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.

Variantes genéticas da N-acetiltransferase 2, CYP2E1 e glutationa S-transferase: relação com a segurança terapêutica em pacientes com tuberculose / Genetic variants of N-acetyltransferase 2, CYP2E1 and glutathione S-transferase: relation with therapeutic safety in patients with tuberculosis

Polimorfismos nos genes da n-acetiltransferase 2 (NAT2), CYP2E1 e glutationa S-transferase (GST) têm sido associados a diferenças na resposta ao tratamento da tuberculose. O papel de variantes dos genes NAT2, CYP2E1 e GSTM1/GSTT1, no perfil de segurança do tratamento da tuberculose, foi avaliado em 99 pacientes com tuberculose, sem co-infecção por HIV ou vírus da hepatite, tratados por 6 meses. Amostras de sangue foram colhidas antes e durante o tratamento para avaliação de marcadores de lesão hepatocelular (ASL T e AST), colestase (ALP, GGT e bilirrubinas) e função renal (creatinina). O DNA genômico foi extraído de sangue colhido em EDTA pelo método precipitação salina. Os polimorfismos NAT2 foram analisados por PCR-RFLP e seqüenciamento de DNA. Os polimorfismos da região promotora do CYP2E1 foram detectados por PCR-RFLP e para a análise dos genótipos nulos de (GSTM1*0) foi utilizada a PCR multiplex. Durante o tratamento, 59,6% dos pacientes apresentaram reações adversas aos medicamentos (RAM) e alterações nos marcadores de lesão hepatocelular e colestase, com aumento de 1 a 4 vezes o limite superior de referência. Foi observada forte relação entre RAM e alterações nos marcadores séricos (p< 0,05) e também com o uso de medicação concomitante (p< 0,001)...

Frequency and risk factors of hepatotoxicity of anti Tuberculous drugs

Hepatotoxicity is reported in patients using first-line anti-tuberculous drugs regimen, among them 6-12% die. Identifying the risk factors for developing hepatotoxicity would probably reduce morbidity and mortality associated with T.B management. To study the frequency and risk factors of hepatotoxic reactions in patients receiving firat-line anti-tuberculous drugs. In addition to determine the relation between acetylator phenotype and anti-tuberculous drug hepatotoxicity. Seventy seven patients consecutively presenting to Suez Chest Hospital with active T.B diseases [WHO criteria], who were eligible for anti- tuberculous regimens [WHO guidelines] were included. Child B or C cirrhotic patients or Child A with liver enzymes exceeding double the normal were excluded in addition patients suffering from chronic renal or cardiac disease, hypersensitivity to anti-tuberculous drugs or receiving potentially hepatotoxic medications for other reasons were also excluded. 1-Rate of hepatotoxic reactions according to the diagnostic criteria. 2- Rates of fast and slow acetylator phenotypes. 3- Rate of risk factors among patients with hepatotoxicity versus patients without hepatotoxicity. Hepatotoxic reactions have been diagnosed in seven [9.1%] patients. By univariate analysis, age over 60 years [p = 0.02], alcoholism [p = 0.02], extra-pulmonary tuberculosis [p = 0.02] and severe forms of tuberculosis [p = 0.03] were statistically significant risk factors. Fifty eight [75.3%] of the study sample were slow acetylators, while 8 [10.4%] were fast acetylators. Three out of the eight [37.5%] of fast acetylators and only [6.9%] of the slow acetylators developed hepatotoxicity [p = 0.03]. Logistic regression models showed that fast acetylator phenotype was the only significant [p = 0.04] risk factor for early hepatotoxicity. Alcoholism [p = 0.01] was a significant risk factor for late hepatotoxicity. Hepatotoxic reactions among patients receiving anti-tuberculous drugs remain a considerable problem. Two patterns of liver injury can be observed. The first occurs earlier and is associated with fast acetylator phenotype. The second occurs later and is associated with alcoholism and HCV infection

Hepatoprotective effect of tocopherol against isoniazid and rifampicin induced hepatotoxicity in albino rabbits.

Antitubercular drug induced hepatotoxicity is a major hurdle for an effective treatment of tuberculosis. The present study was undertaken to assess the hepatoprotective potential of tocopherol (50 mg/kg and 100 mg/kg, ip) and to compare it with cimetidine (120 mg/kg, ip). Hepatotoxicity was produced by giving isoniazid (INH, 50 mg/kg, po) and rifampicin (RMP, 100 mg/kg, po) combination to albino rabbits for 7 days. Assessment of liver injury was done by estimating levels of alanine transaminase (ALT) and argininosuccinic acid lyase (ASAL) in serum and by histopathological examination of liver. Results revealed that pretreatment with high dose of tocopherol (100 mg/kg) prevented both biochemical as well as histopathological evidence of hepatic damage induced by INH and RMP combination. Moreover, tocopherol (100 mg/kg) was found to be a more effective hepatoprotective agent as compared to cimetidine.

Effect of cimetidine on hepatotoxicity induced by isoniazid-rifampicin combination in rabbits.

OBJECTIVE: To evaluate the hepatoprotective potential of cimetidine in hepatotoxicity induced by isoniazid-rifampicin combination in albino rabbits. METHODS: Six groups of six rabbits each were studied. Three groups received saline (control), isoniazid (50 mg/Kg/d) alone or isoniazid with rifampicin (100 mg/Kg/d) daily orally for 7 days. Other groups received intraperitoneal cimetidine (50 mg/Kg/d) alone or cimetidine (50 or 120 mg/Kg/d) along with isoniazid-rifampicin combination. Serum levels of liver enzymes were measured at baseline and on day 8 and liver histology was studied on day 8. RESULTS: Rabbits receiving isoniazid alone for 7 days showed no increase in serum ALT and AST levels, whereas those receiving isoniazid-rifampicin combination had a 3-4-fold increase in these levels (p=0.02). Animals receiving cimetidine pre-treatment did not show a significant increase in ALT and AST levels. Histological changes in the liver were more common with isoniazid-rifampicin combination than with isoniazid only. These changes were reduced in animals receiving low-dose cimetidine and prevented in those receiving high-dose cimetidine. CONCLUSION: Cimetidine in high dose can prevent hepatotoxicity induced by isoniazid-rifampicin combination.

Hepatotoxicidad por fármacos antituberculosos en Pediatría / Hepatotoxicity caused by antituberculosis drugs in Pediatrics

El perfil clínico de la hepatotoxicidad inducida por fármacos antituberculosos es variable y la reintroducción de la terapia a los pacientes que la han desarrollado es controversial. Se presentan 5 casos pediátricos atendidos en un periodo de 10 años en el Servicio de Pediatría del Hospital Nacional Hipólito Unanue. 2 casos mostraron elevación asintomática de transaminasas, 2 presentaron hepatitis y 1 presentó insuficiencia hepática fulminante. La mayoría fueron escolares del sexo femenino y como factores de riesgo se encontró la desnutrición y la continuación de la terapia una vez que el daño hepático se inicia. Proponemos un esquema de reintroducción escalonada de estos agentes luego de la recuperación de la hepatitis.

The clinical profile of hepatotoxicity induced by tuberculosis drugs varies and the re-introduction of therapy for patients who developed this condition is controversial. 5 pediatric cases treated throughout a period of 10 years in the Pediatric Department of Hipolito Unanue National Hospital are presented. 2 individuals showed an asymptomatic increase of transaminases, 2 individualshad hepatitis, and 1 individual had acute liver failure. Most patients were female school students. Malnutrition and therapy continuation once the hepatic damage was started were found to be the risk factors. A staged reintroduction scheme for these agents after recovery from hepatitis is proposed.

Prevalence of antitiuberculous drug-induced cytolytic hepatitis of tuberculous meningitises

The aim of this work was to specify the prevalence and the description of scondary cytolytic hepatitis of the antituberculous drugs used in treatment of tuberculous meningitis in the intensive care units. Method: We have been included retro-spectively [January 1998 - December 2002] patients having a tuberculous meningitis treated with antituberculous drugs who developed a cytolytic hepatitis defined by an increase of the alanin-aminotransferase [ALAT] level more than two times of its normal upper limit. Six cases have been included among 74 patients [prevalence of 8,1%], three women and three men aged 17 to 45 years. The delay of apparition of cytolytic hepatitis varied from four days to five weeks. ALAT rates varied from two and half to 26 times the normal level. No other potentialy hepatotoxic medication has been prescribed. Three patients normalized their ALAT after reducing the rifam picin dose to half measure, in another case a definitive stoppage of isoniazid was required. Ytolytic hepatitis regressed spotaneously in one patient whereas another died as a result of a nosocomial infection. The prevalence of secondary cytolytic hepatitis of antituberculous drugs during treatment of tuberculous meningitis in the intensive care unit raised to 8,1%, the evolution is most often favourable after adaptation of doses

Hepatoprotective effect of rhinax on antitubercular drug-induced hepato-toxicity in rats.

Rhinax, a polyherbal formulation, exhibited hepatoprotective function when tested against antitubercular drug-induced hepatotoxicity in rats. Suppression of GSH and antioxidant enzymes "superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), gultathionle peroxidase (GPx) and glutathione S-transferase (GST) were noticed in the liver of antitubercular chemotherapeutic agents (namely isoniazid, rifampicin and pyrazinamide) treated animals accompanied with an increase in cytochrome P-450 contents and increased production of lipid peroxidation. Rhinax afforded hepatoprotection by inhibiting lipid peroxidation and, as a result, the animals showed improved antioxidant status.

Plants from Puerto Rico with anti-Mycobacterium tuberculosis properties

OBJECTIVE: This study assesses the antitubercular potential of natural products obtained from plants reputed to have medicinal properties and collected from the tropical flora of Puerto Rico. BACKGROUND: The increase in persons infected with Mycobacterium tuberculosis (MTB) the world over and the development of resistance to antibiotics by this microbe and other infectious bacteria has created the need for new drugs to replace those which have lost effectiveness. METHOD: In Phase I of this study, ethanolic leaf extracts of fifty local plants were submitted to preliminary screening to assess their in vitro Mycobacterium smegmatis inhibitory activity using the Bauer-Kirby disk diffusion method. In Phase II, the definitive screening of the six most promising extracts which inhibited M. smegmatis were assayed for their MTB inhibitory activity using the BACTEC 460 susceptibility test method. The brine shrimp bioassay was used as a toxicity bioassay and the mice inoculation test was used to determine mice tolerance to the effect of the daily intraperitoneal inoculations of the plant extracts. RESULTS: MTB showed varying degrees of susceptibility to each plant extract. This effect was dependent upon the plant species, dose and time of exposure. Evidence is provided suggesting that: (1) Six crude plant extracts (12 per cent) tested possessed inhibitory capacity at the amount of 500 micrograms per disc; (2) Mammea americana extract yielded the strongest inhibitory effect at 50 micrograms per disc, followed by Marchantia polymorpha, Mangifera indica, Callistemon citrinus, Syzygium jambos and Momordica charantia; (3) the bactericidal inhibitory pattern of MTB growth, exposed to Mammea americana extract, was comparable to streptomycin; and (4) the transitory reduction pattern of MTB growth, produced by Callistemon citrinus, Marchantia polymorpha extracts at 100 micrograms and 250 micrograms, was similar to that of bacteriostatic agents. CONCLUSION: Of 50 plants screened six extracts tested for their anti-MTB activity yielded positive results with varying degrees of inhibition. Mammea americana showed the greatest inhibitory activity suggesting that certain plant species yield valuable anti-Mycobacterium tuberculosis substances. The procedures employed in this study, including the BACTEC 460 modified method, are useful for in vitro screening of plant extracts with potential antitubercular activity.

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.