RESUMO
Drug induced liver injury (DILI) is a rare but well recognized serious adverse reaction. Pre-marketing studies may not detect liver injury, and DILI becomes very often apparent after the drug is launched to the market. Specific biomarkers for DILI prediction or diagnosis are not available. Toxic liver reactions present with a wide spectrum of phenotypes and severity, and our knowledge on the mechanisms underlying idiosyncratic reactions and individual susceptibility is still limited. To overcome these limitations, country-based registries and multicenter research networks have been created in Europe and North America. Reliable epidemiological data on DILI in Latin America (LA), a region with a large variety of ethnic groups, were however lacking. Fortunately, a LA network of DILI was set up in 2011, with the support of the Spanish DILI Registry from the University of Malaga. The primary aim of the Latin DILI Network (LATINDILIN) Registry was to prospectively identify bona fide DILI cases and to collect biological samples to study genetic biomarkers. Physicians involved in the project must complete a structured report form describing the DILI case presentation and follow-up which is submitted to a Coordinator Center in each country, where it is further assessed for completeness. During the last four years, several LA countries (Argentina, Uruguay, Chile, Mexico, Paraguay, Brazil, Ecuador, Peru, Venezuela and Colombia) have joined the network and committed with this project. At that point, to identify both our strengths and weaknesses was a very important issue. In this review, we will describe how the LATINDILI Registry was created. The aims and methods to achieve these objectives will be discussed in depth. Additionally, both the difficulties we have faced and the strategies to solve them will be also pinpointed. Finally, we will report on our preliminary results, and discuss ideas to expand and to keep running this network.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Sistema de Registros , Doença Hepática Induzida por Substâncias e Drogas/etnologia , Humanos , Cooperação Internacional , América do Sul , EspanhaRESUMO
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.
Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Acetilação , Adulto , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Antituberculosos/metabolismo , Argentina/epidemiologia , Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/metabolismo , Bolívia/etnologia , Doença Hepática Induzida por Substâncias e Drogas/etnologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Distribuição de Qui-Quadrado , Estudos Transversais , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Etnicidade , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Logísticos , Masculino , Razão de Chances , Fenótipo , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Adulto JovemRESUMO
BACKGROUND: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most prevalent and serious adverse drug reactions in the course of anti-tuberculosis (TB) treatment. Some researchers suggested that determination of N-acetyltransferase 2 (NAT2) genotype may be clinically useful to identify patients at high risk of developing ATDH. AIM: To evaluate whether the NAT2 genotype could be as a predictor for ATDH in Chinese community TB population. MATERIAL AND METHODS: A total of 4304 community-based TB patients were followed up six to nine months prospectively. A nested case-control study was designed. Each ATDH case was 1:4 matched with controls by age (within 5 years old), gender, treatment history, disease severity and drug dosage. The polymorphisms of NAT2 were determined using polymerase chain reaction with restriction fragment length polymorphism. Conditional Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. RESULTS: A total of 89 ATDH cases and 356 controls were included in this study. Allele frequency of NAT2*5, NAT2*6 and NAT2*7 in cases and controls were 4.5 and 3.2%, 25.3 and 26.5%, and 13.5 and 13.5%, respectively. Frequencies of genotypes and alleles of NAT2*5, NAT2*6 and NAT2*7 did not differ significantly between cases and controls. The OR of intermediate acetylator and slow acetylator compared with rapid acetylator was 1.040 (95%CI 0.616-1.758) and 0.990 (95%CI 0.509-1.925), respectively. The NAT2 haplotype distribution in cases was similar to controls. CONCLUSIONS: In conclusion, we did not find significant association between NAT2 genotype and ATDH in community-based Chinese population. It may be deficient to take NAT2 genotype as a predictor for ATDH in Chinese community TB patients.
Assuntos
Antituberculosos/efeitos adversos , Arilamina N-Acetiltransferase/genética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Polimorfismo Genético , Acetilação , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/etnologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Distribuição de Qui-Quadrado , China/epidemiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Estudos Prospectivos , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Two months of rifampin and pyrazinamide (RIF/PZA) for tuberculosis prevention has been advocated as a way to improve adherence in mobile populations, such as recent immigrants. However, RIF/PZA requires intensive patient and laboratory monitoring for hepatotoxicity. OBJECTIVES: To describe the feasibility and outcomes of using RIF/PZA for TB prevention during a tuberculosis outbreak in a Mexican immigrant community, where 23 adults and 11 children were treated with RIF/PZA between August 2001 and October 2001. METHODS: Retrospective chart review and interviews with health department employees were conducted to assess completion rates, hepatotoxicity, cost, and feasibility of monitoring. RESULTS: Ten (91%) children and 13 (57%) adults completed RIF/PZA. One child (9%) and four adults (17%) developed drug-induced hepatitis. Cultural barriers affected care. The adults resisted the biweekly blood draw, believing it would "drain them of energy." RIF/PZA, plus monitoring, was twice as costly as 4 months of rifampin. CONCLUSIONS: RIF/PZA was associated with significant hepatotoxicity, poor completion, and cultural barriers to monitoring, and was more costly than standard therapy. Tuberculosis prevention must address potential clinical, cultural, and economic barriers to completion and monitoring of short-course therapy in immigrants.