ADIH were diagnosed 3 times. Diagnosed lung tuberculosis
with congenital cytomegalovirus infection, cerebral palsy. Histories of taking anti-
tuberculosis treatment were found in her brother and sister. Her neighborhood also
with persistent bloody cough got anti-tuberculosis injected treatment. According to
modify ATS guideline, after began reintroduction of rifampicin and followed by
isoniazid, this patient failed to reached full doses of isoniazid. The liver enzyme
always confirmed with elevated liver function tests and normalized after anti-
tuberculosis drug were stopped. However, this child was considered can’t tolerate
isoniazid therapy, then the therapy was modified with only got single anti-tuberculosis
therapy, rifampicin in full doses. After this paper was made the therapy last for period
of 3 months. And showed improvement of clinical condition.

DISCUSSION

This is the first study to report unusual recurrence of anti-tuberculosis drug induced
hepatotoxicity in South East Asia, where the liver function is closely monitored
during TB treatment.

The definition of drug-induced hepatitis differs in the literature, making comparisons

between studies difficult. The World Health Organization (WHO), for example,
divides the intensity of hepatitis into four grades: I (slight), ALT ≤ 2.5 times the ULN;
II (mild), ALT 2.6-5.0 the ULN; III (moderate), 5-10 times the ULN; and IV (severe),
>10 times the ULN. In this study, three patients presented severe hepatitis according
to the WHO definitions. The American Society for the Study of the Liver states that a
three-fold increase in ALT above the ULN plus a two-fold increase in the ULN of
total bilirubin and verification of clinical data are necessary to define toxic hepatitis.

The American Thoracic Society guidelines are rifampicin followed by isoniazid. 1 In

addition, the American Thoracic Society states that in case of symptom recurrence or
a rise in transaminase, the last drug added should be stopped. It also states that in case
of patients with prolonged or severe hepatotoxicity who tolerate rifampicin and
isoniazid, addition of pyrazinamide may be hazardous.1 In such cases, it is advisable
to discontinue pyrazinamide completely and to extend the duration of therapy to 9
months. A suggested regimen by WHO in such patients is a 2-month initial phase
comprising daily streptomycin, isoniazid and ethambutol, followed by a 10-month
continuation phase of isoniazid and ethambutol (2SHE/10HE).2
British Thoracic Society recommends no treatment in case a well patient or a
patient with a noninfectious form of tuberculosis experiences drug induced
heptotoxicity till the liver functions normalize.3 However, if the patient is unwell or
the sputum smear is positive within 2 weeks of starting therapy, use of ethambutol
along with streptomycin is advised. Once the liver function becomes normal,
challenge dosages of the original drugs can be reintroduced sequentially in the order
isoniazid, rifampicin, pyrazinamide, with daily monitoring of the patient’s clinical
condition and liver function.3 Isoniazid should be introduced initially at 50 mg/day,
increasing sequentially to 300 mg/day after 2–3 days if no reaction occurs, and then
continued. After a further 2–3 days without reaction, rifampicin at a dose of 75
mg/day can be added, increasing to 300 mg after 2–3 days, and then to 450 mg (<50
kg) or 600 mg (>50 kg) as appropriate for the patient’s weight after a further 2–3 days
without reaction, and then continued. Finally, pyrazinamide is added at 250 mg/ day,
increasing to 1.0 g after 2–3 days and then to 1.5 g (<50 kg) or 2 g (>50 kg). If there
is no further reaction, standard chemotherapy can be continued and any alternative
drugs introduced temporarily can then be withdrawn.3

REFERENCES

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