Paediatrica Indonesiana

VOLUME 49 NUMBER 6 November 2OO9

Original Article
342 Paediatr Indones, Vol. 49, No. 6, November 2009
Incidence and characteristics of antituberculosis drug-
induced hepatotoxicity in children: a preliminary study
Bina Akura, Hanifah Oswari, Bambang Supriyatno, Najib Advani
From the Department of Child Health, Medical School, University of
lndonesia, Cipto Man,unkusumo Hospital, Jakarta, lndonesia
Reprint request to: Bina Akura, MD, Department of Child Health,
Medical School, Universitv of lndonesia, Cipto Man,unkusumo Hospital,
Jl. Salemba 6, Jakarta 1O13O, lndonesia. 1el. 62-21-39O7712. lax. 62-21-
39O7713. l-mail: bnaakr72_vahoo.co.id
1
uberculosis (1B) is a disease known for
vears. New cases of 1B are increasin, and
most of them are in developing countries.
Demo,raphic data shows that tuberculosis in
children is 5 to 6' from total tuberculosis cases.
1
ln 19o9,
World Health r,anization (WH) predicted that everv
vear there were 1.3 thousand new cases of 1B in children
and 15O,OOO cases under 15 vears old died.
Antituberculosis dru,s such as rifampicin (RMP),
isoniazid (lNH), pvrazinamide (PzA), ethambutol
(lMB), and streptomvcin ,ive ,ood efficacv but also
many adverse effects.
1-2
Antituberculosis dru,-induced
hepatotoxicitv is one of the adverse effects which
causes increase of transaminases, bilirubin, icterus,
anorexia, nausea, and vomiting.
1-3
WH toxicitv
classification standards
4
categorize hepatotoxicity
into mild hepatotoxicity if aspartat aminotransferase
(AS1) and/or alanin aminotransferase (Al1) increase
3 to 5 times from upper normal limits (121-2OO U/l),
moderate hepatotoxicitv if transaminases increase 5
to 1O times from upper normal limits (2O1-1OO U/l),
severe hepatotoxicity if transaminases increase to
>1O times from upper normal limits (>1OO U/l).
Abstract
Background Antituberculosis dru,s show ,ood efficacv but have
adverse effects including hepatotoxicity.
Objective 1o find the incidence and characteristics of
antituberculosis hepatotoxicitv in children durin, the first 2
weeks of therapv.
Methods A cohort studv was performed in Cipto Man,unkusumo,
Persahabatan, and 1an,eran, Hospitals from Au,ust 2OOo
toMarch 2OO9. 1he dia,nosis of tuberculosis (1B) based on
1B scorin, svstem. laboratorv tests were performed includin,
transaminase enzymes, bilirubin, G-O1, albumin, ureum, and
creatinine before and after 2 weeks of treatment. Patients were
monitored durin, the first 2 weeks of therapv. lnformed consent
obtained from the parents.
Results Six of o1 subjects had hepatotoxicitv reaction. Most of
the patients were 1 to 5 vears old (65') and well nourished (5O').
lxtrapulmonarv tuberculosis found in 67' of cases. 1hirtv-three
percents of patients received four a,ents. 1hirtv-three percents of
cases received 1 a,ents combined with other hepatotoxic dru,s.
Six subjects had hepatotoxicitv (1 hepatitis, 2 mixed case, and
3 asvmptomatic). 1wo of 5O children (1') with pulmonarv 1B
and 1 out of 31 (13') children with extrapulmonarv 1B had
hepatotoxicitv reaction. Antituberculosis dru, doses were similar
between the hepatotoxicitv ,roup and control.
Conclusions lncidence of antituberculosis hepatotoxicitv in the
first 2 weeks of therapv was 7', consisted of hepatitis (1 cases),
mixed (2 cases), and asvmptomatic (3 cases). 1here was no
difference in sex as well as in nutritional state distribution found in
cases with hepatotoxicitv. [Paediatr Indones. 2009;49:342-8].
Keyword: antituberculosis, hepatotoxicity, incidence,
characteristics
Bina Akura et al : Antituberculosis dru,s induced-hepatotoxicitv in children
Paediatr Indones, Vol. 49, No. 6, November 2009 343
Studv in Japan showed transient elevation of
hepatocellular enzvmes in 1O' subjects with isoniazid
and rifampicin and in 1 to 2 ' subjects had to be
stopped due to fulminant hepatitis.
5
Hepatotoxicity
usually occurs in the first month of therapy and mostly
happens in the first 2 weeks.
6,7
Concomitant therapy
with isoniazid and rifampicin can cause hepatotoxicitv
in less than 1O dav.
8
Chang et al
9
found that
antituberculosis dru,-induced hepatitis occured in O.3
to 11.1 weeks mostlv in 1.1 weeks. Mahmood K et al
1O
found 19.76' hepatotoxicitv due to antituberculosis.
Most of the subjects (61') suffered from hepatotoxiciv
in 2 weeks after startin, therapv with mild and
moderate transaminases elevation. Schaberg et al
11
found that median interval of hepatotoxicitv between
antituberculosis dru,s was not different, isoniazid was
16.5 (95' Cl 7 to 17) davs, rifampicin is 17.5 (95'
Cl 11 to 33) davs, and pvrazinamide was 1o.5 (95'
Cl 17 to 29) davs.
Many studies investigated clinical parameters
associated with susceptibilitv to hepatotoxicitv due to
antituberculosis drugs, but mainly in adult subjects.
1-
5,12-1o
ln contrast, little is known about the risk factors
of hepatotoxicity due to antituberculosis therapy
in children.
5
1herefore it is a necessicitv to identifv
incidence and characteristics of hepatotoxicity during
antituberculosis therapv in children. 1his studv
intended to find the incidence and characteristics
of antituberculosis dru, induced-hepatotoxicitv in
children.
Methods
1his was a cohort studv carried out in Cipto
Man,unkusumo, Persahabatan and 1an,eran,
Hospitals from Au,ust 2OOo to March 2OO9. 1he
dia,nosis of 1B based on 1B scorin, svstem. Sample
size was calculated usin, the formula for estimatin,
sin,le population proportion19 with A~O.O5,
estimated prevalence of 3O', and accuracv of 1O'
revealing minimum sample size of 89 children.
Subjects were selected from outpatient clinic and in-
patient ward with inclusions criteria: a,e from O to 1o
vear old, dia,nosed 1B and received antituberculosis
dru,s. Children with chronic liver diseases, kidnev
diseases, chronic diarrhea, gastritis, metabolic diseases,
HlV infection, historv of familial liver diseases, low
adherence to antituberculosis drugs therapy and
disapproval of studv were excluded.
Laboratory tests performed before and after
2 weeks of treatment to measure transaminase
enzvmes (AS1, Al1), bilirubin, G-O1 (,amma-
,lutamvl transferase), albumin, ureum, and creatinin.
Patients were monitored durin, the first 2 weeks
of therapv. Patients were classified into those who
received 3 antituberculosis agents consisted of
isoniazid, rifampicin, and pyrazinamide and those
who received 1 antituberculosis a,ents consisted of
isoniazid, rifampicin, pvrazinamide and ethambutol/
streptomycin.
Hepatotoxicitv was cate,orized into asvmptomatic,
hepatitis, cholestasis or mixed case (hepatitis-
cholestasis).
2O
Hepatitis was defined if there was
transaminases elevation ~ 5 times upper normal limit
or ~ 3 times upper normal limit with svmptoms of
icteric, anorexia, nausea, vomiting, fever, abdominal
pain and hepatomegaly.
1,1
Cholestasis was defined if
there was direct bilirubin elevation > 1 m,/dl for total
bilirubin < 5 m,/dl or if total bilirubin > 5 m,/dl,
direct bilirubin was > 2O' of total bilirubin.21 Mixed
case was defined if the patient had svmptoms and si,ns
of hepatitis and cholestasis.
4
Asvmptomatic case was
defined if the patient had transaminases elevation ~ 3
and < 5 times upper normal limit without svmptoms.
4
lnformed consent was obtained from the parents. 1he
studv was approved bv the lthical Committee, lacultv
of Medicine, Universitv of lndonesia. Studv results
were processed usin, the SPSS version 15 pro,ram and
presented in textual and tabular forms.
Results
Durin, the studv period there were o9 subjects
collected. 1hree subjects did not fulfill the inclusion
criteria. ne patient died durin, two weeks therapv
due to tuberculous menin,itis. lour subjects were
excluded due to poor adherence to antituberculosis
therapv. At the end of the studv period, onlv o1
subjects could be analyzed. Most of the subjects
had pulmonarv 1B (62') and 3o' subjects had
extrapulmonarv 1B. liftv-four percents subjects with
pulmonarv 1B were female, but male dominated in
extrapulmonarv 1B cases with comparison of male :
female was 2:1. Most of the subjects (55') were 5 to
Bina Akura et al : Antituberculosis dru,s induced-hepatotoxicitv in children
344 Paediatr Indones, Vol. 49, No. 6, November 2009
1o vear old and 59' were malnourished. Most of the
subjects (33') were Sundanese, 2O' Javanese, and
the others (Batak, Betawi, other ethnic) were in small
proportion. Majoritv of the subjects (77') came from
a low social economic status. (Table 1)
1here were six from o1 subjects who suffered
from hepatotoxocitv, with equal number of male and
female patients. 1here were 1/6 patients a,ed 1-5 vears
and 3/6 patients had ,ood nutritional status (Table 2).
Clinical characteristics of these subjects in two weeks
of monitoring are presented in Table 3.
Amon, the pulmonarv 1B subjects, there were
1 mixed case and 1 asvmptomatic case, while amon,
the extrapulmonarv 1B subjects there were 1 hepatitis,
1 mixed case, and 2 asvmptomatic cases. 1here were
2 of 5O subjects (1') with pulmonarv 1B and 1
of 31 subjects (13')with extrapulmonarv 1B had
hepatotoxicitv. (1able 1) 1here was no difference in
the antituberculosis dru, dose between subjects with
hepatotoxicitv and those without. (Table 5)
No difference was found in sex nor in nutritional
status distribution in subjects with hepatotoxicitv
but in those without hepatotoxicitv male (52') and
malnourished (67') were predominant. Both subjects
with and without hepatotoxicitv had normal albumin
level (67' vs o1'). Most of hepatotoxicitv subjects
(1/6) had extrapulmonarv 1B and 61' subjects without
hepatotoxicitv had pulmonarv 1B. (Table 6)
Table 2. Demographic characteristics in subjects with hepatotoxicity
(n=6)
Characteristics Hepatotoxicity
n
Sex
Male
Female
Age
<1 years
1-5 years
5-18 years
Nutritional status
Overweight
Good
Mild
Severe
3
3
1
4
1
0
3
1
2
Table 3. Clinical characteristics of patient with hepatotoxicity
Age Sex Symptoms Disease extent Therapy
Concomitant
hep drugs
Hepatotoxicity
3 yr
2 yr
2 yr
4 yr
7 yr
10 mth
M
M
F
M
F
F
Fever, vomiting, nausea,
malaise
Anorexia, nausea,
vomiting
Fever, malaise, anoreksia,
icteric, hepatomegaly
No symptoms
No symptoms
No symptoms
Meningeal TB
Spondilitis TB
Pulm TB
Meningeal TB
Coxitis TB
Pulm TB
4 drugs
4 drugs
3 drugs
4 drugs
4 drugs
3 drugs
Phenytoin
Cotrimoxazole,
paracetamol
-
-
-
Paracetamol
Hepatitis
Mixed
Mixed
Asymptomatic
Asymptomatic
Asymptomatic
M= male, F= female, extra TB = extrapulmonary TB, Pulm TB= Pulmonary TB, yr= years, mth= month, d= days, hep drugs= others
hepatotoxicity drugs
Table 1. Demographic characteristics of subjects (n=81)
Characteristics
Pulmonary Extrapulmonary
Total (%)
n (%) n
Number
Sex
Male
Female
Age (years)
<1
1-5
5-18
Nutritional status
Severe
Mild
Good
Overweight
Ethnic/Race
Sundanese
Javanese
Betawi
Batak
Others**
Mixed***
Social-economic
Low
Middle
High
50
23
27
6
17
27
4
35
10
1
15
10
8
6
4
7
35
15
0
(62)
(46)
(54)
(12)
(34)
(54)
(8)
(70)
(20)
(2)
(30)
(20)
(16)
(12)
(8)
(14)
(70)
(30)
31
19
12
1
12
18
1
13
16
1
12
6
4
1
5
3
27
4
0
81
42
39
7
29
45
5
48
26
2
27
16
12
7
9
10
62
19
0
(100)
(52)
(48)
(9)
(36)
(55)
(6)
(59)
(32)
(3)
(33)
(20)
(15)
(9)
(11)
(12)
(77)
(23)
**Others = Bangka, Dayak, Madura, Menado, Melayu, Minahasa,
Padang, Palembang. ***Mixed = Batak-Makasar, Betawi-Javanese,
Betawi-Sundanese, Cirebon-Betawi, Javanese-Batak, Javanese-
Betawi, Javanese-Palembang, Javanese-Sundanese, Sundanese-
Flores
Bina Akura et al : Antituberculosis dru,s induced-hepatotoxicitv in children
Paediatr Indones, Vol. 49, No. 6, November 2009 345
Discussion
1his was a preliminarv studv usin, cohort desi,n due
to ethical reason for not giving antituberculosis drug
in normal children. limitation of this studv was no
statistical analysis performed due to small subjects
with hepatotoxicitv. 1his studv could not show which
antituberculosis agents as the cause of hepatotoxicity
because durin, the first 2 weeks of therapv, all subjects
received 3 or 4 drugs.
Most of the subjects were male (52') with a,e
ran,e of 5-1o vears (55'). Re,ardin, sex distribution,
1sa,aropoulou-Stin,a et al
22
and hkawa et al.
5
found
that hepatotoxicitv incidence was not correlated with
sex.
ln this studv, most of the subjects with hepato-
toxicitv was 1 to 5 vear old (67'). hkawa et al
5
found
that all children with hepatotoxicitv was under 5 vears
(mean a,e 2.31.5 vear old) and predominantlv male
(oo') compared to control onlv 15 ' male. 'Brien
et al
23
found that most of the subjects were from 1
to 1 vears (19'). 1sa,aropoulou-Stin,a et al
22
found
mean a,e of subjects was 1.5 vears (1 months-11
vears). Risk of complication increases in voun,er a,e
(O to 1 vears old).
21
Most of our subjects were malnourished (59').
Decrease of bodv wei,ht mav be due to 1B infection.
ln this studv, ethnicitv of the subjects consisted of
Sundanese, Javanese, Batak, Betawi and others.
'Brien et al
23
found 1B infection in 1o' black
race and 1O' white race. Most of our subjects came
from low social economic status, where 1B was still
endemic.
Most of our subjects with hepatotoxicitv had
,ood nutritional status (5O'). Studv of Mahmood et
al
1O
found that most of the subjects with hepatotoxicitv
was malnourished (91'), lernandez-Villar et al
4
found
2o.6' malnourished children with hepatotoxicitv, but
hkawa et al
5
did not find malnourished subjects with
hepatotoxicitv. 1his condition mavbe due to difference
in population study.
ln this studv, there were 6 of o1 patients with
hepatotoxicitv, consisted of 3 asvmptomatic, 1
Table 6. Charateristics subjects with and without hepatotoxicity
Variable With
hepatotoxicity
n=6
Without
hepatotoxicity
n=75 (%)
Sex
Male
Female
Age (years)
0-5
5-18
Nutritional status
Malnourished
Good
Albumin level
Low
Normal
Diseases extent
Extrapulmonary TB
Pulmonary TB
Therapy
3 drugs
4 drugs
3 drugs + OH
4 drugs +OH
3
3
5
1
3
3
2
4
4
2
1
2
1
2
39 (52)
36 (48)
31 (41)
44 (59)
50 (67)
25 (33)
12 (16)
63 (84)
27 (36)
48 (64)
39 (52)
18 (24)
11 (15)
7 (9)
OH= other hepatotoxic drugs
Table 5. Mean dose of antituberculous agents among subjects
with hepatotoxicity and without hepatotoxicity
Agents
With hepatotoxicity
(mg/kg/day) *
Without hepatotoxicity
(mg/kg/day) *
INH
RMP
PZA
EMB
9.07 (2.2)
13.85 (2.7)
23.97 (4.1)
19.42 (3.8)
8.08 (2.2)
13.33 (6.9)
23.26 (7.2)
18.51 (5.6)
INH= isoniazid, RMP= rifampicin, PZA= pyrazinamide,
EMB= ethambutol
* Mean (SD)
Table 4. Mean titer of transaminase, bilirubin, and G-GT in subjects with hepatotoxicity and without
hepatotoxicity
With hepatotoxicity* Without hepatotoxicity*
Before Week II Before Week II
SGOT/AST (U/L)
SGPT/ALT (U/L)
Total bilirubin (mg/dL)
Direct bilirubin (mg/dL)
Indirect bilirubin (mg/dL)
63.33 (29.1)
40.33 (13.8)
0.55 (0.3)
0.30 (0.2)
0.25 (0.2)
220.16 (88.1)
220.66 (100.3)
2.36 (0.3)
1.36 (2.2)
0.99 (1.4)
52.10 (57.1)
33.10 (32.5)
0.49 (0.3)
0.19 (0.2)
0.30 (0.2)
41.20 (19.4)
28.89 (19.1)
0.47 (0.2)
0.20 (0.2)
0.26 (0.1)
* Mean (SD)
Bina Akura et al : Antituberculosis dru,s induced-hepatotoxicitv in children
346 Paediatr Indones, Vol. 49, No. 6, November 2009
hepatitis and 2 mixed cases. hkawa et al
5
found
that o of 99 children with 1B had hepatotoxicitv.
'Brien et al
23
found 16 cases with hepatotoxicitv of
o71 children with 1B. 1sa,aropoulou-Stin,a et al
22
found hepatotoxicitv in 36 from 11 children with 1B
and 15 of them had hepatitis. 1his studv was different
from 1sa,aropoulou-Stin,a due to different dru, dose
,iven to the subjects. 1he dose ,iven in the previous
studv was 15-2O m,/k,/dav for isoniazid and 15 m,/
k,/dav for rifampicin. Ramachandran et al
25
found
incidence of hepatitis in 5O' patients with isoniazid
dose 2O m,/k,/dav and 2O' cases with isoniazid dose
of 12 m,/k,/dav. Palusci et al
26
found hepatitis in 3.5'
children given isoniazid. Meta analysis by Steele et
al
27
showed that hepatitis was found in 6.9' children
given isoniazid and rifampicin.
Svmptoms in subjects with hepatotoxicitv were
fever, malaise, anorexia, nausea, vomiting, icterus, and
hepatomegaly. Shakya et al
2
also found similar results.
Black et al
11
found gastrointestinal manifestation
in 55' cases and viral infection svndrome in 35'
cases.
ln this studv, most of the subjects with hepato-
toxicitv was under 5 vear old (o3') and 5 to 1o vear
old (17'). Meanwhile, most of the subjects without
hepatotoxicitv was from 5 to 1o vear old (59'). A
studv in Japan showed that o' of hepatotoxicitv
was under 5 vear old.
5
Logistic regression analysis
showed that a,e and pvrazinamide were si,nificantlv
related to the risk of severe hepatotoxicitv (P<O.O5).
1sa,aropoulou-Stin,a et al
22
also found mean age of
hepatitis after antituberculosis therapv was 1.5 vears
old (1O'). 'Brien et al
23
did not find any correlation
between a,e and hepatotoxicitv.
Albumin level was normal in 67' subjects
with hepatotoxicitv and o1' subjects without
hepatotoxicitv. hkawa et al
5
found albumin levels
were normal in control subjects (1.1O.3 ,/dl) and
subjects without hepatotoxicitv (1.3O.1 ,/dl).
Mahmood et al
1O
found that 27.1' patients with
hepatotoxicitv had albumin <3.5 ,/dl. Patients
with hvpoalbuminemia had two times hi,her risks
of havin, hepatotoxicitv. ln malnutrition, ,lutation
store is depleted causing someone more vulnerable
of having hepatotoxicity. Malnourished subjects also
have slower dru, metabolisms.
2
ln this studv, most of the subjects with
hepatotoxicitv had extrapulmonarv 1B (67'),
contrarv to subjects without hepatotoxicitv.
hkawa et al
5
found that 1 of o patients with
hepatotoxicitv had extrapulmonarv 1B and showed
si,nificant relation (P<O.O5). Shakva et al
2
found
that the severitv of the disease was the risk factor
of havin, hepatotoxicitv. 'Brien et al
23
found that
extrapulmonarv 1B (milliarv 1B and menin,itis
1B) had risk of havin, hepatotoxicitv 3 times
hi,her than pulmonarv diseases (6.9' vs 1.9').
Rahajoe et al
2o
found hepatitis in 6 of 22 (27.3')
subjects of menin,itis 1B who received isoniazid,
rifampicin, and streptomvcin. ln severe 1B cases,
there are micro lesions of tubercle in the liver. Liver
damage in this case may be due to the tuberculin
effect or tubercle product that is release in the liver
after antituberculosis therapy. Hepatotoxicity in
subjects with extrapulmonarv 1B mavbe due to other
concomitant hepatotoxic drugs.
29
ln this studv, most of our subjects with
hepatotoxicity received 4 antituberculosis drugs
(33') and 1 antituberculosis dru,s with other
concomitant hepatotoxic dru,s (33'). Subjects
without hepato toxi citv received 3 antituberculosis
dru,s (52'). Steele et al
27
found that incidence of
hepatitis was 6.9' in children receivin, isoniazid
and rifampicin and 1.O' in 177 children receivin,
multiple isoniazid a,ents without rifampicin.
Schaberg et al
11
found that other concomitant
hepatotoxic dru,s was not correlated si,nificantlv
with severe adverse effect includin, hepatotoxicitv
from standard antituberculosis therapv (P~O.oO,
R: 1.1, 95' Cl O.1 to 2.o). ln this studv, the cause
of hepatotoxicitv could not be determined whether
due to antituberculosis agents or other concomitant
hepatotoxic dru,s. 1his was due to the small number
of subjects receiving other concomitant hepatotoxic
drugs, therefore statistical analysis could not be
performed. Other concomitant hepatotoxic drugs
that were ,iven to the subjects with hepatotoxicitv
were acetaminophen, phenvtoin, and cotrimoxazole.
Acetaminophen can cause hepatocellular damage,
while phenvtoin and cotrimoxazole can cause mixed
case.
ln conclusion we found that the incidence of
antituberculosis hepatotoxicitv in the first 2 weeks
of therapv was 7.1'. No difference in sex as well as
in nutritional status distribution found in cases with
hepatotoxicity.
Bina Akura et al : Antituberculosis dru,s induced-hepatotoxicitv in children
Paediatr Indones, Vol. 49, No. 6, November 2009 347
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