Approximately 10.4 million people developed tuberculosis (TB) worldwide in 2016, of which 1 million (10%) are children. Furthermore, there are 1.3 million cases of TB deaths, with 82% of them occurring in low- and middle-income countries mostly in Africa and South-East Asia.1 Antituberculosis drug-induced liver injury (ATLI) is one of the most frequent and serious adverse reactions during TB treatment.2 Isoniazid, rifampicin and pyrazinamide are the most potentially hepatotoxic first-line anti-TB drugs, whereas ethambutol and streptomycin have no known hepatotoxicity reactions.3
ATLI has a significant role in diminishing treatment effectiveness by increasing patient morbidity and mortality and disrupting therapy adherence.4,5 As an independent predictor of prolonged TB treatment,6 the high occurrence of ATLI results in discontinuation of therapy and potentially treatment failure. In adults, various factors, such as advanced age, female sex, malnutrition, HIV/AIDS, preexistent liver disease (eg, hepatitis B/C infections), alcohol intoxication, hepatotoxic comedications and genetics, are reported to be associated with higher risk to develop ATLI.3
The incidence and factors associated with ATLI in children have been studied insufficiently compared with adults. Even though the incidence of ATLI is lower than in adults, ATLI can develop in children at any age or any dosage of anti-TB drugs, with signs and symptoms are frequently ignored in many cases.7 Similarly, data about ATLI in the Indonesian pediatric population are limited. An earlier study in Indonesia reported that the rate of ATLI in children was about 7.4%.8 In the study, liver function tests (LFTs) were only performed in the first 2 weeks of therapy so that the actual incidence of ATLI was underestimated. Based on the 2014 World Health Organization guideline on the management of TB in children, routine monitoring of liver functions is not mandatory during TB treatment. It is only recommended if liver tenderness, hepatomegaly or jaundice occur during therapy.9 In addition, according to the national guidelines for childhood TB by the Indonesian Pediatric Society (IDAI), LFTs are only performed if hepatic dysfunction is suspected before the treatment, or symptoms of hepatotoxicity (eg, jaundice) appear during therapy.10 In this context, this study aims to determine the incidence and risk factors associated with ATLI in Indonesian pediatric patients during the first 2 months (ie, the intensive phase) of TB treatment.
PATIENTS AND METHODS
We conducted a prospective observational study at the Department of Child Health of the M Djamil Hospital in Padang, Indonesia, from September 2015 to April 2016. All consecutive inpatients or outpatients from 1 to 15 years of age, diagnosed with active pulmonary TB or extra-pulmonary TB and treated with isoniazid, rifampicin and pyrazinamide with/without ethambutol were eligible for inclusion in this study. TB was clinically diagnosed using the pediatric TB scoring system developed by the IDAI (Table, Supplemental Digital Content 1A, http://links.lww.com/INF/D280).10 Other procedures such as cerebrospinal fluid analysis and head computed tomographic scan to confirm TB meningitis (TBM) were performed if applicable.
Patients were treated by pediatricians of the M Djamil Hospital and were excluded if they had suspected multidrug resistance TB or low adherence and failure to complete the treatment. Patients with suspected pre-existing liver diseases before starting medication such as baseline aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 3× the upper limit of normal (ULN), viral hepatitis B/C or clinical symptoms like hepatomegaly and jaundice were also excluded.3 Suspected viral hepatitis B and/or C infections were defined by anamnesis of the clinical history, including perinatal transmission, blood transfusion history, sexual contact, infected household contact and direct percutaneous exposure to blood. All TB patients were screened and tested for HIV, and all HIV coinfected patients were initially treated with anti-TB drugs only and had not started antiretroviral therapy until the completion of the intensive phase of therapy. Other comedications concomitantly used with anti-TB drugs were evaluated with the LiverTox Database for detailed information on drugs potentially causing drug-induced liver injury.11
During the first 2 months of therapy, patients received a drug combination regimen based on the 2013 IDAI guideline in accordance with the 2014 World Health Organization guidance for the national TB programs on the management of TB, consisting of isoniazid, rifampicin and pyrazinamide for pulmonary TB and lymphadenitis TB; or isoniazid, rifampicin, pyrazinamide and ethambutol for extensive pulmonary TB, TB meningitis and osteoarticular TB.9,10 The drug doses are described in the Table, Supplemental Digital Content 1B, http://links.lww.com/INF/D280.
Demographic data and clinical history were collected at pre-treatment for each patient. Nutritional status was assessed by measuring length/stature-for-age and weight-for-age percentiles based on the 2000 Centers for Disease Control and Prevention Growth Charts.12 LFTs, including ALT, AST and total bilirubin, were performed at baseline and 2 weeks after initiation of therapy. Subsequent ALT, AST and total bilirubin were taken at 4, 6 and 8 weeks if the initial 2-week measurement was abnormal or if symptoms of hepatotoxicity such as anorexia, nausea, vomiting, abdominal pain or jaundice were reported.13 The reference normal values in our laboratory are ALT, <41 IU/L (male) and <31 IU/L (female); AST: <38 IU/L (male) and <32 IU/L (female); total bilirubin <1 mg/dL; serum albumin >3.7 g/dL.
Diagnosis and Management of ATLI
ATLI was defined as elevation of ALT/AST to more than 3× the ULN. To stop TB treatment caused by ATLI, at least one of the following criteria must be fulfilled: (1) elevation of transaminase levels >3× the ULN with clinical symptoms of hepatotoxicity (nausea, vomiting, abdominal pain and jaundice) or >5× the ULN without the presence of symptoms; and (2) a rise in total bilirubin to more than 2 mg/dL in the presence of jaundice, both with normalization of liver enzymes and resolving of symptoms of hepatotoxicity after withdrawal of all anti-TB drugs.3,14,15 For those who stopped TB treatment, liver functions were measured weekly until the symptoms resolved, and transaminase levels declined to less than 2× the ULN. As suggested by the IDAI guideline, the original regimen was restarted simultaneously when the symptoms and liver enzymes normalized. Patients who have increased transaminases >3× the ULN without the presence of symptoms of hepatotoxicity still continued the treatment with closely followed-up.10
Demographics and clinical factors considered for the study were age, sex, nutritional status, type of TB, albumin status, HIV status, concomitant hepatotoxic drugs and baseline LFTs, including ALT, AST and total bilirubin. These variables were analyzed univariately using χ2/Fisher exact test to identify risk factors for ATLI. Multivariate binary logistic regression analysis was then used to identify independent risk factors for the development of ATLI. All variables with P value <0.2 in the univariate analysis with numbers in both exposed and nonexposed groups >25% were included in multivariate analysis. Statistical significance was accepted at P < 0.05. All data were analyzed with IBM SPSS Statistics version 23.0.
Ethical clearance was granted by the Research Ethics Committee, Faculty of Medicines, Andalas University (No: 076/KEP/FK/2015). Written informed consent was obtained from parents/guardians before the commencement of the study.
Forty-nine patients were screened and included in the study. Eight of these were excluded from analysis; 3 patients had withdrawn from the study and 5 patients had incomplete clinical data due to technical problems during laboratory measurements (n = 2), and 3 patients diagnosed with TBM died within the first 2 weeks of treatment due to severity of the disease before the LFTs could be measured. Of the 41 patients available for analysis, there were 11 and 14 patients with abnormal ALT and AST, respectively. Among them, there were 2 patients with baseline ALT >2× the ULN and 3 patients with AST >2× the ULN. None of those who have baseline transaminases above 2× the ULN then developed into ATLI. Patient characteristics of the study population are presented in Table, Supplemental Digital Content 2, http://links.lww.com/INF/D281.
During the first 2 months of therapy, ATLI was detected in 11 (26.8%) patients within 14 to 42 days from the start of treatment. Six patients developed ATLI after 2 weeks of treatment, 3 patients developed ATLI after 4 weeks and 2 patients after 6 weeks. Of the 11 patients who developed ATLI, 5 increased in both ALT and AST, 3 increased in AST, 2 increased in ALT and 1 rose in bilirubin. All of the patients who developed ATLI were considered to have a stable condition including 9 inpatients with TBM and 2 outpatients with pulmonary TB.
There were 6 of 11 patients (5 with TBM and 1 with pulmonary TB) in which all anti-TB drugs were stopped immediately. Among them, 3 patients with both ALT and AST >3× the ULN showed the symptoms of fever and nausea (2 patients); and nausea, vomiting as well as abdominal pain (1 patient). Two patients both experienced fever with ALT/AST >5× the ULN developed ATLI without other specific symptoms of hepatotoxicity. The remaining 1 patient who rose in bilirubin >2 mg/dL experienced jaundice and anorexia. Both clinical symptoms and liver function profiles resolved within 1 week in 5 patients and within 2 weeks in the other one. After reintroducing anti-TB drugs, we performed LFTs fortnightly for all those 6 patients, and no ATLI recurrence was observed until the completion of the study.
The univariate analysis, shown in Table 1, demonstrated that TBM [P = 0.003; odds ratio (OR): 12.37; 95% confidence interval (CI): 2.18–69.99], hypoalbuminemia (P = 0.029; OR: 6.22; 95% CI: 1.33–29.01) and hepatotoxic comedications (P = 0.001; OR: 20.00; 95% CI: 2.24–178.94) were significantly associated with ATLI. Sex, age, nutritional status, HIV status and abnormality of baseline LFTs (ALT, AST and total bilirubin) had no significant association with ATLI. Multivariate logistic regression analysis identified hypoalbuminemia (P = 0.083; OR: 5.31; 95% CI: 0.80–35.21) and concomitant hepatotoxic drugs (P = 0.078; OR: 12.74; 95% CI: 0.75–216.12) tend to be independently associated with ATLI but not found statistically significant (Table 2). Potential hepatotoxic comedications used by patients who developed ATLI were phenobarbital in 7 (63.6%), paracetamol in 5 (45.4%), omeprazole in 2 (18.2%), ranitidine in 2 (18.2%), phenytoin in 1 (9.1%) and captopril in 1 (9.1%) patients.
In our study, 27% of the patients were categorized as having ATLI and 15% stopped TB treatment caused by ATLI. This result was higher than reported in recent similar studies of children, such as in Indonesia (7.4%),8 in Japan (8.1%)16 and in India (15.2%).17 This higher incidence could be related to transient and asymptomatic elevations of transaminases, most of which represents hepatic adaptation with spontaneous resolution.14 As drug reintroduction regimens were well-tolerated in those who developed ATLI, it was likely that the initial hepatotoxic event could have been the result of hepatic adaptation. Because there is no golden standard to distinguish between true ATLI and hepatic adaptation, patients who had treatment interrupted in our study were more likely of concern for evolving ATLI rather than because of established hepatotoxicity. However, treatment discontinuation based on biochemical thresholds and symptoms monitoring as suggested by standard guidelines would benefit to prevent severe progression of hepatic failure at an earlier stage.18
More patients in our study developed the clinical manifestation of nausea, and only few patients had jaundice, vomiting, anorexia and abdominal pain, which were the most frequent symptoms occurring in other studies.19,20 Notably, 7 patients who developed ATLI in our study (including 2 patients who stopped TB treatment) were asymptomatic or had prodromal symptoms (eg, fever). Shang et al20 showed that a third of their patients who developed ATLI were asymptomatic, including patients with severe hepatotoxicity. In some cases, severe hepatotoxicity may have progressed into liver failure requiring liver transplantation.21,22 As severe hepatotoxicity can occur without clinical symptoms, routine monitoring has proven to be effective in identifying asymptomatic liver damage reducing the need for hospitalization.23
The higher incidence of ATLI in children with TBM was supported by Donald7 who showed that abnormal LFTs and jaundice were recorded, respectively, in 53% and in 10% of children during TB therapy. The reason why patients with TBM are more likely to have ATLI compared with other types of TB is still unclear but could be related to severity of the underlying disease.24 In addition, all patients with TBM in our study had used potentially hepatotoxic comedications, such as paracetamol and phenobarbital. Other studies also showed an association between hepatotoxic comedications with ATLI.25,26
The higher risk of hepatotoxicity in patients with hypoalbuminemia may be related to depletion of glutathione stores, making patients more vulnerable to oxidative injuries and disrupting hepatic drug metabolism.19 It seems that malnutrition as identified by hypoalbuminemia itself might be the sign of hepatic dysfunction, and the possibility that it was partly caused by liver damage cannot be ruled out. However, it is unlikely that this short term of hepatotoxicity would have resulted in hypoalbuminemia as both clinical symptoms and liver function profiles resolved in all patients after stopping TB treatment, and no recurrent hepatotoxicity after drug reintroductions. Several previous studies also reported malnutrition including hypoalbuminemia and low Body Mass Index (BMI) to be associated with increased ATLI.19,25,27,28
Many studies reported that patients who are at higher risk of developing ATLI are associated with female sex, younger age (<5 years), abnormal baseline LFTs and HIV positive.3,14 Nevertheless, we did not find similar results. Several possible mechanisms could be responsible for these differences, such as sample size, variations of pharmacokinetics and genetics.
Our study has several limitations that should be considered. Because all of the patients were diagnosed clinically instead of bacteriologically confirmed with TB, there was still a possibility of diagnosis interchange between latent TB infection and TB disease. This aspect could limit reproducibility and extrapolation of the results. Our diagnostic tool (IDAI TB scoring system) also needs to be confirmed in studies with diverse population before it can be generalized. We acknowledge that baseline elevation of transaminases above the ULN but below the exclusion threshold of 3× the ULN could be the sign of pre-existing hepatic dysfunctions. However, there was no firm diagnosis that could explain these abnormalities in our study as we only excluded the possibility of viral hepatitis B or C coinfections by clinical anamnesis and were not able to test for viral hepatitis biomarkers. Because Indonesia is reported to have a moderate to high incidence of hepatitis B, and governmental pediatric vaccination against hepatitis B virus was only started since 1997, mothers of the included children were probably not immunized against it.29 If the mother was infected and transmitted the virus before the child got vaccinated, and no hepatitis B immunoglobulin was simultaneously administered within 24 hours of birth, the child would not be protected by vaccination. This possibly resulted in misclassification of viral hepatitis to ATLI in some patients.
Apart from the relatively small sample size of patients which limits the power of the study, we monitored the liver functions only for the first 2 months of TB treatment. Although hepatotoxicity most often occurs in the first 2 months, the actual eventual hepatotoxicity rate by the end of therapy could be higher. Our method was also unable to clearly clarify asymptomatic hepatotoxicity after 2 weeks as LFTs at 4, 6 and 8 weeks were only performed for patients with symptomatic disease. Then, we acknowledge that AST is not as specific as ALT to determine hepatotoxicity related to anti-TB drugs although both ALT and AST have been used as biomarkers of ATLI in various studies.3 The increase of AST alone cannot clearly define hepatocellular injury and may lead to the inclusion of patients without ATLI. Therefore, our exclusion criteria, specific monitoring of LFTs and a low threshold for defining hepatotoxicity potentially resulted in an underestimation of ATLI. Further studies with larger sample sizes over a longer time frame would provide a clearer picture of ATLI in children.
In conclusion, the incidence rate of ATLI in children treated with anti-TB drugs is quite high. Patients with hypoalbuminemia and those who use concomitant hepatotoxic drugs are suggested to be monitored closely for the development of ATLI. These findings can aid clinicians to be aware of the problem particularly in patients with hypoalbuminemia and benefit for patients who could avoid hepatotoxic comedications during TB therapy.
The authors thank all the patients for their participation in the study and the pediatricians, pediatric residents as well as nursing staff at the Department of Child Health of the M. Djamil Hospital for their assistance during the follow-up of these patients. We also thank the Indonesia Endowment Fund for Education (LPDP) for their purely financial support.
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