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Febrinasari
4, 2016 December:
et al., Increasing
173-183 serum transaminase is not associated with the serum isoniazid
DOI: http://dx.doi.org/10.19106/JMedSci004804201504
ABSTRACT
Tuberculosis (TB) remains a major health problem in the world. Isoniazid (INH) and rifampicin
are first-line antituberculosis that can cause hepatotoxicity characterized by an increase
of serum transaminase level. Previous study showed the increase in transaminase level
of TB patients due to INH and rifampicin. However, it did not explain about its correlation
with the drugs concentration. The aim of this study was to evaluate the relationship
between the increase of serum INH and rifampicin concentrations and the increase of
serum transaminase level in TB patients. This was a cross sectional study involving 31
TB patients who underwent intensive phase of treatment with fixed-dose combination
antitubercuosis therapy (FDC-ATT) in Yogyakarta. Serum transaminase levels i.e. AST
and ALT before and at the end of the intensive phase of treatment were determined by
an automatic chemical analyzer. Serum INH and rifampicin concentrations at the end
of the intensive phase of treatment were measured by HPLC. t- test, Mann Whitney,
Fisher and Spearman tests were used to analyze the data. Mean of INH and rifampicin
concentrations were 2.72 ± 0.46 µg/mL and 4.12 ± 0.42 µg/mL, respectively. Mean
of INH and rifampicin concentrations of TB patients with high AST level (5.03 ± 4.14
µg/mL and 8.52 ± 3.06 µg/mL) tended to be higher than those with normal AST level
(2.47 ± 0.27 µg/mL and 3.64 ± 0.32 µg/mL). However, they were not significantly
difference (p>0.05). Furthermore, mean of INH and rifampicin concentrations of TB
patients with high ALT level (7.07 ± 6.24 µg/mL and 10.67 ± 3.76 µg/mL) also tended
to be higher than those with normal AST level (2.42 ± 0.26 µg/mL and 3.66 ± 0.30
µg/mL). However, they were not also significantly difference (p>0.05). In conclusion,
there are no correlation between INH and rifampicin concentrations and the increase of
transaminase level in TB patients after intensive phase of treatment.
ABSTRAK
Tuberkulosis (TB) masih menjadi masalah kesehatan utama di dunia. Isoniasid (INH) dan
rifampisisn adalah antituberkulosis lini pertaman yang dapat menyebabkan hepatotoksik
yag ditandai dengan kenaikan kadar transaminase serum. Penelitian sebelumnya
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J Med Sci, Volume 48, No. 4, 2016 December: 173-183
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Febrinasari et al., Increasing serum transaminase is not associated with the serum isoniazid
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J Med Sci, Volume 48, No. 4, 2016 December: 173-183
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Febrinasari et al., Increasing serum transaminase is not associated with the serum isoniazid
Based on ALT level showed that most of it was not significantly different (p = 0.05).
subjects were also male (24 subjects or 77.4%), Similarly result was observed in the serum
only 7 (22.6%) subjects were female (TABLE rifampicin level. The serum rifampicin level
1). Subjects with high ALT level were similar in subjects with high ALT level (10.67 ± 3.76
between male and female, whereas subjects µg/mL) was also higher than it in subjects
with normal ALT level were dominated by with normal ALT level (3.66 ± 0.30 µg/mL).
male 23 (79.3%) and only 6 or 20.7% subjects However, it was not significantly different (p
were female. = 0.25) (TABLE 3).
Similar result was observed between One (50%) subjects with high ALT
serum INH and rifampicin levels in relation level and 23 (79.3%) subjects with normal
with AST level and with ALT level. Although ALT were given 3 tablets of FDC-ATT and 1
the serum INH level in subjects with high ALT (50.0%) subjects with high ALT level and 6
level (7.07 ± 6.24 µg/mL) was almost three (20.7%) subjects with normal AST level were
time higher than it in subjects with normal given 4 tablets of FDC-ATT (TABLE 3).
ALT level (2.42 ± 0.26 µg/mL). However,
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J Med Sci, Volume 48, No. 4, 2016 December: 173-183
ALT level
Characteristic High Normal p
(n=2) (n=29)
Age (mean ± SD year) 37.5 ± 2.1 45.4 ± 13.5 0.42a
Sex [n (%)]
Male 1 (50.0) 23 (79.3)
0.40b
Female 1 (50.0) 6 (20.7)
Weight (mean ± SD kg) 49.5 ± 9.2 50.0 ± 6.5 0.75a
Height (mean ± SD m) 1.63 ± 0.12 1.64 ± 0.06 0.95a
Body Mass Index (mean ± SD) 18.2 ± 0.1 18.6 ± 2.3 0.78a
Nutritional status (%)
Normal 0/2 (0) 13/29 (46.4)
0.49b
Low 2/2 (100) 16/29 (53.6)
Isoniazid level (mean ± SEM µg/mL) 7.07 ± 6.24 2.42 ± 0.26 0.81c
Rifampicin level (mean ± SEM µg/mL) 10.67 ± 3.76 3.66 ± 0.30 0.31a
Dose FDC-ATT [n (%)]
4 tablets 1 (50.0) 6 (20.7)
0.40b
3 tablets 1 (50.0) 23 (79.3)
a
Independent t-test; Fisher’s exact test; Mann-Whitney U test
b c
Correlation beween isoniazid and rifam- FDC-ATT as well as nutritional status and the
picin levels and AST and ALT levels difference in the ALT and AST levels were
No significant correlation between the observed in thi study (TABLE 4).
serum INH and rifampicin levels, dose of
TABLE 4. Correlation between isoniazid, rifampicin levels, dose of FDC-ATT and nutritional
status with ALT and AST levels
To evaluate the influence of the INH and of high serum AST level 13.5 greater than
rifampicin levels, dose of FDC-ATT and age those with low serum INH level (< 5 µg/mL).
on the serum AST level, the Fisher’s exact However, it was not statistically significant
test was performed (TABLE 5). Subjects with (OR=13.5;95% CI: 0.0-924.6).
high serum INH level (≥ 5 µg/mL) had risk
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Febrinasari et al., Increasing serum transaminase is not associated with the serum isoniazid
TABLE 5. Influence of serum INH and rifampicin levels, dose of FDC-ATT as well as
age on the risk of increase in serum AST level
AST
Variabel x2, p OR (95% CI)
High Normal
Isoniazid level
High 1 1
0.18 13.5 (0.0-924.6)
Normal 2 27
Rifampisin level
Normal 1 0
0.97 ─
Low 2 28
FDC-ATT
4 tablets 1 6
0.55 1.83 (0.0-35.4)
3 tablets 2 22
Age
Old 1 16
0.57 0.38 (0.01-6.37)
Young 2 12
Analysis with Fisher’s Exact Test
Furthermore, the risk of developing high To evaluate the influence of the INH and
serum AST levels in subjects with dose of rifampicin levels, dose of FDC-ATT and age
4 tablets FDC-ATT was 1.83 times greater on the serum ALT level, the Fisher’s exact
than those with dose of 3 tablets FDC-ATT. test was performed (TABLE 5). Subjects with
However, it was not also statistically significant high serum INH level (≥ 5 µg/mL) had risk
(OR = 1.83; 95 % CI: 0.0-35.4). Age had no of high serum AST level 28.0 greater than
effect on the increase in serum AST level (OR those with low serum INH level (< 5 µg/mL).
= 0.38; 95% CI: 0.01 to 6.37). However, it was not statistically significant
(OR=28.0;95% CI: 0.0-6844.55).
TABLE 6. Influence of serum INH and rifampicin levels, dose of FDC-ATT as well as age
on the risk of increase in serum ALT level
ALT
Variabel x2, p OR (95% CI)
High Normal
Isoniazid level
High 1 1
0.13 28.0 (0.0-6844.55)
Normal 2 28
Rifampisin level
Normal 1 0
0.65 ─
Low 1 29
FDC-ATT
4 tablets 1 6
0.55 3.83 (0.0-171.00)
3 tablets 2 22
Analysis with Fisher’s Exact Test
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J Med Sci, Volume 48, No. 4, 2016 December: 173-183
Furthermore, the risk of developing high concentration was 13.6 µg/mL. Although the
serum ALT levels in subjects with dose of median of serum INH concentration in this
4 tablets FDC-ATT was 3.83 times greater study was different compare to that reported
than those with dose of 3 tablets FDC- McIlleron et al.,12 however the range of serum
ATT. However, it was not also statistically INH concentration was similar.
significant (OR = 3.83; 95 % CI: 0.0-171.00). The mean serum INH concentration of
subjects with high ALT level was almost three
Characteristics of subjects who have time higher than it in subjects with normal
extreme data ALT level although it was not significantly
One of the subjects in this study had the different. The increase of ALT level until
highest serum drugs level compared to other five times of normal was found in one (3.3%)
subjects. Serum INH and rifampicin levels subjectin this study. The increase of ALT
of this subject were 13.32 µg/mL and 14.43 level of patients who underwent tuberculosis
µg/mL, respectively. Characteristics of this treatment was reported in previou studies.
subject was a man with 39 years old, 55 kg An increase of ALT level until five times on
body weight and low nutritional status (BMI 0.56% of tuberculosis patients who treated
of 17.9). He received 4 tablets FDC-ATT with single dose of INH was reported.13
containing INH 300 mg and rifampicin 600 mg An another study also reported an increase
daily during the intensive phase of treatment. of serum transaminases until three times of
The serum AST and ALT levels of this subject normal on 0.3% of laten tuberculosis patients
before the intensive of treatment were normal. after treatment.14
However, this serum AST and ALT levels Previous studies reported that INH
increased five time at the end of the intensive hepatotoxicity was associated with the patient
of treatment, whereas his serum urea level acetylator status in the N-acetyltransfrase
(13 mg/dL) and serum creatinine level (0.96 2 (NAT2) genotype.15-18 Slow acetylator
mg/dL) were normal. This subject underwent status was a significant risk factor for drug-
intensive phase compliance of treatment, induced liver injury (DILI) in TB patients.19-22
therefore he underwent continuos phase of Isoniazid is metabolized to acetylisoniazid
treatment with drug-induced hepatotoxicity by NAT, which is then hydrolyzed to
monitoring. acetylhydazine. Acetylhydrazine can be
transformed into diacetylhydrazine by
DISCUSSION acetylation process and oxidized by CY2E1
to form hepatotoxic metabolites. Low NAT
Effect of serum INH concentration on activity in slow acetylator status will increase
serum transaminase the risk of hepatotoxicity due to the majority
The mean serum INH concentration acetylhydrazine is oxidized.23
two hours after FDC-ATT on 31 subjects
was 2.72 ± 0.46 µg/mL varied from 0.53 to Effect of serum rifampicin concentation on
13.32 µg/mL with the median of 2.21 µg/ serum transaminase
mL. McIlleron et al.12 reported that two hours The mean serum rifampicin concentration
after INH ingestion the median serum INH two hours after FDC-ATT on 31 subjects was
concentration was 5.0 µg/mL with the lowest 4.12 ± 0.46 µg/mL varied from 0.49 to 14.43
concentration was 0.4 µg/mL and the highest µg/mL. This serum rifampicin concentration
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Febrinasari et al., Increasing serum transaminase is not associated with the serum isoniazid
was relatively low therefore it did not influence et al.30 reported that serum transaminase
serum transaminase of the patients. Van increased in older TB patient (>35 years).
Crevel et al.24 reported that serum rifampicin Gender was not also associated with
concentration two hours after ingestion can the increase of serum transaminase in this
be categorized into subtherapeutic levels (<4 study. The serum transaminase level of male
µg/mL), low concentration (4-8 µg/mL), TB patients was not significantly different
therapeutic levels (8- 20 µg/mL), and toxic compare to female TB patients. However,
levels (> 20 µg/mL). Furthermore, it was previous studies reported that the increase
also reported that 70% of the TB patients had of serum transaminase was more frequent
subtherapeutic rifampicin concentrations (<4 in female TB patients.30,31 Similar with this
µg/mL) and no toxic rifampicin concentration study, the nutritional status was reported not
in serum was observed.24 Another study associated with the serum transaminase.17,30,31
reported 64% of TB patients had plasma
rifampicin concentration less than 8 µg/mL AKNOWLEDGEMENTS
after rifampicin treatment.25 In this study, 55%
The authors would like to thank all patients
of the TB patients had subtherapeutic, 40%
who participated in this study. This study
of those had low therapeutic and only 3%
could be conducted after supported by directos
of those had therapeutic level. The different
of the Community Health Care and Center
in drug preparation may influence the serum
for Pulmonary Disease Treatment (BP4) in
rifampicin of TB patients. In this study
Yogyakarta
rifampicin were given in FDC-ATT.
The mean serum rifampicin concentration
CONCLUSION
of subjects with high ALT level was also
almost three time higher than it in subjects In conclusion, the increase of serum
with normal ALT level although it was not transaminase is not associated with serum
significantly different. It was indicated that INH and rifampicin levels in pulmonary
serum rifampicin level did not affect the tuberculosis patients receiving FDC-ATT.
increase in serum transaminase. Previous
studies conducted on TB patients showed the REFERENCES
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Geneva: World Health Organization, 2009.
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on serum transaminases penanggulangan tuberkulosis. Jakarta :
No association between age and serum Departemen Kesehatan RI, 2007.
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different compare to those older patients (>40 Geneva: World Health Organization, 2007.
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