Hepatitis C virus point-of-care microelimination approach in a vulnerable population in the South of Spain.

Background: Since the introduction of direct-acting antivirals, thousands of chronic hepatitis C patients have been successfully treated. However, vulnerable populations have a higher prevalence of hepatitis C virus (HCV) infection and face barriers that impede their access to antivirals. We carried out an HCV microelimination program focused on vulnerable population groups in Malaga. Methods: People in drug addiction treatment centers and homeless shelters in Malaga who participated in the program between October 2020 and October 2021 were included. After providing participants with educational information on HCV, a dry drop test (DDT) was used to collect blood for subsequent screening for HCV infection. The participants who were diagnosed with HCV infection were scheduled for comprehensive healthcare assessments, including blood tests, ultrasonography, elastography, and the prescription of antivirals, all conducted in a single hospital visit. Sustained viral response (SVR) was analysed 12 weeks after end of treatment. Results: Of the 417 persons invited to participate, 271 (65%) agreed to participate in the program. These participants were screened for HCV infection and 28 of them were diagnosed with HCV infection (10%). These hepatitis C-infected patients had a mean age of 53 ± 9 years; 86% were males and 93% were or had been drug users. Among 23 patients with HCV infection, HCV genotype 1a predominated (74%). Medical exams showed that 19% (4/21) had advanced fibrosis (F3-4), and 5% (1/21) had portal hypertension. Finally, 23 infected patients received treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir and SVR was confirmed in 22 patients (96%). Conclusions: Drug users and homeless people have a higher prevalence of HCV infection than the general population. The microelimination program with educational activity and screening tools achieved a high participation rate, easy healthcare access, and a high rate of SVR despite the SARS-CoV-2 pandemic.

Prior drug allergies are associated with worse outcome in patients with idiosyncratic drug-induced liver injury: A machine learning approach for risk stratification.

The impact of prior drug allergies (PDA) on the clinical features and outcomes of patients who develop idiosyncratic drug-induced liver injury (DILI) is largely unknown. We aimed to assess the clinical presentation and outcomes of DILI patients based on the presence or absence of PDA and explore the association between culprit drugs responsible for DILI and allergy. We analysed a well-vetted cohort of DILI cases enrolled from the Spanish DILI Registry. Bootstrap-enhanced least absolute shrinkage operator procedure was used in variable selection, and a multivariable logistic model was fitted to predict poor outcomes in DILI. Of 912 cases with a first episode of DILI, 61 (6.7%) had documented PDA. Patients with PDA were older (p = 0.009), had higher aspartate aminotransferase (AST) levels (p = 0.047), lower platelet count (p = 0.011) and higher liver-related mortality than those without a history of drug allergies (11% vs. 1.6%, p < 0.001). Penicillin was the most common drug associated with PDA in DILI patients (32%). A model including PDA, nR-based type of liver injury, female sex, AST, total bilirubin, and platelet count showed an excellent performance in predicting poor outcome in patients from the Spanish DILI Registry (area under the ROC curve [AUC] 0.887; 95% confidence interval [CI] 0.794 - 0.981) and the LATINDILI Network (AUC 0.932; 95% CI 0.884 - 0.981). Patients with suspected DILI should be screened for PDA as they would require a close monitoring for early detection of worsening clinical course.

Lack of complete biochemical response in autoimmune hepatitis leads to adverse outcome: First report of the IAIHG retrospective registry.

BACKGROUND AND AIMS: The International Autoimmune Hepatitis Group retrospective registry (IAIHG-RR) is a web-based platform with subjects enrolled with a clinical diagnosis of autoimmune hepatitis (AIH). As prognostic factor studies with enough power are scarce, this study aimed to ascertain data quality and identify prognostic factors in the IAIHG-RR cohort. METHODS: This retrospective, observational, multicenter study included all patients with a clinical diagnosis of AIH from the IAIHG-RR. The quality assessment consisted of external validation of completeness and consistency for 29 predefined variables. Cox regression was used to identify risk factors for liver-related death and liver transplantation (LT). RESULTS: This analysis included 2559 patients across 7 countries. In 1700 patients, follow-up was available, with a completeness of individual data of 90% (range: 30-100). During a median follow-up period of 10 (range: 0-49) years, there were 229 deaths, of which 116 were liver-related, and 143 patients underwent LT. Non-White ethnicity (HR 4.1 95% CI: 2.3-7.1), cirrhosis (HR 3.5 95% CI: 2.3-5.5), variant syndrome with primary sclerosing cholangitis (PSC) (HR 3.1 95% CI: 1.6-6.2), and lack of complete biochemical response within 6 months (HR 5.7 95% CI: 3.4-9.6) were independent prognostic factors. CONCLUSIONS: The IAIHG-RR represents the world's largest AIH cohort with moderate-to-good data quality and a relevant number of liver-related events. The registry is a suitable platform for patient selection in future studies. Lack of complete biochemical response to treatment, non-White ethnicity, cirrhosis, and PSC-AIH were associated with liver-related death and LT.

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. 53 years, 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.

Study design for development of novel safety biomarkers of drug-induced liver injury by the translational safety biomarker pipeline (TransBioLine) consortium: a study protocol for a nested case-control study.

A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder early- and late-stage drug development and remains a challenge in clinical practice. The Innovative Medicines Initiative's TransBioLine consortium comprising academic and industry partners is developing a prospective repository of deeply phenotyped cases and controls with biological samples during liver injury progression to facilitate biomarker discovery, evaluation, validation and qualification.In a nested case-control design, patients who meet one of these criteria, alanine transaminase (ALT) ≥ 5 × the upper limit of normal (ULN), alkaline phosphatase ≥ 2 × ULN or ALT ≥ 3 ULN with total bilirubin > 2 × ULN, are enrolled. After completed clinical investigations, Roussel Uclaf Causality Assessment and expert panel review are used to adjudicate episodes as DILI or alternative liver diseases (acute non-DILI controls). Two blood samples are taken: at recruitment and follow-up. Sample size is as follows: 300 cases of DILI and 130 acute non-DILI controls. Additional cross-sectional cohorts (1 visit) are as follows: Healthy volunteers (n = 120), controls with chronic alcohol-related or non-alcoholic fatty liver disease (n = 100 each) and patients with psoriasis or rheumatoid arthritis (n = 100, 50 treated with methotrexate) are enrolled. Candidate biomarkers prioritised for evaluation include osteopontin, glutamate dehydrogenase, cytokeratin-18 (full length and caspase cleaved), macrophage-colony-stimulating factor 1 receptor and high mobility group protein B1 as well as bile acids, sphingolipids and microRNAs. The TransBioLine project is enabling biomarker discovery and validation that could improve detection, diagnostic accuracy and prognostication of DILI in premarketing clinical trials and for clinical healthcare application.

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

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans.

Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. Here, we identify, confirm, and replicate the biomarker performance characteristics of candidate proteins in patients with DILI at onset (DO; n = 133) and follow-up (n = 120), acute non-DILI at onset (NDO; n = 63) and follow-up (n = 42), and healthy volunteers (HV; n = 104). Area under the receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase, argininosuccinate synthase, carbamoylphosphate synthase, fumarylacetoacetase, fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieved near complete separation (range: 0.94-0.99) of DO and HV. In addition, we show that FBP1, alone or in combination with glutathione S-transferase A1 and leukocyte cell-derived chemotaxin 2, could potentially assist in clinical diagnosis by distinguishing NDO from DO (AUC range: 0.65-0.78), but further technical and clinical validation of these candidate biomarkers is needed.

Evaluation of diagnostic and prognostic candidate biomarkers in drug-induced liver injury vs. other forms of acute liver damage.

AIMS: Detection and characterization of idiosyncratic drug-induced liver injury (DILI) currently rely on standard liver tests, which are suboptimal in terms of specificity, sensitivity and prognosis. Therefore, DILI diagnosis can be delayed, with important consequences for the patient. In this study, we aimed to evaluate the potential of osteopontin, cytokeratin-18 (caspase-cleaved: ccK18 and total: K18), α-glutathione-S-transferase and microRNA-122 as new DILI biomarkers. METHODS: Serial blood samples were collected from 32 DILI and 34 non-DILI acute liver injury (ALI) cases and a single sample from 43 population controls without liver injury (HLC) and analysed using enzyme-linked immunosorbent assay (ELISA) or single-molecule arrays. RESULTS: All biomarkers differentiated DILI and ALI from HLC with an area under receiver operator characteristic curve (AUC) value of >0.75 but were less efficient in distinguishing DILI from ALI, with ccK18 (0.79) and K18 (0.76) demonstrating highest potential. However, the AUC improved considerably (0.98) for ccK18 when comparing DILI and a subgroup of autoimmune hepatitis cases. Cytokeratin-18, microRNA-122 and α-glutathione-S-transferase correlated well with traditional transaminases, while osteopontin correlated most strongly with the international normalized ratio (INR). CONCLUSIONS: ccK18 appears promising in distinguishing DILI from autoimmune hepatitis but less so from other forms of acute liver injury. Osteopontin demonstrates prognostic potential with higher levels detected in more severe cases regardless of aetiology.

Nitrofurantoin-induced liver injury: long-term follow-up in two prospective DILI registries.

Nitrofurantoin is a synthetic antibiotic that is recommended as first-choice treatment for uncomplicated urinary tract infections. The prescription of this drug has increased dramatically, especially in Latin American countries. We described the demographics, clinical characteristics, biochemical features, and outcome of nitrofurantoin-induced liver injury. We analyzed 23 cases from the Latin American DILI Network (LATINDILI) and the Spanish DILI Registry. Causality was assessed with the RUCAM and RECAM scale. Of the 23 DILI cases included in our series, 96% patients were women, and the mean age of the whole cohort was 61 years. The median time of drug exposure was 175 days (interquartile range [IQR] 96-760), with 11 patients who were prescribed nitrofurantoin for more than six months. Hepatocellular damage was the most frequent pattern of liver injury (83%), and nearly half of the patients had an asymptomatic presentation (52%). Neither death nor liver transplantation was documented in this series. Overall, 65% of the patients (n = 15) presented with positive autoantibody titres. The median time to resolution was 81 days (IQR 57-141), and 15 patients (83%) recovered within six months. Five patients (22%) developed nitrofurantoin-induced autoimmune-like hepatitis (NI-AILH), of whom two were characterized by a persistent increase in transaminases that required immunosuppressive treatment to achieve normalization of liver enzymes. Clinicians who prescribe nitrofurantoin should be aware that patients who had taken nitrofurantoin for a long term may be at risk of developing nitrofurantoin-induced autoimmune-like hepatitis.

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

BACKGROUND: The use of corticosteroids to treat patients with idiosyncratic drug-induced liver injury (DILI) relies on empirical clinical decisions. AIM: 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. METHODS: We analysed bona fide idiosyncratic 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. RESULTS: 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). CONCLUSION: 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.

A new framework for advancing in drug-induced liver injury research. The Prospective European DILI Registry.

BACKGROUND & AIMS: No multi-national prospective study of drug-induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short-term outcomes of the cases and controls is reported. METHODS: Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016-2021. DILI cases or non-DILI acute liver injury controls following causality assessment were enrolled. RESULTS: Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre-existing liver disease. DILI cases and non-DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin-clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug-induced autoimmune-like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver-related death), and another six received liver transplantation. CONCLUSIONS: In this first multi-national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI.

Microbiota diversity in nonalcoholic fatty liver disease and in drug-induced liver injury.

The gut microbiota could play a significant role in the progression of nonalcoholic fatty liver disease (NAFLD); however, its relevance in drug-induced liver injury (DILI) remains unexplored. Since the two hepatic disorders may share damage pathways, we analysed the metagenomic profile of the gut microbiota in NAFLD, with or without significant liver fibrosis, and in DILI, and we identified the main associated bacterial metabolic pathways. In the NAFLD group, we found a decrease in Alistipes, Barnesiella, Eisenbergiella, Flavonifractor, Fusicatenibacter, Gemminger, Intestinimonas, Oscillibacter, Parasutterella, Saccharoferementans and Subdoligranulum abundances compared with those in both the DILI and control groups. Additionally, we detected an increase in Enterobacter, Klebsiella, Sarcina and Turicibacter abundances in NAFLD, with significant liver fibrosis, compared with those in NAFLD with no/mild liver fibrosis. The DILI group exhibited a lower microbial bacterial richness than the control group, and lower abundances of Acetobacteroides, Blautia, Caloramator, Coprococcus, Flavobacterium, Lachnospira, Natronincola, Oscillospira, Pseudobutyrivibrio, Shuttleworthia, Themicanus and Turicibacter compared with those in the NAFLD and control groups. We found seven bacterial metabolic pathways that were impaired only in DILI, most of which were associated with metabolic biosynthesis. In the NAFLD group, most of the differences in the bacterial metabolic pathways found in relation to those in the DILI and control groups were related to fatty acid and lipid biosynthesis. In conclusion, we identified a distinct bacterial profile with specific bacterial metabolic pathways for each type of liver disorder studied. These differences can provide further insight into the physiopathology and development of NAFLD and DILI.

Role of Corticosteroids in Drug-Induced Liver Injury. A Systematic Review.

Introduction: Apart from cessation of the implicated agent leading to drug-induced liver injury (DILI), there is no standard therapy for DILI. Corticosteroids have been used in DILI, although their efficacy is unclear. Published data showed either beneficial effects or no improvement associated with steroid therapy. The aim of the current study was to perform a systematic review of the role of corticosteroids in the treatment of DILI. Methods: A search was performed in PubMed, searching for the terms: "corticosteroids" and "drug-induced liver injury". Observation studies were included, but case reports excluded. Results: A total of 24 papers were retrieved. Most of these were observational studies on the effects of corticosteroids in moderate/severe DILI (n = 8), reports on the corticosteroid treatment in patients with drug-induced autoimmune hepatitis (DI-AIH) (n = 5), and effects of corticosteroids in drug-induced fulminant acute liver failure (ALF, n = 2). Furthermore, treatment of corticosteroids in patients with liver injury due to check point inhibitors (CPIs) was addressed in nine studies. In moderate/severe DILI, six out of eight studies suggested steroid treatment to be beneficial, whereas two studies showed negative results. All five observational studies on the effects of corticosteroids in DI-AIH showed good therapeutic response with rapid and long lasting effects after discontinuation of corticosteroids and without evidence of relapse. Steroid therapy was not associated with improved overall survival in patients with drug-induced fulminant ALF. CPIs-induced liver injury was found to improve spontaneously in 33-50% without corticosteroids, and the rate of patients who were treated responded to steroids in 33-100% (mean 72%). Conclusions: The majority of studies analyzing the effects of corticosteroids in moderate/severe DILI have demonstrated beneficial effects. However, this was not the case in drug-induced fulminant ALF. Patients with DI-AIH had an excellent response to corticosteroids. The majority of those with CPIs-induced liver injury responded to corticosteroids; however, patients without treatment usually recovered spontaneously. The observational design and comparison with historical controls in these studies makes it very difficult to draw conclusions on the efficacy of corticosteroids in DILI. Therefore, there is a strong need for a randomized controlled trial to properly assess the role of corticosteroids in DILI.

Role of Ursodeoxycholic Acid in Treating and Preventing Idiosyncratic Drug-Induced Liver Injury. A Systematic Review.

Introduction: Treatment is generally not available for drug-induced liver injury (DILI) patients except in some specific circumstances. The management of DILI is based on the withdrawal of the responsible drug and monitoring the patients and only a few patients need to be referred to a transplant center. Some studies on the role of ursodeoxycholic acid (UDCA) in DILI have been published. The aim of this study was to perform a systematic review of the role of UDCA in the treatment and prevention of DILI. Methods: A search was undertaken in PubMed, with the key words ursodeoxycholic acid, drug-induced liver injury and hepatotoxicity following the PRISMA guidelines. Results: A total of 33 publications were identified: 25 case reports and 8 case series. In 18 of the 25 cases reports (22 patients), authors reported improvement of liver injury associated with UDCA therapy whereas 7 case reports did not show clinical or biochemical improvement after UDCA treatment. There were 4 studies evaluating the role of UDCA in the treatment of DILI, three prospective (one being a clinical trial) and one retrospective studies. Three studies observed liver profile improvements associated with UDCA. In addition, four studies evaluated UDCA in the prevention of DILI: one pilot study, two randomized clinical trials (RCT) and one retrospective study. Three of these studies observed a lower percentage of patients with an increase in transaminases in the groups that used UDCA for DILI prevention. Conclusion: According to available data UDCA seems to have some benefits in the treatment and prevention of DILI. However, the design of the published studies does not allow a firm conclusion to be drawn on the efficacy of UDCA in DILI. A well designed RCT to evaluate the role of UDCA in DILI is needed.

Lymphocyte Profile and Immune Checkpoint Expression in Drug-Induced Liver Injury: An Immunophenotyping Study.

The identification of specific HLA risk alleles in drug-induced liver injury (DILI) points toward an important role of the adaptive immune system in DILI development. In this study, we aimed to corroborate the role of an adaptive immune response in DILI through immunophenotyping of leukocyte populations and immune checkpoint expressions. Blood samples were collected from adjudicated DILI (n = 12), acute viral hepatitis (VH; n = 13), acute autoimmune hepatitis (AIH; n = 9), and acute liver injury of unknown etiology (n = 15) at day 1 (recognition), day 7, and day >30. Blood samples from patients with nonalcoholic fatty liver disease (NAFLD; n = 20) and healthy liver controls (HLCs; n = 54) were extracted at one time point. Leukocyte populations and immune checkpoint expressions were determined based on cell surface receptors, except for CTLA-4 that was determined intracellularly, using flow cytometry. At recognition, DILI demonstrated significantly higher levels of activated helper T-cell (P < 0.0001), activated cytotoxic T-cells (P = 0.0003), Th1 (P = 0.0358), intracellular CTLA-4 level in helper T-cells (P = 0.0192), and PD-L1 presenting monocytes (P = 0.0452) than HLC. These levels approached those of HLC over time. No significant differences were found between DILI and VH. However, DILI presented higher level of activated helper T-cells and CTLA-4 than NAFLD and lower PD-L1 level than AIH. Our findings suggest that an adaptive immune response is involved in DILI in which activated CD4+ and CD8+ play an important role. Increased expression of negative immune checkpoints is likely the effect of peripheral tolerance regulation.

Serious liver injury induced by Nimesulide: an international collaborative study.

Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to analyze the clinical phenotype, outcome, and histological features of nimesulide-induced liver injury (nimesulide-DILI). We analyzed 57 cases recruited from the Spanish and Latin American DILI registries. Causality was assessed by the RUCAM scale. Mean age of the whole case series was 59 years (86% women) with a median time to onset of 40 days. A total of 46 patients (81%) were jaundiced. Nimesulide-DILI pattern was hepatocellular in 38 (67%), mixed in 12 (21%), and cholestatic in 7 (12%) cases. Transaminases were elevated with a mean of nearly 20-fold the upper limit of normality (ULN), while alkaline phosphatase showed a twofold mean elevation above ULN. Total bilirubin showed a mean elevation of 13-fold the ULN. Liver histology was obtained in 14 cases (25%), most of them with a hepatocellular pattern. Median time to recovery was 60 days. Overall, 12 patients (21%) developed acute liver failure (ALF), five (8.8%) died, three underwent liver transplantation (5.3%), and the remaining four resolved. Latency was ≤ 15 days in 12 patients (21%) and one patient developed ALF within 7 days from treatment initiation. Increased total bilirubin and aspartate transaminase levels were independently associated with the development of ALF. In summary, nimesulide-DILI affects mainly women and presents typically with a hepatocellular pattern. It is associated with ALF and death in a high proportion of patients. Shorter (≤ 15 days) duration of therapy does not prevent serious nimesulide hepatotoxicity, making its risk/benefit ratio clearly unfavorable.

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

BACKGROUND & AIMS: 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. METHODS: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. RESULTS: 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%). CONCLUSIONS: 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. LAY SUMMARY: 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.