Brief Review of Literature: Two Cases of Unusual Recurrence of Anti-

Tuberculosis Drug Induced Hepatotoxicity in Children

Heda Melinda Nataprawira1, Ahmad Hafidz2
1
Department of Child Health Faculty of Medicine Universitas Padjadjaran, Dr. Hasan
Sadikin General Hospital, Bandung, West Java, Indonesia
2
Department of Child Health Faculty of Medicine Universitas Padjadjaran, Dr. Hasan
Sadikin General Hospital, Bandung, West Java, Indonesia

Corresponding Authors information:

Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of
this paper.

Abstract
Background. New cases of Tuberculosis (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, British Thoracic Society (BTS) and the
American Thoracic Society (ATS) had guidelines for re-introduction regimes for
treating ADIH. However, there are no guidelines for treating ADIH children in terms
of efficacy and ease of administration and followup. ADIH is not so common in
children. It requires stopping all the potential hepatotoxic anti-tuberculosis drugs with
a systematic and regular monitoring of liver enzymes. Baseline liver function
assessment before starting therapy for TB 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.

Case Report. Both cases are reccurence of ADIH and have received TB drug for
reintroduction for several months. TB therapy reintroduction consists of rifampicin
(RMP), isoniazid (INH). Laboratory finding found increased of total bilirubin and
liver function test. Hepatitis markers showed negative results. ADIH were managed
by modified ATS guideline by our institution. The treatment are differ from both
cases. One of them were stopped anti-tuberculosis drug and showed in good clinical
conditions, and the other were continuing one regime of anti-tuberculosis drug.

Conclusions. Diagnosis of ADIH is still clinical and of exclusion. The reintroduction

after ADIH is to be taken with care, and should be treated under supervision of a
qualified physician. There were no guidelines to treat ADIH in children. In the case of
confirmed moderate or severe drug-induced hepatotoxicity, treatment should be
interrupted and reintroduced after the hepatotoxicity has resolved.

Keywords: Antituberculosis, children, drug, hepatotoxicity.

INTRODUCTION

TB 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 6month 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 TB.
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 228% 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 Sadikins general hospital.
Regarding to this issue, the management of reccurence anti-TB drugs induced
hepatotoxicity, we report two difficult cases in Hasan Sadikins general hospital are 18
months old girl and 48 months old boy.

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 7th 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
stopping anti-tuberculosis treatment for this patient, the child in good clinical
condition, gaining 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. Had diagnosed with lung
tuberculosis, 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 cant tolerate
isoniazid therapy, then the therapy was modified with only got single anti-tuberculosis
therapy, rifampicin in full doses. After this 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.

Guidelines for management of ADIH have been published by theAmerican Thoracic

Society (ATS), the British Thoracic Society (BTS) and the Task Force of the European
Respiratory Society, the WHO and the International Union Against Tuberculosis and
Lung Disease. The management of ADIH depends on the supposed cause, therefore
no unambiguous advice can be given. The hepatocellular pattern of liver injury, which
is seen in isoniazid, rifampicin and pyrazinamide toxicity, has a predominant initial
elevation of alanine aminotransferase. Therefore, this biochemical parameter is most
often used to monitor the liver function during antituberculosis treatment. In
summary, TB should be treated under supervision of a qualified physician. Patients
should be advised to seek medical care if they experience any signs or symptoms of
hepatotoxicity (i.e.jaundice, malaise, nausea and vomiting). During treatment, the
liver function only has to be monitored on a regular basis on indication (e.g. in
patients with chronic liver disease or increased serum transaminases prior to
treatment). In the case of signs or symptoms of hepatotoxicity, the liver function
should be examined. In the case of confirmed moderate or severe drug-induced
hepatotoxicity, treatment should be interrupted and reintroduced after the
hepatotoxicity has resolved. Although the guidelines from the ATS, BTS and the Task
Force are more or less the same, there are some differences. The ATS does not
recommend baseline liver function testing for healthy patients, but only advises it in
patients with possible risk for ADIH (e.g. patients with liver disorders), whereas the
Task Force and BTS advise performing baseline liver function testing in all patients.
After TB treatment has been stopped because of hepatotoxicity, both the BTS and
ATS advise restarting the antituberculosis drugs one at a time. The Task Force advises
restarting all the drugs simultaneously; after a second episode of hepatotoxicity the
drugs need to be reintroduced consecutively. In many low-income countries, where
the burden of TB is often high, liver function tests cannot be performed. In those
situations one has to rely on clinical symptoms of hepatotoxicity, such as jaundice,
abdominal pain, nausea and vomiting. The cause of hepatitis during TB treatment can
either be the antituberculosis drugs or something else, so the other possibilities have
to be excluded before deciding that the hepatitis is drug-induced. If moderate or
severe ATDH is diagnosed (i.e. serum aminotransferase level >5 times the upper limit
of normal [ULN] or >3 times.

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. 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).
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. 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 patients clinical condition and
liver function. Isoniazid should be introduced initially at 50 mg/day, increasing
sequentially to 300 mg/day after 23 days if no reaction occurs, and then continued.
After a further 23 days without reaction, rifampicin at a dose of 75 mg/day can be
added, increasing to 300 mg after 23 days, and then to 450 mg (<50 kg) or 600 mg
(>50 kg) as appropriate for the patients weight after a further 23 days without
reaction, and then continued. Finally, pyrazinamide is added at 250 mg/ day,
increasing to 1.0 g after 23 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.

REFERENCES

1. Saukkonen JJ, Cohn DL, Jasmer RM, et al; American Thoracic Society
(ATS). Hepatotox- icity of antituberculosis therapy subcommittee: an
official ATS statement: hepatotoxicity of an- tituberculosis therapy. Am J
Respir Crit Care Med 2006;174(8):93552.
2. Bhatia S, Tullu MS, Kannan S, Gogtay NJ, Thatte UM1, Lahiri KR. An
unusual recurrence of antitubercular drug induced hepatotoxicity in a
child. J Postgrad Med. 2011;57 (2):14752.
3. Sharma SK, Singla R, Sarda P, et al. Safety of 3 different reintroduction
regimens of antituberculosis drugs after development of antituberculosis
treatmentinduced hepatotoxicity. Clin Infect Dis. 2010; 50:83339 (in
 this issue).
4. Bina Akura, Hanifah Oswari, Bambang Supriyatno, Najib Advani.
Incidence and characteristic of antituberculosis drug-induced
hepatotoxicity in children: a preliminary study. Paediatr Indones.
2009;49(6):428.
5. Graham S. Treatment of paediatric TB: revised WHO guidelines. Paed
Respir Rev. 2011:12; 2226.
6. Donald R. Antituberculosis drug-induced hepatotoxicity in children. Paed
Rep. 2011:3;51-64.
7. Joint Tuberculosis Committee of British Thoracic Society. BTS
Guidelines. Control and prevention of tuberculosis in the United Kingdom:
Code of Practice 2000. Thorax. 2000:55;887-901.
8. Tostmann A. Boeree MJ. Aarnouste RE. De Lange WC. Van der Ven AJ.
Dekhuijzen R. Antitiberculosis drug-induced hepatotoxicity: concise up-
to-date review. J Gastrol Hepatol. 2008:23;192-202.
9. David S. hamilton J. Drug-induced liver injury. US Gastroenterol Hepatol
Rev. 2010:6;73-80.
10. Russmann S. Jetter A. Kullak-Ublick GA. Pharmacogenetics of drug-
induced liver injury. Hepatol. 2010:52(2);748-61.
11. Pandit A. Sachdeva T. Bafna P. Drug-induced hepatotoxicity: a review. J
appl Pharmaceul Sci. 2012:2(5);233-43.
12. World Health Organization. Global tuberculosis report 2012. Tersedia dari:
http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf.
13. Mansukhani S. Shah I. Hepatic dysfunction in children with tuberculosis
on treatment with antituberculous therapy. Ann Hepatol.2012:11(1);96-9.
14. Ferrajolo C. Capuano A. Verhamme K. Schuemie M. Rossi F. Stricker B.
Drug-induced hepatic injury in children: a case/non case study of
suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol.
2010:70(5);721-8.
15. Devarbhavi H. Antituberculous drug-induced liver injury: current
perspective. Trop Gastroenterol. 2011:32(3):167-74.