[Show abstract][Hide abstract] ABSTRACT: Cyproterone acetate (CPA), an antiandrogenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA-induced DILI.
Twenty-two males (70±8 years; range 54-83) developing liver damage due to CPA therapy (dose: 150±50 mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed.
From 1993 to 2013, 22 patients were retrieved. Latency was 163±97 days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18±13 x ULN, ALP 0.7±0.7 x ULN, and total serum bilirubin 14±10 mg/dL. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%), and fatal in 3 (14%). Five patients developed ascitis, and 4 encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although 3 required steroid therapy (2 of them had high ANA titres). Liver biopsy was performed in 7 patients (2 hepatocellular collapse, 1 submassive necrosis, 2 cholestatic hepatitis, 1 cirrhosis with iron overload, and 1 autoimmune hepatitis). RUCAM category was "highly probable" in 19 (86%), "probable" in 1 (4%), and "possible" in 2 (9%).
CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Full-text · Article · Jun 2015 · Liver international: official journal of the International Association for the Study of the Liver
[Show abstract][Hide abstract] ABSTRACT: Background
We have observed an increase in hepatotoxicity (DILI) reporting related to the use of anabolic androgenic steroids (AAS) for bodybuilding.AimTo characterise phenotype presentation, outcome and severity of AAS DILI.Methods
Data on 25 cases of AAS DILI reported to the Spanish (20) and Latin-American (5) DILI Registries were collated and compared with previously published cases.ResultsAAS DILI increased from representing less than 1% of the total cases in the Spanish DILI Registry in the period 2001–2009 to 8% in 2010–2013. Young men (mean age 32 years), requiring hospitalisation, hepatocellular injury and jaundice were predominating features among the AAS cases. AAS DILI caused significantly higher bilirubin values independent of type of damage when compared to other drug classes (P = 0.001). Furthermore, the cholestatic AAS cases presented significantly higher mean peak bilirubin (P = 0.029) and serum creatinine values (P = 0.0002), compared to the hepatocellular cases. In a logistic regression model, the interaction between peak bilirubin values and cholestatic damage was associated with the development of AAS-induced acute kidney impairment (AKI) [OR 1.26 (95% CI: 1.035–1.526); P = 0.021], with 21.5 ×ULN being the best bilirubin cut-off point for predicting AKI risk (AUCROC 0.92). No fatalities occurred.Conclusions
Illicit recreational AAS use is a growing cause of reported DILI that can lead to severe hepatic and renal injury. AAS DILI is associated with a distinct phenotype, characterised by considerable bilirubin elevations independent of type of damage. Although hepatocellular injury predominates, acute kidney injury develops in cholestatic cases with pronounced jaundice.
No preview · Article · Nov 2014 · Alimentary Pharmacology & Therapeutics
[Show abstract][Hide abstract] ABSTRACT: Purpose of review:
Idiosyncratic drug-induced liver injury (iDILI) is a relatively rare condition, but can have serious consequences for the individual patient, public health, regulatory agencies and the pharmaceutical industry. Despite increased awareness of iDILI, its underlying mechanism is still not fully understood. This review summarizes the current understanding of the molecular mechanism behind iDILI.
Genetic variations in drug metabolizing genes are in line with proposed mechanisms based on acetaminophen hepatotoxicity, whereby reactive metabolites covalently bind to cellular proteins and disturb the redox balance. In addition, immune-mediated effects have been reported for flucloxacillin hepatotoxicity, demonstrating both haptenization and direct binding between the drug and immune receptors.
Idiosyncratic DILI development is believed to be orchestrated by multiple events, such as reactive metabolite formations, oxidative stress and signalling pathway inductions, with the mitochondria taking centre stage. Evidence also points towards the immune system (innate and adaptive responses) as important components in iDILI. Interindividual differences in one or more of these events, due to genetic variations and environmental factors, are likely to contribute to the idiosyncratic nature of this condition and subsequently distinguish between patient susceptibility and tolerance.
No preview · Article · Jun 2014 · Current Opinion in Allergy and Clinical Immunology
[Show abstract][Hide abstract] ABSTRACT: Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort.
A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (-1774G>del, -1549A>G, -24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5' allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed.
None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 -1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 -1774G/-1549A/-24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI.
Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 -1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.
[Show abstract][Hide abstract] ABSTRACT: & Aims: Hy´s Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is widely used to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy´s Law and to develop a model for predicting ALF in patients with DILI.
We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry in Spain, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL).
Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL>2-fold the upper limit of normal (xULN) and either ALT>3xULN, an R value (ALT x ULN/ alkaline phosphatase x ULN) ≥5, or an nR value (ALT or AST, whichever produces the highest xULN/ alkaline phosphatase x ULN value) ≥5. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels >2xULN. An algorithm based on AST>17.3 x ULN, TBL >6.6 x ULN, and AST:ALT >1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity.
When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.
[Show abstract][Hide abstract] ABSTRACT: The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases.
High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls.
The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07).
HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.
[Show abstract][Hide abstract] ABSTRACT: Background & aims:
Several pharmaceutical compounds have been shown to exert inhibitory effects on the bile salt export pump (BSEP) encoded by the ABCB11 gene. We analysed the combined effect on drug-induced liver injury (DILI) development of the ABCB11 1331T>C polymorphism and the presence of specific chemical moieties, with known BSEP inhibiting properties, in the causative drug.
Genotyping using a TaqMan 5' allelic discrimination assay was performed in 188 Spanish DILI patients, 219 healthy controls and 91 sex-, age- and drug-matched controls. A chemical structure analysis was performed for each individual causative drug.
The CC genotype was significantly associated with hepatocellular damage [odds ratio (OR) = 2.1, P = 0.001], particularly in NSAID DILI cases (OR = 3.4, P = 0.007). In addition, the CC genotype was found to be significantly linked to DILI development from drugs causing <50% BSEP inhibition (OR = 1.8, Pc = 0.011). Of the BSEP inhibitory chemical moieties, 59% of the causative drugs contained a carbocyclic system with at least one aromatic ring, corresponding to 61% of the total cases. The C allele was significantly more frequent in DILI cases containing this chemical moiety, which appear to be conditioned on the ABCB11 1331T>C polymorphism in the absence of other BSEP inhibitory structures.
Patients carrying the C allele in the ABCB11 1331T>C polymorphism are at increased risk of developing hepatocellular type of DILI, when taking drugs containing a carbocyclic system with aromatic rings.
Full-text · Article · Apr 2013 · Liver international: official journal of the International Association for the Study of the Liver