INTERNATIONAL REPORTS

Incidence of Hepatotoxicity Due to Antitubercular Medicines and

Assessment of Risk Factors
Rajani Shakya, B Subba Rao, and Bhawana Shrestha

BACKGROUND:

Antitubercular drugs cause derangement of hepatic function revealed by clinical examination and abnormal liver
function test results. Potential hepatotoxicity of some of the first-line antitubercular agents remains a problem, especially during the
initial period of treatment.

OBJECTIVE:

To determine the incidence of antitubercular druginduced hepatotoxicity in a Nepalese urban population and assess
the risk factors.

METHOD:

Fifty patients diagnosed with active tuberculosis infection with normal pretreatment liver function were monitored clinically
as well as biochemically in a prospective cohort analysis.

RESULTS: Antitubercular drugs were found to be associated with derangement of hepatic function, resulting in elevation of liver enzymes
to a variable extent (t = 4.550, p < 0.01 for aspartate aminotransferase [AST]; t = 5.467, p < 0.01 for alanine aminotransferase [ALT] at
95% CI). Thirty-eight percent of patients had 2 times and 30% had >3 times elevation of ALT. Similarly, 40% and 29% of patients
showed 2 and >3 times elevation of the AST level, respectively. Four patients (8%) developed drug-induced hepatotoxicity.
Jaundice was the presenting symptom in all patients. The time interval for onset of hepatotoxicity after initiation of therapy was
1260 days (median 28). Antitubercular druginduced hepatotoxicity was found more often in younger patients (6% vs 2%; p =
0.368, OR 2.75). Female gender was also a higher risk (p = 0.219, OR 4.2). Most patients who had developed hepatitis were
diagnosed per sputum-smear positive reactions. Nutritional status, assessed by body mass index and serum albumin level, was the
next predisposing factor.
CONCLUSIONS:

A finding of an 8% incidence of hepatotoxicity is considerably high. Risk factors of hepatotoxicity included female
gender, disease extent, and poor nutritional status. Timely detection and temporary withdrawal of the offending agent can
completely cure antitubercular druginduced hepatotoxicity.

KEY WORDS: hepatotoxicity, isoniazid, liver function tests, Nepal, pyrazinamide, rifampin, tuberculosis.

Ann Pharmacother 2004;38:1074-9.

Published Online, 30 Apr 2004, www.theannals.com, DOI 10.1345/aph.1D525

uberculosis (TB) is a great health problem worldwide,

T
and the most effective control method is to cure the infection with antitubercular (anti-TB) drugs. Essential anti1

TB drugs are isoniazid, rifampin, pyrazinamide, ethambutol,

and streptomycin. Despite being effective chemotherapeutic
agents, hepatotoxicity caused by some of these first-line
drugs is common, which may limit their use and lead to interruption of therapy. Isoniazid and pyrazinamide are the
major hepatotoxins, while rifampin, which is a powerful enzyme inducer, may enhance the hepatotoxicity of isoniazid.2,3
Ethambutol and streptomycin do not have hepatotoxic poten-

Author information provided at the end of the text.

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The Annals of Pharmacotherapy

tial. The clinical, biochemical, and histopathologic features

of drug-induced hepatitis are indistinguishable from those
of viral hepatitis.4 Hepatotoxicity can range from asymptomatic elevation of serum transferases to hepatic failure
requiring liver transplantation.3
In the UK and US, 3 4% of patients taking anti-TB
drugs develop adverse hepatic reactions.5 These reactions
also occur in Nepal, but the incidence is not known. In
Nepal, more than half of the adult population is infected
with TB, and most of the patients are from poor socioeconomic areas.6 Apart from the disease worsening their condition, drug-induced hepatitis results in further complications. The Centers for Disease Control and Prevention and
the American Thoracic Society have recommended edu-

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cating patients about adverse effects and monitoring (clinical as well as biochemical) the patient closely during the
entire treatment period. Recent studies have also suggested
that, since the advent of routine monitoring, the risk of severe hepatotoxicity has been substantially reduced.
Hepatotoxic effects of anti-TB drugs are well known;
however, further reports on the incidence and predisposing
factors will be helpful in minimizing these reactions. To
contribute to the available information for healthcare practitioners regarding this adverse effect, we have attempted
to determine the incidence of anti-TB druginduced hepatotoxicity in urban Nepalese people.
The present study was designed to elucidate the fact that
anti-TB treatment elevates the serum levels of liver enzymes compared with the levels shown in the pretreatment
period. Identification of patients at increased risk for antiTB druginduced hepatotoxicity is important because hepatotoxicity causes significant morbidity and mortality and
may require modification of the therapeutic regimen.
Therefore, another objective of this study was to assess the
risk factors for anti-TB druginduced hepatotoxicity, that
is, to establish the relationship between age, gender, alcohol intake, nutritional status, and disease extent of drug-induced hepatotoxicity.
Methods
PATIENTS

The study was conducted in the TB clinic of the German Nepal Tuberculosis Project (GENETUP) from December 2001 to November
2002. The study included 37 (74%) patients with active pulmonary TB
and 13 (26%) with active extrapulmonary TB infection. Among those 13
patients, 6 had tuberculous pleural effusion and 7 had tuberculous lymphadenopathy.
The patients were negative for hepatitis B surface antigen, antiHCVAb, and HIV. At the beginning of treatment, liver function tests
showed normal levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, alkaline phosphatase (ALP), albumin, and total protein. Patients receiving potentially hepatotoxic drugs
in addition to the anti-TB drugs and patients with relapsed TB were excluded. Fifty patients who fulfilled these criteria were selected from the
total of 128 patients registered in the clinic during the study period. Patients gave written informed consent after approval by the ethics committee of the clinic.

toxicity after withdrawal of all anti-TB drugs and the presence of at least
one of the following criteria during use of anti-TB drug therapy7: (1) a
rise to 5 times the normal level of ALT and/or AST, (2) an increase to
>1.5 mg/dL in the level of serum total bilirubin, and (3) any increase in
AST and/or ALT levels above pretreatment values together with anorexia, nausea, vomiting, and jaundice. The normal maximum values in our
laboratory are ALT 35 IU/L, AST 40 IU/L, and ALP 115 IU/L.
Drug-induced hepatitis is classified as hepatocellular and cholestatic
hepatitis. In hepatocellular hepatitis, there is marked increase in serum
levels of ALT and AST (>5 upper limit of normal [ULN] range), but
mildly increased ALP and -glutamyl transferase. In cholestatic hepatitis,
there is a mildly elevated serum transferase level (<3 ULN) with
markedly increased ALP (>3 ULN) and bilirubin.
DESIGN

Liver function was monitored by measuring the serum levels of AST,

ALT, ALP, bilirubin (total and direct), total protein, and albumin with the
help of an auto-analyzer in the pathology laboratory of Dhulikhel Hospital.
Pretreatment liver function tests were conducted and, after drug therapy was initiated, were performed a week later, then biweekly for at least 2
months. The tests were repeated later whenever symptoms suggestive of
hepatotoxicity (eg, nausea, anorexia, malaise, vomiting, organomegaly,
jaundice) occurred. Patients were observed closely and instructed to report any unusual signs and symptoms during their treatment period.
If a patient developed hepatotoxicity, medications were stopped immediately and serum enzymes were measured twice weekly until symptoms resolved and the levels decreased to 2 times the ULN.8
Low body weight was considered as 10% below normal for gender and
height; values <20 kg/m2 were considered low body mass index (BMI).
The socioeconomic status of the patients was determined by interviewing
them regarding their occupation, number of family members (earning/nonearning members), and total monthly income. For hypoalbuminemia, 3.5
mg/dL was considered the value of the lowest normal serum albumin level. Alcohol consumption was considered a risk factor in patients who had
drunk >6 units (48 g ethanol) per day for more than one year.
DATA ANALYSIS

The incidence of hepatotoxicity was determined from the rate of hepatic adverse reaction cases obtained from the population beginning antiTB therapy. The incidence of hepatotoxicity was defined as the number
of hepatic adverse reactions causing at least one weeks interruption during a given treatment period divided by the number of patients registered
during the same period.
Elevations in serum AST and ALT levels (pretreatment vs peak levels during the treatment period) were analyzed by paired t-test. Statistical
analysis was performed using SPSS version 10.0. Rates of hepatotoxicity due to anti-TB drugs were also calculated for several subgroups of the
cohort (male vs female, elder [>35 y] vs younger [1535 y], alcoholic vs
non-alcoholic). Comparisons of ratings were determined using the
means of the Fishers exact test (Epi Info, version 6.00).

DRUG REGIMENS

Treatment was planned as recommended by our National Tuberculosis Control Program. The total treatment period was 8 months, comprising an intensive phase of 2 months followed by a continuation phase of 6
months (Table 1). Patients received directly observed treatment, short
course from the medical staff of the clinic (ie, pts. were observed taking
each dose of drug).
Doses were fixed according to the total body weight of the patient. Daily doses were as follows: isoniazide 300 mg/day regardless of body
weight; rifampin 300 mg (2539 kg), 450 mg (4054 kg), or 600 mg (
55 kg); pyrazinamide 1000 mg (2539 kg), 1500 mg (4054 kg), or 2000
mg (55 kg); and ethambutol 800 mg (2539 kg), 1000 mg (4054 kg), or
1200 mg (55 kg).

Table 1. Treatment Regimen According to National

Tuberculosis Control Program of Nepal
Treatment
Category

Regimen
Intensive Phase
(2 mo)

Continuation Phase
(6 mo)

Ia

isoniazid, rifampin, pyrazinamide, isoniazid, ethambutol

ethambutol

IIIb

isoniazid, rifampin, pyrazinamide

isoniazid, ethambutol

TB = tuberculosis.
New sputum smearpositive pulmonary TB, newly diagnosed seriously ill patients with severe forms of TB.
b
Sputum smearnegative pulmonary TB with limited parenchymal involvement, extrapulmonary TB (less severe form).
a

DIAGNOSIS OF DRUG-INDUCED HEPATOTOXICITY

Anti-TB druginduced hepatotoxicity was defined as normalization

of liver enzyme levels and resolution of signs and symptoms of hepato-

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R Shakya et al.

Results
The study was conducted in GENETUP, which is one of
the first projects in South East Asia to use directly observed short-term therapy. It is situated in the heart of
Nepals capital city (Kalimati, Kathmandu).
There were 22 (44%) female and 28 (56%) male patients enrolled in the study (Table 2). Their ages ranged between 15 and 57 years. Patients 1535 years of age were
considered younger, and those >36 years of age were considered older. Thirty-seven (74%) patients had active pulmonary TB and 13 (26%) had active extrapulmonary TB
infection.
During the study period, 4 of 50 patients with active TB
developed hepatotoxicity, detected by clinical examination
and confirmed by liver function tests. Based on this finding, we project that 8% of the urban Nepalese population
is susceptible to hepatic adverse effects of anti-TB drugs.
Administration of anti-TB drugs was associated with an
elevation of liver enzymes. The mean SD pretreatment
serum level of ALT was 23.50 7.58 IU/L, and for AST it
was 26.05 16.89 IU/L. These values were elevated to
58.47 34.23 IU/L for ALT (t = 5.467; p < 0.01) and
42.56 28.98 IU/L for AST (t = 4.55; p < 0.01 for AST).
ALT was elevated to 2 times the pretreatment level in 38%

Table 2. Baseline Demographic Characteristics of Patients

Characteristic

Patients (n = 50)a

Age (y)

30.5 14.5

Gender (M/F)

28/22

Height (m)

1.520 0.1

Weight (kg)

42.8 6.427

BMI (kg/m2)

18.7 2.5

Albumin level (mg/dL)

2.8 1.6

BMI = body mass index.

a
Mean SD.

of the patients and >3 times in 30% of the patients. Similarly, 40% and 29% of patients showed 2 and >3 times elevation of AST, respectively. Asymptomatic patients showing
elevation in transferases (>3 but <5 ULN) were continuing their anti-TB regimen, but under strict observation.
Fortunately, their enzyme levels normalized within a few
days of continued treatment. There were almost proportionate increases in the levels of AST and ALT. Serum levels of albumin and total protein remained constant. There
were no significant changes in bilirubin levels in our patients except in those developing hepatotoxicity.
The time interval from initiation of treatment to the onset
of hepatotoxicity was 1260 days (median 28). Among the
4 patients who had developed hepatotoxicity, 3 had shown
characteristics of cholestatic hepatitis (Table 3). ALP and
bilirubin levels were raised significantly (ALP >3 ULN,
total bilirubin >1.5 mg/dL). One patient showed hepatocellular hepatitis. He had significantly elevated transferase
levels (AST and ALT >5 ULN); the bilirubin level was
also raised.
Symptoms shown by all patients developing drug-induced hepatitis were very similar. They had shown gastrointestinal manifestations such as nausea, vomiting, abdominal
discomfort, anorexia, and jaundice. Immediately after druginduced hepatitis was diagnosed, anti-TB therapy was withheld temporarily until the patients clinical and biochemical
picture normalized. The rest of the patients continued treatment without complications, and liver enzymes normalized
within a few days of continued treatment.
Patients belonging to the younger age group were found
to be at higher risk for anti-TB druginduced hepatotoxicity than those in the older group (6% vs 2%; p = 0.368; OR
2.75), respectively (Table 4). The transferase indexes of
patients belonging to both age groups were almost the
same. Female gender was found to be another predisposing factor (p = 0.219; OR 4.2). The BMI of our patients
was low (<20 kg/m2), and they had hypoalbuminemia.
Three patients developing hepatotoxicity had positive sputum smears. They had severe TB, proven microbiological-

Table 3. Reports of 4 Patients Showing Hepatotoxicity

Bilirubin
Treatment Categorya
III: 1 pt. with hepatocellular hepatitis
Basal levelb
Peak levelc
After recovery
I: 3 pts. with cholestatic hepatitisd
Basal level
Peak level
After recovery

ALT

AST

32.5
210.5
85.7

31.0
224.5
63.5

22.43 6.98
53 2.87
34.5 2.2

23.33 1.63
79.4 5.25
30.5 2.1

ALP

Total

Direct

96.0
109.5
102.5

0.7
4.9
1.1

0.2
3.2
0.4

160.67 62.8
332 1.98
187.3 32.8

0.31 0.02
3.7 1.98
0.9 0.1

0.16 0.08
2.73 1.94
0.42 0.02

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase.

a
Category I = intensive phase comprising isoniazid, rifampin, pyrazinamide, ethambutol in intensive phase of 2 months followed by isoniazid and
ethambutol in continuation phase of 6 months. Category III = Same as Category I except ethambutol is not used in the intensive phase.
b
Pretreatment level.
c
Level at the onset of hepatotoxicity. Patient in Category III showed peak elevation of liver enzymes and bilirubin within 32 days; patients in Category I showed peak values within 12, 26, and 60 days after starting therapy.
d
Mean SD.

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Hepatotoxicity Due to Antitubercular Medicines

ly as well as radiologically. The extent of the disease is

probably another predisposing factor for anti-TB druginduced hepatotoxicity (Table 4).
Discussion
Isoniazid, rifampin, and pyrazinamide have been successful therapeutic agents for the treatment of TB because
of their high therapeutic efficacy and good patient acceptance. However, a variety of adverse reactions to these
drugs has been reported. Liver toxicity is the most common adverse effect, especially during short-course therapy,
which often leads to interruption of treatment.6
In the present study, 8% of the patients developed hepatotoxicity, which is higher than the figures reported in previous studies from the US and UK.5 Wide variations have
been found in the reported incidences of hepatotoxicity during anti-TB therapy. A Japanese study investigating 77 patients indicated an incidence rate of 18.25% of patients developing adverse hepatic reactions in the first month of isoniazid and rifampin treatment.9 Asian patients have
increased susceptibility to anti-TB druginduced hepatotoxicity. This is supported by an observation done in Taipei, in
which an incidence of 14.7% of anti-TB druginduced hepatotoxicity was reported.10 A recent study performed in
Hong Kong showed an incidence of 13% in Chinese patients.11 The risk of hepatotoxicity, based on data from 4
prospective Indian studies, was 11.5% compared with 4.3%
in 14 published studies from the Western hemisphere.12
The incidence of hepatotoxicity due to anti-TB drugs is
much higher in studies from developing countries compared with those from developed countries, despite use of
similar regimens.9,13 The reasons for the increased incidence

Table 4. Demographic Characteristics of

Patients with Hepatotoxicity
Characteristic
Total pts.
(n = 50)
Gender
male (n = 28)
female (n = 22)
Age (y)
1535 (n = 27)
3660 (n = 23)
Disease extent
sputum-positive (n = 37)
sputum-negative (n = 13)
Alcohol intake
yes (n = 9)
no (n = 41)
Albumin (g/dL)
3.5 (n = 22)
<3.5 (n = 28)
BMI (kg/m2)
20 (n = 15)
<20 (n = 35)
BMI = body mass index.

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Hepatotoxicity
Cases (n)
Incidence (%)
4

1
3

4
14

3
1

11
4

3
1

8
8

0
4

0
10

1
3

4.5
10.7

1
3

6.7
8.6

of hepatotoxic reactions in developing countries are unclear. Perhaps poor nutrition, widespread parasitism, chronic infections, indiscriminate use of various drugs, ethnic
factors, severity of the disease, chronic alcoholism, or genetic predisposition may play roles individually or collectively.10,14 In a study from India, Kumar et al.15 highlighted
another reason for this disparity. They confirmed hepatitis
A and B in 45% of 40 patients who developed acute hepatitis during anti-TB therapy with isoniazid and rifampin. The
burden of TB worldwide lies heavily in Asia, and patients
requiring anti-TB chemotherapy might have the aforementioned concomitant predisposing factors for hepatotoxicity.
Presence of viral hepatitis can lead to misdiagnosis of druginduced hepatitis. To avoid such confusion and make the
diagnosis of drug-induced hepatitis reliable, patients with
positive serologic tests for hepatitis B and C and HIV were
excluded in our study. Although all of the patients showed
elevation in hepatic enzymes, in most cases it was <3 times
the ULN. These asymptomatic elevations of biochemical
markers returned to normal levels despite continued use of
medication. The reason for this tolerance is not known. The
Joint TB Committee of the British Thoracic Society states
...transient increase in hepatic transferases are common after the start of treatment and require no action unless the patient has the symptoms of jaundice or hepatitis or is an alcoholic or has other liver disease.16
The elevations of ALP and bilirubin were significant
(ALP >3 ULN; bilirubin >1.5 mg/dL) in patients showing characteristics of cholestatic hepatitis. Cholestatic injury represents altered bile flow through inflammation, disruption, or destruction of bile ductules or resulting from a
larger bile duct. One patient had markedly elevated aminotransferase levels (AST, ALT >5 ULN), suggesting hepatocellular hepatitis. Hepatocellular hepatitis mimics viral
hepatitis with markedly elevated aminotransferase values.4,17 The actual cause of the hepatocyte injury or cell
death is direct damage to or destruction of cellular membranes or covalent binding of toxic metabolites to liver
macromolecules, leading to impairment of calcium homeostasis, mitochondrial dysfunction, or failure of other cellular systems.18-20
Jaundice was seen in our patients as the presenting
symptom of anti-TB druginduced hepatotoxicity.2,21,22
Jaundice can result from either hepatocellular or cholestatic injury of the liver. All cases of drug-induced hepatotoxicity developed within 2 months of initiation of therapy.23-25
Patients enrolled in the study were taking a combination
of anti-TB drugs. Because of this, it is difficult to conclude
which drug was the main culprit for hepatitis. Although
isoniazid is the major drug incriminated, the role of other
possibly hepatotoxic drugs (eg, rifampin, pyrazinamide)
can also be speculated. Previous studies have proven that
the order of risk is isoniazid + rifampin > isoniazid > pyrazinamide > rifampin > ethambutol.26
Most patients enrolled in our study were of the younger
age group (median 28 y). This may be the reason for the
high rate of hepatotoxicity shown in younger patients. We
found that female gender was an independent predictor of

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R Shakya et al.

anti-TB druginduced hepatotoxicity.4,17,21,27 Although the

frequency of drug-induced liver injury was found to be
higher in females, the severity of hepatotoxicity was not
related to gender. The difference in the incidence of drugassociated hepatotoxicity between males and females is
mainly due to:
1. pharmacokinetic variations, probably slower biotransformation and subsequent clearance of exogenous molecules due to lower levels of microsomal enzymes; and
2. women probably being acetylators (slow acetylator
enzymatic pattern shows male:female ratio of 4:1).28
The nutritional status (assessed by BMI and serum albumin)29 of our patients seemed poor (mean BMI 18.7 kg/m2,
serum albumin 2.8 mg/dL). This may be one of the risk
factors for drug-induced hepatotoxicity.11,22,27 We found
that patients with pretreatment hypoalbuminemia had a
twofold higher risk of developing hepatotoxicity. In malnutrition, glutathion stores are depleted, which makes one
vulnerable to oxidative injury. In a malnourished person,
the liver metabolizes drugs at a slower pace. In a study
conducted in India, the incidence of hepatotoxicity was
found to be 3 times higher in malnourished patients.30
Drug-induced hepatotoxicity may be fatal if detected
late. Prompt recognition of the condition with immediate
withdrawal of the offending agent is the mainstay of therapy. The British Thoracic Society suggests that, if there is a
rise in ALT and/or AST to >3 times the ULN or an increase in bilirubin, or if the patient shows clinical symptoms of hepatitis, then drugs should be stopped and reintroduced sequentially when these parameters fall to within
normal levels. In our study, abnormalities of liver biochemistries and symptoms shown by 4 patients suggested
discontinuing treatment. Within a few days after cessation
of drug therapy, liver enzymes returned to normal levels.
Normalization of liver enzyme levels once administration
of anti-TB drugs has been halted proves that all signs and
symptoms shown by the patient are related to the administration of anti-TB drugs.31
Once serum transferase levels have normalized and plateaued, reinstitution of anti-TB therapy was done. It is a
well-accepted fact that the risk of adverse effects must be
balanced with the benefits of effective TB treatment. Prolonged interruption of treatment may lead to undesired drug
resistance and may prolong the therapy. In the present study,
anti-TB therapy was reintroduced according to the severity
of hepatotoxicity. In the case of mild hepatotoxicity, all
drugs were reintroduced simultaneously, initially in lower
doses that were increased on subsequent days, with daily
monitoring of the patients clinical and biochemical conditions. If hepatotoxicity was severe, then after recovery, low
doses of isoniazid and ethambutol were reintroduced and
the patient was monitored closely. If liver function test values remained normal and the patient remained asymptomatic for a week, then other drugs were added, initially with
low doses that were increased on subsequent days.
All of our patients were closely monitored during their
treatment period, and none showed a recurrence of hepatotoxicity. They completed their anti-TB treatment success1078

The Annals of Pharmacotherapy

fully without further complications. It can therefore be

concluded that it is possible to reintroduce potentially hepatotoxic agents easily after recovery.22
Our study has resulted in some changes in the treatment
strategy in the clinic in which the study was conducted. We
have started monitoring patients more closely with the
above-stated risk factors. Pretreatment liver function tests
are performed on all patients. Patient education (regarding
adverse effects of anti-TB drugs) is now given highest priority because most mishaps can be controlled by patients
involvement in their treatment.
Summary
With the increasing incidence of TB worldwide, a
greater number of patients are exposed to the risk of potentially serious hepatotoxic effects of anti-TB drugs. The factor of greatest clinical importance in treatment of TB is
probably early recognition of hepatic dysfunction, which is
possible only by regular monitoring of the patient. Patients
who ultimately die or require liver transplants frequently
have a history of continued use of these medicines even after symptoms of hepatotoxicity, including jaundice, have
appeared. Further study should be performed with larger
numbers of patients from all areas of Nepal to generate precise toxicity data that could be applied to evaluate medical
interventions and assist in the development of health policy.
Rajani Shakya MPharm, Lecturer, Department of Pharmacy, Kathmandu University, Dhulikhel, Nepal

B Subba Rao MPharm, Head of Department, Department of Pharmacy, Kathmandu University

Bhawana Shrestha MD, Director, German Nepal Tuberculosis
Project (GENETUP), Kalimati, Kathmandu, Nepal
Reprints: Rajani Shakya MPharm, Department of Pharmacy, Kathmandu University, Dhulikhel, Nepal, fax 00977-11-61443, rajani@
ku.edu
We thank the staff of GENETUP for their active participation in this study.

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EXTRACTO
TRASFONDO: Los medicamentos antituberculosos alteran la funcin
heptica, y sta se demuestra mediante un examen clnico y las pruebas
de funcin heptica. El potencial de hepatotoxicidad de algunos de los
agentes antituberculosos de primera seleccin sigue siendo un problema
hoy da, especialmente durante la etapa inicial del tratamiento.

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OBJETIVO: Determinar la incidencia de la hepatotoxicidad inducida por

medicamentos antituberculosos en la poblacin urbana nepalesa y
evaluar los factores de riesgo.
MTODOS: Cincuenta pacientes diagnosticados con tuberculosis activa y
funcin heptica normal antes del tratamiento fueron monitorizados
clnica y bioqumicamente en un anlisis de cohorte prospectivo.
RESULTADOS: Se encontr que los medicamentos antituberculosos estn
asociados con una alteracin de la funcin heptica que causa un aumento
variable de las enzimas del hgado (t = 4.550, p = 0.00 para el aspartato
aminotransferasa, y t = 5.467, p = 0.00 para la alanina aminotransferasa,
95% CI). Treinta y ocho por ciento de los pacientes tuvieron una
elevacin de 2 veces ms de la ALT, y 30 por ciento tuvo una elevacin
mayor de 3 veces ms de la ALT. Similarmente, el 40 por ciento y el 29
por ciento demostraron una elevacin de la AST de 2 veces ms y de 3
veces ms, respectivamente. Cuatro pacientes (8 por ciento) desarrollaron
hepatotoxicidad inducida por medicamentos. Todos presentaron ictericia.
El intervalo de tiempo del inicio de la hepatotoxicidad fue de 12 a 60 das
(28 das, mediana). Se encontr que la hepatotoxicidad inducida por
medicamentos antituberculosos fue mayor en pacientes jvenes (6 por
ciento vs 2 por ciento, p > 0.05, p = 0.368, Odds Ratio [OR]; 2.75). Las
mujeres demostraron un riesgo mayor (p > 0.05, p = 0.219, Odds ratio
[OR]; 4.2). La mayora de los pacientes que desarrollaron hepatitis
tuvieron una prueba de esputo positiva. El prximo factor de
predisposicin fue la condicin nutricional, evaluada por el ndice de
masa corporal (IMC) y el nivel de albmina srico.
CONCLUSIONES: El hallazgo de una incidencia de un 8 por ciento de la
tasa de hepatotoxicad es considerablemente alta. Los factores de riesgo
de la hepatotoxicidad incluyeron el sexo femenino, la extensin de la
enfermedad, y una condicin nutricional deficiente. La deteccin
oportuna y el retiro temporal del medicamento causante pueden curar la
hepatotoxicidad inducida por los medicamentos antituberculosos.

Rafaela Mena
RSUM
INTRODUCTION: Les agents antituberculeux peuvent entraner une

dysfonction hpatique qui se traduit par des signes cliniques et des tests de
la fonction hpatique anormaux. Lhpatotoxicit potentielle de quelques
agents antituberculeux de premire intention est toujours un problme
lheure actuelle, particulirement durant la priode initiale de traitement.
OBJECTIF: Dterminer lincidence de lhpatotoxicit induite par les
agents antituberculeux chez la population urbaine du Npal et en tablir
les facteurs de risque.
MTHODOLOGIE: Cinquante patients avec un diagnostic de tuberculose
active et une fonction hpatique normale avant le traitement ont t inclus
dans une cohorte prospective. Des paramtres cliniques et biochimiques
ont t compils et analyss pour lensemble de ces patients.
RSULTATS: Les agents antituberculeux ont t associs une dysfonction
hpatique rsultant en une lvation des enzymes hpatiques un degr
variable (t = 4.55, p = 0.00, p < 0.05 pour lAST et t =-5.467, p = 0.00,
p < 0.05 pour lALT avec un intervalle de confiance 95%). Trentehuit
pour cent des patients ont eu 2 reprises et 30% plus de 3 reprises une
lvation de lALT. De faon similaire, 40% et 29% des patients ont eu
des lvations dAST 2 et plus de 3 reprises, respectivement. Quatre
patients (8%) ont dvelopp une hpatotoxicit mdicamenteuse, dont
lictre tait le symptme principal. Lhpatotoxicit est apparue en 12
60 jours, avec une mdiane de 28 jours. Lhpatotoxicit induite par les
agents antituberculeux a t plus frquente chez les jeunes patients (6%
vs 2%, p > 0.05, p = 0.368, [OR]: 2.75). Le sexe fminin tait aussi un
facteur de risque (p > 0.05, p = 0.219, [OR]: 4.2). La majorit des
patients ayant dvelopp une hpatite taient ceux avec des crachats
positif pour la tuberculose, donc ceux avec une maladie plus svre. Le
statut nutritionnel, dtermin par lindice de masse corporelle et le
niveau srique dalbumine, tait aussi un facteur prdisposant.
CONCLUSIONS: Un taux dincidence dhpatotoxicit de 8% est
considrablement lev. Les facteurs de risque sont le sexe fminin,
ltendue de la maladie, et un mauvais tat nutritionnel. La dtection
prcoce et la suspension temporaire de lagent en cause peut gurir
compltement lhpatotoxicit induite par les agents antituberculeux.

The Annals of Pharmacotherapy

Esthel Rochefort

2004 June, Volume 38

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