Effect of gene-gene and gene-environment interactions associated with antituberculosis drug-induced hepatotoxicity.

OBJECTIVES: This study evaluated the association between environmental factors and genetic variations in enzymes that metabolize antituberculosis (anti-TB) drugs [arylamine N-acetyltransferase 2, cytochrome P450 2E1 (CYP2E1), glutathione S-transferase theta 1 (GSTT1), and glutathione S-transferase mu 1] with antituberculosis drug-induced hepatotoxicity (ATDH). We also investigated the potential gene-gene and gene-environment interactions as well as their association with ATDH development in a population of hospitalized TB patients from Buenos Aires. PATIENTS AND METHODS: We investigated 364 TB patients who received anti-TB drugs. Physicians collected demographic and clinical data to identify environmental risk factors for ATDH development. Polymorphisms were detected using gene sequencing, PCR, and PCR-restriction fragment length polymorphisms. A binary logistic regression analysis was carried out to compare the results of TB patients with and without the development of hepatotoxicity. The multifactor dimensionality reduction method was used to examine genetic and environmental interactions in association with ATDH. RESULTS: This study suggests that the slow acetylator profile [odds ratio (OR): 3.02; 95% confidence interval (CI): 1.82-5.00; P<0.001], genotypes carrying the c2 variant (OR: 2.16; 95% CI: 1.33-3.51; P=0.002) or the A4 variant of CYP2E1 (OR: 2.13; 95% CI: 1.06-4.29; P=0.050), and female sex (OR: 1.94; 95% CI: 1.20-3.14; P=0.006) were independent predictor variables for ATDH. Patients carrying the slow acetylator profile and the c2 variant showed an increased risk (OR: 7.068; 95% CI: 3.34-14.95; P<0.001). We also identified a synergic interaction (epistasis) between GSTT1 and CYP2E1 associated with an increased risk for ATDH. A meaningful gene-environment interaction was associated with an increased risk of ATDH [testing balance accuracy=0.675 (P=0.001) and cross-validation consistency=10/10]. CONCLUSION: ATDH is a severe and prevalent adverse drug reaction and leads to drug discontinuation in 11% of TB patients. Our study created a prediction model that properly classified the 67.5% of TB patients in their risk of developing ATDH. The considerable number of TB patients in our country supports the use of pharmacogenetic testing and a comprehensive clinical history to identify patients with a high risk of suffering hepatotoxicity.

tagSNP rs1495741 as a useful molecular marker to predict antituberculosis drug-induced hepatotoxicity.

INTRODUCTION: It has been widely reported that the slow acetylator phenotype of N-acetyltransferase 2 (NAT2) is associated with the development of antituberculosis drug-induced hepatotoxicity (ATDH). The aim of this report was to evaluate the level of agreement and accuracy of two recently recommended markers, the two-single nucleotide polymorphisms (SNP) (C282T and T341C) and tagSNP of NAT2 (rs1495741) genotypes, to predict the seven-SNP-inferred NAT2 phenotype in Bolivian and Argentinian tuberculosis (TB)-patient populations. In addition, we analyzed the association of these markers with ATDH. METHODS: We examined 331 TB patients who had been treated with anti-TB drugs. TagSNP of NAT2 genotyping was determined using PCR-restriction fragment length polymorphisms. The seven SNPs of NAT2 were determined using sequencing. Concordance analysis was carried out using Kendall's tau-b coefficient (w) and the degree of agreement with Cohen's κ coefficient (κ). Receiver operating characteristic receiver operating characteristic curves were obtained to measure the specificity and sensitivity of the method. A binary logistic regression was performed to identify variables associated with the development of ATDH. RESULTS: Both predictors showed a remarkable concordance (>95.0%) and an almost perfect agreement (κ>0.945; P<0.0001) with the predicted acetylator profile. However, the sensitivity of the tagSNP genotypes to predict the NAT2 acetylator phenotype was lower in the Bolivian population (92.3%) compared with the Argentinian population (100.0%). CONCLUSION: A nearly perfect agreement between both predictors and the predicted acetylation profile was observed with very high levels of sensitivity (>97%) and specificity (>98.0%). Furthermore, and as expected, both the two-SNP (C282T, T341C) and tagSNP were found to be independent variables in predicting ATDH with the same strength as seven-SNP of NAT2.

Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs.

BACKGROUND AND AIM: Treatment with antituberculosis (TB) drugs produces liver damage in a large proportion of patients. Isoniazid, an antibacterial drug, is primarily responsible for this hepatotoxicity. Several polymorphisms of the N-acetyltransferase 2 (NAT-2) and cytochrome P450 2E1 enzymes, which are involved in the metabolism of isoniazid, may be directly associated with the development of hepatotoxicity. This study was designed to analyze the association between the NAT-2 and CYP2E1 polymorphisms with the development of anti-TB drug-induced hepatotoxicity (ATDH). METHODS: One hundred and seventy-five TB patients who had been treated with anti-TB drugs were studied. The allelic and genotypic frequency distributions of the NAT-2 and CYP2E1 enzymes were studied using polymerase chain reaction-restriction fragment length polymorphisms methodology. A binary logistic regression analysis was used to compare the results between TB patients with and without the development of hepatotoxicity. RESULTS: Having a slow acetylator status (odds ratio [OR] = 2.615; confidence interval [CI] = 1.264-5.411; P = 0.01), being female (OR = 2.734; CI = 1.325-5.639, P = 0.006), and having Bolivian ethnicity (OR = 2.711; CI = 1.307-6.625, P = 0.007) were found to be independent predictor variables for ATDH. CONCLUSIONS: This study showed that a patient's NAT-2 acetylator status, gender, and ethnic origin may be regarded as important risk factors for developing hepatotoxicity. Contrary to expectations, the CYP2E1 c1/c2 polymorphism did not show a significant association with hepatotoxicity in this study. Given the increases in TB cases and ATDH incidence levels, as well as the associated hospitalization costs, it may also be helpful to know patients' acetylator status prior to or at the beginning of the TB treatment regimen.

[Community acquired pneumonia and pulmonary hemorrhage in leptospirosis in the Buenos Aires metropolitan area]. / Neumonía aguda de la comunidad y hemorragia pulmonar por leptospirosis en el área metropolitana Buenos Aires.

The aim of this paper is to report the epidemiological, clinical and diagnosis findings of pneumonia and pulmonary hemorrhage observed in patients with leptospirosis in the period January 2007 to October 2009. A 64% (20/31) of patients diagnosed with leptospirosis presented pneumonia. Fifteen of them (75%) had severe pneumonia, of which seven (35%) were pulmonary hemorrhage. In ten patients (32%) reason for consultation and clinical early stage was a secretory gastroenteritis with fever and abdominal pain. Jaundice was only expressed in eleven patients (35%). The technique of chain reaction (PCR) was useful for diagnosis in samples obtained post mortem. A strain classified in serogroup canicola was isolated from blood culture. Pneumonia was classified into three types: non-severe pneumonia course with little overall impact; severe pneumonia associated with systemic clinical forms with jaundice, renal failure, thrombocytopenia, and pulmonary hemorrhage, and of serious course, not associated with jaundice, kidney failure or thrombocytopenia. Antibiotic treatment started in the early stages of disease (average 3.2 days) had no influence on the development of severe pneumonia. It is puggested to consider three clinical forms of leptospirosis: anicteric, icteric (with its evolutionary variants) and pulmonary hemorrhage.

Neumonía aguda de la comunidad y hemorragia pulmonar por leptospirosis en el área metropolitana Buenos Aires / Community acquired pneumonia and pulmonary hemorrhage in leptospirosis in the Buenos Aires metropolitan area

El objetivo del trabajo es comunicar los hallazgos epidemiológicos, clínicos y de diagnóstico de la neumonía y hemorragia pulmonar por leptospirosis, en el período enero 2007 a octubre 2009. Un 64% (20/31) de pacientes con diagnóstico de leptospirosis tuvieron neumonía. Quince de ellos (75%) presentaron neumonía grave, de los cuales siete (35%) desarrollaron hemorragia pulmonar. En diez enfermos (32%) el motivo de consulta e inicio del cuadro clínico fue una gastroenteritis secretoria con fiebre y dolor abdominal. La ictericia sólo se manifestó en once pacientes (35%). La técnica de reacción en cadena de la polimerasa (PCR) fue útil para el diagnóstico en muestra obtenida post mortem. De un hemocultivo se aisló una cepa clasificada dentro del serogrupo canicola. Se clasificaron las neumonías en tres tipos: neumonías de curso no grave con escasa repercusión general; neumonías graves asociadas a formas clínicas sistémicas con ictericia, insuficiencia renal, trombocitopenia y hemorragia pulmonar; también de curso grave, no asociada a ictericia, insuficiencia renal o trombocitopenia grave. El tratamiento antibiótico iniciado en los primeros días de enfermedad (promedio 3.2 días) no tuvo influencia en la evolución de las neumonías graves. Se plantea además considerar tres formas clínicas de leptospirosis: anictérica, ictérica (con sus variantes evolutivas) y hemorragia pulmonar.

The aim of this paper is to report the epidemiological, clinical and diagnosis findings of pneumonia and pulmonary hemorrhage observed in patients with leptospirosis in the period January 2007 to October 2009. A 64% (20/31) of patients diagnosed with leptospirosis presented pneumonia. Fifteen of them (75%) had severe pneumonia, of which seven (35%) were pulmonary hemorrhage. In ten patients (32%) reason for consultation and clinical early stage was a secretory gastroenteritis with fever and abdominal pain. Jaundice was only expressed in eleven patients (35%). The technique of chain reaction (PCR) was useful for diagnosis in samples obtained post mortem. A strain classified in serogroup canicola was isolated from blood culture. Pneumonia was classified into three types: non-severe pneumonia course with little overall impact; severe pneumonia associated with systemic clinical forms with jaundice, renal failure, thrombocytopenia, and pulmonary hemorrhage, and of serious course, not associated with jaundice, kidney failure or thrombocytopenia. Antibiotic treatment started in the early stages of disease (average 3.2 days) had no influence on the development of severe pneumonia. It is puggested to consider three clinical forms of leptospirosis: anicteric, icteric (with its evolutionary variants) and pulmonary hemorrhage.

Norfloxacin monodose use in patients with cholera in Salta Argentina

The use of monodose (800 mg) per os of Norfloxacin was evaluated in 32 patients with cholera at Salvador Mazza's Hospital, Salta, Argentina. It was considered the celerity in negativization of stool culture (100 of cases: 12 hours post administration), it efficiency along time (24/24 controlled patients were negative at 10th day) and MIC of isolated strains (100 of strains were sensitive: range 0.008 to 0.016 micrograms/ml). It was included oral administration of sorbitol 70 in peanut oil in order to study patients at 10th day's control. This method could be an alternative one in the study of asymptomatic carrier. Norfloxacin monodose shows good performance in early negativization of stool culture and it was also effective along the whole observation period, suggesting it could prevent carriage.

Evaluación de test de movilidad-inmovilidad como alternativa de diagnóstico rápido en cólera / Evaluation of the motility-inmobilization test as an alternative foor rapid diagnosis in cholera

La típica movilidad de V. cholerae y su inmovilización por el antisuero específico, observados en microscopia, de muestras frescas de materia fecal de enfermos con diagnóstico presuntivo de cólera, fue confrontada como técnica diagnóstica con el cultivo. A tal fin, se estudiaron en terreno 32 pacientes, asistidos en el Hospital de Salvador Mazza, Salta, Argentina, en el período comprendido entre el 28 de enero y el 8 de marzo de 1993. La correlación fue del 80 por ciento. Cinco sobre seis muestras, en las que la técnica no fue efectiva, correspondían a materias fecales cuyas características no eran típicas de cólera. Se considera la técnica como un método útil de diagnóstico orientativo rápido y de bajo costo, pero no se recomienda en pacientes con baja descarga de vibrios en materia fecal

Evaluación de test de movilidad-inmovilidad como alternativa de diagnóstico rápido en cólera / Evaluation of the motility-inmobilization test as an alternative foor rapid diagnosis in cholera

La típica movilidad de V. cholerae y su inmovilización por el antisuero específico, observados en microscopia, de muestras frescas de materia fecal de enfermos con diagnóstico presuntivo de cólera, fue confrontada como técnica diagnóstica con el cultivo. A tal fin, se estudiaron en terreno 32 pacientes, asistidos en el Hospital de Salvador Mazza, Salta, Argentina, en el período comprendido entre el 28 de enero y el 8 de marzo de 1993. La correlación fue del 80 por ciento. Cinco sobre seis muestras, en las que la técnica no fue efectiva, correspondían a materias fecales cuyas características no eran típicas de cólera. Se considera la técnica como un método útil de diagnóstico orientativo rápido y de bajo costo, pero no se recomienda en pacientes con baja descarga de vibrios en materia fecal (AU)