Occurrence Of Drug-induced Liver Injury Research Articles

Does diabetes mellitus comorbidity increase the risk of drug-induced liver injury during tuberculosis treatment?

The growing burden of diabetes worldwide is a threat to tuberculosis (TB) control. Drug-induced liver injury (DILI) due to TB drugs is a significant concern and there is currently limited evidence on the effect of diabetes on TB DILI. This study sought to investigate the effect of diabetes as a risk factor for DILI and to further study any potential co-factors. An unmatched case-control study. Cases were TB patients on 2RHZE/4RH presenting with DILI from 2013-2017 in Porto Alegre, Brazil. Controls were contemporaneous TB patients without DILI being treated in any one of the same five Porto Alegre TB clinics. The exposure variables were diabetes (main exposure variable), age, sex, alcohol misuse, human immunodeficiency virus (HIV), hepatitis C (HCV) and B (HBV) viruses, concomitant hepatotoxic drugs, other liver diseases and TB site. The outcome variable was the occurrence of DILI. Odds of DILI were increased by: older age group 51-60, 61-70 and 71-93 years (adjusted OR 2.39, 95%CI 1.30-4,38; adjusted OR 4.37, 2.28-8,35; adjusted OR 12.91, 5.81-28,66, respectively), HIV positive status (adjusted OR 3.59, 95%CI 2.25-5.73), HCV positive status (adjusted OR 3.49, 95%CI 1.96-6.21) and having concurrent pulmonary and extrapulmonary TB (adjusted OR 3.16, 95%CI 1.93-5.19). Diabetes, gender, and other hepatotoxic drugs were not associated with DILI. This study confirms the association between TB DILI and well-known risk factors but did not demonstrate increased odds of TB DILI in patients with diabetes.

Impact of m6A demethylase (ALKBH5, FTO) genetic polymorphism and expression levels on the development of pulmonary tuberculosis.

The m6A methylation was involved in the pathogenesis of pulmonary tuberculosis (PTB), and our study aimed to reveal the potential association of m6A demethylase (ALKBH5, FTO) genes variation, expression levels and PTB. Eight SNPs (ALKBH5 gene rs8400, rs9913266, rs12936694, rs4925144 and FTO gene rs6499640, rs8047395, rs1121980, rs9939609) were selected for genotyping by SNPscan technique in 449 PTB patients and 463 healthy controls. The mRNA expression levels of ALKBH5, FTO were detected by qRT-PCR. There were no significant differences in genotype, allele distributions of all SNPs between PTB patients and healthy controls. Haplotype analysis demonstrated that the frequency of FTO gene GAAA haplotype was significantly reduced in PTB patients when compared to controls. ALKBH5 rs8400 AA genotype, A allele frequencies were associated with the decreased risk of sputum smear-positive, while AA genotype frequency was related to the increased risk of hypoproteinemia in PTB patients. In addition, rs9913266 variant was linked to the occurrence of drug-induced liver injury, sputum smear-positive, and rs4925144 variant was associated with leukopenia among PTB patients. In FTO gene, rs8047395 GG genotype and G allele frequencies were significantly higher in the PTB patients with drug resistance than that in the PTB patients without drug resistance. The ALKBH5, FTO expression levels were significantly decreased in PTB patients in comparison to controls. Moreover, ALKBH5 level was increased in PTB patients with drug resistance, and FTO level was decreased in PTB patients with sputum smear-positive. FTO gene polymorphisms might be associated with PTB susceptibility, and ALKBH5, FTO levels were decreased in PTB patients, suggesting that these m6A demethylase played important roles in PTB.

Nonclinical Safety Signals in PharmaPendium Improve the Predictability of Human Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a leading cause of candidate attrition during drug development in the pharmaceutical industry. This study evaluated liver toxicity signals for 249 approved drugs (114 of "most-DILI concern" and 135 of "no-DILI concern") using PharmaPendium and assessed the association between nonclinical and clinical injuries using contingency table analysis. All animal liver findings were combined into eight toxicity categories based on nature and severity. Together, these analyses revealed that cholestasis [odds ratio (OR): 5.02; 95% confidence interval (CI) 1.04-24.03] or liver aminotransferase increases (OR: 1.86; 95% CI 1.09-3.09) in rats and steatosis (OR-1.9; 95% CI 1.03-3.49) or liver aminotransferase increases (OR-2.57; 95% CI 1.4-4.7) in dogs were significant predictors of human liver injury. The predictive value further improved when the liver injury categories were combined into less severe (steatosis, cholestasis, liver aminotransferase increase, hyperbilirubinemia, or jaundice) and more-severe (liver necrosis, acute liver failure, or hepatotoxicity) injuries. In particular, less-severe liver injuries in the following pairs of species predicted human hepatotoxicity {[dog and mouse] (OR: 2.70; 95% CI 1.25-5.84), [dog and rat] (OR-2.61; 95% CI 1.48-4.59), [monkey and mouse] (OR-4.22; 95% CI 1.33-13.32), and [monkey and rat] (OR-2.45; 95% CI 1.15-5.21)} were predictive of human hepatotoxicity. Meanwhile, severe liver injuries in both [dog and rat] (OR-1.9; 95% CI 1.04-3.49) were significant predictors of human liver toxicity. Therefore, we concluded that the occurrence of DILI in humans is highly likely if liver injuries are observed in one rodent and one nonrodent species and that liver aminotransferase increases in dogs and rats can predict DILI in humans. Together, these findings indicate that the liver safety signals observed in animal toxicity studies indicate potential DILI risk in humans and could therefore be used to prioritize small molecules with less potential to cause DILI in humans.

Frequency of null genotypes of glutathione S-transferase M1 and T1 in Japanese patients with drug-induced liver injury.

Previous reports suggest that the null genotype (*0/*0) of glutathione S-transferase (GST) M1 and/or GSTT1 could be risk factors for drug-induced liver injury (DILI). However, multi-institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients. Blood samples of 270 DILI patients from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp-2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week-Japan score, as well as genotypes of GSTM1 and GSTT1 in each patient with DILI. The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of the GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and Digestive Disease Week-Japan scores was not observed. The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients.

Is the hepatotoxicity of metamizole significant in clinical practice?

In December 2020 representatives of the responsible entities in consulation with European Medicines Agency and Office for Registration of Medicinal Products, Medical Devices and Biocidal Products published a safety communication on the possible occurrence of drug-induced liver injury (DILI) in the use of metamizolecontaining medicinal products. According to the message, metamizole should not be re-used in patients with a history of liver damage during treatment with metamizole, when no other cause that could lead to liver damage has been identified. Clinical practice, including spontaneous monitoring of side effects, shows that metamizole is still an effective and safe analgesic, which is included in the current recommendations for the treatment of acute, postoperative and cancer patients.

Drug-Induced Liver Injury (DILI) in Patients with Depression Treated with Antidepressants: A Retrospective Multicenter Study.

Drug-induced liver injury (DILI) is the 4th most common cause of liver damage in Western countries and can be caused by antidepressants. Against the background of increasing antidepressant prescriptions and increasing use of polypharmacy, we analyzed administered antidepressants and other pharmacological substances, liver toxicity, comorbid somatic secondary diseases together with the occurrence of DILI in a patient population of 6 centers throughout Germany. The majority of the enrolled 329 patients received polypharmacological treatment in an inpatient setting. During antidepressant treatment 5.1% of the patients had elevated serum transaminase levels, whereby exactly and not more than 1 criterion proposed to be indicative for DILI, was fulfilled by 3 patients (0.9%). During patient characterization it becomes clear that a sensitization for relevant risk constellations causing liver injury in MDD patients is relevant to prevent further serious adverse events.

Use of Statins in Patients with Chronic Liver Disease and Cirrhosis: Current Views and Prospects.

The purpose of this study is to analyze the current evidence regarding the use of statins in patients with chronic liver disease and cirrhosis. Chronic liver disease (CLD), cirrhosis, and its complications, including hepatocellular carcinoma (HCC), are significant public health problems. The use of statins in patients with CLD has been a matter of concern, and physicians are often reluctant to its prescription in these patients. This mainly relates to the potential occurrence of drug-induced liver injury. However, newer evidence from pre-clinical and clinical research has shown that statins are drugs with a potentially beneficial impact on the natural history of cirrhosis, on portal hypertension, and in HCC prevention. In this review, we summarize current evidence regarding the influence of statins in endothelial dysfunction in CLD, their ability to modulate hepatic fibrogenesis, and their vasoprotective effects in portal hypertension; we also focus on existing data about the impact of statins in cirrhosis development, progression, and complications and critically assess the current concerns about its use in patients with CLD.

DRUG-INDUCED LIVER INJURY AND PYRAZINAMIDE USE

In the 1950s, high doses (40-70 mg/kg/day) of pyrazinamide were reported to cause drug-induced liver injury (DILI). It remains unclear whether adding pyrazinamide (Z) at the currently accepted low dose (20-25 mg/kg/day) to a regimen of isoniazid (H), rifampicin (R), and ethambutol (E) increases the risk of DILI. We reviewed adult patients admitted for smear-positive tuberculosis who were treated with a daily HRE or HRZE regimen. A Cox model was used to analyze the impact of pyrazinamide on the occurrence of DILI. We reviewed 195 patients (123 men [63%], 72 women [37%], average age 65 ± 19 years, 65 HRE patients [33%], 130 HRZE patients [67%]). The incidence of DILI in the first two months was 15% (29/195). The HRZE regimen was not associated with DILI (hazard ratio 0.55, P = 0.263). Addition of low-dose (20-25 mg/kg/day) pyrazinamide to the HRE regimen does not appeared to be associated with increased DILI incidence during the first two months of treatment.

The clinical characteristics of anti-tuberculosis drug induced liver injury in 2457 hospitalized patients with tuberculosis in China

Anti-tuberculosis drug induced liver injury (ATDILI) ranks the first in all kinds of drug-induced liver injuries. ATDILI causes not only economic loss of public health system and patients, but also mental burden of patients, and often leads to treatment interruption or drug resistance. To investigate the clinical characteristics and predisposing factors of ATDILI, the clinical characteristics of 2457 hospital-admitted cases treated with anti-tuberculosis (TB) drugs during 2005 and 2009 and their correlative factors were retrospectively analyzed. The incidence of ATDILI among 2457 TB patients who were treated for the first time was 10.9% (267/2457), that is 13.6% (148/1085) in female and 8.7% (119/1372) in male. Female TB patients were more prone to have ATDILI as compared to male TB patients (P<0.05). The incidence of ATDILI in TB patients who were not treated with liver protectants (13.8%, 80/581) was significantly higher than that in patients who were treated with liver protectants (10.0%, 187/1876, P<0.05). 13.2% (139/1050) patients treated with isoniazid (H), rifampin (R), and pyrazinamide (Z)/ethambutol (E) (HRZ/E) regime had ATDILI, which was significantly higher than that in TB patients treated with HRE (9.1%, 128/1407, P<0.05). Susceptible patients of ATDILI should take appropriate preventive measures to avoid the occurrence of drug-induced liver injury. Key words: Liver injury, anti-tuberculosis drugs, clinical characteristics, predisposing factor.

Can statins be used safely in coronary heart disease patients of Hepatitis B virus carriers?

Clinical trials have been shown that use of statins reduces the cardiovascular morbidity and mortality in a wide range of circumstances. However, in spite of the proven benefits of statins, they have the potential hepatotoxicity [1].Patients with underlying liver disease may be at increased risk for hepatotoxicity of statins and should be given attention. Literature has indicated that use of statins in patients with non-alcoholic fatty liver disease [2], Hepatitis C infection [3] and primary biliary cirrhosis [4] is safe, but there was no study about statins' security in patients with Hepatitis B infection which is epidemic globally, especially in China [5,6]. Hy's rule concluded that the patient mortality rate due to the occurrence of drug-induced liver injury can be as high as 10–50% [7], even with the discontinue of use of related drugs. Clearly, more information is needed about the potential effects of statins in HBV-infected patients before these medications are considered for study.

The Application of Metabonomics to Predict Drug-Induced Liver Injury

The occurrence of drug-induced liver injury (DILI) presents a significant safety issue for patients and represents a major cause of regulatory action. The methods that are in current use for early detection and prediction of DILI in patients are not adequate. The liver is the major site of synthesis of endogenous metabolites, and data suggest that alterations in the profiles of endogenous metabolites ("the metabolome") may precede development of clinically overt DILI. Metabonomics involves the application of analytical technologies such as nuclear magnetic resonance and mass spectrometry to detect changes in the metabolome. In this review, we describe the emerging role of metabonomics in predicting and understanding the mechanisms underlying DILI. Recent human clinical trials of drugs, including acetaminophen (APAP) and ximelagatran, have shown that the metabonomics of biofluids (plasma and urine) collected before and immediately after dosing can identify individual patients who are likely to develop DILI. These studies support the need to include metabonomic investigations in clinical trials of potentially hepatotoxic medications.