Hígado y terapia antituberculosa / Hepatotoxicity of antituberculosis therapy

La toxicidad hepática en pacientes tratados con drogas antituberculosas es relativamente infrecuente, probablemente debido a este hecho no contamos con una buena definición de toxicidad hepática. Existen algunas condiciones de los enfermos en que la hepatotoxicidad es más frecuente, tales como pacientes envejecidos, bebedores de alcohol, desnutrición, uso de ciertas drogas e hipoalbuminemia. Las drogas antituberculosas más frecuentemente involucradas en hepatotoxicidad son la pirazinamida, la isoniacida y la rifampicina. En este artículo analizamos el problema clínico de la hepatotoxicidad de la terapia antituberculosa y proponemos el manejo de diferentes situaciones. Discutimos cuando se debe suspender la administración de una droga, cómo se debe evaluar el daño hepático y qué drogas alternativas pueden usarse durante el tratamiento de la tuberculosis.

Liver toxicity in patients being treated with antituberculosis drugs is relatively uncommon, although transient elevation of liver enzymes is very common. Probably because of this there is not a good definition for liver toxicity. There are conditions in which hepatotoxicity is more frequent, such as elderly patients, alcohol consumption, malnutrition, use of certain drugs, and hypoalbuminemia. Pirazinamide, isoniazid and rifampicin are the antituberculosis drugs more commonly involved in liver toxicity. In this article we analyze the clinical problem of hepatotoxicity of antituberculosis therapy and propose the management of different situations. We discuss when a drug administration should be discontinued, how liver damage should be assesed and which alternative drugs should be used during the antituberculosis treatment.

Hepatotoxicity of antituberculous drugs: incidence, severity and risk factors

Antituberculous drug [ATD]-induced hepatotoxicity can cause permanent 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. 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. 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. 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

Risk factors for hepatotoxicity induced by antituberculosis drugs

To evaluate the risk factors involved in antituberculosis treatment-induced hepatotoxicity. In a retrospective study we analyzed the rate of drug-induced hepatotoxicity in a sample of 456 patients. Patients received a combination of drugs including isoniazid, rifampin, pirazinamide and streptomycinor or ethambutol. The association among hepatotoxicity and several risk factors (age, sex, alcoholism and HIV infection) was studied by univariate methods, stratified analysis and the multiple logistic regression model. Signs of liver injury were found in 9.86 percent of the treated patients. In the logistic model, the adjusted odds ratios (OR) and significance were found as follows: a) for alcoholism, OR=17.31 (95 percent CI:6.35-47.16), p<0.001; b) for HIV infection, OR=3.23 (95 percent CI:1.47-7.11), p=0.003 and c) for female Sex, OR=2.44 (95 percent CI:1.22-4.86), p=0.011. Age was not significantly associated with hepatotoxicity. Alcoholism, HIV infection and female sex were associated with an increased risk of hepatotoxicity in this study.