Influence of sex on the exposure to isoniazid in patients with pulmonary tuberculosis

ABSTRACT Isoniazid is a key component of tuberculosis treatment. Adequate exposure is a determinant for therapeutic success; however, considerable inter- and intraindividual variations in drug plasma levels can lead to unfavorable outcomes. While some predictors of isoniazid levels are well-known, others, such as sex, yield controversial results, requiring further investigation to optimize exposure. This study investigates whether the sex of patients influences the dose administered and the concentrations of isoniazid in plasma. Levels of isoniazid were associated with the N-acetyltransferase 2 phenotypes. A total of 76 male and 58 female patients were included. Isoniazid was measured by high-performance liquid chromatography, and N-acetyltransferase 2 phenotypes were assessed using molecular techniques. The results show that the dose administered, expressed in mg/kg, was higher in females, but the plasma levels were similar between both sexes. Among patients, 46.2%, 38.8%, and 15% were slow, intermediate, and fast acetylators, respectively. As expected, isoniazid levels were associated with the acetylation phenotypes, with higher concentrations in the slow acetylators. Thus, sex-related difference in isoniazid levels is due to the body weight of patients, and the optimized dose regimen based on patient weight and acetylator phenotypes can improve the treatment outcomes.

Complicaciones tromboembólicas asociadas con tuberculosis: reporte de un caso pediátrico / Thromboembolic complications associated with tuberculosis: A pediatric case report

Resumen: La tuberculosis es una de las enfermedades infecciosas más comunes en el mundo. Aunque la mortalidad en niños es prácticamente nula cuando el diagnóstico y el tratamiento son oportunos, puede asociarse con complicaciones como la trombosis venosa profunda y la superficial a partir de la respuesta inflamatoria sistémica frente a la infección, lo que propicia la coagulación y ocasiona una significativa morbimortalidad. Se reporta el caso de una adolescente de 14 años con tuberculosis pulmonar en tratamiento combinado quien, de forma atípica, presentó dos episodios de tromboembolia venosa: el primero en el riñón y el segundo en los pulmones. Tras descartar el síndrome nefrótico y el antifosfolipídico, los estudios de tomografía de tórax y abdomen fueron una herramienta fundamental para su diagnóstico. Se inició tratamiento con heparina de bajo peso molecular con mejoría de los síntomas. Teniendo en cuenta las necesidades de anticoagulación no fue posible realizar estudios adicionales de ampliación. Las complicaciones tromboembólicas en pacientes con tuberculosis y sin otros factores de riesgo obligan a considerar el efecto coagulante que resulta de la reacción inflamatoria sistémica, la cual podría, por sí sola, ser la causa de una complicación significativa pero prevenible, aunque frecuentemente escapa al diagnóstico. En este sentido, se recomienda considerar la posibilidad de la tromboembolia venosa en estos pacientes y hacer un seguimiento estricto que permita aplicar el tratamiento anticoagulante tempranamente y prevenir, así, resultados adversos.

Abstract: Tuberculosis is one of the most common infectious diseases around the world. With timely diagnosis and treatment, mortality in children is practically zero. It is usually associated with a diverse number of complications that can cause significant morbidity and mortality, such as deep and superficial vein thrombosis. This event has been associated with a procoagulant state caused by the systemic inflammatory response to infection. We report the case of a 14-year-old adolescent with pulmonary tuberculosis under the initial four-drug regimen. She presented two episodes of venous thromboembolism, the first in the kidneys and the second in the lungs. After ruling out diseases such as nephrotic and antiphospholipid antibody syndrome, chest and abdomen tomographies were performed as a fundamental tool for the diagnosis. Thereafter, treatment with low molecular weight heparin was initiated and the symptoms improved. Given the requirement for anticoagulation, further image studies could not be done. Thromboembolic complications in patients with no other risk factors, associated only with a previous pulmonary tuberculosis diagnosis, offer evidence to consider the procoagulant effect resulting from the systemic inflammatory response that, by itself, could be the cause of a serious complication, often underdiagnosed but also preventable. Therefore, it is recommended to consider the predisposition for venous thromboembolism in these patients and to establish strict surveillance so early anticoagulant therapy can be provided to prevent adverse outcomes.

Características clínicas de la hepatotoxicidad asociada a la pirazinamida en pacientes de un hospital de Lima, Perú / Clinical characteristics of pyrazinamide-associated hepatotoxicity in patients at a hospital in Lima, Peru

RESUMEN Con el objetivo de determinar las características de la enfermedad hepática inducida por el medicamento (DILI) se realizó un estudio de pacientes adultos con diagnóstico de tuberculosis y esquema de tratamiento antituberculoso con pirazinamida. El análisis de causa efecto de la DILI fue mediante el proceso de reexposición. Se encontraron 10 pacientes con DILI asociada a pirazinamida, la mediana de edad y de estancia hospitalaria fue de 40,5 años (rango 22-76) y 41 días (rango 11-130), respectivamente. La mediana de presentación del evento fue de 14 días (rango 3-46), 4 pacientes presentaron ictericia, 5 tuvieron patrón hepatocelular, 3 mixtas y 2 colestásicos. La presentación de la DILI fue leve en 6 casos (60%) y moderados en 3 (30%). En conclusión, la DILI asociada a la pirazinamida requiere estancia hospitalaria prolongada, se presenta con ictericia en un poco más de un tercio de los casos siendo el patrón predominante el hepatocelular.

ABSTRACT In order to determine the characteristics of drug-induced liver injury (DILI), adult patients diagnosed with tuberculosis and with an anti-tuberculosis treatment scheme including pyrazinamide were studied. The re-exposure process was used for the cause-effect analysis of the DILI. A total of 10 patients were found with pyrazinamide-associated DILI; the median age and hospital stay were 40.5 years (from 22 to 76 years) and 41 days (from 11 to 130 days), respectively. The median time in which the events appeared was 14 days (from 3 to 46 days); jaundice was observed in 4 patients and radiological patterns such as hepatocellular, mixed and cholestatic were found in 5, 3 and 2 patients, respectively. Mild presentation of DILI was observed in 6 cases (60%) and moderate in 3 (30%). In conclusion, pyrazinamide-associated DILI required prolonged hospital stay, presented jaundice in little more than a third of the cases, and radiologically, the hepatocellular pattern predominated.

Seizures in a child with tuberculomas: case report

Central tuberculomas, occurring because of the haematogenous spread of' M. tuberculosis, can present variably with the symptoms ranging from headache, decreased level of consciousness, neck stiffness to altered mental status, seizures and focal deficits. Diagnostic investigations include but are not limited to CSF analysis, MRI Brain, CT head, and AFB smear, mycobacterial cultures or CBNAAT of the CSF sample. Magnetic resonance spectroscopy can help distinguishing the tuberculoma from its differentials by showing a peculiar lipid peak. Treatment with the antituberculosis drugs over a prolonged period of time along with dexamethasone usually shows significant clinical improvement. Authors present to you the case report of an 8 year old boy who presented to the pediatric emergency with generalized tonic clonic seizures and was subsequently detected with the tuberculoma with the help of MRI Brain and CBNAAT (cartridge based nucleic acid amplification test) of CSF sample. The objective of this case report is to discuss the symptoms, pathogenesis, detection and management of tuberculomas, which are still quite common in the developing countries and if left untreated are associated with high morbidity and mortality.

Ameliorative effect of Pergularia daemia (Forssk.) Chiov. leaves extract against anti-tuberculosis drugs induced liver injury in rats

Objective: To evaluate therapeutic potential of hydroethanolic extract of Pergularia daemia (P. daemia) against anti-tuberculosis drugs (ATDs) induced liver injury. Methods: Wistar albino rats were divided into seven groups of six animal in each. The ATDs and P. daemia extract (100, 200 and 400 mg/kg, p.o.) were conjointly administered for 8 weeks and various biochemical, histoarchitectural, ultrastructural studies were performed. Results: Administration of ATDs significantly increased aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, triglycerides, cholesterol, bilirubin and decreased glucose and albumin level. Increased lipid peroxidation and reduction in glutathione, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase were found after ATDs exposure. Administration of P. daemia extract maintained serum biochemical indices as well as antioxidant status similar to control and diminished oxidative stress in dose dependent manner. Histological and ultra-structural observations substantiated biochemical findings. Conclusions: P. daemia has therapeutic potential against ATDs induced liver injury and may be of clinical significance after extensive studies.

Propolis modulates cellular biochemistry, antioxidants, cytokine profile, histological and ultra-morphological status against antituberculosis drugs induced hepatic injury

Objective: To evaluate hepatic injury induced by antituberculosis drugs (ATDs) when administered orally for 2, 4, 6 and 8 weeks and the therapeutic potential of propolis (bee hive product) against ATDs induced hepatic injury. Methods: The ATDs were administered for 8 weeks as well as propolis extract at three different doses (100, 200, 400 mg/kg) conjointly for 8 weeks in rats. Silymarin (50 mg/kg) was given as positive control. Animals were euthanized after 8 weeks; blood and liver samples were collected to perform various biochemicals, serological and histopathological and ultramorphological studies. Results: Significant increase (P < 0.05) in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, triglyceride and cholesterol along with reduction in glucose and albumin level were noted after ATDs induced hepatic injury. Significant increase (P < 0.05) in lipid peroxidation, triglyceride, cholesterol and CYP2E1 activity; decline in reduced glutathione, catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase, glucose-6-phosphatase dehydrogenase activity were observed after ATDs intoxication. Due to presence of a wide range of flavonoids and polyphenols in propolis extract, its administration reduced hepatic injury and maintained biochemical indices towards control. Histopathological and electron microscopic observations indicated hepatoprotective potential of propolis at cellular level whereas, TNF-α, IL-6 and IGF-1 confirmed therapeutic potential of propolis at molecular level. Conclusions: It can be concluded that propolis possess hepatoprotective potential against ATDs induced hepatic injury that may prove itself as a clinically useful natural product in management of drug induced liver injury.

Ameliorative effect of Pergularia daemia (Forssk.) Chiov. leaves extract against anti-tuberculosis drugs induced liver injury in rats

Objective:To evaluate therapeutic potential of hydroethanolic extract of Pergularia daemia (P. daemia) against anti-tuberculosis drugs (ATDs) induced liver injury.Methods:Wistar albino rats were divided into seven groups of six animal in each. The ATDs and P. daemia extract (100, 200 and 400 mg/kg, p.o.) were conjointly administered for 8 weeks and various biochemical, histoarchitectural, ultrastructural studies were performed.Results:Administration of ATDs significantly increased aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, triglycerides, cholesterol, bilirubin and decreased glucose and albumin level. Increased lipid peroxidation and reduction in glutathione, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase were found after ATDs exposure. Administration of P. daemia extract maintained serum biochemical indices as well as antioxidant status similar to control and diminished oxidative stress in dose dependent manner. Histological and ultra-structural observations substantiated biochemical findings.Conclusions:P. daemia has therapeutic potential against ATDs induced liver injury and may be of clinical significance after extensive studies.

Propolis modulates cellular biochemistry, antioxidants, cytokine profile, histological and ultra-morphological status against antituberculosis drugs induced hepatic injury

Objective:To evaluate hepatic injury induced by antituberculosis drugs (ATDs) when administered orally for 2, 4, 6 and 8 weeks and the therapeutic potential of propolis (bee hive product) against ATDs induced hepatic injury.Methods:The ATDs were administered for 8 weeks as well as propolis extract at three different doses (100, 200, 400 mg/kg) conjointly for 8 weeks in rats. Silymarin (50 mg/kg) was given as positive control. Animals were euthanized after 8 weeks; blood and liver samples were collected to perform various biochemicals, serological and histopathological and ultramorphological studies.Results:Significant increase (P < 0.05) in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, triglyceride and cholesterol along with reduction in glucose and albumin level were noted after ATDs induced hepatic injury. Significant increase (P < 0.05) in lipid peroxidation, triglyceride, cholesterol and CYP2E1 activity; decline in reduced glutathione, catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase, glucose-6-phosphatase dehydrogenase activity were observed after ATDs intoxication. Due to presence of a wide range of flavonoids and polyphenols in propolis extract, its administration reduced hepatic injury and maintained biochemical indices towards control. Histopathological and electron microscopic observations indicated hepatoprotective potential of propolis at cellular level whereas, TNF-α, IL-6 and IGF-1 confirmed therapeutic potential of propolis at molecular level.Conclusions:It can be concluded that propolis possess hepatoprotective potential against ATDs induced hepatic injury that may prove itself as a clinically useful natural product in management of drug induced liver injury.

Research on characteristics of liver injury induced by rifampicin in mice / 局解手术学杂志

Objective To observe the symptom and characteristics of liver injury induced by different dosage of long-term administration of rifampicin(RIF) in mice.Methods Twenty-four healthy female ICR mice were randomly divided into 4 groups(6 mice in each group):control group,low dosage group,medium dosage group and high dosage group.The four groups were treated with 0,100,200,400 mg·kg-1·d-1 RIF respectively for 2 weeks.Mice blood and liver tissue samples were collected at 6 hours after the last administration for serological test and liver histological observation.Results No mice died before execution.The TBA,DBIL and TBIL of high dosage group all increased compared with the control group, but the ALT,AST and ALP showed no obvious change.The TBA and DBIL of medium dosage group increased compared with the control group, while the TBIL,ALT,AST and ALP showed no obvious change.In the low dosage group,there was no obvious change in terms of TBA,DBIL,TBIL,ALT,AST,and ALP compared with the control group.Obvious pathological change occured in the liver of mice in all the experimental groups.HE staining showed edema and feather steatosis in liver cells, accompanied by a large number of inflammatory cells infiltration and a few sporadic cholestasis.With the increasing of RIF dosage,the liver pathological change became more obviously.In the experimental group,electron microscope showed that there were a lot of fat droplets in the liver cells wrapped slurry,and part of the capillary bile duct were slightly expanded with different electron density and irregular shape of bile sample material inside.The pathologic changes get more obvious with the increase of the concentration of rifampicin as well.Conclusion RIF could induce liver injury after 2 weeks' treatment at different dosages,mainly pathological changes included liver cell steatosis,inflammatory cell infiltration,and cholestasis.Rifampicin induced liver injury in a concentration-dependent manner.However,the mechanism of rifampicin-induced liver injury in mice needs further study.

Evaluation of crystal violet decolorization assay for minimal inhibitory concentration detection of primary antituberculosis drugs against Mycobacterium tuberculosis isolates

In this study we evaluated the crystal violet decolorization assay (CVDA) for detection of minimum inhibitory concentration (MIC) of antituberculosis drugs. 53 isolates were tested in this study and 13 of them were multidrug resistant (MDR) isolates. The antibiotics concentrations were 2-0.06 mg/L for isoniazid (INH) and rifampicin (RIF) and were 16-0.25 mg/L for streptomycin (STM) and ethambutol (EMB). Crystal violet (CV-25 mg/L) was added into the microwells on the seventh day of incubation and incubation was continued until decolorization. Decolorization of CV was the predictor of bacterial growth. Overall agreements for four drugs were detected as 98.1%, and the average time was detected as 9.5 ± 0.89 day after inoculation. One isolate for INH and two isolates for STM were determined resistant in the reference method, but susceptible by the CVDA. One isolate was susceptible to EMB by the reference method, but resistant by the CVDA. All results were concordant for RIF. This study shows that CVDA is a rapid, reliable and suitable for determination of MIC values of Mycobacterium tuberculosis. And it can be used easily especially in countries with limited-sources.

Utilidad del método de la nitrato reductasa para la detección de resistencia a drogas antituberculosas de segunda línea / Usefulness of the nitrate reductase method to detect resistance to second-line anti-tuberculosis drugs

Introducción: el creciente hallazgo de cepas de Mycobacterium tuberculosis multidrogorresistentes extremadamente resistentes ratifica la importancia de ofrecer, de forma rápida, los resultados de susceptibilidad de M. tuberculosis a drogas de primera y segunda línea como única alternativa para evitar la transmisión. Objetivo: comparar el método de la nitrato reductasa y el de las proporciones para la detección de susceptibilidad a drogas antituberculosas de segunda línea en aislamientos clínicos de M. tuberculosis, recuperados de pacientes cubanos con tuberculosis multidrogorresistente. Métodos: se investigó, mediante el método de las proporciones en Löwenstein-Jensen y el de la nitrato reductasa, la susceptibilidad a la ofloxacina, la kanamicina y a la capreomicina en 34 aislamientos de M. tuberculosis multidrogorresistentes. Resultados: en tres aislamientos se evidenció un comportamiento extremadamente resistente por ambos métodos. Mediante el método de la nitrato reductasa los resultados estuvieron disponibles entre 7 y 14 días. La sensibilidad fue de 100 por ciento, 90,0 por ciento y 77,8 por ciento para la ofloxacina, la kanamicina y la capreomicina, respectivamente, mientras que la especificidad fue superior al 95,0 por ciento y el valor de kappa fue superior a 0,85 para las tres drogas. Conclusión: de acuerdo con los resultados alcanzados, consideramos que el método de la nitrato reductasa constituye una valiosa alternativa para la detección oportuna de tuberculosis extremadamente resistente en países con limitados recursos económicos(AU)

Introduction: the increase of multidrug resistant and extensively drug resistant tuberculosis underlines the urgent need to obtain early results of Mycobacterium tuberculosis susceptibility both to first and second line antituberculosis drugs in order to avoid dissemination of resistant isolates. Objective: the aim of this research was to compare the performance of the nitrate reductase assay and the proportion method for to detect the susceptibility to second line antituberculosis drugs in multidrug resistant clinical isolates of M. tuberculosis. Methods: the susceptibility to ofloxacin, kamamycin and capreomycin of 34 M. tuberculosis multidrug resistant isolates was investigated using the proportion method in Löwenstein-Jensen and the nitrate reductase assay. Results: three isolates were identified as extensively drug resistant by both methods. The results of the nitrate reductase assay were obtained between 7-14 days achieving 100 percent, 90.0 percent and 77.8 percent of sensitivity for ofloxacin, kamamycin and capreomycin, respectively while specificity was higher than 95.0 percent and kappa value was higher to 0,85 for all drugs. Conclusion: the nitrate reductase assay represents a useful tool for the rapid identification of extensively drug resistant tuberculosis in low resources setting(AU)

Curative effect of thalidomide combined with anti-tuberculosis drugs on treating pulmonary tuberculosis / 中国综合临床

Objective To analyze the clinical efficacy of thalidomide combined with anti tuberculosis drugs in the treatment of pulmonary tuberculosis,in order to evaluate its application value and safety. Methods Seventy-two pulmonary tuberculosis patients in the Qianshan Hospital of Anshan from Jan. 2012 to Aug. 2014 were selected as the subject. Patients were randomly divided into control group and observation group with 36 cases in each group. Patients in the control group were only received anti-tuberculosis drug treatment,while in the treatment group were given thalidomide combined with anti tuberculosis drug treatment. Efficacy rate of thalidomide treatment after two weeks was evaluated by X-ray examination. Incidence of sputum smear negative conversion rate and adverse reaction were recorded. Results There were 10 cases with obvious tuberculosis absorption,19 cases with lesions absorption,7 cases with no absorption in observation group. In control group, there were 5 cases with obvious tuberculosis absorption,12 cases with lesions absorption,17 cases with no absorption and the lesion increased in 2 cases. The focus absorption in observation group was superior to the control group( Z =11. 854,P ﹤0. 001 ). There were 6 cases with void closure,4 cases with decreased void closure,1 cases with unchanged and 1 cases with new cavity in observation group. There were 1 cases with void closure,3 cases with decreased void closure,6 cases with unchanged and 3 cases with new cavity in control group,and there was significant difference(Z=15. 536,P﹤0. 001). Sputum smear negative rate in observation group after treatment was 85. 0%(17/20),significantly higher than that in control group(50. 0%(11/22),χ2=5. 775,P=0. 016). Cases of adverse reactions in observation group was 8(22. 2%),lower than that in control group(17 cases,(47. 2%);χ2 =4. 963,P=0. 026). There were 2 cases with abnormal liver function without changing the original treatment symptomatic liver after treatment,in observation group. Of 8 cases with abnormal liver function in control group,5 cases change treatment schedule including 3 cases of modified pyrazinamide for streptomycin,2 cases converted to rifampicin for Levofloxacin. The syndromes including eukopenia,skin rash, anorexia and lethargy were disappeared after treatment. Conclusion The effect of Thalidomide combined with anti tuberculosis drugs in the treatment of pulmonary tuberculosis is significant and safety,which can be used as a routine drug treatment of tuberculosis in clinical trials.

Antituberculosis Drug - Induced Elevation in Serum Alanine Aminotransferase (ALT) Levels: A Comparison between Patients with and without HIV Seropositivity in Yenagoa, Nigeria.

Introduction: The prevalence of rifampicin, isoniazid and pyrazinamide induced elevations in serum alanine aminotransferase (ALT) levels were compared in a cohort of Nigerians with and without HIV seropositivity. Methods: Records of all the patients with pulmonary tuberculosis (251 HIV positive and 205 HIV negative), aged above 15 years treated in the TB program of the Federal Medical Centre, Yenagoa from January 2013 to December 2014 were analysed for this study. The WHO 4 grades of hepatotoxicity using ALT were used. ALT of less than 50 U/L was taken as normal. Grade 1 (very mild hepatotoxicity): <2.5 x upper limit of normal (ULN) i.e. ALT 51-125 U/L. Grade 2 (mild): 2.6 – 5 x the ULN (ALT 126-250 U/L). Grade 3 (moderate): 5-10 x the ULN (ALT 251 – 500 U/L). Grade 4 (severe) >10 x the ULN (ALT > 500 U/L). Results: No patient with or without HIV seropositivity had ALT value in the grade 3 and 4 category ≥251 U/L. There was no statistically significant difference in ALT values between cohorts with or without HIV in the 3 ALT categories obtained while on antituberculous drugs (P = 0.761, 0.367 and 0.197). Conclusion: All the observed hepatotoxicity were mild. The average rate of hepatotoxicity in the HIV uninfected pulmonary tuberculosis cohort was 16.6%, 9.8% and 5.4% for ALT1, ALT2 and ALT3 respectively. The rate in the HIV infected cohorts was 15.5%, 8.8% and 16.4% for ALT1, ALT2 and ALT3. It is encouraging to find a low rate of antituberculosis drug induced hepatotoxicity than one would expect based on the high prevalence of risk factors in our environment.

Superoxide Dismutase Gene (SOD1, SOD2, and SOD3) Polymorphisms and Antituberculosis Drug-induced Hepatitis

PURPOSE: Drug-induced liver injury (DILI) is a serious issue often leading to discontinuation of the proper regimen of antituberculosis drugs (ATD). Previous studies have suggested that antioxidant enzymes play an important role in DILI. METHODS: We explored whether polymorphisms in superoxide dismutase genes, including Cu/Zn superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2) and extracellular superoxide dismutase (SOD3) are associated with ATD-induced hepatitis. Genotype distributions of four single nucleotide polymorphisms (SNPs) in three genes (rs2070424, SOD1; rs4880, SOD2; rs2536512, and rs1799895, SOD3) were compared between 84 patients with ATD-induced hepatitis and 237 patients tolerant to ATD. RESULTS: Intron SNP rs2070424 of SOD1 showed a significant association with ATD-induced hepatitis. The frequency of genotypes carrying minor alleles (GA or GG) was significantly higher in the case group than that of controls (P=0.019, OR=2.26, 95% CI 1.14-4.49). For the other SNPs of SOD2 and SOD3, there were no differences in genotype frequencies between ATD-induced hepatitis and ATD-tolerant controls. CONCLUSIONS: These findings suggest that rs2070424 of SOD1 is significantly associated with ATD-induced hepatitis. This genetic variant may be a risk factor for ATD-induced hepatitis in individuals from Korea.

Antituberculous drug-induced liver injury: current perspective.

Drug-induced liver injury (DILI) is a minor but significant cause of liver injury across all regions. Antituberculosis drug-induced liver injury (TB DILI) is a leading cause of DILI and drug-induced acute liver failure (DIALF) in India and much of the developing world. Single center registries of DILI continue to highlight the high incidence of DILI and DIALF, much of it due to diagnostic errors and inappropriate prescriptions. The clinical spectrum includes asymptomatic elevation in liver tests to acute hepatitis and acute liver failure. TB DILI can occur across all age groups including children with significant morbidity and mortality. Although TB DILI develops more commonly in males, ALF is noted to be commoner in females with a worse prognosis. Contrasting reports on the role of genetic and environmental factors continue to be published. Since DILI is a diagnosis of exclusion, acute viral hepatitis particularly hepatitis E needs to be excluded in such cases. The presence of jaundice, hypoalbuminemia, ascites, encephalopathy and high prothrombin time are poor prognostic markers. Recent reports of the beneficial role of N-acetylcysteine in DIALF and in preventing TB DILI in elderly individuals needs further investigation. Reintroduction of antitubercular therapy must be balanced with the knowledge of adaptation a common occurrence with antituberculosis drugs. Although monitoring and rechallenge practices vary greatly, the importance of early clinical symptoms cannot be underestimated. Simultaneous rechallenge with combination drugs or sequential treatment have similar incidence of DILI, although increasing reports about the role of pyrazinamide in DILI and on rechallenge warrants its careful use. The combined affliction of HIV or chronic hepatitis B or C and tuberculosis poses multiple challenges including the greatly increased risks of DILI.

Antituberculosis drug-induced hepatotoxicity: a comparison between patients with and without human immunodeficiency virus seropositivity / Hepatotoxicidade induzida pelos tuberculostáticos: comparação em pacientes com e sem soropositividade para o vírus da imunodeficiência humana

INTRODUCTION: The prevalence and risk factors for rifampin, isoniazid and pyrazinamide hepatotoxicity were evaluated in HIV-infected subjects and controls. METHODS: Patients with tuberculosis (30 HIV positive and 132 HIV negative), aged between 18 and 80 years-old, admitted to hospital in Brazil, from 2005 to 2007, were selected for this investigation. Three definitions of hepatotoxicity were used: I) a 3-fold increase in the lower limit of normal for alanine-aminotransferase (ALT); II) a 3-fold increase in the upper limit of normal (ULN) for ALT, and III) a 3-fold increase in the ULN for ALT plus a 2-fold increase in the ULN of total bilirubin. RESULTS: In groups with and without HIV infection the frequency of hepatotoxicity I was 77 percent and 46 percent, respectively (p < 0.01). Using hepatotoxicity II and III definitions no difference was observed in the occurrence of antituberculosis drug-induced hepatitis. Of the 17 patients with hepatotoxicity by definition III, 3 presented no side effects and treatment was well tolerated. In 8 (36.4 percent) out of 22, symptoms emerged and treatment was suspended. Alcohol abuse was related to hepatotoxicity only for definition I. CONCLUSIONS: Depending on the definition of drug-induced hepatitis, HIV infection may or may not be associated with hepatotoxicity. The impact that minor alterations in the definition had on the results was impressive. No death was related to drug-induced hepatotoxicity. The emergence of new symptoms after initiating antituberculosis therapy could not be attributed to hepatotoxicity in over one third of the cases.

INTRODUÇÃO: Avaliou-se a prevalência e os fatores de risco para hepatotoxicidade aos tuberculostáticos em pacientes HIV positivos e controles. MÉTODOS: Selecionou-se 162 pacientes com tuberculose, tratados com rifampicina, isoniazida e pirazinamida, na faixa etária de 18 a 80 anos, internados em hospital público no Brasil, entre 2005 e 2007. Eles foram divididos em dois grupos: 30 infectados pelo HIV e 132 controles. Adotou-se três definições para hepatotoxicidade: I) aumento de três vezes no valor inferior normal da alanina-aminotransferase (ALT); II) aumento de três vezes no valor superior normal (VSN) da ALT; III) aumento de três vezes no VSN da ALT e duas vezes no VSN da bilirrubina total. RESULTADOS: Nos grupos com e sem infecção pelo HIV, a frequência de hepatotoxicidade I foi de 77 por cento e 46 por cento, respectivamente (p<0,01). Para as definições II e III a frequência de hepatotoxicidade não diferiu entre os grupos estudados. De 17 pacientes com hepatotoxicidade induzida por droga (definição III), três não apresentaram sintomas e o tratamento foi mantido sem intercorrências. Oito (36,4 por cento) de 22 indivíduos apresentaram efeitos colaterais e interromperam o tratamento, mas não apresentavam hepatotoxicidade pela definição III. O abuso de álcool associou-se à hepatotoxicidade apenas para a definição I. CONCLUSÕES: Na dependência da definição escolhida, a infecção pelo HIV pode ou não associar-se à hepatotoxicidade. Foi grande o impacto que pequenas alterações na definição de hepatotoxicidade tiveram nos resultados. Nenhuma morte associou-se ao uso de tuberculostáticos. O surgimento de sintomas não pôde ser atribuído aos tuberculostáticos em um terço dos casos.

Tuberculosis exrremadamente drogorresistente (xdr): una amenaza perannente

La tuberculosis (TB) es una enfermedad que afecta al mundo entero, sobretodo a países pobres. Durante mucho tiempo constituyó la primera causa de muerte por enfermedades infecciosas a nivel mundial, siendo después superada por la pandemia del VIH/SIDA.Ahora, nuevamente la tuberculosis ha tomado importancia por el surgimiento de cepas multidrogorresistentes en cuyo extremo de letalidad esta la tuberculosis extremadamente drogoresistente (TB XDR).

Tuberculosis (TB) is an illness that affects worldwide countries, mostly affecting poor countries. For a long time, tuberculosis was the first cause of death by infectious illness in the world, until the VIH/AIDS took that place. Lastly, tuberculosis isgettingthe same importance than before, because ofthe emergency of multidrug-resistantTB strains, with an extremely lethal form called extensively drug-resistantTB (XDRTB).

Toxicidad hepática por medicamentos antituberculosos / Hepatotoxicity induced by antituberculosis drugs

El fenómeno de la toxicidad hepática inducida por medicamentos cobró relevancia hace algunos años con el estudio de las reacciones adversas a medicamentos. El daño producido en el hígado por un xenobiótico que altera su función es lo que se conoce como toxicidad hepática. La importancia de reconocer y diagnosticar la toxicidad hepática por medicamentos estriba en su gravedad potencial; no en vano es la causa más frecuente por la que la industria farmacéutica retira medicamentos. La tuberculosis es una pandemia que afecta a gran parte de la población mundial y junto con el VIH es una enfermedad cada vez más frecuente en Colombia. Esta enfermedad se puede considerar como una situación especial porque para su tratamiento es preciso suministrar, por largos períodos, medicamentos con potencial tóxico para el hígado.El objetivo de este artículo es revisar algunos aspectos relacionados con la toxicidad hepática secundaria a medicamentos antituberculosos, tales como: epidemiología, factores de riesgo, mecanismos de toxicidad, manifestaciones clínicas, diagnóstico, tratamiento y seguimiento.

Hepatotoxicity is the alteration of liver structure and function induced by either drugs or other substances. The importance of its proper diagnosisrests on its potential severity. It is the most frequent reason by which the pharmaceutical industry withdraws its products. Tuberculosis is a pandemicinfection affecting a large proportion of the world population. Together with HIV infection it is becoming ever more frequent in Colombia. Tuberculosisposes a special challenge because itstreatment requires the administration, during long periods, of drugs with the potential of inducing liver injury. In this article some aspects of hepatotoxicity induced by antituberculosis drugs are reviewed, namely: epidemiology, risk factors, mechanisms, clinical manifestations, diagnosis, treatment and follow-up.

A Case of Lichenoid Drug Eruption with Whole Body and Oral Mucosal Involvement Caused by Antituberculosis Drugs / 대한피부과학회지

Lichenoid drug eruption can arise as a result of exogenous compound exoposures and closely mimic idiopathic lichen planus. A 45-year-old man who had taken antituberculosis drugs (isoniazid, rifampin, ethambutol, pyrazinamide) for 2 months developed pruritic violaceous papules and plaques with silvery scales on the whole body. On close inspection, he had superficial erosions on the lips and reticulate white papules on the buccal mucosa. Histopathologic findings were hyperkeratosis, parakeratosis, and hypergranulosis in the epidermis and band-like lymphohistiocytic infiltration, numerous eosinophils, and perivascular lymphohistiocytic infiltration in the dermis. The skin lesions improved leaving hyperpigmentation after cessation of the antituberculosis drugs and application of topical corticosteroid.

Scintigraphy of the hepatobiliar system in patients with pulmonary tuberculosis

The objective of this paper was to evaluate the hepatobiliary function of patients with pulmonary tuberculosis under triple treatment, using the technetium-99m-DISIDA (99mTc-DISIDA) hepatobiliary scintigraphy. Ten men and three women with pulmonary tuberculosis were subjected to hepatobiliary scintigraphy at the beginning of triple treatment (M1) and two months after it (M2). Patients were from the urban area, of low socioeconomic level, malnourished, and chronic alcohol and/or tobacco users. Ten normal individuals were evaluated as controls. Radiotracer images were acquired on a computerized gamma camera (Orbiter-Siemens) and T1/2 uptake and excretion values were calculated. Nutritional status and serum hepatic enzyme levels for each patient were evaluated at M1 and M2. None presented clinical or laboratory antecedent of hepatobiliary disease. At M1, there were no hepatic serum or kinetic alterations of the 99mTc-DISIDA. At M2, patients presented better nutritional conditions than at M1; there was increased serum aspartate aminotransferase (AST) and reduced excretion time for 99mTc-DISIDA, which was interpreted as a more adaptive than toxic phenomenon, yet not all alterations were significant and none manifested clinically. Apparently, triple treatment acted on the liver inducing the P450 cytochrome enzymatic system, accelerating radiotracer excretion, which follows the same path as the bilirubins.