Efeitos adversos às drogas antituberculose: hepatotoxicidade / Adverse effects to antituberculosis drugs: hepatotoxicity

Objetivo: Verificar a frequência de efeitos adversos em pacientes em uso de drogas antituberculose de primeira linha, além dos fatores de risco associados aos efeitos adversos e à hepatotoxicidade. Métodos: Estudo transversal, envolvendo 196 pacientes portadores de tuberculose em Maceió (AL), de agosto de 2017 a junho de 2018. Os efeitos adversos foram classificados de acordo com o Manual de Recomendações para Controle da Tuberculose de 2011, do Ministério da Saúde, em efeitos menores (queixas gastrintestinais, cutâneos, articulares e neurológicos) e maiores (psicose e hepatotoxicidade). Os fatores de risco avaliados foram: idade superior a 40 anos, etilismo, sexo feminino, anemia, doença hepática anterior, diabetes e infecção por HIV. Resultados: Foram observados efeitos adversos às drogas antituberculose em 85 pacientes (43,4%); destes, 40,8% eram menores e 8,2%, maiores. Os mais frequentes foram distúrbios gastrintestinais (25,5%) e cutâneos (15,3%). Identificaram-se como fatores de risco anemia, diabetes e doença hepática anterior. Hepatotoxicidade foi diagnosticada em 15 pacientes (10,6%), dos quais 80% eram sintomáticos, sendo fatores de risco doença hepática anterior e diabetes. Houve suspensão da terapia em todos os casos de hepatotoxicidade com modificação do esquema em 80% dos casos. Conclusão: Demonstrou-se frequência elevada de efeitos adversos às drogas antituberculose, associada à doença hepática anterior e ao diabetes. A hepatotoxicidade representou o efeito adverso mais grave, responsável pela suspensão e pela adequação do esquema terapêutico.

Objective: To determine the adverse effects frequency in patients on first-line antituberculosis drugs, as well as the risk factors associated with adverse effects and hepatotoxicity. Methods: Cross-sectional study, involving 196 tuberculosis patients in Maceió (AL), from August 2017 to June 2018. Adverse effects were classified according to the Manual de Recomendações para Controle da Tuberculose, of the Brazilian Health Ministry, in minor effects (gastrointestinal, cutaneous, articular, neurologic complaints) and major effects (psychosis and hepatotoxicity). The risk factors evaluated were age over 40 years, alcoholism, female sex, anemia, previous hepatic disease, diabetes, and infection by HIV. Results: Adverse effects to the antituberculosis drugs were observed in 85 patients (43.4%) and, among those, 40.8% were minor and 8.2% were major effects. The most frequent were gastrointestinal (25.5%) and skin (15.3%) disorders. Risk factors were identified as anemia, diabetes, and previous hepatic disease. Hepatotoxicity was diagnosed in 15 patients (10.6%), from which 80% were symptomatic, with previous hepatic disease and diabetes being the risk factors. Therapy was discontinued in all cases of hepatotoxicity with regimen modification in 80% of cases. Conclusion: An elevated frequency of adverse effects to antituberculosis drugs was demonstrated. Hepatotoxicity represented the most severe adverse effect, being responsible for the discontinuation and adaptation of the therapeutic regimen.

Hepatotoxicidade induzida por azatioprina em portadora da síndrome de Vogt-Koyanagi-Harada / Azathioprine-induced hepatotoxicity in a Vogt-Koyanagi-Harada syndrome patient

Este relato teve como objetivo apresentar um caso de hepatotoxicidade colestática induzida por azatioprina em portadora da síndrome de Vogt-Koyanagi-Harada. À admissão, apresentava icterícia +3/+4, acolia fecal e colúria, além de aumento de marcadores hepáticos, sendo compatível com síndrome colestática, cuja etiologia foi confirmada após exclusão de outras causas possíveis e retirada da azatioprina. A paciente evoluiu, após 1 semana de retirada do fármaco, com diurese livre de coloração menos escura e evacuação presente, sem acolia. Além disso, houve melhora nos exames que precederam a alta hospitalar

This report aimed at presenting a case of azathioprine-induced cholestatic hepatotoxicity in a patient with Vogt-Koyanagi-Harada syndrome. On admission, she presented with jaundice +3/+4, acholic feces, and choluria, as well as increased hepatic markers, all consistent with cholestatic syndrome, the etiology of which was confirmed after other possible causes were ruled out and azathioprine was discontinued. After 1 week of the drug discontinuation, the patient progressed with free diuresis of lighter color and defecation, with no acholia. In addition, tests performed before discharge were improved.

Early monitoring for detection of antituberculous drug-induced hepatotoxicity

BACKGROUND/AIMS: We investigated the time of onset of antituberculous drug-induced hepatotoxicity (ADIH) and related characteristics. METHODS: Adult patients (n = 1,031) treated with first-line antituberculous drugs between February 2009 and January 2013 were enrolled. RESULTS: Of the 1,031 patients, 108 patients (10.5%) developed ADIH a mean of 39.6 +/- 43.7 days after treatment initiation. Twenty-eight patients (25.9%) developed ADIH within 7 days, 73 (67.6%) within 30 days, and the rest after 30 days. The 30-day group. In subgroup analysis, the 40 IU/L (odds ratio [OR], 2.995; 95% confidence interval [CI], 1.580 to 5.680; p = 0.001) and presence of anti-hepatitis C virus (OR, 4.204; 95% CI, 1.822 to 9.700, p = 0.001) were independent risk factors for development of ADIH. CONCLUSIONS: Approximately 70% of the cases of ADIH occurred in the first month of antituberculous treatment, and were associated with continuation of the first-line drug regimen.

Time-course changes in the expression levels of miR-122, -155, and -21 as markers of liver cell damage, inflammation, and regeneration in acetaminophen-induced liver injury in rats

Drug-induced liver injury (DILI) is a significant threat to patient health and a major concern during drug development. Recently, multiple circulating microRNAs (miRNAs) have been reported to be potential biomarkers for DILI. To adapt and validate miRNAs for clinical use, we investigated the time-course changes in miR-122 expression levels in an acetaminophen-induced liver injury model in rats. In addition, miR-155 and miR-21 were evaluated as makers of inflammation and regeneration, respectively, to characterize liver status. Our results revealed that miR-122 is an early and sensitive biomarker of hepatocellular injury at a stage when alanine transaminase, aspartate transaminase, and total bilirubin were not detectable. However, no significant differences in the expression levels of other miRNAs (miR-155 and -21) were observed between treatment and vehicle groups. Collectively, these time-course changes in the expression levels of miRNAs may be useful as markers for clinical decision-making, in the diagnosis and treatment of DILI.

Therapeutic efficacy of Nigella sativa Linn. seed extract against CCl4 induced hepatic injury in wistar rats.

Carbon tetrachloride (CCl4) intake damages liver. We evaluated therapeutic potential of aqueous extract of Nigella sativa seeds against CCl4 induced liver damage in rats. The hepatic damage induced by CCl4 @ 1.5 mL/kg, ip was evidenced by a significant increase in the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, protein and urea lipid peroxidation (LPO) as well as reduction in hepatic antioxidant system e.g. reduced glutathione. Hepatic total protein and glucose-6-phosphatase activity were found decreased. Histological studies substantiated the above biochemical findings. However, after 48 h of administration of aqueous extract of N. sativa seeds (250, 500 and 750 mg/kg, po) it not only detoxified the toxicity but also reversed LPO, GSH, AST, ALT and serum protein changes at all the three doses. Both higher doses of extract were found effective in monitoring urea, albumin, total protein and G-6-Pase activity. However, on the basis of percent protection highest dose i.e., 750 mg/kg proved better. The result suggests that the aqueous extract of N. sativa seeds can be used as a hepatoprotective agent.

Causes, Features, and Outcomes of Drug-Induced Liver Injury in 69 Children from China

BACKGROUND/AIMS: Drug-induced liver injury (DILI) is a frequent cause of pediatric liver disease; however, the data on DILI are remarkably limited. METHODS: All 69 children hospitalized with DILI between January 2009 and December 2011 were retrospectively studied. RESULTS: A total of 37.7% of the children had medical histories of respiratory infection. The clinical injury patterns were as follows: hepatocellular 89.9%, cholestatic 2.9%, and mixed 7.2%. Liver biopsies from 55 children most frequently demonstrated chronic (47.3%) and acute (27.3%) hepatitis. Hypersensitivity features, namely, fever (31.9%), rash (21.7%), and eosinophilia (1.4%), were found. Twenty-four children (34.8%) developed chronic DILI. Antibiotics (26.1%) were the most common Western medicines (WMs) causing DILI, and the major implicated herbs were Ephedra sinica and Polygonum multiflorum. Compared with WM, the children whose injuries were caused by Chinese herbal medicine (CHM) showed a higher level of total bilirubin (1.4 mg/dL vs 16.6 mg/dL, p=0.004) and a longer prothrombin time (11.8 seconds vs 17.3 seconds, p=0.012), but they exhibited less chronic DILI (2/15 vs 18/39, p=0.031). CONCLUSIONS: Most cases of DILI in children are caused by antibiotics or CHM used to treat respiratory infection and present with hepatocellular injury. Compared with WM, CHM is more likely to cause severe liver injury, but liver injury caused by CHM is curable.

Drug-induced Hepatotoxicity of Anti-tuberculosis Drugs and Their Serum Levels

The correlation between serum anti-tuberculosis (TB) drug levels and the drug-induced hepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whether anti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in blood samples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liver function test abnormality were diagnosed on the basis of laboratory and clinical criteria. Serum anti-TB drug levels and other clinical factors were compared between the hepatotoxicity and non-hepatotoxicity groups. A total of 195 TB patients were included in the study, and the data were analyzed retrospectively. Seventeen (8.7%) of the 195 patients showed hepatotoxicity, and the mean aspartate aminotransferase/alanine aminotransferase levels in the hepatotoxicity group were 249/249 IU/L, respectively. Among the 17 patients with hepatotoxicity, 12 showed anti-TB DIH. Ten patients showed PZA-related hepatotoxicity and 2 showed INH- or RMP-related hepatotoxicity. However, intergroup differences in the serum levels of the 4 anti-TB drugs were not statistically significant. Basal serum drug concentration was not associated with the risk anti-TB DIH in patients being treated with the currently recommended doses of first-line anti-TB treatment drugs.

Drug-induced Hepatotoxicity of Anti-tuberculosis Drugs and Their Serum Levels

The correlation between serum anti-tuberculosis (TB) drug levels and the drug-induced hepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whether anti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in blood samples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liver function test abnormality were diagnosed on the basis of laboratory and clinical criteria. Serum anti-TB drug levels and other clinical factors were compared between the hepatotoxicity and non-hepatotoxicity groups. A total of 195 TB patients were included in the study, and the data were analyzed retrospectively. Seventeen (8.7%) of the 195 patients showed hepatotoxicity, and the mean aspartate aminotransferase/alanine aminotransferase levels in the hepatotoxicity group were 249/249 IU/L, respectively. Among the 17 patients with hepatotoxicity, 12 showed anti-TB DIH. Ten patients showed PZA-related hepatotoxicity and 2 showed INH- or RMP-related hepatotoxicity. However, intergroup differences in the serum levels of the 4 anti-TB drugs were not statistically significant. Basal serum drug concentration was not associated with the risk anti-TB DIH in patients being treated with the currently recommended doses of first-line anti-TB treatment drugs.

Protective effect of secondary plant metabolites from Ipomoea aquatica Forsk. against carbofuran induced damages.

Plausible interactions between food contaminants and natural constituents in vivo and protective effect of polyphenols present in I. aquatica against carbofuran toxicity in Charles Foster rats were evaluated. Determinations based on antioxidant enzyme activities showed significant alterations in glutathione, glutathione peroxidase, superoxide dismutase and catalase in tissues (liver and brain) and plasma of pesticide treated group while polyphenolic extracts from I. aquatica (IAE) attenuated their activities when given alongwith carbofuran. IAE decreased enhanced lipid peroxidation levels in plasma and erythrocyte membrane and cholesterol levels in brain and plasma. IAE also minimized histopathological degenerative changes produced by carbofuran. While single cell gel electrophoresis showed that secondary metabolites in leafy vegetables produced a combinatorial effect with pesticide at cellular level, DNA fragmentation level in bone marrow cells showed a decline in the IAE treated rats. Food safety adversely affected by various chemical contaminants can be retained by plant polyphenols and secondary plant constituents that can be found together in bolus. Therefore, the present study gives an insight into the protective role of naturally found polyphenols against pesticide toxicity.

Hepato and reno protective action of Calendula officinalis L. flower extract.

Flower extract of C. officinalis L. was evaluated for its protective effect against CCl4 induced acute hepatotoxicity and cisplatin induced nephrotoxicity. The activities of serum marker enzymes of liver injury like glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase (SGOT) and alkaline phosphatase (ALP) which were increased by CCl4 injection was found to be significantly reduced by the pretreatment of the flower extract at 100 and 250 mg/kg body weight. The lipid peroxidation in liver, the marker of membrane damage and the total bilirubin content in serum were also found to be at significantly low level in the extract pretreated group, indicating its protective role. The kidney function markers like urea and creatinine were significantly increased in cisplatin treated animals. However, their levels were found to be lowered in the extract pretreated groups (100 and 250 mg/kg body weight). Moreover, cisplatin induced myelosuppression was ameliorated by the extract pretreatment. Treatment with the extract produced enhancement of antioxidant enzymes--superoxide dismutase and catalase and glutathione. Results suggest a protective role of the flower extract of C. officinalis against CCl4 induced acute hepatotoxicity and cisplatin induced nephrotoxicity. Extract has been found to contain several carotenoids of which lutein, zeaxanthin and lycopene predominates. Possible mechanism of action of the flower extract may be due to its antioxidant activity and reduction of oxygen radicals.

Antituberculosis drug-induced hepatitis: risk factors, prevention and management.

Apart from infectious or viral hepatitis, other most common non-infectious causes of hepatitis are alcohol, cholestatic, drugs and toxic materials. The most common mode that leads to liver injuries is antituberculosis drug-induced hepatitis. The severity of drug-induced liver injury varies from minor nonspecific changes in hepatic structure to fulminant hepatic failure, cirrhosis and liver cancer. Patients receiving antitubercular drug frequently develop acute or chronic hepatitis. The time required for the metabolites to reach hepatotoxic levels is much earlier with isoniazid plus rifampicin treatment than isoniazid alone and this has been shown to be synergistic rather than additive. Antituberculosis drug (ATT)-inducible cytochrome P-4502E1 (CYP2E1) is constitutively expressed in the liver. Recent studies show that polymorphism of the N-acetyltransferase 2 (NAT2) genes and glutathione-S-transferase (GST) are the major susceptibility risk factors for ATT-induced hepatitis. The hepatic NAT and GST are involved in the metabolism of several carcinogenic arylamines and drugs. The NAT2 enzyme has a genetic polymorphism in human. N-acetyltransferase 2 genes (NAT2) have been identified to be responsible for genetic polymorphism of slow and rapid acetylation in humans. Slow acetylators of NAT2 prove to develop more severe hepatotoxicity than rapid acetylators making it a significant risk factor. Deficiency of GST activity, because of homozygous null mutations at GSTM1 and GSTT1 loci, may modulate susceptibility to drug and xenobiotic-induced hepatotoxicity. Polymorphisms at GSTM1, GSTT1 and NAT2 loci had been linked to various forms of liver injury, including hepatocellular carcinoma.

Induction of oxidative stress in antitubercular drug-induced hepatotoxicity.

BACKGROUND AND AIM: Oxidative stress could play a role in the pathogenesis of antitubercular drug (ATD)-induced hepatotoxicity. We therefore studied the plasma level of reduced glutathione (GSH) and malondialdehyde (MDA) in patients with ATD-induced hepatotoxicity (cases), ATD-treated controls (disease controls) and in healthy volunteers. METHODS: This study was carried out in a case-control design. Twenty-one cases, 21 age- and sex-matched disease controls, and 10 healthy volunteers were enrolled. Plasma levels of GSH and MDA were measured. RESULTS: Plasma levels of GSH (median [range] 11.5 [6.2-21.2] mmol/dL) and MDA (1390 [560-2310] nmol/dL) of cases were significantly different (p<0.01) from GSH (18.4 [10.5-24.4]) and MDA (290 [240-550]) of disease controls. Further, plasma GSH and MDA levels of both the ATD-treated groups were different from those in healthy controls. CONCLUSION: Lower levels of plasma GSH and higher levels of MDA may be due to oxidative stress resulting from ATD therapy.

Protective effect of turmeric (Curcuma longa L.) extract on carbon tetrachloride-induced liver damage in rats.

The protective effect of tumeric extract (TE) in diet on CCl4-treated rats was studied. Rats were divided into 5 groups: (1) untreated, (2) CCl4 treated, (3) pre-TE for 2 weeks followed by CCl4, (4) TE + CCl4 given concurrently and (5) 5% TE as positive control. The serum levels of bilirubin, cholesterol, aspartate aminotransferase, (AST), alanine amino transferase (AST), (ALT) and alkaline phosphatase were estimated after 1, 2 and 3 months. CCl4 caused a maximum increase (2-3-fold in all the above parameters. As compared to CCl4 group, a short pre-treatment of TE showed reduction in cholesterol, bilirubin, AST, ALT and alkaline phosphatase activity whereas concurrent treatment of TE + CCl4 reduced to a greater extent the levels of all parameters except ALT. To conclude, concurrent treatment of TE gave significant protection against CCl4 though the values did not reach the normal levels.