Tuberculosis (TB) is a global pandemic and the incidence is on rise (Snider Jr and
Roper, 1992). WHO declared TB a global emergency in 1993, since then efforts
have been made to expand partnerships and bring all stakeholders on board in order
to control this disease more effectively (WHO, 2010). High number of tubercular
cases occurs in the Southeast Asia region, which accounts for about a one third of
global prevalence (WHO, 2010).
TB occurs frequently in Pakistan and unfortunately it has been one of the neglected
health issues in the past. The disease prevalence of 263/100 000 has been reported
in Pakistan, (Ejaz et al., 2010). Pakistan ranks sixth in the world in terms of TBburden
(Javaid et al., 2008). About 44% of TB-burden is contributed by Pakistan in
the Eastern Mediterranean Region while TB is responsible for 5.1% of the total
national disease-burden in Pakistan. TB-impact on socio economic status is
substantial (Tanveer et al., 2008; Hussain et al., 2003).
The treatment of TB by using chemotherapeutic agents like rifampicin, isoniazid,
pyrazinamide, ethambutol and streptomycin proves often successful. However druginduced
hepatotoxicity poses a real problem. Occasionally, this hepatotoxicity is
predictable and dose dependent, but for most, it may be idiosyncratic and dependent
on other factors like drug dosage, age, gender, and body mass index (BMI) (Aithal et
al., 1999; Björnsson et al., 2007). Underlying renal and/or liver diseases, the
concurrent use of certain food and drugs as well as pregnancy may also play a
significant role. Anti-TB drug induced-hepatotoxicity is variable and its occurrence is
high in the developing countries; 2%-28%, in comparison to the developed countries;
3%-4%, despite similar regimens used (Tostmann et al., 2008).
A number of risk factors have been implicated, including older age, female gender,
poor nutritional status, high alcohol intake, pre-existing liver disease, hepatitis B
carriage, increased prevalence of viral hepatitis in developing countries,
hypoalbuminaemia and advanced TB (Faustini et al., 2006). Inappropriate use of
drugs, acetylator status and immunogenetic factors, have also been implicated
(Sharma et al., 2002). Viral infections like hepatitis C and human immunodeficiency
virus (HIV) have also been reported to increase such risk (Padmapriyadarsini et al.,
A hospital-based prospective survey in Malaysia, indicated lower mean BMI, lower
serum albumin and higher serum globulin, relating-factors in those who developed
hepatitis by using anti-TB drugs (Fauzi et al., 2004). Among other reported risk
factors, only chronic hepatitis B carrier status remained to be more prevalent. A
through review of literature indicates the absence of any known published data on
the prevalence of anti-TB drug-induced hepatitis in the urban population of
Bahawalpur district, Punjab-Pakistan. Further, there is no data on the significance of
multiple risk factors, contributing to the development of anti-TB drug-induced
hepatitis in the part of this region. This study was designed therefore to examine
MATERIALS AND METHODS
This was a population-based cross-sectional study which was carried out from
August 10, 2009 to August 09, 2010. 1161 peoples (both sex) of different age and
professions of urban areas of Bahawalpur, Pakistan, selected by random sampling
were screened out for anti-tubercular drug induced hepatitis and promoting factors
(Zaman et al., 2009).
Population selection and division criteria
Selected sample of population of both sex, age; 15 years was divided into three
groups i.e. young (1535 years), mature (3550 years) and old (>50 years). The
male and female of same age were grouped together. A willingness certificate for cooperation
in carrying out the purpose of present study was obtained, singed by each
individual/parents/guardians before his/her inclusion in the study (Zaman, 2006).
Interview and blood collection
All of the participants were interviewed in person at enrollment. Information on
socioeconomic characteristics, dietary habits, personal medical and surgical history,
family history of major diseases, and anti-T.B. drug treatments were obtained by
using a structured questionnaire. A 5-mL blood sample was collected from each
participant (Yang et al., 2008; Zaman, 2009).
Evaluation of specimen
All the specimens were evaluated immediately following their collections for liver
biochemistries (serum albumin, globulin, aspartate aminotransferase, alanine
aminotransferase and bilirubin). Liver function tests (LFT) and HBsAg and Anti-HCV
were performed by using commercially available kits. The anti-TB treatment
regimens were either a combination of streptomycin, isoniazid, rifampicin and
pyrazinamide (SHRZ), or a combination of ethambutol, isoniazid, rifampicin and
pyrazinamide (EHRZ) (Behal et al., 2008; Yang et al., 2008; Zaman et al., 2009).
The data was analyzed statistically by the application of proportions and confidence
interval (CI of 95%) by modified Wald method (Bonett and Price 2006). “P” values
were determined. Differences were considered non-significant at p>0.05, significant
at p<0.05 and highly significant at p<0.001 (Zaman et al., 2011).
Prevalence of anti-TB drug induced hepatitis
A total of 1161 peoples (>15 years; 589 male and 572 female) were included in the
study. 148 patients had evidence of hepatitis, but only 146 were eligible and 2 were
excluded. Those excluded were with non-specific pretreatment of hepatitis (Table 1).
Age specific prevalence
Over all prevalence of anti-TB drugs induced (ATB) hepatotoxicity (HT) was 14.38%
(95% CI; 0.095 to 0.211); maximum 17.54% (95% CI; 0.096 to 0.296) in old group
followed by mature (15.09%, 95% CI; 0.076 to 0.273) and young (8.33%, 95% CI;
0.021 to 0.226) groups (Table 1).
Gender specific prevalence
The prevalence of ATB-induced HT in male was 13.58% (95% CI: 0.076 to 0.229)
compared to 15.39% (95% CI: 0.084 to 0.263) in female. The difference was found
to be statistically insignificant (Table 1).
Socioeconomic status specific prevalence
The distribution of participants according to socioeconomic status; income
and education is shown in Table 2. Maximum prevalence was observed in the
peoples with low income and low education (18.03%, 95% CI: 0.102 to 0.297
and 17.11%, 95% CI: 0.101 to 0.272 respectively).
Medical illness and treatment regimens specific prevalence
Slightly greater prevalence was found in the non-diabetics in comparison to
the diabetics (14.67%, 95% CI: 0.082 to 0.246 verses 14.08%, 95% CI: 0.076
to 0.242) while hepatitis B and/or hepatitis C carriers developed HT by ATB,
100% (95% CI: 0.718 to 1.000). The prevalence was slightly greater with
EHRZ than SHRZ treatment regimens (14.49%, 95% CI: 0.079 to 0.249 and
14.29%, 95% CI: 0.080 to 0.240) (Table 3).
Anti-TB drugs-induced changes in biochemical parameters
ATB slightly reduced mean serum albumin levels both in hepatitis B and/or C
careers and non-hepatitis careers before against after treatment for 21 days
(Table 4). While serum globulin, serum ALT, serum AST and serum total
bilirubin levels were highly significantly (p<0.001) increased in hepatitis B
and/or C careers as well as non-hepatitis careers, pre-treatment versus posttreatment
with ATB (Table 4).
Hepatotoxic side effect of anti-TB drugs (ATB) has been under extensive
discussion and studies to confirm their frequency and outcome in patients, all
over the world (Tariq et al., 2009).
The prevalence of ATB-induced hepatitis observed in the present study was
14.38%, comparable with those reported in other Asian countries, ranging
from 8% to 39% (Parthasarathy, et al., 1986; Türktas et al., 1994). The
observed prevalence is high as compared to those of developed countries;
around 3%-4% (Combs et al., 1990). Possibly due to higher viral hepatitis
prevalence in developing countries (Parthasarathy, et al., 1986; Türktas, et
al., 1994; Kumar, et al., 1991).
The findings of present study showed that there was a direct relationship between
the hepatitis B and/or hepatitis C infection with the development of hepatoxicity
(Table 3). All the patients with positive hepatitis B and/or hepatitis C markers
developed hepatoxicity by ATB treatment and prevalence was 100% (95% CI: 0.718
to 1.000). However, data indicated almost similar prevalence in diabetics compared
with non-diabetics (14.08%, 95% CI: 0.076 to 0.242 and 14.67%, 95% CI: 0.082 to
0.246 respectively). Similarly, both the treatment regimens, tested in this study;
SHRZ (streptomycin, isoniazid, rifampicin, pyrazinamide) and EHRZ (ethambutol,
isoniazid, rifampicin, pyrazinamide) showed slightly different prevalence (14.29%,
95% CI: 0.080 to 0.240 and 14.49%, 95% CI: 0.079 to 0.249 respectively) (Table 3).
This finding is in accord with the reports of Chang et al., (2008); Lee et al., (2005);
Kishore et al., (2007).
Socioeconomic parameters like income and education level of population have also
been reported to be important in determining the prevalence of hepatitis (Zaman,
2009; Zaman et al., 2009). The study showed maximum prevalence (18.03%, 95%
CI: 0.102 to 0.297) in the minimum followed by moderate and high income groups.
Low educated people also exhibited highest prevalence (17.11%, 95% CI: 0.101 to
0.272) and minimum in the high educated population (Table 2).
The study showed that hepatotoxicity was more common in females (15.39%, 95%
CI: 0.084 to 0.263) in comparison to male in tested population and this matches
other studies conducted (Teleman et al., 2002; Shakya et al., 2006). This increased
incidence in females is mainly due to differences in pharmacokinetics and slow
acetylator status (Naz et al., 2010). Regarding age, study showed increased
incidence in old (17.54%, 95% CI: 0.096 to 0.296) followed by mature and young
groups (Table 1). Finding strengthened previous studies (Masako, 2005; Tariq et al.,
2009). It may be due to aging factor where decline of drug metabolism is a
contributory factor (Masako, 2005).
In a study by Shakya et al., (2006) ATB was found to be associated with
derangement of hepatic function, resulting in elevation of liver enzymes where 2
times increase in ALT was observed in 38% of patients and more than 3 times
elevation in 30% patients within 12–60 days (Tariq et al., 2009). Data of present
study showed a highly significantly increase in ALT (53.37±3.74, 95% CI: -42.366 to
-41.094) in hepatitis B and/or hepatitis C positive population, similarly a highly
significantly increase in ALT (33.81±1.93, 95% CI: -21.387 to -20.713) in hepatitis B
and/or hepatitis C negative population by ATB (Table 4). The study further indicated
similar findings in serum AST and Bilirubin in hepatitis B and/or hepatitis C positive
and negative volunteers (Table 4). Finding is in accord with the reports of Masako,
(2005) and Marzuki et al., (2008).
Nutritional status (serum albumin) of tested population showed poor normal albumin
level (3.5±0.09 in hepatitis and 3.8±0.82 in normal population). It may be one of the
risk factor for the ATB-induced hepatotoxicity (Shakya et al., 2006). The patients
showed highly significant hypoalbuminaemia post-treatment in comparison with
pretreatment both in hepatitis B and/or hepatitis C positive and negative population
(Table 4). In malnutrition, glutathione stores are depleted which makes one
vulnerable to oxidative injury. In a malnourished person liver metabolizes drug like
ATB at a slower rate (Shakya et al., 2006; Lin et al., 2010). It was found that poor
nutritional status increases the risk of hepatotoxicity. Decreased glutathione stores
and slower rate of liver metabolism are the possible causes of increased vulnerability
among malnourished individuals (Naz et al., 2010).
The data further showed a highly significant change in serum globulin (Table 4);
post-treatment in comparison with pretreatment both in hepatitis B and/or hepatitis C
positive and negative patients. The observation was consistent with the findings of
Marzuki et al., (2008) and Adhvaryu et al., (2007).
In conclusion, the prevalence of anti-TB drug-induced hepatitis in tested population
14.38% may be associated with lower pretreatment serum albumin, higher
pretreatment serum globulin, hepatitis viral infection and poverty.
The author would like to thank Dr Akhtar MS, Professor, Department of Pharmacy,
University of Sargodha, Pakistan for his consistent patronage and support. NGO
groups provided the co-operation and support as well.
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