Drug-induced liver injury (DILI) is an important adverse effect of antituberculosis (TB) drugs. First-line anti-TB drugs including isoniazid, rifampicin, and pyrazinamide have been shown to have potential hepatotoxicity.1–4 Anti-TB drug-induced liver injury (ATLI) can range from asymptomatic elevation of aminotransferase to severe hepatotoxicity, or in some cases hepatic failure. Prevention of ATLI is crucial for patient safety and the control of TB. A number of strategies have been proposed to prevent or ameliorate ATLI, including regular monitoring of liver function, the pharmacogenetic approach of detecting high-risk genes for drug metabolizing enzymes, adjustment of anti-TB regimens, and the administration of hepato-protective agents.1,5–15 Of these suggestions, regular monitoring of liver function seems to be the simplest way of preventing ATLI. However, evidence to support the value of liver function monitoring is sparse, and support for it is based primarily on expert opinion, as opposed to evidence.
The National Institute for Health and Clinical Excellence (NICE) of the UK, the American Thoracic Society (ATS), and the World Health Organization (WHO) suggest that regular monitoring of liver function is only necessary in patients at high-risk of hepatotoxicity, such as those with baseline liver abnormalities, pre-existing liver disease, chronic alcohol consumption, viral hepatitis, or prior DILI.6–8 In contrast, the guidelines by the Taiwanese Centers of Disease Control (CDC) recommend checking liver function tests at 2, 4, and 8 weeks after the start of anti-TB treatment in all patients.5 Regular monitoring of liver function was found to be unnecessary in patients receiving statins, because of their low incidence of hepatotoxicity, even in high-risk patients such as those with viral hepatitis or nonalcoholic fatty liver disease.16,17 Therefore, whether regular monitoring of liver function in all patients receiving anti-TB treatment is beneficial to prevent ATLI needs to be verified.
The aim of the present study was to investigate the liver test monitoring status of patients receiving anti-TB treatment in Taiwan, and assess the impact of scheduled liver function monitoring on the risk of ATLI.
2.1. Patients enrolled
All patients who were confirmed of having TB and received treatment at our hospital, a tertiary referral hospital, between 2009 and 2017 were enrolled in the current study.
The inclusion criteria were as follows: (1) patients diagnosed as having an active TB infection, which was verified by a positive acid-fast stain, a nucleic acid amplification test, or a Mycobacterium TB culture; (2) those who received first-line anti-TB therapy; and (3) those completed the whole treatment course at the hospital. The exclusion criteria were as follows: (1) aged <18 years; (2) infected by non-TB mycobacterium or multiple-drug resistance TB; (3) received second-line anti-TB treatment at the beginning; and (4) were lost during follow up.
Baseline and follow-up data of serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin, creatinine, hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV) antibodies, alcohol habits, HIV infection status, concurrent medications, cancer status, and physician adherence to liver function monitoring were analyzed.
The enrolled patients were divided into two groups according to their liver function monitoring status. The good monitoring group included those who received liver function assessment at baseline and the 2, 4, and 8 weeks of treatment, according to the Taiwanese CDC anti-TB guidelines, while patients with incomplete liver function monitoring were assigned to the poor monitoring group.5
According to the US Drug-Induced Liver Injury Network (DILIN) criteria, the definition of ATLI was (1) serum ALT or AST greater than five times the upper limit of normal (ULN) among patients with normal baseline liver functions; (2) serum ALT or AST greater than five times the baseline level in patients with abnormal baseline liver functions; (3) serum total bilirubin > 2.5 mg/dL with an elevation of ALT, AST, or ALP and without known hemolysis.18 A liver abnormality was defined as an increase in serum ALT, AST, ALP, or total bilirubin greater than two times the ULN or baseline.19
The severity of ATLI was assessed from grade 1 (mild) to grade 5 (fatal), based on the DILIN index definitions.18 Active cancer was defined as the existence of vital cancer undergoing any treatment.20 The ATS risks for ATLI were chronic alcohol consumption, positive HBsAg or anti-HCV, pre-existing liver diseases, current pregnancy, 3 months postpartum, or HIV infection as suggested by the ATS.1,6
The present study was approved by the Institutional Review Board of our hospital (approval no. 2017-10-015AC), and was performed in accordance with the Helsinki Declaration of 1975.
2.3. Statistical analysis
Data were expressed as the mean ± SD, except where otherwise stated. Patient parameters between the different groups were examined using a Student’s t test or χ2 test as appropriate. Multivariate logistic regression was used to evaluate the risk of ATLI. All data were analyzed using SPSS 21.0 for windows (SPSS Inc., Chicago, IL, USA). A p value <0.05 was considered to indicate a statistically significant difference.
A total of 1062 patients were enrolled in the present study. Their mean age was 67.1 ± 18.8 years, and 748 (70.4%) were male. A total of 106 (10.0%) patients were hepatitis B virus (HBV) carriers and 16 (15.1%) of them received anti-HBV treatment. A total of 43 patients (4%) were hepatitis C carriers and five (11.6%) of them received interferon treatment before their anti-TB treatment. A total of 196 (18.5%) patients had extrapulmonary TB, and the most common type was TB pleurisy (20.4%), followed by lymph node (17.3%) and spine (11.2%) invasion. A total of 105 (9.9%) patients had active cancer, with the most common type being lung cancer (21.9%). The baseline characteristics of all patients are listed in Table 1.
A total of 169 (15.9%) patients had liver abnormalities after their anti-TB treatment, and 100 patients (9.4%) were diagnosed as having ATLI. A total of three patients with liver dysfunction were not considered as ATLI because there were other causes for their elevated liver enzymes, such as autoimmune hepatitis, pancreatic head cancer with obstructive jaundice, and transarterial chemoembolization for hepatocellular carcinoma.
The mean latency of ATLI was 33.8 ± 34.6 days. A total of 21 (21.0%) of the 100 patients with ATLI had severe to fatal DILI. In the study cohort, five patients died from liver injury, 15 patients died from TB, 16 patients died from cancer, and 13 died from other causes. There was no patient who underwent liver transplantation due to ATLI in the study cohort (Table 2).
A total of 469 (44.2%) patients were allocated to the good monitoring group, while 593 (55.8%) patients were allocated to the poor monitoring group. Compared with the poor monitoring group, the good monitoring group had significantly higher baseline serum ALT (p = 0.04) and AST (p < 0.01) levels, and significantly more HBV carriers (12.6% vs 7.9%, p = 0.01) (Table 3). The percentage of patients in the good monitoring group increased significantly year by year (p < 0.01) (Fig. 1). The incidence of both liver abnormalities (23.5% vs 9.9%, p < 0.01) and ATLI (14.7% vs 5.2%, p < 0.01) were significantly higher in the good monitoring group compared with the poor monitoring group. Monitoring status was not associated with ATLI-related mortality (p = 0.11). However, the peak ALT level was lower in the good monitoring group (276.1 ± 346.5 vs 507.1 ± 604.8, p = 0.05) compared with the poor monitoring group. The good monitoring group had a significantly shorter latency time (21.4 ± 25.6 vs 61.6 ± 36.2 days, p < 0.01) compared with the poor monitoring group.
For the management of ATLI, 91 out of 100 patients (91%) had their anti-TB drugs discontinued after ATLI occurred. A total of 80 (80%) of 100 patients were rechallenged using first-line anti-TB drugs after their liver function tests returned to normal or near-normal levels, and 57 (57%) of them were rechallenged successfully. A total of 21 (21%) patients failed to rechallenge the first-line drugs or changed to the second-line regimen upon the ATLI occurred, and only two of them could not endure the second-line therapy (Table 4). There was no significant difference in the management of ATLI between the good monitoring group and the poor monitoring group.
Multivariate logistic regression revealed that positive HBsAg, positive anti-HCV, age > 65 years, disseminated TB, and active cancer were associated with the susceptibility to ATLI (Table 5). Furthermore, positive anti-HCV and age > 65 years were found to increase the risk of severe and fatal ATLI. Active cancer had a trend for increasing the risk of severe and fatal ATLI but its effect was not statistically significant (Table 5).
ATLI is one of the most common adverse effects of anti-TB treatment. In the present study, it was found that regular liver function monitoring played a crucial role in the detection of ATLI in all patients receiving anti-TB treatment. Furthermore, carriers of HBV, HCV, the elderly, and those with disseminated TB or active cancer were associated with a higher risk of ATLI.
Although it is generally believed that liver function monitoring is important for the prevention and mitigation of ATLI, there was no consensus on how to implement the monitoring strategy. Most guidelines recommend regular monitoring among patients with a higher risk of ATLI. The NICE guidelines suggest monitoring of liver function in patients with coexisting liver disease, abnormal liver functions at baseline, or a history of alcohol misuse or drugs.7 The WHO recommends monitoring of liver functions in patients with pre-existing liver disease.8 The ATS recommends regular liver function monitoring in patients with chronic alcohol consumption, viral hepatitis, pre-existing liver diseases, current pregnancy, 3 months postpartum, concurrent use of hepatotoxic agents, or prior DILI or HIV infection.1,6 On the contrary, the Taiwanese CDC guidelines recommend liver function monitoring in all patients who receive anti-TB treatment, regardless of the patient’s baseline liver function or whether they have coexisting liver diseases.5
As for the frequency of monitoring, neither NICE nor the WHO mentioned this in their guidelines.7,8 The ATS suggests checking liver functions at baseline in all patients, and regular monitoring of liver functions every 2 to 4 weeks for the first 2 to 3 months of treatment among high-risk patients.1 The Taiwanese CDC recommends monitoring of liver functions at baseline and 2, 4, and 8 weeks of treatment.5 The Taiwanese CDC guidelines were designed to ensure early recognition of ATLI and to prevent grave hepatotoxicity. The present study validated the value of the Taiwanese CDC guidelines, which indicated that regular monitoring of liver functions could detect more ATLI cases earlier with less liver injury.
In the present study, the good monitoring group had a significantly higher rate of baseline liver function abnormality and HBV carriers, which are known to be risk factors for ATLI.1,21–24 The incidence of disseminated TB was also significantly higher in the good monitoring group. The severity of TB and the existence of risk factors may urge physicians to check liver functions more frequently. However, there were some patients who did not return for liver function tests on time, which may cause underestimation of a physician’s adherence. In the present study, it was also noted that the pulmonologist had better adherence to the Taiwanese CDC guidelines, compared with other subspecialists, such as doctors of infectious disease or surgeons (data not shown). There was a significantly shorter latent period in the good monitoring group compared with the poor monitoring group. Also, the percentage of patients in the good monitoring group increased year by year due to improved education and advocacy. The early onset of liver dysfunction often leads to a close follow-up and may prevent progression to ATLI. Asymptomatic ATLI may be missed in the poor monitoring group, which can cause underestimation of the incidence of ATLI. Regular monitoring of liver function seems to increase the detection rate of ATLI.
Chih et al14 analyzed severe ATLI patients who reported to the Taiwan Drug Relief Foundation and found that the nonmonitoring group had more severe hepatotoxicity and a higher mortality rate compared with the monitoring group. Another retrospective cohort studied by Wu et al15 revealed that scheduled monitoring could reduce hospitalization rates and was thought to lessen hepatotoxicity and reduce mortality. However, the current study could not verify the association between monitoring status and ATLI-related mortality. The possible reasons for this discrepancy were as follows: (1) Chih’s study included patients who reported voluntarily, while Wu’s study only enrolled patients with ATLI. Neither of these previous studies included consecutive patients as in the present study; (2) Chih’s study included cases with more severe liver injuries than those included in the present study; (3) The patients in the current study were older than those in the other studies, which may have influenced the results; and (4) The mortality rate in the current study was too low to be statistically significant.
Chih et al14 revealed a mean latency of 8.2 weeks in all ATLI patients. A recent study by Abbara et al25 in the UK found that the median latency for ATLI was 12.5 days, and 87.6% occurred within 8 weeks. In the REMoxTB study in the UK, ATLI was recognized in 58 of the 1928 (3.0%) included patients at a median time of 28 days.26 In a retrospective study in Korea, 67.6% patients developed ATLI within 30 days.27 The mean latency of 33.8 ± 34.6 days observed in the present study was in agreement with these previous findings, and supports the current guidelines from the ATS and the Taiwanese CDC that scheduled liver function monitoring should be implemented in the first 2 months of treatment.5,6
The present study found that patients aged >65 years (p < 0.01) and with positive anti-HCV (p < 0.01) had a significantly higher risk of severe and fatal ATLI, which was comparable with previous studies.1,21–24,28 Therefore, regular surveillance of liver functions is highly recommended in these high-risk patients.
Patients with coexisting active cancer were also found to have a higher risk of ATLI in the current study; however, the reason why these patients were vulnerable to ATLI is unknown. Abnormality of the immune system, poor nutrition status, and coadministration of chemotherapeutic agents in these patients may augment liver injury.1
Good monitoring can increase the detection of ATLI among all patients, which supports the policy suggested by the Taiwanese CDC. Although the mortality rates in the good monitoring and poor monitoring groups were similar, this was probably due to early discontinuation of anti-TB drugs in patients with ATLI and the limited number of expired cases.
There were some limitations to the present study. First, the amount of alcohol consumption and comorbidities may not have been accurately recorded, which could interfere with the designation of the patient’s susceptibility to hepatotoxicity. Second, the incidence of ATLI in the poor monitoring group may have been underestimated since asymptomatic ATLI could be missed without regular surveillance. Third, the study was a retrospective study, not a prospective one. As the study aimed to assess the adherence of physician’s to Taiwanese CDC guidelines, the prospective study did not meet the aimed requirements and was not ethical.
In conclusion, in the current study less than half of the patients who received anti-TB drugs received regular monitoring of their liver function. Scheduled liver function monitoring could enable the early identification of more ATLI cases, and therefore results in less liver injury. The implementation of periodic liver function monitoring tests in patients receiving anti-TB treatment should be re-emphasized and encouraged.
This study was supported by the grand from Taipei Veterans General Hospital (V108C-007, V108A-008).
We thank tuberculosis case manager, Chiao-Ping Li and study nurse, Dai-Ling Lin.
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