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REGULAR ARTICLE
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.
©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.
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.
©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*
regular, frequent blood testing throughout therapy. In a few In our study, elevated transaminases were slightly more
paediatric studies from the 1970s, where liver enzymes were common in boys than in girls, but this difference was not
tested regularly, 7–17% of the patients had elevations, and statistically significant. A Japanese study reported a similar
levels rose to more than two times ULN in only 1% (10,12). finding (15). However, other studies among adults have
Exposure to certain drugs evokes physiologic adaptive shown either no differences in sex ratio or a tendency
responses in the liver. In particular, mild ALT elevation towards higher incidence among women (15–17).
probably reflects this nonprogressive injury to the hepato- Although the absolute numbers are small, resolved
cyte (4). On the other hand, AST elevations may signal hepatitis B was not found to be a risk factor for drug-
mitochondrial damage. We therefore included the results of induced liver injury; this is well in line with previous studies
both analyses in our descriptive study. (18,19). The only patient with chronic hepatitis B who had
None of our patients developed fulminant hepatitis, in severely elevated transaminases was also the only one who
accordance with other studies. Life threatening liver failure was positive for hepatitis B e antigen. In fact, an American
can occur, but is fortunately rare (13,14). However, the study of Vietnamese immigrants suggested that active but
proportion of our patients who developed moderate and not quiescent hepatitis B may be a risk factor for isoniazid-
severe elevations of transaminases was considerably higher induced liver injury (19).
than in other studies. The rate in adults is as low as Isoniazid is mostly cleared in the liver through acetyla-
0.1–0.5% (15–17). As our study was population-based and tion by N-acetyl transferase 2. Genetic polymorphisms of
all treated children were included, the rate of moderate this enzyme correlate with slow, fast and intermediate
or severe elevations is probably not an effect of positive acetylation phenotypes. Results have been contradictory
selection bias. 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*
©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 479–484 483
Acta Pædiatrica ISSN 0803-5253
REGULAR ARTICLE
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.
©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 479–484 479