Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury.

UNLABELLED: Drug-induced liver injury (DILI) susceptibility has a potential genetic basis. We have evaluated possible associations between the risk of developing DILI and common genetic variants of the manganese superoxide dismutase (SOD2 Val16Ala) and glutathione peroxidase (GPX1 Pro200Leu) genes, which are involved in mitochondrial oxidative stress management. Genomic DNA from 185 DILI patients assessed by the Council for International Organizations of Medical Science scale and 270 sex- and age-matched controls were analyzed. The SOD2 and GPX1 genotyping was performed using polymerase chain reaction restriction fragment length polymorphism and TaqMan probed quantitative polymerase chain reaction, respectively. The statistical power to detect the effect of variant alleles with the observed odds ratio (OR) was 98.2% and 99.7% for bilateral association of SOD2 and GPX1, respectively. The SOD2 Ala/Ala genotype was associated with cholestatic/mixed damage (OR = 2.3; 95% confidence interval [CI] = 1.4-3.8; corrected P [Pc] = 0.0058), whereas the GPX1 Leu/Leu genotype was associated with cholestatic injury (OR = 5.1; 95%CI = 1.6-16.0; Pc = 0.0112). The presence of two or more combined risk alleles (SOD2 Ala and GPX1 Leu) was more frequent in DILI patients (OR = 2.1; 95%CI = 1.4-3.0; Pc = 0.0006). Patients with cholestatic/mixed injury induced by mitochondria hazardous drugs were more prone to have the SOD2 Ala/Ala genotype (OR = 3.6; 95%CI = 1.4-9.3; Pc = 0.02). This genotype was also more frequent in cholestatic/mixed DILI induced by pharmaceuticals producing quinone-like or epoxide metabolites (OR = 3.0; 95%CI = 1.7-5.5; Pc = 0.0008) and S-oxides, diazines, nitroanion radicals, or iminium ions (OR = 16.0; 95%CI = 1.8-146.1; Pc = 0.009). CONCLUSION: Patients homozygous for the SOD2 Ala allele and the GPX1 Leu allele are at higher risk of developing cholestatic DILI. SOD2 Ala homozygotes may be more prone to suffer DILI from drugs that are mitochondria hazardous or produce reactive intermediates.

[Hepatotoxicity, a global problem with local features: toward the creation of a Pan-American Hepatotoxicity Network]. / Hepatotoxicidad, un problema global con especificidades locales: hacia la creación de una Red Hispano Latinoamericana de Hepatotoxicidad.

Drug-induced liver damage is one of the most complex liver diseases due to its similar presentation to other acute or chronic liver processes, its potential severity and the absence of specific biomarkers to confirm diagnosis, which is based on clinical suspicion and exclusion of alternative causes. Because the drug development process fails to completely screen out hepatotoxic molecules and identify susceptible individuals, postmarketing pharmacovigilance remains essential. Hepatotoxicity registries are the ideal instrument for systematic and continual data collection, using preestablished criteria based on consensus. The present article briefly describes the contributions of the Spanish Hepatotoxicity Registry and those of other international registries. Hopefully, Latin American registries will be incorporated into existing initiatives, which will stimulate research and improve understanding of the complex mechanisms involved in this adverse reaction.

Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex.

Increased age and female sex are suggested risk factors for drug-induced hepatotoxicity (DILI). We studied the influence of these variables on the propensity to develop DILI, as well as its clinical expression and outcome. All cases of DILI submitted to the Spanish Registry between April 1994 and August 2007 were analyzed. Six hundred three DILI cases (310 men; mean age, 54 years) showed a similar sex distribution, reaching two peaks in the 40- to 49-year-old and 60- to 69-year-old age groups. No cases were recorded in the 20- to 29-year-old group. Patients aged > or =60 years accounted for 46% of the cases, with a male predominance (158 males, 118 females; P= 0.009), as opposed to younger patients. Older age was independently associated with cholestatic type of injury (odds ratio for an age interval for 1 year: 1.024 [95% confidence interval: 1.010-1.038]; male/female ratio, 1:2; P = 0.001) and younger age with hepatocellular damage (odds ratio: 0.983 [95% confidence interval: 0.972-0.994]; female/male ratio, 1:2; P = 0.002). In the mixed group, no age effect was evident. Outcome with fulminant liver failure/liver transplantation was more frequently encountered in women (P < 0.01). conclusion: Neither older age nor female sex are predisposing factors to overall DILI. However, older age is a determinant for cholestatic damage with a male predominance, whereas younger age is associated with cytolytic damage and a female overrepresentation. Women distinctly exhibit the worst outcome. Knowledge of these phenotypic associations could guide differential diagnosis and attribution of causality in DILI.

Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury.

UNLABELLED: Individual vulnerability to drug-induced liver injury (DILI) might result from deficiencies in the detoxification process, which determines the level of exposure to the reactive metabolite. We evaluated whether a genetically determined reduction in the ability to detoxify electrophilic compounds, such as that expected among individuals with glutathione S-transferase (GST) null genotypes, might play a role in determining the risk for DILI and its clinical expression. Genomic DNA from 154 patients (74 men, 80 women; mean age, 53 years) with a diagnosis of DILI as assessed with the Council for International Organizations of Medical Science scale and 250 sex- and age-matched healthy controls were analyzed. A multiplex polymerase chain reaction-based method was used to detect GSTM1 and GSTT1 gene deletions. Carriers of double GSTT1-M1 null genotypes had a 2.70-fold increased risk of developing DILI compared with noncarriers (odds ratio 2.70, 95% confidence interval 1.45-5.03; P = 0.003). The odds ratio for DILI patients receiving antibacterials, and NSAIDs were 3.52 (P = 0.002), and 5.61 (P = 0.001), respectively. Patients with amoxicillin-clavulanate hepatotoxicity (n = 32) had a 2.81-fold increased risk (P = 0.037). Patients classified by the combined GSTT1 and GSTM1 null genotypes did not differ with regard to the type of injury, clinical presentation, or outcome, except for the predominance of women in the combined null genotype (P < 0.001). CONCLUSION: The double-null genotype for GSTT1 and GSTM1 might play a role in determining the susceptibility to develop DILI, as a general mechanism that occurs regardless of the type of drug involved, and predominantly in women.

Analysis of IL-10, IL-4 and TNF-alpha polymorphisms in drug-induced liver injury (DILI) and its outcome.

BACKGROUND/AIMS: The aim of this study was to assess whether genetic polymorphism of three important candidate cytokine genes, IL-10 (-1082G/A, -819C/T, and -592C/A), IL-4 (-590C/T) and TNF-alpha (-308G/A), play a role in the susceptibility to developing drug-induced liver injury (DILI), and in determining its phenotypic expression and severity. METHODS: Cytokine genotyping was analysed using TaqMan 5' allelic discrimination assay in 140 DILI patients (mean age 51 y, range 13-82, with equal sex distribution) included in the Spanish Registry and 268 healthy controls. RESULTS: Genotypes, haplotypes and allele frequencies were similar for both cases and controls. The low IL-10 producing haplotype was more prevalent in DILI patients with the absence of peripheral blood eosinophilia (Pc=0.004, OR=5.29, 95% CI: 2.04-13.67), revealing significantly lower median eosinophil counts (0.19 x 10(9)L; P<0.0002) compared to the intermediate (0.24 x 10(9)L) and high (0.40 x 10(9)L) IL-10 haplotypes. All cases with serious DILI outcome carried low or intermediate IL-10 producing haplotype and had normal or low eosinophil counts. CONCLUSIONS: IL-10, IL-4 and TNF-alpha genetic polymorphisms were not related to the risk of developing DILI. Low IL-10 producing haplotype is associated with low eosinophil count, absence of eosinophilia and may be associated with worse clinical outcome from DILI.

Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry.

A chronic adverse reaction may occur in some instances of drug-induced liver injury (DILI), even despite drug cessation. In our study, we obtained records from a Spanish registry and evaluated cases of DILI with biochemical evidence of long-term damage. Chronic outcome was defined as a persistent biochemical abnormality of hepatocellular pattern of damage more than 3 months after drug withdrawal or more than 6 months after cholestatic/mixed damage. Data on 28 patients with a chronic clinical evolution (mean follow-up 20 months) between November 1995 and October 2005 were retrieved (18 female; overall mean age 55 yr) and accounted for 5.7% of total idiosyncratic DILI cases (n = 493) submitted to the registry. The main drug classes were cardiovascular and central nervous system (28.5% and 25%, respectively), which, in contrast, represented only 9.8% and 13%, respectively, of all DILI cases. The most frequent causative drugs were amoxicillin-clavulanate (4 of 69 cases), bentazepam (3 of 7 cases), atorvastatin (2 of 7 cases), and captopril (2 of 5 cases). Patients with cholestatic/mixed injury (18 of 194 cases [9%]) were more prone to chronicity than patients with hepatocellular injury (10 of 240 cases; P < .031). In the case of chronic hepatocellular injury, 3 patients progressed to cirrhosis and 2 to chronic hepatitis. In the cholestatic/mixed group, liver biopsy indicated cirrhosis in 1 patient and ductal lesions in 3 patients. In conclusion, cholestatic/mixed type of damage is more prone to become chronic while, in the hepatocellular pattern, the severity is greater. Cardiovascular and central nervous system drugs are the main groups leading to chronic liver damage.

Hepatotoxicidad, un problema global con especificidades locales: hacia la creación de una Red Hispano Latinoamericana de Hepatotoxicidad / Hepatotoxicity, a global problem with local features: toward the creation of a Pan-American Hepatotoxicity Network

El daño hepático tóxico inducido por fármacos (DILI) es una de las afecciones hepáticas más compleja debido a su capacidad de presentarse como cualquier otra enfermedad hepática aguda o crónica, potencial gravedad, y la ausencia de biomarcadores específicos para establecer la certeza diagnóstica que se sustenta en su sospecha y exclusión de causas alternativas. La incapacidad del proceso de desarrollo de los medicamentos de cribar completamente las moléculas hepatotóxicas e identificar a los sujetos susceptibles continúa haciendo imprescindible la farmacovigilancia poscomercialización. Los registros de hepatotoxicidad se convierten en un instrumento idóneo para la recogida sistemática, según criterios consensuados y con continuidad de datos bien definidos. Se describen sumariamente las aportaciones del Registro Español de Hepatotoxicidad, y de otros registros internacionales, y se invoca la oportunidad de incorporar a Latinoamérica en las iniciativas en marcha lo que promoverá la investigación y la comprensión de los complejos mecanismos involucrados en esta reacción adversa (AU)

Drug-induced liver damage is one of the most complex liver diseases due to its similar presentation to other acute or chronic liver processes, its potential severity and the absence of specific biomarkers to confirm diagnosis, which is based on clinical suspicion and exclusion of alternative causes. Because the drug development process fails to completely screen out hepatotoxic molecules and identify susceptible individuals, postmarketing pharmacovigilance remains essential. Hepatotoxicity registries are the ideal instrument for systematic and continual data collection, using preestablished criteria based on consensus. The present article briefly describes the contributions of the Spanish Hepatotoxicity Registry and those of other international registries. Hopefully, Latin American registries will be incorporated into existing initiatives, which will stimulate research and improve understanding of the complex mechanisms involved in this adverse reaction (AU)