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.

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.

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.

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.

The Metagenomic Composition and Effects of Fecal-Microbe-Derived Extracellular Vesicles on Intestinal Permeability Depend on the Patient's Disease.

The composition and impact of fecal-microbe-derived extracellular vesicles (EVs) present in different diseases has not been analyzed. We determined the metagenomic profiling of feces and fecal-microbe-derived EVs from healthy subjects and patients with different diseases (diarrhea, morbid obesity and Crohn's disease (CD)) and the effect of these fecal EVs on the cellular permeability of Caco-2 cells. The control group presented higher proportions of Pseudomonas and Rikenellaceae_RC9_gut_group and lower proportions of Phascolarctobacterium, Veillonella and Veillonellaceae_ge in EVs when compared with the feces from which these EVs were isolated. In contrast, there were significant differences in 20 genera between the feces and EV compositions in the disease groups. Bacteroidales and Pseudomonas were increased, and Faecalibacterium, Ruminococcus, Clostridium and Subdoligranum were decreased in EVs from control patients compared with the other three groups of patients. Tyzzerella, Verrucomicrobiaceae, Candidatus_Paracaedibacter and Akkermansia were increased in EVs from the CD group compared with the morbid obesity and diarrhea groups. Fecal EVs from the morbid obesity, CD and, mainly, diarrhea induced a significant increase in the permeability of Caco-2 cells. In conclusion, the metagenomic composition of fecal-microbe-derived EVs changes depending on the disease of the patients. The modification of the permeability of Caco-2 cells produced by fecal EVs depends on the disease of the patients.

The influence of the SARS-CoV-2 pandemic on in-hospital mortality in a gastroenterology service.

INTRODUCTION: The pandemic caused by SARS-CoV-2 has drastically changed the global health landscape. Our objective was to verify if, after the start of the pandemic, there was an increase in in-hospital mortality in patients admitted to a Gastroenterology Service of a 3rd level hospital. MATERIAL AND METHODS: The 1039 admissions registered at the Virgen de la Victoria University Hospital in Malaga (Spain) were retrospectively analysed in the period between 1 December 2019 and 30 November 2020 (12 months), which were divided into 4 quarters (pre-wave, first wave, inter-wave and second wave) and mortality and other variables (globally and by disease group) were analysed. RESULTS: No statistically significant differences were observed in terms of overall in-hospital mortality in the different periods. (p 0.23). The greatest burden of disease corresponded to biliopancreatic group and, within them, acute pancreatitis (p 0.04), followed by non-variceal gastrointestinal bleeding. In the second semester, mortality increased in the biliopancreatic group (p 0.01). Patients admitted for gastrointestinal bleeding took longer to request care after the start of the pandemic, especially in the second wave (p 0.03). The same was observed in admissions due to tumours, with the time elapsed until the emergency visit more than double in the second semester, with a consequent increase in mortality (p 0.00). CONCLUSIONS: The global in-hospital mortality in a Gastroenterology Service in a 3rd level hospital has not increased with the onset of the SARS-CoV-2 pandemic, however, a higher in-hospital mortality has been recorded in biliopancreatic diseases and digestive tumours diagnosed on an in-patient basis between June and November 2020.

Endoscopic septotomy of Zenker's diverticulum with Stag-Beetle Knife™: A descriptive observational study and literature review. / Septotomía endoscópica del divertículo de Zenker mediante Stag-Beetle-KnifeTM: estudio observacional descriptivo y revisión de la literatura.

INTRODUCTION: Zenker's diverticulum (ZD) is a protrusion of the hypopharyngeal mucosa with a prevalence of 2/100,000 inhabitants. The symptoms of the patients determine the need for treatment, which can be surgical or endoscopic. The latter, known as endoscopic septotomy or diverticulotomy (ED), this involves dissecting the diverticular septum, which can be performed with different dissection devices. AIM: The aim of our study was to evaluate the efficacy and safety of ED with Stag-Beetle-Knife™ device, as well as to conduct a literature review to assess the position of the technique in the current scientific panorama. MATERIAL AND METHODS: Descriptive retrospective study that includes patients who underwent ED with SB-Knife™ between June 2017 and February 2020. Literature review of the available evidence between January 2013 and April 2020 of ED with SB-Knife™ technique and its variants. RESULTS: Twelve patients (66% male) with a median age of 70.5 years were collected. The median size of diverticular was 32.5mm and complete remission was observed in 75% of the cases. Fourteen interventions were performed with a technical success of 92.8. There were no serious complications. A literature review was carried out, finding 13 papers, of which 8 were finally included (6 retrospective studies, a series of cases and a clinical case). CONCLUSION: Based on our experience and the reviewed literature, we consider ED with SB-Knife™ is a safe, effective and reproducible technique, and may be a better alternative to surgery in patients with ZD.

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.

Recreational Drugs and the Risk of Hepatocellular Carcinoma.

Recreational or aesthetic drug use is a distinctive behavior of humans, principally attested in the last century. It is known that recreational and illegal drugs are major contributors to the universal morbidity rate worldwide. Many of these substances have a well-established hepatotoxic potential, causing acute or chronic liver injury, liver fibrosis and cirrhosis, but their implications for hepatocellular carcinoma or other varieties of liver tumors are little known. In this article, we perform an extensive literature review, aiming to provide updated information about recreational drug use and the risk of developing liver tumors. Khat use and pyrrolizidine alkaloid consumption (present in some natural plants) have been linked to liver cirrhosis. Kava intake is associated with different liver tumors in animal models but not in humans. Cannabis' potential to accelerate liver fibrosis in chronic hepatitis is controversial according to the existing data. Cigarette smoking is an important contributor to hepatocellular carcinoma, and anabolic androgen steroids are well-defined causes of a variety of liver cancers and other hepatic tumors. Long-term follow-up studies of subjects who have developed injuries in association with the use of recreational drugs are warranted so as to better define the risk of developing hepatocellular carcinoma in association with these substances and, thus, to implement health care policies to combat this preventable cause of cancer.

Modeling drug-induced liver injury: current status and future prospects.

INTRODUCTION: Idiosyncratic drug-induced liver injury (iDILI) is a challenging and unpredictable multifactorial condition. At present, validated preclinical models for the prediction of the hepatotoxic potential of a given drug are scarce. AREAS COVERED: This review intends to sum up the current knowledge about in vitro (including hepatocyte 2D cultures, cocultures with non-parenchymal cells, 3D configurations and non-typical closer to reality in vitro models), in vivo (covering models for immunological and oxidative stress features, humanized mouse-based and non-rodent models) and in silico approaches for iDILI modeling, highlighting the recent advances in each topic. EXPERT OPINION: The future strategy for iDILI modeling should be patient-centered. Future animal and cell-based models, with more predictive value, will be easier to design by using a more translational approach based on mechanisms demonstrated in humans. Genetic and epigenetic information gathered from iDILI patients, together with data from in vitro and in vivo studies, could be used to develop sophisticated predictive in silico models to find compounds with iDILI potential. Collecting genetic, metabolic, and biomarker data from patient cohorts might be another option to create a 'fingerprint' characteristic of people at risk, allowing for the development of new, mechanistic strategies to enhance iDILI in vitro evaluation.

Liver injury after methylprednisolone pulses: A disputable cause of hepatotoxicity. A case series and literature review.

Background and Objectives: Corticosteroids are often empirically used to treat idiosyncratic hepatotoxicity with severe features. Interestingly, intravenous methylprednisolone (MP) is increasingly being recognized as being responsible for liver injury. We aimed to characterize MP-induced liver injury by analyzing demographical, clinical, laboratory and outcome data of three MP-induced hepatotoxicity cases and compared this information with that of previously published cases. Case series: Three females with multiple sclerosis (MS) were treated intravenously with MP, mean daily dose 767 mg. Liver damage occurred 2 to 6 weeks after exposure. Severity was mild to moderate. Two patients suffered positive rechallenge. Literature review: We identified 50 published cases of MP hepatotoxicity. Most of these cases were female (86%) and main treatment indications were MS (29 cases) and Graves' ophthalmopathy (13 cases). Hepatocellular damage predominated and mean time to onset was 6 weeks. Four patients died and rechallenge occurred in 19 cases. Conclusion: MP pulses can induce severe liver injury, often with an autoimmune phenotype, particularly in patients with MS and Graves' ophthalmopathy. Consequently, these patient groups should have liver tests monitored when treated with MP to provide safer patient care.

Septotomía endoscópica del divertículo de Zenker mediante Stag-Beetle-KnifeTM: estudio observacional descriptivo y revisión de la literatura / Endoscopic septotomy of Zenker's diverticulum with Stag-Beetle Knife™: A descriptive observational study and literature review

Introducción: El divertículo de Zenker (DZ) es una protrusión de la mucosa hipofaríngea con una prevalencia de 2/100.000 habitantes. La clínica condiciona la necesidad del tratamiento, pudiendo ser quirúrgico o endoscópico. Este último, denominado septotomía o diverticulotomía endoscópica (DE), consiste en la disección del septo diverticular, pudiendo realizarse con distintos dispositivos disectores. Objetivo: El objetivo del estudio es evaluar la eficacia y seguridad de la DE mediante el dispositivo Stag-Beetle Knife™, así como realizar una revisión de la literatura para valorar el posicionamiento de la técnica en el panorama científico actual. Material y métodos: Estudio retrospectivo descriptivo que incluye pacientes intervenidos mediante DE con SB-Knife™ entre junio de 2017 y febrero de 2020. Revisión de la literatura de la evidencia disponible entre enero de 2013 y abril 2020 de la DE mediante la técnica con SB-Knife™ y sus variantes. Resultados: Se recopilaron 12 pacientes (66% varones) con una mediana de 70,5 años. El tamaño diverticular fue de 32,5mm de mediana y la remisión completa se objetivó en el 75% de los casos. Se realizaron 14 intervenciones con un éxito técnico del 92,8%. No se produjeron complicaciones graves. Se realizó una revisión de la literatura encontrando 13 trabajos de los cuales se incluyeron finalmente 8 (6 estudios retrospectivos, una serie de casos y un caso clínico). Conclusiones: En función de nuestra experiencia y a la bibliografía revisada, consideramos que la DE mediante SB-Knife™ es una técnica segura, eficaz y reproducible, pudiendo ser una mejor alternativa a la cirugía en pacientes con DZ.(AU)

Introduction: Zenker's diverticulum (ZD) is a protrusion of the hypopharyngeal mucosa with a prevalence of 2/100,000 inhabitants. The symptoms of the patients determine the need for treatment, which can be surgical or endoscopic. The latter, known as endoscopic septotomy or diverticulotomy (ED), this involves dissecting the diverticular septum, which can be performed with different dissection devices. AimThe aim of our study was to evaluate the efficacy and safety of ED with Stag-Beetle-Knife™ device, as well as to conduct a literature review to assess the position of the technique in the current scientific panorama. Material and methods: Descriptive retrospective study that includes patients who underwent ED with SB-Knife™ between June 2017 and February 2020. Literature review of the available evidence between January 2013 and April 2020 of ED with SB-Knife™ technique and its variants. Results: Twelve patients (66% male) with a median age of 70.5 years were collected. The median size of diverticular was 32.5mm and complete remission was observed in 75% of the cases. Fourteen interventions were performed with a technical success of 92.8. There were no serious complications. A literature review was carried out, finding 13 papers, of which 8 were finally included (6 retrospective studies, a series of cases and a clinical case). Conclusion: Based on our experience and the reviewed literature, we consider ED with SB-Knife™ is a safe, effective and reproducible technique, and may be a better alternative to surgery in patients with ZD.(AU)

The influence of the SARS-CoV-2 pandemic on in-hospital mortality in a gastroenterology service / Influencia de la pandemia por SARS-CoV-2 en la mortalidad intrahospitalaria en un servicio de aparato digestivo

Introduction: The pandemic caused by SARS-CoV-2 has drastically changed the global health landscape. Our objective was to verify if, after the start of the pandemic, there was an increase in in-hospital mortality in patients admitted to a Gastroenterology Service of a 3rd level hospital. Material and methods: The 1039 admissions registered at the Virgen de la Victoria University Hospital in Malaga (Spain) were retrospectively analysed in the period between 1 December 2019 and 30 November 2020 (12 months), which were divided into 4 quarters (pre-wave, first wave, inter-wave and second wave) and mortality and other variables (globally and by disease group) were analysed. Results: No statistically significant differences were observed in terms of overall in-hospital mortality in the different periods. (p 0.23). The greatest burden of disease corresponded to biliopancreatic group and, within them, acute pancreatitis (p 0.04), followed by non-variceal gastrointestinal bleeding. In the second semester, mortality increased in the biliopancreatic group (p 0.01). Patients admitted for gastrointestinal bleeding took longer to request care after the start of the pandemic, especially in the second wave (p 0.03). The same was observed in admissions due to tumours, with the time elapsed until the emergency visit more than double in the second semester, with a consequent increase in mortality (p 0.00). Conclusions: The global in-hospital mortality in a Gastroenterology Service in a 3rd level hospital has not increased with the onset of the SARS-CoV-2 pandemic, however, a higher in-hospital mortality has been recorded in biliopancreatic diseases and digestive tumours diagnosed on an in-patient basis between June and November 2020.(AU)

Introducción:La pandemia ocasionada por el SARS-CoV-2 ha modificado drásticamente el panorama sanitario mundial. Nuestro objetivo fue comprobar si tras el inicio de esta se produjo un aumento en la mortalidad intrahospitalaria en los pacientes ingresados en un servicio de aparato digestivo de un hospital de tercer nivel. Material y métodos: Se analizaron retrospectivamente 1.039 ingresos en el Servicio de Aparato Digestivo del Hospital Universitario Virgen de la Victoria en el periodo comprendido entre el 1 de diciembre de 2019 y el 30 de noviembre de 2020 (12 meses), se dividieron en 4 trimestres (preoleada, primera oleada, interoleada y segunda oleada) y se analizó la mortalidad y otras variables (de forma global y por grupo de enfermedades). Resultados: No se observaron diferencias estadísticamente significativas en cuanto a mortalidad intrahospitalaria global en los diferentes periodos (p=0,23). La enfermedad con mayor predominio fue la biliopancreática y, dentro de ella, las pancreatitis agudas (p=0,04), seguidas del sangrado digestivo no varicoso. En el segundo semestre aumentó la mortalidad en el grupo biliopancreático (p=0,01). Los pacientes que ingresaron por hemorragia digestiva tardaron más en solicitar asistencia tras la pandemia, especialmente en la segunda oleada (p=0,03). Esto mismo se objetivó en los ingresos por tumores, siendo el tiempo transcurrido hasta la consulta a Urgencias mayor del doble en el segundo semestre, con el consecuente aumento en la mortalidad (p=0,00). Conclusiones: La mortalidad global intrahospitalaria en el Servicio de Aparato Digestivo no ha aumentado con la sobrevenida de la pandemia por SARS-CoV-2, si bien se ha registrado una mayor mortalidad intrahospitalaria en las enfermedades biliopancreáticas y los tumores digestivos diagnosticados en régimen de hospitalización entre junio y noviembre de 2020.(AU)