Acta Pædiatrica ISSN 0803-5253

REGULAR ARTICLE

Elevated transaminases are common in children on prophylactic treatment

for tuberculosis
Sara Leeb (sara.leeb@karolinska.se), Charlotte Buxbaum, Bj€orn Fischler
Department of Pediatrics, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden

Keywords ABSTRACT
Hepatotoxicity, Isoniazid, Prophylactic Treatment, Aim: The aim of this study was to assess the prevalence of elevated transaminase levels in
Rifampicin, Tuberculosis
children undergoing prophylactic treatment for tuberculosis (TB) infection.
Correspondence
Methods: All children living in a geographically defined area, who started TB prophylaxis
Sara Leeb, MD, Barngatan B57, Karolinska University
Hospital, SE-14186 Stockholm, Sweden. during 2009–2011, were included. Data on background factors, treatment regimes and
Tel: +4658580000 | transaminase levels at baseline and follow-up were collected retrospectively.
Fax: +4658581410 |
Email: sara.leeb@karolinska.se
Results: Of the 277 children who were treated, 113 (41%) had elevated transaminase
levels. Of these, 97 (35%) had levels that were less than three times the upper limit of the
Received
23 July 2014; revised 27 November 2014;
normal range and 16 (6%) had levels that were more than three times the normal range.
accepted 17 December 2014. Four patients had to discontinue isoniazid treatment and were successfully switched to
DOI:10.1111/apa.12908
rifampicin. In 17 patients, the highest transaminase peak did not occur until after 6 months
of treatment. Elevated transaminases were significantly more common in patients below
9 years of age (62%) than in those aged 10–18 years (28%). Transaminases were
elevated in 44% of all boys and 36% of all girls (p = 0.17).
Conclusion: Transaminase elevation was common in children receiving prophylactic
treatment for TB and started at different points throughout the treatment period. Younger
patients faced an increased risk. Regular blood tests are recommended throughout
treatment.

INTRODUCTION received prophylactic treatment for TB infection between

Tuberculosis (TB) is still a major health concern in many
parts of the world. Sweden had a low incidence of TB for
many years, but an influx of immigrants from low-income
and conflict-ridden regions has increased the incidence over
the last decade, to 6.3 cases per 100 000 in 2013 (1,2). The
risk of developing TB disease, once infected, differs accord-
ing to age. The risk is highest in the youngest children, under
1 year of age (50%), and lowest in young school children
(<5%) before rising again in adolescence (3).
In Stockholm county, TB is detected in children at risk
through systematic health screening with the tuberculin skin
test (TST) and/or interferon-gamma release assay. When TB
disease has been ruled out, infected children and adolescents
are offered prophylactic treatment, usually isoniazid.
Isoniazid is hepatotoxic, more so in adults than in children
(4). Guidelines from the Department of Communicable
Disease Control and Prevention, Stockholm, recommend
liver enzyme testing at baseline and after 1, 2, 4 and 6 months
of treatment (5). The aim of this study was to assess the
prevalence of elevated transaminases in children of multi-
ethnic origin undergoing prophylactic treatment for TB.
MATERIALS AND METHODS
This was an observational, retrospective, population-based
study of all children, aged from birth to 18 years of age, who
2009 and 2011 at the Department of Paediatrics, Karolinska
University Hospital, Huddinge. The care of children with
TB is split between two physically distinct units that cover
the northern and southern parts of Stockholm, respectively.
In 2011, the Karolinska hospital at Huddinge, which is in
the southern catchment area, included 214 000 children
aged from birth to 18 years of age (personal communication
Ulla Moberg, Statistics Sweden).
Most of the patients included were identified through
contact investigation or screening of immigrants from
endemic areas. Prophylactic treatment was offered to those
who fulfilled any of the following criteria: (i) a positive TST
Key notes
 The aim of this retrospective study was to assess the
prevalence of elevated transaminase levels in children
undergoing prophylactic treatment for tuberculosis
infection.
 We found that 41% of 277 of the children we treated
had supranormal transaminase levels, with onset
throughout the treatment period, and that younger
patients faced an increased risk.
 Hepatotoxicity was common and we recommend reg-
ular transaminase testing during treatment.

©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 479–484 479
Prophylactic tuberculosis treatment and liver function Leeb et al.

test in an individual originating from a high incidence

Table 1 Characteristics of patients on prophylactic treatment for tuberculosis
region (>/=100/100.000) (6); (ii) a positive TST in a non-
2009–2011
Bacillus Calmette–Guerin (BCG) immunised individual
Elevated Normal
who had been exposed to TB, regardless of where they
transaminase levels transaminase levels
originated from; (iii) a positive TST test plus positive
(Group A, n = 113) (Group B, n = 164)
interferon-gamma release assay during screening or a n (% in each group) n (%) p-value
positive TST test in a BCG-immunised individual identified
during contact investigation and (iv) a patient under the age Age
of 1 year who had been exposed to a suspected, contagious <6 months 7 (6.2) 4 (2.4) <0.001
TB case. The cut-off point for a positive TST was an 6 months–4 years 18 (15.9) 13 (7.9)
5–9 years 39 (34.5) 22 (13.4)
induration equal to, or more than, 10 mm.
10–14 years 20 (17.7) 72 (43.9)
Patients with signs or symptoms of active disease,
15–18 years 29 (25.7) 53 (32.3)
including radiological features of TB, were excluded. Sex
Blood samples were drawn routinely according to Male 68 (60.2) 85 (51.8) 0.17
recommendations (5), at baseline before treatment, after Female 45 (39.8) 79 (48.2)
1 month, after 2 months and then every 2 months until BMI Z-score
the end of the treatment, for analysis of haemoglobin, ≥ 2 SD 17 (15) 27 (16.5) 0.443
platelets, white blood cell count, creatinine, urea, alanine Drugs
aminotransferase (ALT) and aspartate aminotransferase Isoniazid 91 (80.5) 140 (85.4) 0.184
(AST). The prevalence of HIV in this population was Isoniazid+rifampicin 14 (12.4) 22 (13.4) 0.476
Rifampicin 8 (7.1) 3 (1.8) 0.030
expected to be low, in 2011, at 9.36 per 100 000
HIV pos 2 (2.8)* 0* 0.166
(personal communication Lars Naver, paediatric HIV
Hepatitis B markers 7 (6.2)** 9 (5.5)** 0.5
unit in Stockholm).
Resolved 5 7
Medical charts were reviewed retrospectively to collect HBeAg positive 1 0
data about background factors (Table 1). Data on ALT HBeAg negative 1 2
and AST levels at baseline and during treatment and Birth origin
clinical side effects were also collected. Type and duration Sweden 32 (28.3) 29 (17.7) 0.026
of treatment was also noted. Standard treatment was Europe outside 3 (2.7) 8 (4.9) 0.169
isoniazid (5–10 mg/kg/day) for 6–9 months. Alternative Sweden
treatment was either dual therapy with rifampicin East Africa 32 (28.3) 45 (27.4) 0.489
(10–15 mg/kg/day) and isoniazid (5–10 mg/kg/day) West Africa 6 (5.3) 11 (6.7) 0.183
Central Africa 6 (5.3) 12 (7.3) 0.161
for 3 months or monotherapy with just rifampicin
Middle East 14 (12.4) 16 (9.8) 0.121
(10–15 mg/kg/day) for 4 months. Dual therapy was
Central Asia 0 3 (1.8) 0.206
reserved for children who were likely to have difficulties East Asia 4 (3.5) 4 (2.4) 0.424
completing standard treatment, or who were suspected to South-East Asia 5 (4.4) 20 (12.2) 0.014
have been exposed to an isoniazid resistant strain, until Indian subcontinent 5 (4.4) 7 (4.3) 0.587
the drug sensitivity of the index case was known. South America 6 (5.3) 8 (4.9) 0.540
Monotherapy with rifampicin was used in children with
*Out of 71 patients in group A and 125 patients in group B who were tested
known exposure to the isoniazid resistant strain and
for HIV.
children with moderate or severe elevation of transami-
**Out of 70 patients in group A and 125 patients in group B who were
nases, as defined below. tested for hepatitis B.
The management of patients with elevated AST and
ALT was also recorded. For both these laboratory
analyses, the levels were divided into four categories
according to severity: a normal level was defined as Patients were excluded if treatment lasted less than
<0.7 microkat/L, corresponding to 40 IU/L, which is the 2 months, if they were lost to follow-up in the first
upper limit of normal range (ULN) in our hospital 2 months or if they had elevated transaminases at baseline
laboratory; mild elevation was set at 0.7–1.99 microkat/ that did not normalise within 1 month (Fig. 1).
L, which is equal to one to three times the ULN; Data from patients who developed elevated transami-
moderate elevation was 2.0–4.99 microkat/L, which is nases during treatment, designated Group A, were com-
equal to three to seven times the ULN and severe pared with data from those whose levels remained normal
elevation was >5 microkat/L, which exceeds the ULN throughout treatment, Group B. Additional comparisons
by seven times. with regard to age within Group A were also performed.
Serum levels of albumin and international normalised The Fisher exact test and chi-square test were used to
ratio (INR), that is, markers of hepatic synthetic function, calculate differences between the groups. p-values of <0.05
were analysed in patients with moderate and severe eleva- were considered significant.
tions of transaminases. Viral infections other than hepatitis The study was approved by the Regional Ethics commit-
B were not routinely tested for. tee in Stockholm.

480 ©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 479–484
Leeb et al. Prophylactic tuberculosis treatment and liver function

311
All children
treated

113 164 34
Elevated Normal
transaminases transaminases Excluded

2
97 25 7
8 8 Pathological
Mild Moderate Severe Lost to Treated < 2 m transaminases
follow up at start

96 1 7 1 3 5
Completed Stopped due Completed Stopped; not Completed
treatment to pruritius infected Stopped INH
treatment treatment

3
Continued
after
1 1
2 week Restarted
Restarted INH Treated > 6 m
succesfully RMP

INH = isoniazid 1
RMP = rifampicin Restarted
RMP
w = week
m = month

Figure 1 Children who received prophylactic treatment for tuberculosis infection 2009–2011. INH, isoniazid; RMP, rifampicin; w, weeks, m, months.

RESULTS birth to 6 months, 6 months to 4 years and 5 to 9 years,

Of the 277 children eligible for follow-up, 113 (41%) had
elevated transaminases during the treatment (Fig. 1). Of
these, 97 children (35%) had mild elevations that norma-
lised while treatment continued, eight (3%) had moderate
elevations and eight (3%) had severe increases in enzyme
activity (Fig. 1). For each patient with pathological trans-
aminase levels, the AST and ALT elevations were of
comparable severity. In the group with mild elevations,
one patient had to stop TB prophylaxis due to pruritus but
was able to restart after 2 weeks with no side effects.
Other than that, no subjective side effects were reported
in any group and none of the patients developed liver
failure.
The 16 patients with moderate or severe elevation of
transaminases are described in detail in Tables 2 and 3. In
one patient with severe elevation, the use of rifampicin as
an alternative treatment was associated with a mild trans-
aminase elevation, while the other patients’ transaminase
levels remained normal. Thus, all children could complete
one of the regimens (Tables 2 and 3).
The highest transaminase level occurred within the first
4 months in 81 (72%) of the patients with elevated
transaminases, but in 17 patients (15%), it occurred as late
as after 6 months of treatment (Fig. 2).
When we compared the children in Group A and Group
B, there was no statistical difference in terms of body mass
index, HIV or hepatitis B status (Table 1). None of the
patients was on immunosuppressive treatment. One was
receiving carbamazepine due to epileptic seizures and one
had metoprolol due to arrhythmia.
In the three youngest age groups, a higher percentage
developed elevated transaminases (64%, 58% and 64% for
respectively) than in the older age groups (22% and 35% for
ages 10–14 years and 15–18 years, respectively, p < 0.001).
Among the 113 patients in Group A, most of the youngest
children only had mild elevations. Of the 16 patients with
moderate and severe elevations, only two were under
4 years old (Tables 2 and 3).
Transaminase increase was detected in 44% of all treated
boys and 36% of all treated girls (p = 0.17).
The incidence of transaminase elevation did not seem to
vary with ethnic origin, with the single exception that it was
less common in children from South-East Asia (p = 0.03)
(Table 1). Being born in Sweden was more common among
children with elevated transaminase levels than without,
but the ethnic background of this group was highly
heterogeneous. Three of the 113 children with elevated
transaminases had parents who were both born in Sweden.
DISCUSSION
There is a lack of recent data on the incidence and outcome
of biochemical liver abnormalities associated with the
prophylactic treatment of TB infection in low-incidence
settings. Given the worldwide trend towards developing
and expanding prophylactic treatment strategies, it is
important to know how to manage possible side effects,
particularly from drugs given to children who are in fact
asymptomatic.
We found that a higher percentage of our patients (41%)
has elevated transaminase levels at some point during
prophylactic treatment for TB than the levels of about 10%
reported by most of the other studies (7–11). One possible
explanation for this difference is that our study employed

©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 479–484 481
Prophylactic tuberculosis treatment and liver function Leeb et al.

Table 2 Characteristics of patients with severe elevation of transaminase levels >5 microkat/L, that is >7 times the upper limit of normal range, corresponding to >285 IU/L
Timing of peak Normalised
BMI/ Drug, dose in transaminases transaminases after
Pat no. Sex Age Birth origin Z-score Hepatitis B status HIV status mg/kg in months Clinical management treatment completion*

1 Girl 14 West Africa 0 Neg Neg INH 2 Stopped treatment. Yes

6.8 When transaminases
normalised restart
with RMP 4 m
2 Girl 7 Sweden +2.5 n.d. n.d. INH 2 Stopped treatment. Yes
7.7 When transaminases
normalised restart
with RMP 4 m
3 Boy 16 Middle East +1.5 Neg Neg INH 6.5 Shortened treatment Yes
4.3 from 9 m to 6.5 m
4 Boy 13 Sweden 1.5 n.d. n.d. RMP 2 Continued treatment Yes
14.3 with close monitoring
5 Boy 14 East Africa 0 HBsAg pos Neg INH 4 Stopped treatment. No**
HBeAg pos 6 When transaminases
normalised restart
with RMP 4 m
6 Boy 18 East Africa 0 Neg Neg INH 5 Continued treatment Yes
4.8 with close monitoring
7 Boy 7 East Africa +1.5 Neg Pos INH 1.5 Stopped treatment. Yes
10.3 When transaminases
normalised restart
with RMP 4 m
8 Boy 5 East Asia +3 Neg Neg INH 1 Stopped treatment. Yes
5.8 New attempt with
INH had to be
stopped. When
transaminases
normalised restart
with RMP 4 m

*Time for transaminases to normalise was 1–6 months.

**Continued follow-up for chronic hepatitis B by paediatric hepatologist.
INH, isoniazid; RMP, rifampicin; n.d., not done.

regular, frequent blood testing throughout therapy. In a few
paediatric studies from the 1970s, where liver enzymes were
tested regularly, 7–17% of the patients had elevations, and
levels rose to more than two times ULN in only 1% (10,12).
Exposure to certain drugs evokes physiologic adaptive
responses in the liver. In particular, mild ALT elevation
probably reflects this nonprogressive injury to the hepato-
cyte (4). On the other hand, AST elevations may signal
mitochondrial damage. We therefore included the results of
both analyses in our descriptive study.
None of our patients developed fulminant hepatitis, in
accordance with other studies. Life threatening liver failure
can occur, but is fortunately rare (13,14). However, the
proportion of our patients who developed moderate and
severe elevations of transaminases was considerably higher
than in other studies. The rate in adults is as low as
0.1–0.5% (15–17). As our study was population-based and
all treated children were included, the rate of moderate
or severe elevations is probably not an effect of positive
selection bias.
In our study, elevated transaminases were slightly more
common in boys than in girls, but this difference was not
statistically significant. A Japanese study reported a similar
finding (15). However, other studies among adults have
shown either no differences in sex ratio or a tendency
towards higher incidence among women (15–17).
Although the absolute numbers are small, resolved
hepatitis B was not found to be a risk factor for drug-
induced liver injury; this is well in line with previous studies
(18,19). The only patient with chronic hepatitis B who had
severely elevated transaminases was also the only one who
was positive for hepatitis B e antigen. In fact, an American
study of Vietnamese immigrants suggested that active but
not quiescent hepatitis B may be a risk factor for isoniazid-
induced liver injury (19).
Isoniazid is mostly cleared in the liver through acetyla-
tion by N-acetyl transferase 2. Genetic polymorphisms of
this enzyme correlate with slow, fast and intermediate
acetylation phenotypes. Results have been contradictory
concerning the effect of acetylation rate on isoniazid

482 ©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 479–484
Leeb et al. Prophylactic tuberculosis treatment and liver function

Table 3 Characteristics of patients with moderate elevations of transaminases, 2–5 microkat/L, that is three to seven times of upper limit of normal range, corresponding to 114–
285 IU/L
Timing of peak Normalised transaminases
Hepatitis B Drug, dose in transaminases after treatment
Pat no. Sex Age Birth origin BMI/Z-score status HIV status mg/kg in months Clinical management completion*

1 Girl 6 Sweden 0 n.d. n.d. INH 1 Continued treatment Yes

7.1 with close monitoring
2 Boy 16 Middle East 0 Neg Neg INH 4 Continued treatment Yes
4.3 with close monitoring
3 Girl 6 East Africa 0 n.d. n.d. INH 1 Continued treatment Yes
6.3 with close monitoring
4 Girl 1 Sweden 0 Neg Neg INH 1 Continued treatment Yes
5.7 with close monitoring
5 Girl 14 East Africa +1.5 Neg Neg INH 6 Peak values at end Yes
4.4 of treatment
6 Girl 1 Sweden 0 n.d. n.d. INH+ RMP 2 Prophylactic treatment Yes
9+9 stopped. New TST
negative, no more
treatment needed
7 Boy 6 East Africa 0 Neg Neg INH 2 Continued treatment n.d.**
8 with close monitoring
8 Boy 11 West Africa +3 Neg Neg INH 3 Continued treatment n.d.**
4.6 with close monitoring

*Time for transaminases to normalise was 1–6 months.

**Lost to follow-up after TB treatment was completed.
INH, isoniazid; RMP, rifampicin; n.d., not done; TST, tuberculin skin test.

ethnic background and this could make our comparisons

Figure 2 Timing of highest peak of transaminases. m, months.
hepatotoxicity. Early studies suggested that fast acetylators
had a higher risk of developing isoniazid-induced liver
injury, but more recent studies have pointed in the opposite
direction (4,17,20,21). The fact that fewer children from
South-East Asia had transaminase elevations is in accor-
dance with the later studies, as almost 90% of oriental
ethnic groups are fast acetylators, whereas Caucasian and
black populations have approximately equal proportions of
fast and slow acetylators (22). It should be pointed out that
the patients with Swedish birth origin were of heterogenous
on the subject less reliable.
All children with moderate or severe elevation of
transaminases were on monotherapy with isoniazid.
According to the literature, rifampicin is per se less
hepatotoxic than isoniazid but can potentiate the liver
toxicity of isoniazid (4,7). Although the numbers are small,
our data suggest that combined therapy is not more
hepatotoxic than monotherapy. A study by Spyridis et al.
from 2007 found less hepatic abnormalities in patients
given a short course of combined therapy compared to
those given longer monotherapy (9).
This is a retrospective study and one limitation is that
other causes for elevated transaminases may have been
underestimated. For example, viral infections other than
hepatitis B affecting the liver, such as hepatitis A, cyto-
megalovirus or Epstein-Barr virus were not routinely
tested for.
In summary, this observational study showed a high
number of children with elevated transaminase levels
during isoniazid treatment. A possible risk factor could be
young age. Although relatively few patients developed
moderate or severe elevations, several of them required
treatment modification or temporary withdrawal. However,
all children were ultimately able to complete one regimen
of prophylactic TB drugs. The fact that abnormalities in
transaminase levels can occur late during treatment – and
that practically all patients are asymptomatic – is of clinical
relevance. Therefore, we conclude that regular blood tests
are valuable throughout TB prophylaxis.

©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 479–484 483
 Acta Pædiatrica ISSN 0803-5253

REGULAR ARTICLE

Elevated transaminases are common in children on prophylactic treatment

for tuberculosis
Sara Leeb (sara.leeb@karolinska.se), Charlotte Buxbaum, Bj€orn Fischler
Department of Pediatrics, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden

Keywords ABSTRACT
Hepatotoxicity, Isoniazid, Prophylactic Treatment, Aim: The aim of this study was to assess the prevalence of elevated transaminase levels in
Rifampicin, Tuberculosis
children undergoing prophylactic treatment for tuberculosis (TB) infection.
Correspondence
Methods: All children living in a geographically defined area, who started TB prophylaxis
Sara Leeb, MD, Barngatan B57, Karolinska University
Hospital, SE-14186 Stockholm, Sweden. during 2009–2011, were included. Data on background factors, treatment regimes and
Tel: +4658580000 | transaminase levels at baseline and follow-up were collected retrospectively.
Fax: +4658581410 |
Email: sara.leeb@karolinska.se
Results: Of the 277 children who were treated, 113 (41%) had elevated transaminase
levels. Of these, 97 (35%) had levels that were less than three times the upper limit of the
Received
23 July 2014; revised 27 November 2014;
normal range and 16 (6%) had levels that were more than three times the normal range.
accepted 17 December 2014. Four patients had to discontinue isoniazid treatment and were successfully switched to
DOI:10.1111/apa.12908
rifampicin. In 17 patients, the highest transaminase peak did not occur until after 6 months
of treatment. Elevated transaminases were significantly more common in patients below
9 years of age (62%) than in those aged 10–18 years (28%). Transaminases were
elevated in 44% of all boys and 36% of all girls (p = 0.17).
Conclusion: Transaminase elevation was common in children receiving prophylactic
treatment for TB and started at different points throughout the treatment period. Younger
patients faced an increased risk. Regular blood tests are recommended throughout
treatment.

INTRODUCTION received prophylactic treatment for TB infection between

Tuberculosis (TB) is still a major health concern in many
parts of the world. Sweden had a low incidence of TB for
many years, but an influx of immigrants from low-income
and conflict-ridden regions has increased the incidence over
the last decade, to 6.3 cases per 100 000 in 2013 (1,2). The
risk of developing TB disease, once infected, differs accord-
ing to age. The risk is highest in the youngest children, under
1 year of age (50%), and lowest in young school children
(<5%) before rising again in adolescence (3).
In Stockholm county, TB is detected in children at risk
through systematic health screening with the tuberculin skin
test (TST) and/or interferon-gamma release assay. When TB
disease has been ruled out, infected children and adolescents
are offered prophylactic treatment, usually isoniazid.
Isoniazid is hepatotoxic, more so in adults than in children
(4). Guidelines from the Department of Communicable
Disease Control and Prevention, Stockholm, recommend
liver enzyme testing at baseline and after 1, 2, 4 and 6 months
of treatment (5). The aim of this study was to assess the
prevalence of elevated transaminases in children of multi-
ethnic origin undergoing prophylactic treatment for TB.
MATERIALS AND METHODS
This was an observational, retrospective, population-based
study of all children, aged from birth to 18 years of age, who
2009 and 2011 at the Department of Paediatrics, Karolinska
University Hospital, Huddinge. The care of children with
TB is split between two physically distinct units that cover
the northern and southern parts of Stockholm, respectively.
In 2011, the Karolinska hospital at Huddinge, which is in
the southern catchment area, included 214 000 children
aged from birth to 18 years of age (personal communication
Ulla Moberg, Statistics Sweden).
Most of the patients included were identified through
contact investigation or screening of immigrants from
endemic areas. Prophylactic treatment was offered to those
who fulfilled any of the following criteria: (i) a positive TST
Key notes
 The aim of this retrospective study was to assess the
prevalence of elevated transaminase levels in children
undergoing prophylactic treatment for tuberculosis
infection.
 We found that 41% of 277 of the children we treated
had supranormal transaminase levels, with onset
throughout the treatment period, and that younger
patients faced an increased risk.
 Hepatotoxicity was common and we recommend reg-
ular transaminase testing during treatment.

©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 479–484 479