Spanish Drug-induced Liver Injury Registry Research Articles

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

Clinical presentation, causative drugs and outcome of patients with autoimmune features in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) with autoimmune features is a liver condition with laboratory and histological characteristics similar to those of idiopathic autoimmune hepatitis (AIH), which despite being increasingly reported, remains largely undefined. We aimed to describe in-depth the features of this entity in a large series of patients from two prospective DILI registries. DILI cases with autoimmune features collected in the Spanish DILI Registry and the Latin American DILI Network were compared with DILI patients without autoimmune features and with an independent cohort of patients with AIH. Out of 1,426 patients with DILI, 33 cases with autoimmune features were identified. Female sex was more frequent in AIH patients than in the other groups (p = .001). DILI cases with autoimmune features had significantly longer time to onset (p < .001) and resolution time (p = .004) than those without autoimmune features. Interestingly, DILI patients with autoimmune features who relapsed exhibited significantly higher total bilirubin and transaminases at onset and absence of peripheral eosinophilia than those who did not relapse. The likelihood of relapse increased over time, from 17% at 6 months to 50% 4 years after biochemical normalization. Statins, nitrofurantoin and minocycline were the drugs most frequently associated with this phenotype. DILI with autoimmune features shows different clinical features than DILI patients lacking characteristics of autoimmunity. Higher transaminases and total bilirubin values with no eosinophilia at presentation increase the likelihood of relapse in DILI with autoimmune features. As the tendency to relapse increases over time, these patients will require long-term follow-up.

Immunophenotyping to improve the mechanistic understanding of idiosyncratic drug-induced liver injury: clinical implications and future directions

The late event onset of a fraction of idiosyncratic drug-induced liver injury (DILI) cases and the link observed by genome-wide association studies (GWASs) of certain human leucocyte antigen (HLA) alleles with DILI due to specific drugs support the crucial role of the immune system (both innate and adaptive) in the pathogenesis of DILI. Recent advances in both flow and mass cytometry have allowed the profiling of all major immune cell types in a given sample. Therefore, determining the lymphocyte populations in samples from patients with DILI would facilitate the development of specific biomarkers for DILI diagnosis and prognosis. To date, a few studies have explored the immune landscape in DILI. In a recent study of leukocyte immunophenotyping using flow cytometry from the Spanish DILI Registry, an important role of adaptive immune response in DILI is suggested. DILI patients had significantly higher levels of T helper 1 (Th1) cells and activated helper and cytotoxic T cells than healthy controls. Furthermore, the increased expression of negative immune checkpoints and ligands in DILI patients could reflect a restoration of the immune homeostasis. Differences in the profile of cytokines in DILI patients from the Drug-Induced Liver Injury Network (DILIN) also suggest an involvement of both innate and adaptive immune systems in DILI development and prognosis. Moreover, several studies based on immunophenotyping of liver infiltrates showed a distinctive pattern of cellular infiltrates in patients with immune checkpoint inhibitors (ICIs)-DILI, with lower levels of plasma cells, CD20+ B cells and CD4+ T cells than in autoimmune hepatitis (AIH) patients. These pioneering studies highlight the importance of immunophenotyping for the mechanistic understanding of DILI. In this review, available data on immunophenotyping in DILI are gathered, and the potential clinical applications of cutting-edge, novel immunophenotyping techniques are discussed.

Potential benefit and lack of serious risk from corticosteroids in drug-induced liver injury: An international, multicentre, propensity score-matched analysis.

The use of corticosteroids to treat patients with idiosyncratic drug-induced liver injury (DILI) relies on empirical clinical decisions. To investigate the relationship between corticosteroids and risk of acute liver failure (ALF) in patients with DILI and to assess if corticosteroid therapy was associated with improved outcomes in DILI patients. We analysed bona fideidiosyncratic DILI cases from the Spanish DILI Registry and Indiana University School of Medicine. Patients treated with corticosteroids were compared to those who did not receive any treatment. Nearest neighbour propensity score matching analyses were conducted. We enrolled 724 patients, 106 under corticosteroid therapy, in whom there was over-representation of more severe injury and autoimmune features, and 618 who did not receive any treatment. In an analysis of 80 pairs of propensity score-matched patients, corticosteroid administration was not associated with an increased risk of developing ALF (odds ratio=0.65; 95% confidence interval [CI]: 0.18-2.40; p=0.518). Furthermore, in an additional analysis, a Cox regression model that included 41 propensity score-matched pairs showed that patients receiving corticosteroids had a significantly higher normalisation rate of liver enzymes than untreated patients (hazard ratio [HR]=1.84; 95% CI: 1.02-3.32; p=0.043), particularly in patients with serious injury who did not resolve within 30 days (HR=2.79; 95% CI: 1.20-6.50; p=0.018). Corticosteroid therapy did not worsen outcome in DILI patients. Indeed, corticosteroid administration was associated with a greater rate of normalisation of liver enzymes in patients with serious DILI.

Herbal and dietary supplement induced liver injury: Highlights from the recent literature.

Herbal-induced liver injury (HILI) is an important and increasingly concerning cause of liver toxicity, and this study presents recent updates to the literature. An extensive literature review was conducted encompassing September 2019 through March 2021. Studies with clinically significant findings were analyzed and included in this review. We emphasized those studies that provided a causality assessment methodology, such as Roussel Uclaf Causality Assessment Method scores. Our review includes reports of individual herbals, including Garcinia cambogia, green tea extract, kratom as well as classes such as performance enhancing supplements, Traditional Chinese medicine, Ayurvedic medicine and herbal contamination. Newly described herbals include ashwagandha, boldo, skyfruit, and ‘Thermo gun’. Several studies discussing data from national registries, including the United States Drug-Induced Liver Injury (DILI) Network, Spanish DILI Registry, and Latin American DILI Network were incorporated. There has also been a continued interest in hepatoprotection, with promising use of herbals to counter hepatotoxicity from anti-tubercular medications. We also elucidated the current legal conversation surrounding use of herbals by presenting updates from the Federal Drug Administration. The highlights of the literature over the past year indicate interest in HILI that will continue as the supplement industry in the United States grows.

From the Editor’s Desk...

From the Editor’s Desk...

Elevated bilirubin, alkaline phosphatase at onset, and drug metabolism are associated with prolonged recovery from DILI

Although most drug-induced liver injury (DILI) cases resolve after the offending medication is discontinued, time to recovery varies among patients, with 6 -12% developing a chronic disease. Herein, we investigated clinical factors and drug properties as potential risk determinants that influence the time course for DILI recovery and developed a model to predict its trajectory. We applied an accelerated failure time model to 294 cases collected by the International Drug-Induced Liver Network Consortium (iDILIC). Factors included in the multivariate recovery score model were selected through univariate analysis. The model was externally validated using 257 cases from the Spanish DILI Registry and 191 cases from the LiverTox database. Higher serum bilirubin and alkaline phosphatase (ALP) at DILI onset, a longer time to onset, and non-significant drug metabolism were associated with a longer recovery and were included in the recovery score model. We defined high- and low-risk groups based on the scores assigned by the model. The estimated probability of recovery by 6 months was 0.46 (95% CI 0.26-0.61) for the high-risk group and 0.93 (95% CI 0.58-0.99) for the low-risk group in the iDILIC. Model performance was validated in both validation sets. The high- and low-risk cases identified bythe model showed a significantly different time course for recovery, with a majority of low-risk cases recovering sooner. The trajectory of biochemical recovery from DILI is predicted by the extent of drug metabolism, serum bilirubin and ALP at DILI onset. The model can be used to compute an estimated DILI recovery and, when a significant delay is predicted, clinicians may consider additional investigations such as histologic evaluation or extended follow-up. In this study, we investigated whether drug properties and clinical factors are associated with the time it takes to recover from drug-induced liver injury (DILI). We found that total bilirubin, alkaline phosphatase level at DILI onset, time to onset, and extent of drug metabolism were consistently associated with recovery time. Using these factors, we built a model to predict the trajectory of recovery from DILI and validated this model in 2 independent cohorts. Our findings offer important insights into the factors influencing the trajectory of recovery from DILI. Additional investigations and longer follow-ups can be planned in those for whom a delayed recovery is predicted.

Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry

Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p= 0.0083) and in patients with underlying liver disease (p= 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%). AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management. Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes.

Clinical Characteristics and Outcome of Drug-Induced Liver Injury in the Older Patients: From the Young-Old to the Oldest-Old.

Older patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥ 65years) were categorized according to age: "young" (< 65years); "young-old" (65-74years); "middle-old" (75-84years); and "oldest-old" (≥ 85years). All elderly groups had an increasingly higher comorbidity burden (P<0.001) and polypharmacy (P<0.001). There was a relationship between jaundice and hospitalization (P<0.001), and both were more prevalent in the older age groups, especially in the oldest-old (88% and 69%, respectively), and the DILI episode was more severe (P=0.029). The proportion of females decreased across age groups from the young to the middle-old, yet in the oldest-old there was a distinct female predominance. Pattern of liver injury shifted towards cholestatic with increasing age among top culprit drugs amoxicillin-clavulanate, atorvastatin, levofloxacin, ibuprofen, and ticlopidine. The best cutoff point for increased odds of cholestatic DILI was 65years. Older patients had increased non-liver-related mortality (P=0.030) as shown by the predictive capacity of the Model for End-Stage Liver Disease score (odds ratio (OR)=1.116; P<0.001), and comorbidity burden (OR=4.188; P=0.001) in the 6-month mortality. Older patients with DILI exhibited an increasingly predominant cholestatic phenotype across a range of culprit drugs, other than amoxicillin-clavulanate, with increased non-liver-related mortality and require a different approach to predict outcome. The oldest DILI patients exhibited a particular phenotype with more severe DILI episodes and need to be considered when stratifying older DILI populations.

Incidence and prevalence of acute hepatitis E virus infection in patients with suspected Drug-Induced Liver Injury in the Spanish DILI Registry.

Drug-induced liver injury (DILI) presents with a wide phenotypic spectrum requiring an extensive differential diagnosis. Hepatitis E virus (HEV) is not systematically ruled out during acute hepatitis assessment in Spain. The aims of this study were to establish the role of HEV infection and its phenotypic presentation in patients initially suspected of DILI and to determine the anti-HEV seroprevalence rate. An analysis of 265 patients with suspected DILI and considered for enrolment in the Spanish DILI Registry and 108 controls with normal liver profiles was undertaken. Anti-HEV Immunoglobulin (Ig) G antibodies were analysed in serum from all subjects. In those with serum samples extracted within 6months from liver damage onset (n=144), HEV antigen (Ag) and anti-HEV IgM antibodies were tested in duplicate by ELISA. In addition, RT-PCR was performed externally in eight patients. Out of 144 patients, 12 (8%) were positive for anti-HEV IgM, mean age was 61years. Underlying hepatic diseases (OR=23.4, P<.001) and AST peak>20 fold upper limit of normal (OR=10.9, P=.002) were associated with the diagnosis of acute hepatitis E. The overall anti-HEV IgG seroprevalence rate was 35%, evenly distributed between patients with suspected DILI (34%), and controls (39%). HEV seroprevalence and acute hepatitis E rates are relatively high in Spain. A search for active HEV infection is therefore advised in patients assessed for suspicion of DILI, particularly in patients with underlying liver diseases and high transaminase levels.

FRI-077-Influence of drug categorization according to labelling information in the phenotypic presentation of drug-induced liver injury (DILI): An analysis in the Spanish DILI registry

FRI-077-Influence of drug categorization according to labelling information in the phenotypic presentation of drug-induced liver injury (DILI): An analysis in the Spanish DILI registry

High Prevalence of Ibuprofen Drug-Induced Liver Injury in Spanish and Latin-American Registries

High Prevalence of Ibuprofen Drug-Induced Liver Injury in Spanish and Latin-American Registries

Hepatitis E Virus, A Diagnosis to Consider in Drug Induced Liver Injury Assessment

Drug-induced liver injury (DILI) remains one of the most challenging diseases due to the absence of diagnostic tests and biomarkers. DILI usually presents as an acute hepatitis-like picture requiring extensive differential diagnosis, hepatitis E virus (HEV), which is considered a rare condition in Spain, is not usually ruled out during acute hepatitis assessment. Analysis of a cohort of 180 patients from the Spanish DILI Registry diagnosed with DILI was undertaken. We analyzed HEV immunoglobulin (Ig) G and M from two groups of serum samples based on the time point of collection (27 samples during the episode of liver damage and 153 at different time points after resolution). In patients showing anti-HEV-IgM+, AgHEV and RNA-HEV were performed. Out of 180 patients included, 60 (33, 3%) were tested positive for anti-HEV IgG and 6 for anti-HEV IgM (1 positive for HEV-RNA and 2 for Ag-HEV). In the group of samples collected during the episode, 3/27 (11%) were positive for IgM-HEV. Table. Demographic and clinical data of patients with positive IgM anti-HEV.Tabled 1Case nºAge (years)SexSuspected DrugLatency (days)Peak ALT(1) or AST(2)HEV RNAAg HEV149FemaleParacetamol91840 (2)NegativePositive274MaleCefditoren404191 (1)PositivePositive326FemaleDexketoprofen81561 (1)NegativeNegative456FemaleIsoniazid27 954 (1)NegativeNegative535MaleErythromycin272469 (1)NegativeNegative675MaleAmoxicillin42967 (1)NegativeNegative Open table in a new tab Evidence of hepatitis E infection is present in a significant number of patients suspected to have DILI. Seroprevalence of IgG HEV is also very high. Hepatitis E should be ruled out in all patients suspected to suffer from DILI in Spain.

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Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury

Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis. One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.

The Latin American DILI Registry Experience: A Successful Ongoing Collaborative Strategic Initiative.

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.

WWW.Farmakologiportalen.No – A Common National Database For Pharmacological Laboratory Services

CLiNiCAL diLi NETwoRkS ANd CoNSoRTiA: whAT LESSoNS hAVE wE LEARNT? R.J. Andrade Head, Department of Medicine and Gastroenterology Service, Instituto de Investigacion Biomedica de Malaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Malaga, Malaga, Spain; and Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Madrid, Spain Drug-induced liver injury (DILI) is a rare but potentially severe adverse event concerning mostly patients but also pharmaceutical industry, clinicians, and regulatory authorities. The necessity of concerted efforts to obtain reliable information on DILI causal agents, phenotypes, and risk factors has stimulated groups in USA and Europe to develop large DILI prospective registries. The Spanish DILI Registry (www.spanishdili.uma.es) and the Drug-Induced Liver Injury Network (http://dilin.duke.edu) are collaborative multicenter networks with large databases and biosample collections of prospectively recorded DILI cases in Spain and the US, respectively, and subsequently important resources for hepatotoxicity studies. The Spanish DILI Registry has recently initiated a new branch into South America, the Spanish-Latin American DILI Network (SLATINDILI; www.slatindili.uma.es), and into Europe, leading the EuroProDILI Registry fostered by the European Association for the Study of the Liver. In this presentation I will discuss on how DILI registries have expanded our knowledge on this fascinating yet challenging and complex disease.

Causality assessment: Which is best-expert opinion or RUCAM?

Causality assessment: Which is best-expert opinion or RUCAM?

Use of Hy's Law and a New Composite Algorithm to Predict Acute Liver Failure in Patients With Drug-Induced Liver Injury

Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely 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, 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 greater than 2-fold the upper limit of normal (×ULN) and either ALTlevel greater than 3× ULN, a ratio (R) value (ALT× ULN/alkaline phosphatase× ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest×ULN/ alkaline phosphatase× ULN value) of 5 or greater. 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, the 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 greater than 2× ULN. An algorithm based on AST level greater than 17.3× ULN, TBL greater than 6.6× ULN, and AST:ALT greater than 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.

PP022—Variations in drug-induced liver injury (DILI) between different prospective dili registries

e24 Volume 35 Number 8S PP022—VARIATIONS IN DRUG-INDUCED LIVER INJURY (DILI) BETWEEN DIFFERENT PROSPECTIVE DILI REGISTRIES I. Medina-Caliz; A. Gonzalez-Jimenez; F. Bessone; N. Hernandez; A. Sanchez; M. Di Pace; M. Arrese; J.R. Brahm; A. Ruiz; J. Arancibia; D. Kershenobich; A. Loaeza; M. Girala; N. Mendez-Sanchez; M. Davalos; M. Lizarzabal; E. Mengual; C. Stephens; M. Robles-Diaz; R.J. Andrade; and M.I. Lucena H.U. Virgen de la Victoria, Universidad de Malaga, IBIMA, CIBEReHD, Malaga, Spain; H del Centenario, Rosario, Argentina; H de Clinicas, Montevideo, Uruguay; Pontificia Universidad Catolica de Chile; H Clinico Universitario de Chile, Santiago, Chile; H General de Mexico, Mexico City, Mexico; H. de Clinicas Asuncion, Asuncion, Paraguay; Fundacion Clinica Medica Sur, Mexico City, Mexico; H Rebagliati, Lima, Peru; and H Maracaibo, Maracaibo, Venezuela, Bolivarian Republic Of Introduction: DILI differs across geographical areas due to differential drug polices, prescription habits, drug consumption, and genetic factors. In this study, we have compared DILI cases included in the recently established Latin American DILI Network with those in the Spanish DILI Registry and the US Drug-Induced Liver Injury Network to identify differences in phenotypic presentations and causative agents. Patients (or Materials) and Methods: Demographic, clinical parameters, and causative agents were compared between 98 Latin American, 851 Spanish, and 300 US DILI cases. Results: The Latin American cases had a mean age of 54 years with a predominance of females (61%), whereas mean age and female proportion in the Spanish and US DILI cases were 54 years with 49% females and 48 years with 60% females, respectively. The most common type of liver damage in all 3 registries was hepatocellular injury. Jaundice was frequently seen in the registries, with 70%, 66%, and 69% of the Latin American, Spanish, and US DILI cases, respectively. Hospitalization occurred in 51% of the Latin American DILI cases, with 57% and 60% of the Spanish and US cases requiring hospitalization. Liver-related death or liver transplantation occurred in 5.1%, 3.6%, and 6.0% of the Latin American, Spanish, and US cases, respectively. The main causative agents in Latin America included nimesulide, diclofenac, nitrofurantoin, cyproterone acetate, and various herbal remedies, whereas amoxicillin-clavulanate predominated in the other 2 registries, followed by ibuprofen in Spain and nitrofurantoin in the United States. Conclusion: The Latin American DILI cases demonstrate similar phenotypic characteristics as observed in registers outside Latin America with respect to type of injury and severity. Female sex predominates in the Latin America and US registries. With regard to causative agents, elevated representation of NSAIDs, hormonal treatments, and herbal remedies were seen in Latin America, whereas antibiotics were more common causes of DILI in Spain and the United States. Funding Source: Agencia Espanola del Medicamento, SAS P10CTS-6470, FIS PI12-00620, iSAEC. CIBERehd by ISCIII. Disclosure of Interest: None declared.