Evaluation of Clinical and Immunogenetic Risk Factors
for the Development of Hepatotoxicity during
Antituberculosis Treatment
Surendra K. Sharma, Arumugam Balamurugan, Pradip Kumar Saha, Ravindra M. Pandey, and Narinder K. Mehra
Departments of Medicine, Histocompatibility and Immunogenetics, and Biostatistics, All India Institute of Medical Sciences, New Delhi, India
Though several risk factors for the development of hepatotoxicity
due to antituberculosis drugs have been suggested, involvement
of genetic factors is not fully established. We have studied the ma-
jor histocompatibility complex (MHC) class II alleles and clinical risk
factors for the development of hepatotoxicity in 346 North Indian
patients with tuberculosis undergoing antituberculosis treatment.
Of these, 56 patients developed drug-induced hepatotoxicity (DIH
group), whereas the remaining 290 patients did not (non-DIH
group). The DIH group was comparatively older, had lower pre-
treatment serum albumin, and a higher frequency of moderately/
far advanced disease radiographically than the latter. Further, pa-
tients with high alcohol intake had threefold higher odds of devel-
oping hepatotoxicity. In multivariate logistic regression analysis,
older age (odds ratio [OR] 1.2), moderately/far advanced disease
(OR 2.0), serum albumin  3.5 g/dl (OR 2.3), absence of HLA-
DQA1*0102 (OR 4.0), and presence of HLA-DQB1*0201 (OR 1.9)
were independent risk factors for DIH. Our results suggest that
the risk of hepatotoxicity from antituberculosis drugs is influenced
by clinical and genetic factors.
Keywords: antituberculosis drugs; hepatotoxicity; human leukocyte
antigens
It is estimated that one third of the world’s population is in-
fected with Mycobacterium tuberculosis, resulting in 8.4 million
new tuberculosis (TB) cases in 1999 (1). Antituberculosis ther-
apy with rifampicin, isoniazid, pyrazinamide, and ethambutol/
streptomycin is very effective, but the first three drugs are
hepatotoxic. A higher risk of hepatotoxicity has been reported
in Indian patients (2–5) than in their Western counterparts (6–
8). The risk of hepatotoxicity, based on data from four prospec-
tive Indian studies, was 11.5% (95% confidence interval [CI]:
9.5–13.5), compared with 4.3% (95% CI: 3.4–5.3) in 14 pub-
lished studies from the West (9). The reasons for this higher
rate of hepatotoxicity in Indian patients are unclear. Reported
risk factors for hepatotoxicity include: older age (10), female
sex (11), poor nutritional status (12), high alcohol intake (11),
pre-existing liver disease (13), hepatitis B carriage (14), in-
creased prevalence of viral hepatitis in developing countries (2,
15), hypoalbuminaemia and advanced tuberculosis (16), and in-
appropriate use of drugs and acetylator status (17, 18).
Convincing evidence has been presented for the genetic
association of human leukocyte antigen (HLA)-DR2 with pul-
(Received in original form August 21, 2001; accepted in final form May 9, 2002)
Supported by the Department of Biotechnology (DBT), Ministry of Science and
Technology, Government of India (Grant No. BT/MB/05/005/HG/96).
Correspondence and requests for reprints should be addressed to S. K Sharma,
Professor, Department of Medicine, All India Institute of Medical Sciences, New
Delhi-110029, India. E-mail: surensk@hotmail.com
This article has an online data supplement, which is accessible from this issue’s
table of contents online at www.atsjournals.org
Am J Respir Crit Care Med Vol 166. pp 916–919, 2002
DOI: 10.1164/rccm.2108091
Internet address: www.atsjournals.org
monary tuberculosis in various populations (19–22) and an as-
sociation of NRAMP1 gene variants (23) with susceptibility to
tuberculosis. However, there are no studies on the role of im-
munogenetic factors in the development of hepatotoxicity due
to antituberculosis drugs. The present study was therefore de-
signed to determine the role of various risk factors, including
major histocompatibility complex (MHC) class II alleles, in
the development of hepatotoxicity in Indian patients receiving
short-course antituberculosis chemotherapy. Identification of
patients with risk factors will facilitate monitoring for hepato-
toxicity, which results in mortality of 6–12% if the drugs are
continued even after the onset of symptoms (24).
METHODS
Study Population
We evaluated 361 patients who presented to the Outpatient Depart-
ment or admitted at the All India Institute of Medical Sciences hospi-
tal, New Delhi, between 1996 and 2000. Fifteen patients with chronic
illnesses such as cirrhosis of liver, chronic hepatitis, acute viral hepati-
tis, and/or gastrointestinal, renal, or cardiac diseases, were excluded
from the study, leaving a study population of 346 patients. All patients
were treated for the full duration of antituberculosis chemotherapy
with regular follow-up. Of these patients, 56 developed drug-induced
hepatotoxicity (DIH group) whereas the remaining 290 patients had
no clinical or biochemical evidence of hepatotoxicity (non-DIH
group). The HLA data were compared with those of 275 healthy con-
trol subjects of the same ethnic background and similar socioeco-
nomic status as the patients.
The diagnosis of pulmonary TB was based on the presence of acid-
fast bacilli on sputum smear or M. tuberculosis on sputum culture. In
patients with smear-positive TB, culture was not done unless multi-
drug-resistant TB was strongly suspected. Sputum cultures were done
in all patients with smear-negative pulmonary TB. In patients with
negative smears and cultures, the diagnosis of TB was based on symp-
toms, chest radiographic infiltrates in the upper lobes, and clinical and
radiographic response to antituberculosis drugs. Focal disseminated
TB was diagnosed on the basis of histopathologic and/or microbio-
logic evidence of TB from two noncontiguous sites. A group of pa-
tients with disseminated TB exhibiting classic miliary mottling on
chest radiographs was included as “miliary TB” as described earlier
(25). Lymph node TB was diagnosed by the demonstration of M. tu-
berculosis in the smear and/or culture of lymph node aspirates or bi-
opsy specimens. The DIH group included 13 patients with sputum
smear-positive pulmonary TB, 10 with sputum smear-negative pulmo-
nary TB (2 with positive cultures), 8 with miliary TB, 19 with focal dis-
seminated TB, and 6 with lymph node TB. The non-DIH group
included 126 with sputum smear-positive pulmonary TB, 39 with spu-
tum smear-negative pulmonary TB (8 with positive cultures), 41 with
miliary TB, 42 with focal disseminated TB, and 42 with lymph node
TB (see online data supplement for drug regimens and dosages).
Diagnosis of Drug-induced Hepatotoxicity
DIH was defined as normalization of liver function after withdrawal
of all antituberculosis drugs, and the presence of at least one of the
following criteria: (1) a rise of five times the upper limit of normal lev-
els (50 IU/L) of serum aspartate aminotransferase (AST) and/or ala-
nine aminotransferase (ALT); (2) a rise in the level of serum total
Sharma, Balamurugan, Saha, et al.: Hepatotoxicity and Antituberculosis Chemotherapy
bilirubin  1.5 mg/dl; (3) any increase in AST and/or ALT above
pretreatment levels together with anorexia, nausea, vomiting, and
jaundice; (4) absence of serologic evidence of infection with hepatitis
virus A, B, C, or E.
Laboratory Monitoring
Liver function tests were performed on all patients before antituber-
culosis therapy. During treatment, liver enzymes and bilirubin were
measured monthly and whenever the patients presented with clinical
features of DIH. These tests were repeated after every 2 weeks in all
patients with a history of high alcohol intake (48 g ethanol per day for
more than a year) and in patients with abnormal pretreatment liver
function test results. In the DIH group, medications were stopped and
serum transaminases were measured weekly until they returned to
normal levels. Thereafter, antituberculosis drugs were gradually rein-
troduced. Tests for rheumatoid factor, antinuclear antibodies (Ab),
antineutrophil cytoplasmic Ab, anti-DS DNA Ab, and anti–LKM-1
antibodies were performed in patients with DIH (see online data sup-
plement for test procedures).
DNA Typing for HLA Class II Alleles
Genomic DNA extracted from peripheral blood mononuclear cell
pellet was used for amplification of HLA class II region (second exon)
with a set of 5 and 3 primers, based on published methods (22). Al-
lele-specific polymerase chain reaction (PCR) amplification for high
resolution typing of DR2 was done using generic DRB1 3 primer
with DR2B1 5 primer (TTCCT GTGGCAGCCTAAGAGG). A set
of 36 5 biotinylated sequence specific oligonucleotide (SSO) probes
was used to determine 8 DQA1 and 13 DQB1 alleles by the PCR-
SSOP method.
Statistical Analysis
Normally distributed variables were presented as the mean  SD.
Variables that were not normally distributed are shown as the median
and range. Categorical variables were evaluated by the Chi-square
test. Variables with p  0.2 in bivariate analysis were considered as
potential predictors of DIH in multivariate analysis. Stepwise binary
logistic regression analysis was used to identify independent risk fac-
tors. STATA 7.0 intercooled version (STATA corporation, Houston,
TX) was used for all statistical analysis. A p value of less than 0.05 was
considered as statistically significant.
RESULTS
All patients included in the study had negative serologic tests
for hepatitis A, B, C, and E, and for HIV. Patients in the DIH
group were significantly older than those in the non-DIH
group, but other parameters, including the male/female ratio,
measures of nutritional status and erythrocyte sedimentation
rate were similar in both groups (Table 1). None of the DIH
group patients had positive tests for rheumatoid factors or
other autoantibodies. Except serum albumin levels, pretreat-
TABLE 1. CHARACTERISTICS OF DIH AND NON-DIH
TUBERCULOSIS PATIENTS
DIH Non-DIH
Characteristics (n  56) (n  290)
Age, yr 36 (16–80)* 31 (13–84)
Sex, M/F 27/29 168/122
Height, m 1.6 (0.1) 1.6 (0.1)
Weight, kg 47.0 (10.9) 47.4 (10.4)
BMI, kg/m2 18.6 (3.6) 18.2 (3.3)
MAC, cm 22.5 (3.6) 22.6 (3.6)
TSFT, mm 8.9 (3.5) 8.3 (3.2)
ESR, Westergen, mm/first hour 43 (19) 40 (22)
Definition of abbreviations: BMI  body mass index; DIH  drug-induced hepatotox-
icity; ESR  erythrocyte sedimentation rate; MAC  mid-arm circumference; TSFT 
triceps skin fold thickness.
Data are presented as mean (SD) except age (mean [range]) and sex (M/F).
* p  0.05 as compared with non-DIH group.
917
ment liver function test results were similar in both groups
(Table 2). The maximally abnormal values of serum bilirubin,
AST, ALT, alkaline phosphatase, total protein, and albumin
levels were significantly higher in the DIH than in the non-
DIH group. The median time from the initiation of antituber-
culosis chemotherapy until the development of hepatotoxicity
(latency period) was 4 weeks (range, 1–72). None of the pa-
tients had recurrence of hepatotoxicity with the reintroduc-
tion of antituberculosis drug therapy.
Patients in the DIH group were more likely to have a high
alcohol intake (5% versus 2% in the non-DIH group) and
moderately/far advanced disease (50% versus 33% in the non-
DIH group), but these differences were not statistically signif-
icant. A pretreatment serum albumin of less than 3.5 g/dl was
present in 32% of DIH patients, compared with 16% of non-
DIH group (p  0.01). No mortality was observed in either
group.
HLA Analysis
The frequency of HLA-DRB1*03 was significantly increased
in the DIH group, compared with healthy control subjects
(29% versus 14%, respectively, p  0.01). At the DQ locus,
DQB1*0201 allele was observed significantly more frequently
in the DIH patients, compared with non-DIH patients (52%
versus 33%, respectively, p  0.01) and healthy control sub-
jects (52% versus 36%, respectively, p  0.05). On the other
hand, the frequency of DQA1*0102 was significantly reduced
in the DIH group, compared with the non-DIH patients (6%
versus 27%, respectively, p  0.001) and healthy control sub-
jects (6% versus 25%, respectively, p  0.01) (see Table E1
and E2 in the online data supplement).
Haplotype analysis revealed that DQB1*0201-associated
DRB1*0301 and DRB1*0701 haplotypes occurred more fre-
quently in the DIH patients than the non-DIH group (see Ta-
ble E3 in the online data supplement). Of these, the latter hap-
lotype, DRB1*0701-DQA1*0201-DQB1*0201, was present in
17% of the DIH group but in only 8% of the non-DIH group
(p  0.01). The other DR7 haplotype (DRB1*0701-DQA1*
0201-DQB1*0303) was distributed equally in the two groups.
In the bivariate analysis, DIH patients with advancing age
and presence of specific HLA alleles like DRB1*01, DRB1*03,
and DRB1*07 were positively associated with development
of DIH. However, in multivariate logistic regression analysis,
when the pretreatment variables and HLA alleles were simul-
taneously considered in the model, advancing age, moder-
ately/far advanced disease, hypoalbuminaemia, presence of
HLA-DQB1*0201, and absence of HLA-DQA1*0102 were
found to be significant risk factors for the development of
DIH (Table 3).
DISCUSSION
Identification of patients at increased risk for DIH is impor-
tant because hepatotoxicity causes significant morbidity and
mortality and modification of the drug regimen may be re-
quired. The incidence of DIH has been reported to be higher
in developing countries, and factors such as acute or chronic
liver disease, indiscriminate use of drugs, malnutrition, and
more advanced tuberculosis have been implicated (5, 16, 26).
However, it is unclear if these are independent risk factors for
hepatotoxicity.
A high incidence of viral hepatitis has been reported in TB
patients in developing countries (15, 27), resulting in misdiag-
nosis of DIH if serologic tests are not performed. All patients
with positive serologic tests for hepatitis A, B, C, and E were
excluded from the current study. All of our 56 patients with
918 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 166 2002

TABLE 2. PRETREATMENT AND POST-TREATMENT LIVER FUNCTION TESTS IN 56 DIH AND

290 NON-DIH PATIENTS

Pretreatment (mean [SD]) Posttreatment (median [range])*

Variables DIH Non-DIH DIH Non-DIH

†
Serum bilirubin, mg/dl 0.6 (0.1) 0.6 (0.1) 2.1 (0.5–11.8) 0.6 (0.3–1.0)
AST, IU/L 51 (29) 40 (20) 343 (21–2,662)† 31 (10–155)
ALT, IU/L 41 (27) 34 (22) 406 (28–3,320)† 40 (13–154)
Serum alkaline phosphatase
(normal range, 80–280 IU/L) 179 (71) 177 (65) 278 (111–1,158)‡ 160 (17–329)
Serum protein, g/dl 7.5 (1.1) 8.1 (0.9) 7.9 (5.4–9.3)† 8.1 (1.2–9.7)
Serum albumin, g/dl 3.9 (0.8)† 4.2 (0.8) 3.9 (1.6–5.7)† 4.6 (1.9–8.8)
Serum globulin, g/dl 3.5 (0.9) 3.8 (0.7) 3.5 (1.9–6.6) 3.6 (1.9–5.6)

Definition of abbreviations: ALT  alanine aminotransferase; AST  aspartate aminotransferase; DIHdrug-induced hepatotoxicity.
* Maximum abnormal values in DIH and non-DIH patients.
†
p  0.001.
‡
p  0.05 as compared with the non-DIH patients.

DIH recovered from hepatotoxicity, and antituberculosis (11, 16). Of these, moderately/far advanced pulmonary TB
medications were reintroduced one by one in gradually in- was an independent predictor of DIH.
creasing doses, with careful monitoring of liver function. No Specific HLA alleles have been associated with develop-
patient developed recurrent hepatotoxicity, a finding that is at ment of pulmonary tuberculosis in various populations (19–
variance with experience of others (28). The reasons for this 22) and with pulmonary Mycobacterium avium complex infec-
difference are uncertain. tion among the Japanese (29). We therefore investigated the
We found that advancing age was an independent predictor role of these genes in the development of DIH in TB patients.
of DIH, consistent with previous reports (10), but did not con- PCR-SSO hybridization techniques were employed because
firm previous studies suggesting that females are more likely they are more sensitive than serology and define alleles with
to have DIH (11, 14). Malnourished children have threefold high resolution. Multivariate analysis revealed that the two
increased incidence of DIH (5) and we found that patients HLA-DQ alleles were associated with development of DIH.
with pretreatment hypoalbuminaemia had a twofold higher The HLA-DQ molecules are unique among class II MHC
risk of developing DIH. Other measures of malnutrition, such molecules because both the - and -chains are highly poly-
as BMI and triceps skin fold thickness, were not predictors of morphic and most of the variable amino acid residues are lo-
DIH. We found that high alcohol intake and advanced tuber- cated on the -helical part of the antigen-binding site. We
culosis were associated with DIH, confirming previous reports found that patients without DQA1*0102 have a fourfold risk
of developing DIH, whereas those with DQB1*0201 have a
twofold higher risk of developing hepatotoxicity. Comparison
TABLE 3. RESULTS OF BIVARIATE AND MULTIVARIATE LOGISTIC
of the distribution of HLA alleles in the DIH and non-DIH
REGRESSION ANALYSIS WITH DIH AS BINARY OUTCOME VARIABLE groups involves multiple comparisons. Nevertheless, conser-
vative adjustment for these comparisons by the Bonferronni
Unadjusted Adjusted method reveals that the negative association of DQA1*0102
Odds Ratio Odds Ratio
Variables (95% CI) (95% CI)
with DIH remained statistically significant.
It is interesting to note that although DRB1*15/16 (DR2) is
Age, yr 1.0 (1.01–1.04) 1.2 (1.01–1.04) associated with increased susceptibility to the development
Severity of disease†
and progression of pulmonary TB, these alleles occur with a
Minimal 1.0 1.0
Moderately/Far advanced 2.0 (0.9–4.1) 2.0 (1.0–4.0)
reduced frequency in patients developing hepatotoxicity due
BMI, kg/m2† to short-course chemotherapy. A similar corollary exists in
18 1.0 — rheumatoid arthritis, which is associated with expression of
18 1.1 (0.6–1.8) DR4. In contrast, patients with rheumatoid arthritis who de-
Albumin, g/dl† veloped D-pencillamine–induced polymyositis and nephropa-
 3.5 1.0 1.0
thy were DR4-negative and DR2- and DR3-positive (30, 31).
3.5 2.5 (1.3–4.8) 2.3 (1.1–4.8)
High alcohol intake
Our results suggest that a genetic influence associated with the
No 1.0 — MHC class II region, particularly the DQ locus, plays an im-
Yes 2.7 (0.7–11.0) portant role in the development of DIH. In summary, we
DRB1*15/16 found that tuberculosis patients with advancing age, moder-
Present 1.0 — ately/far advanced disease, pretreatment hypoalbuminaemia,
Absent 1.9 (1.0–3.6)
and the presence/absence of specific HLA-DQ alleles are as-
DRB1*07
Absent 1.0 —
sociated with development of hepatotoxicity. It will be impor-
Present 1.8 (1.0–3.6) tant to evaluate those risk factors in other populations.
DQA1*0102
Acknowledgment : The authors wish to thank Ms. Yogita Dixit and Mr.
Present 1.0 1.0
Mukesh Singh for their help in the conduct of the study.
Absent 5.5 (1.6–20.0) 4.0 (1.1–14.3)
DQB1*0201
Absent 1.0 1.0 References
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