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Hepatotoxicity of Antituberculous Drugs: Incidence, Severity and
Risk Factors
Mahmoud Khedr
Tropical Medicine and infectious diseases Department, Faculty of
Medicine, Tanta University, Egypt
Tanta Med. Sc. J 2007; 2(3):68-76
Article type: Original article
Background/Aim: Antituberculous drug
(ATD)-induced hepatotoxicity can cause perŽmanent injury and death.
It is significantly more frequent and more severe in patients with
hepatotoxicity risk factors. Early recognition and immediate
withdrawal of offending agent is very important to arrest its
development and allow liver to heal. Surveillance studies are needed
to determine the local incidence of ATD-induced hepatotoxicity and
define the possible associated risk factors. The aim of this study
is to assess the incidence, severity and some risk factors
associated with hepatotoxicity of ATD. Patients and methods: A
prospective cohort study including patients with active
tuberculosis, receiving ATD regimens with at least Isoniazid (INH),
Rifampicin (RMP) and Pyrazinamide (PZA), who were following at a
tuberculosis clinic in Taif, Saudi Arabia, between January 2004 and
December 2006. Patients were subjected to clinical and laboratory
investigations to assess hepatotoxicity of ATD and to find out the
possible risk factors. The diagnosis, severity and management of
ATD-induced hepatotoxicity followed the AASLD recommendations on
2004. Results: Out of 214 patients included in the study,
ATD-induced hepatotoxicity was diagnosed in 31(14.2%) of patients,
which is relatively common and deserves further investigation.
Hepatotoxicity was more common in females than males (18.75% vs.
11.86% respectively), and in older patients than younger ones (15%
vs. 13.26% respectively). It was also more frequent in patients with
low hemoglobin, albumin levels and/or malnutrition (BMI < 18.5
kg/m2). Alcohol intake was considered a risk factor in 11% (1/9) of
patients. One hundred and twenty-one (56.5%) patients had one or
more of the defined hepatotoxicity risk factors; 86 (40.2%) had one
risk factor, 95 (44.4%) had two, and 33 (15.4%) had three or more.
The site of disease was pulmonary in 138 (64.5%) cases, abdominal in
35 (16.4%), lymph nodes in 22 (10.3%), spine in 9 (4.2) and other
sites in 10 (4.7%). Hepatotoxicity was most frequently reported
(42.9%) in patients with abdominal tuberculosis. All patients showed
aminotransferase elevations; the majority of them (93.5%) had
mild/moderate hepatotoxicity. Serum bilirubin >3 mg% was reported in
4 patients, who had moderate-severe hepatotoxicity. Hepatotoxicity
was reported in 21(67.7%) patients within 2 weeks of starting
treatment, 8 (25.8%) patients between 2 and 4 weeks and in the other
two patients after one month of treatment. Patients with identified
risk factor(s) were more liable to develop hepatotoxicity and more
liable for progression from mild to moderate degree. Hepatotoxicity
was related to INH in 17 patients (54.8%), to RMF in 10 patients
(32.3%) and to PZA in 4 patients (12.9%). Most cases of INH
hepatotoxicity appeared early, while late hepatotoxicity appeared
more with PZA. Twenty-two (71%) of these patients had normalization
of their liver function tests within two weeks of drug
discontinuation. Conclusions: The reported ATD-induced
hepatotoxicity is relatively common. It is significantly more
frequent and more severe in patients with hepatotoxicity risk
factors. Hepatotoxicity occurs most commonly within the first two
weeks of therapy. Early recognition with immediate withdrawal of
offending agent is very important to arrest its development and
allow liver to heal.
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