Antituberculosis Drug-Induced Liver Injury: An Ignored Fact, Assessment of Frequency, Patterns, Severity and Risk Factors
Antituberculosis Drug-Induced Liver Injury: An Ignored Fact, Assessment of Frequency, Patterns, Severity and Risk Factors
Antituberculosis Drug-Induced Liver Injury: An Ignored Fact, Assessment of Frequency, Patterns, Severity and Risk Factors
Abstract
Background/Aims: Antituberculosis drug-induced liver injury (TB DILI) is a frequent medical
problem in Pakistan. Critical understanding of various aspects of TB DILI is not only important to
manage liver injury but may also prevent unnecessary discontinuation of antituberculosis treat-
ment. The study is aimed to determine the frequency, types, severity and patterns of TB DILI.
Study further evaluates various risk factors of TB DILI. Materials and Methods: This is a prospec-
tive cohort study of two seventy-eight patients with the diagnosis of tuberculosis, where patients
were followed during tuberculosis treatment. TB DILI was defined in accordance to international
DILI expert working group. Results: Out of two seventy eight-patients, ninety-five (34.14%) had
TB DILI. The most common pattern of TB DILI was hepatocellular (63.15%) followed by mixed
(23.15%) and Cholestatic (13.68%). Most of the patients had mild DILI (43.15%) followed by
moderate (30.52%), severe (20.01%) and very severe (5.26%). Age > 35 years, concomitant he-
patotoxic drugs, extrapulmonary TB and malnutrition are important risk factors for TB DILI. Con-
clusion: All patterns of TB DILI with varying severity were present. Age > 35 years, malnutrition,
extrapulmonary TB and concomitant use of hepatotoxic drugs were risk factors for TB DILI.
Keywords
Antituberculosis Drug-Induced Liver Injury, Antituberculosis Treatment,
Subjective Global Assessment, Liver Function Test
1. Introduction
Tuberculosis (TB) continues to be a major health problem, with 9.4 million incident cases and 1.7 million deaths
*
Corresponding author.
How to cite this paper: Naqvi, I.H., Mahmood, K., Talib, A. and Mahmood, A. (2015) Antituberculosis Drug-Induced Liver
Injury: An Ignored Fact, Assessment of Frequency, Patterns, Severity and Risk Factors. Open Journal of Gastroenterology, 5,
173-184. http://dx.doi.org/10.4236/ojgas.2015.512027
I. H. Naqvi et al.
globally in 2009 [1]. Tuberculosis perseveres as an important infectious disease across most of the underdeve-
loped world. It explains a noteworthy socioeconomic strain. The prevalence of tuberculosis in Pakistan is 350
(158 - 618)/100,000 with a mortality rate of 33 (15 - 60)/100,000 [2]. Despite the declining trend in prevalence
and incidence of tuberculosis in the west, the HIV/AIDS rise has set hurdles for its control in developing coun-
tries [3].
TB DILI (Antituberculosis drug-induced liver injury) is defined as the liver injury as a result of antitubercul-
ous drugs in accordance to American Thoracic society and international DILI Expert Working Group. TB DILI
(Antituberculosis drug-induced liver injury) is multifactorial including metabolic idiosyncrasy to HLA suscepti-
bility and generation of various free radical species. Metabolic idiosyncrasy claims to be the basis of Isoniazid
(INH) toxicity where a CYP-generated toxic metabolite of INH induces oxidative stress causing mitochondrial
or other key organelles injury. This concept could explain the enhanced risk of severe liver injury with conco-
mitant intake of rifampicin and pyrazinamide [4]. HLA susceptibility with certain HLA haplotypes where HLA-
DQB1 0201 antigen is present where HLA-DQA1*0102 is absent, has been linked with INH induced liver in-
jury [5].
Rifampicin may itself be hepatotoxic, as observed in cases with positive rechallenge and in situations where it
is used alone (as to relieve pruritus). The meta-analysis showed that regimens combining isoniazid and rifampi-
cin were associated with a higher rate of hepatotoxicity (2.5%) than regimens without this combination (1.1%)
[6]. Pyrazinamide exhibits a wide range hepatotoxicity which includes idiosyncratic dose-dependent, sporting
eosinophilia and granulomatous hepatitis. Pyrazinamide modifies nicotinamide acetyl dehydrogenase levels
consequently generating free radical species.
Regardless of great advantages with a combination of several antitubercular drugs having synergistic effects,
effectivity against different populations of mycobacterium, prevention of drug resistance and the risk of hepato-
toxicity of individual drugs is increased. Even though majority of the patients endure the combination of drugs, a
few develop adverse effects where anti-tuberculosis treatment induced hepatoxicity is the most significant ad-
versity [7] [8] accounting for more than 7.0% of all undesired effects [9] [10]. The incidence of TB DILI varied
from 2.0% to 28.0% which is based on different populations and definitions [7].
TB DILI includes liver damage ranging from a minimal elevation of ALT or AST without symptoms to acute
hepatic failure often fatal or even requiring liver transplantation.
Asymptomatic derangement of liver enzymes is found in 20% of patients (as a consequence of adaptation) [11]
[12]. The less favorable outlook has been reported in patients who develop jaundice, acute liver failure, ascites
and encephalopathy [13]. Moreover, TB DILI reduces efficacy of anti-TB treatment which could cause non-
compliance, treatment failure and eventual recurrence or drug-resistance [14]. These consequences could mo-
mentously hamper effective epidemic TB control.
Various risk factors for TB DILI have been evidenced as old age, female gender, high alcohol ingestion, co-
administration of enzyme inducers & other hepatotoxic drugs, Asian ethnicity and advanced form of the disease.
Prior viral related (HBV & HCV) chronic liver disease, human immunodeficiency virus (HIV) infection and
malnutrition are also established risk factors for TB DILI [7] [15] [16].
Pakistan is an endemic country for TB where various forms of TB are responsible for a mortality rate of 33
(15 - 60)/100,000 [2]. TB DILI leads to treatment failure that may further exacerbate drug resistance causing
eventual collapse of TB eradication programme. Critical understanding of clinical features of TB DILI, such as
the time of onset, degree of severity, early symptomatology and potential outcomes are of crucial importance in
identification of the adverse events with prompt intervention. A primary health care physician should know
when to stop anti-tuberculosis treatment (ATT) in case of DILI. Physicians should have comprehensive know-
ledge of reintroducing strategy as holding ATT even after DILI resolution may lead to rise in TB resistance and
can further hamper TB eradication program in Pakistan. The study is designed to:
Determine the frequency, types, severity and patterns of TB DILI.
Evaluate various risk factors for TB DILI.
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rachi, Pakistan. All confirmed cases of Tuberculosis of age 18 years who had given informed consent were in-
cluded over a period of eight months after commencement of study. Patient with prior history, evidence of liver
injury, suspected multi-drug resistant (MDR) and extensively drug resistant (XDR) TB were excluded.
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and anti-hepatitis C antibody (anti-HCV). Samples from HBsAg + Ve, anti-HB core antibody (anti-HBc) + Ve,
and/or anti-HCV antibody-positive patients were tested for HBV DNA and HCV RNA, respectively. Liver func-
tion tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase
(ALP) and bilirubin were done before initiating anti-TB drugs and subsequently at 1, 2, 4, and 6 weeks later. Pa-
tients were also pursued clinically during anti-tuberculosis therapy.
2.10. Malnutrition
Among various risk factors for DILI in patients on ATT, malnutrition was determined by Subjective Global As-
sessment (SGA) scheme categorizing patients into stage A, B and C [19].
3. Results
Out of 278 patients with a diagnosis of TB, 95 (34.14%) had TB DILI. Most of the patients were male 192
(69.0%). The most common type of TB was pulmonary 59.39% followed by extrapulmonary forms like intes-
tinal, peritoneal, lymph nodes, etc. The demographic detail of patients with comorbids is given in Table 1.
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Symptomatology
Nausea 45 47.36%
Vomiting 39 41.11%
Anorexia 25 26.34%
Dizziness 21 22.21%
Abdominal pain 18 19.13%
Jaundice 43 45.02%
Encephalopathy 03 3.15%
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Table 4. Serial LFTs monitoring in patients on ATT at baseline, 2nd, 4th and 6th week.
Baseline 278 22.94 4.00 0.62 0.08 89.71 26.54 1.156 0.33
nd
At 2 week
LFT normal 183 (65.82% ) 28.35 0.38 0.95 0.07 105.92 6.65 1.18 0.007
LFT deranged 95 (34.17%) 54.95 9.85 1.23 0.02 180.21 13.50 1.20 0.02
At 4th week
LFT deranged 95 (34.17%) 81.18 2.56 1.38 0.05 206.03 9.51 1.44 0.03
th
At 6 week
LFT deranged* 95 (34.17%) 311.85 44.13 4.52 1.439 274.63 74.60 2.81 0.83
*
LFT, Liver function test. ALT, Alanine aminotrasferase. ALP, Alkaline phosphate. INR, International normalized ratio. DILI severity criterion was
applied.
ALT, Alanine aminotrasferase. International normalized ratio. DILI, Drug induced liver injury.
rifampicin and only 5 (5.26%) patients had DILI over reintroduction of Pyrazinamide.
3.6. Gender
Male gender was assessed as a risk factor for DILI. Among 278 tuberculosis patients, 192 (69%) were male and
114 (31%) were female. Out of 192 male patients 60/192 (31.25%) had DILI with calculated odd ratio of 0.66,
(CI 95%, 0.37 - 1.16), relative risk of 0.76, (CI 0.54 - 1.10) and p-value of 0.13 as shown in Table 6.
3.7. Diabetes
Out of 278 tuberculosis patients, 86 (30.93%) had DM. Among patients with DM 50/86 (58.13%) had DILI with
calculated odd ratio of 4.53 (CI 95% 2.54 - 8.11), relative risk of 2.48 (CI 951.78 - 3.21) and p-value of 0.000 as
shown in Table 6.
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I. H. Naqvi et al.
Gender
Age
>35 years (179) 69, 38.54 1.76 (0.94 - 3.13) 1.46 0.004*
DM
SGA-B
SGA-C
3.9. Extrapulmonary TB
Out of 278 tuberculosis patients, 122 (43.88%) had other than pulmonary TB. Among patients with extrapul-
monary TB 122/65 (53.27 %) had DILI with calculated odd ratio of 2.216 (CI 95%, 1.32 - 3.71), relative risk of
1.56 (CI 95%, 1.17 - 2.08) and p-value of 0.00 as shown in Table 6.
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for DILI in tuberculosis patients. Out of 278 tuberculosis patients, 72 (25.89%) were categorized in SGA A.
Among patients in SGA A 18/72 (25%) developed DILI with calculated odd ratio of 0.58 (95% CI .29 - 1.61)
relative risk of 0.66 (95% CI 0.40 - 1.04) and p-value of 0.06. 128 patients with tuberculosis were nutritionally
placed in SGA B category. Among patients in SGA B 26/128 (20.31%) developed DILI with calculated odd ra-
tio of 0.29 (95% CI 0.19 - 0.65) relative risk 0.44, (95% CI, 0.29 - 0.65) and p-value of 0.001. Out of 278 pa-
tients, 78 (28.05%) were categorized into SGA C. Among severely malnourished SGA-C patients 51/7 (65.38%)
had DILI with calculated odd ratio of 6.69, (95% CI, 3.63--14.41) relative risk 2.97, (95% CI, 2.16 - 3.96) and
p-value of 0.001 as shown in Table 6.
4. Discussion
The incidence of hepatotoxicity is more common with multidrug regimens for TB compared to INH monothe-
rapy in anti-TB prophylaxis. In this study TB DILI was manifested in 34.17% which is greater than earlier stu-
dies where the frequency was 8% - 19.8% [20] [21]. A recent Iranian study has shown similar frequency
(31.37%) of TB DILI [22]. Low frequency of TB DILI (5%) was reported in a meta-analysis from the west [23]
Pulmonary TB was the commonest form of TB in this study whereas an earlier study [24] had lesser frequency
of pulmonary TB.
Nausea, anorexia, and vomiting are the main clinical presentation of TB DILI in this study which is congruent
to the former studies [25] [26]. All three types of DILI were observed here including asymptomatic patients with
raised aminotransferase, symptomatic with raised aminotransferase and patients with acute liver fail-
ure/encephalopathy. An earlier study showed various types of TB DILI with acute uncomplicated hepatitis
(72.7%), fulminant hepatic failure (9.1%) and hepatic encephalopathy (18.2%) [26]. Kumar et al. reported low
frequency (5.7%) of ATT induced acute liver failure with high mortality [13].
All three major patterns of DILI (hepatocellular, Cholestatic, mixed) were present in this study. Most preva-
lent (63.15%) DILI pattern was hepatocellular followed by 23.15% mixed and 13.68% Cholestatic type. ATT
DILI severity was noted from mild to severe in this study. Majority of patients having TB DILI 41 (43.15%) had
mild DILI, 29 (30.52%) had moderate DILI while 20 (20.01%) and 05 (5.26%) patients had severe and very se-
vere DILI respectively. Khalili et al. [22] have shown moderate (18.7%), severe (7.8%) and very severe (4.9%)
hepatotoxicity with ATT. Maukof et al. [24] have shown the severity of TB DILI by using modestly different
cut off values for transaminases. In above study mild, moderate and severe DILI were present in 66%, 26.67%
and 13.33% patients respectively. The difference in DILI severity from above study to ours was owing to dif-
ferent cut off values for transaminases used in those two studies. A large Chinese study also showed similarly
severe TB DILI [25] Locally published study on TB DILI showed severity according to elevated level of trans-
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aminases (ALT/AST > 2) 22.3%, (ALT/AST > 3) 14.44% and (ALT/AST > 5) 2.22% although hepatotoxicity or
DILI grading was not in accordance to the International DILI Expert Working Group which includes bilirubin in
grading system [27].
DILI was also documented after reintroduction of ATT in this study. 20% patients had mild DILI with INH
whereas rifampicin and PZA produced DILI in 13.68% and 5.26% on reintroduction. Sharma et al. analyzed re-
challenge of 3 antituberculosis regimens in patients with TB DILI [28]. In this study reintroducing strategy of
ATT were compared in three management groups where group I patients were reintroduced with highest doses
of isoniazid, rifampicin, pyrazinamide simultaneously while group II patients were given therapy according to
ATS guidelines (RIF trailed by isoniazid for 7 days, followed by pyrazinamide for 7 days, all in the maximum
dosages). Patients in group III were reintroduced ATT as British Thoracic Society (BTS) guidelines where iso-
niazid, Rifampicin, and pyrazinamide were given sequentially by achieving the highest dose of each agent.
Sharma et al. accomplished that the re-emergence of DILI was comparable amid the three treatment groups, (p =
0.69) [28]. The frequency of DILI over the reintroduction strategy by American thoracic society as used in this
study was 3.42%.
In contrast, to study by Sharma et al., the Tahaoglu et al. in their study [29] compare the reintroduction regi-
mens of ATT with maximum doses of antituberculosis agents like pyrazinamide and slow reintroduction of ATT
without Pyrazinamide. The above study concluded that reintroduction of ATT with maximum doses were more
hepatotoxic [29]. The dissimilarity between the above mentioned studies could be owing to a lesser sample size,
the lesser treatment restraining limits and possible adaptation [30]. Khalili et al. [22] has shown the overall he-
patotoxicity of RIF, INH and PZA were 1%, 3% and 9% respectively.
Advance stage of TB, underlying acute or chronic liver disease, various degrees of malnutrition and indiscri-
minate use of drugs are considered as major factors for higher prevalence of TB DILI in developing countries.
Conversely, it is imprecise whether they are independent risk factors for hepatotoxicity.
Age > 35 year was proven as a risk factor for TB DILI in this study. Latest studies are harmonious to this
study where patients over 35 years have 4 fold increased possibility of developing TB DILI [31]. A study re-
ported that the rate of TB DILI encompasses 2% to 8% on aging, with an average of 5% [32]. Other studies ac-
counted that DILI ranges from 22% to 33% in patients over 35 years compared with a range from 8% to 17% in
those younger [4] [33]. Mahmood et al. [20] expressed that older age group was affected more with TB DILI
than the younger ones (25.8% and 14.4%, respectively). In contrast Steele et al. [34] observed liver injury (he-
patitis) in 1% - 6.9% of children contrasted to 1.6% - 2.5% of adults instituted isoniazid and rifampicin combi-
nation; involving all age groups at threat of emerging DILI. Shakya et al. reported that the rate of TB DILI is
more in younger sufferers [35]. This could be elucidated by the fact that the majority of patients in their study
were young. A prior Iranian [22] study disapproved age > 35 year to be a risk for developing TB DILI.
The feminine gender is conventionally considered more liable to develop TB DILI. Numerous studies re-
ported increased risk of hepatotoxicity, neither treatment limiting nor the statistically significant [36] [37]. Pa-
pastavros et al. showed a 4-fold rise in the risk of treatment limiting TB DILI in females with an overall inci-
dence of 2% [37]. Mahmood et al. [20] reported a higher frequency of TB DILI in females than males (26.3% vs.
19.7%). In contrast, this study along with other recent studies [38]-[40] did not show female gender to be a
threat for developing TB DILI. In this study, diabetes was established to be a risk factor for TB DILI. Srivastava
RK, et al. [41] also reported that diabetes amplifies TB DILI likewise our study. Earlier studies [42] [43] on the
subject also depicted diabetes as a risk factor for hepatotoxicity. An earlier study [22] defined our study and did
not prove diabetes as a risk factor. Malnutrition is considered to be a risk factor for TB DILI since long. Current
reports keep on validating the significance of low albumin to be a risk factor as well as an indicator of malnutri-
tion mutually for TB DILI. In this study various degree of malnutrition were assessed by SGA scheme and pa-
tients were categorized into stage A, B and C. Malnourished patients with SGA B (Odd ratio = 0.29, 95% CI
0.19 - 0.65 p = 0.001) and SGA C (odd ratio = 6.69, 95% CI, 3.63 - 14.41, p = 0.001) category were at greater
risk of TB DILI in this study. The SGA technique uses the clinical information collected during history taking
and physical examination to determine nutritional status without resorting to objective measurements like anth-
ropometry [19] [44]. SGA method of assessment has been used successfully to assess nutritional status, in gen-
eral medical and surgical patients. Earlier studies demonstrated three-fold elevated risk of increasing TB DILI in
patients with hypoalbuminemia (<3.5 mg/dl) [5] [31]. Recently weight loss has been implicated as a significant
risk factor for DILI [45].
Concomitant use of hepatotoxic drugs with ATT were also instituted to be a significant risk factor for DILI
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I. H. Naqvi et al.
(Odd ratio = 5.34, CI 95%, 2.69 - 10.68, p = 0.000). Previous studies [22] [46] also proved parallel hepatotoxic
drugs as a risk factor for TB DILI. In current study, extrapulmonary TB was found to be a risk factor for TB
DILI. An earlier study also showed a superior risk of TB DILI in extrapulmonary TB when compared to pul-
monary TB [47]. A recent Indian study has also shown that extrapulmonary TB has more ATT DILI compared
to pulmonary TB [48]. Concomitant hepatotoxic drugs and severe malnutrition were found to be independently
associated with TB DILI when assessed by multivariate analysis. Earlier studies [22] [25] [48] were also con-
gruent with this study for independent risk factors but malnutrition was assessed by low serum albumin rather
than SGA staging. Among the risk factors for TB DILI, oxidative stress parameters like Malondialdehyde
(MDA), Glutathione (GSH) and Superoxide dismutase (SOD) are also important. The oxidative stress parame-
ters were not determined here, main shortcoming in this study as their serum level also should have been deter-
mined before and during the treatment. This would have helped in further understanding of endogenous factors
for TB DILI.
5. Conclusion
TB DILI is a frequently reported medical problem in patients with various types of tuberculosis. All patterns of
DILI were present where hepatocellular and mixed were elaborated the commonest. TB DILI ranges from mild
injury to very severe or fatal liver damage. Age more than 35 years, malnutrition, extra pulmonary TB and con-
comitant use of hepatotoxic drugs were identified risk factors for TB DILI. Severe degree of malnutrition and
concomitant use of hepatotoxic drugs were found to be an independent risk factor for TB DILI.
Conflict of Interest
Authors have no conflict of interest.
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