Understanding compound-induced histopathology in rat liver using gene expression network methods

Current drug discovery is a lengthy and costly pipeline; it takes between twelve and fifteen years and costs $1-2 billion (USD). As such, any compound failures represent a sunk cost – exacerbated if such failures occur later in the pipeline. Compound and drug induced liver injury is a significant cause of failures. Current progress to tackle this is based on systems biology, and so falls within the field of toxicogenomics. As such, the databases in the public domain are crucial to progress. DrugMatrix and Open TG-GATEs were identified as containing large, in vivo transcriptomics data with histopathological observations as endpoints, a proxy for toxicity. Due to the size and chemical variety of the databases, data-driven methods led to the novel creation of histopathology signatures, which accounts for dependence between histopathology observations (Chapter 2). Six toxic groups were determined for DrugMatrix and 13 for Open TG-GATEs, and were analysed with a view to enable classification, namely, what is revealed in the gene expression profiles when the histopathology phenotype was present. This led to determining gene-phenotype associations, both known and novel. An example of a novel association was the match of the histopathology signature of ‘glycogen accumulation, mixed infiltration and lymphocytic inflammatory cell infiltration’ to fructose metabolism, gluconeogenesis, and chemokine response pathways (Chapter 3). Concordance was found between histopathologically related toxicity groups between databases and their co-expression networks. From here, the co-expression network methods were applied to determine the concordance of gene expression across time (one day to four/five days), database (DrugMatrix and Open TG-GATEs), and toxicity group. This found underlying biological terms such as RNA transport, ribosome biogenesis and translation as well as toxicity-specific terms (aminoacyl t-RNA synthesis in metabolic processes for the histopathological observations of glycogen accumulation, cellular infiltrate, hepatocellular necrosis and fatty change in liver. Crucially, this work determined that the toxic group membership plays a more significant role in gene co-expression networks compared to the time point of the gene expression measurement (Chapter 4). In conclusion, data driven clustering was performed to create histopathology signatures. Using these, the usefulness of transcriptomics data was determined both to classify toxic state (gene expression data measured when the phenotype was present) and to determine how consistent it is over time scales. This work provided a framework for the comparison of co-expression networks for the deconvolution of gene expression data with respect to a phenotype.EPSR

Pantoprazole-Induced Liver Injury in the Setting of Diabetic Ketoacidosis

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Protocol for risk assessment of “other substances”. The Norwegian Scientific Committee for Food and Environment

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Protocol for a systematic review of long-term physical sequelae and financial burden of multidrug-resistant and extensively drug-resistant tuberculosis

Introduction Multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are major public health threats that are significant causes of physical sequelae and financial consequences for infected people. Treatment for MDR- and XDR-TB are more toxic and take longer duration than for drug-susceptible-TB. As a result, the long-term sequelae are thought to be more common among patients with MDR- and XDR-TB than drug-susceptible-TB, but this is yet to be quantified. Hence, the aim of this systematic review and meta-analysis is to quantify the global burden and types of long-term physical sequelae and financial burden associated with both MDR- and XDR-TB. Method and analysis We will search CINHAL, MEDLINE, Embase, Scopus, and Web of science for studies that report physical and financial sequelae associated with rifampicin-resistant (RR), MDR- and XDR-TB or their treatments. The search will be conducted without time, language, and place restrictions. A random-effects meta-analysis will be conducted to estimate the pooled prevalence of each physical sequela. Heterogeneity will be measured using the Higgins I2 statistics. We will assess publication bias visually using the funnel plot and statistically using Egger’s test. Adjustments for publication basis will be made using Tweedie’s and Duval Trim and Fill analysis. Ethics and dissemination Since the study is based on published evidence, ethics approval is not required. The findings of the systematic review will be presented at various conferences and will be published in a peer-reviewed journal. Protocol registration The protocol is published in the PROSPERO with registration number CRD42021250909

Hepatotoxicidad por antituberculosos en pacientes con tuberculosis multidrogorresistente

Objective: To describe the clinical characteristics of drug-induced liver injury (DILI) in multidrug-resistant tuberculosis (MDR-TB) patients.Materials and methods: A retrospective study conducted in hospitalized patients with MDR-TB and DILI. The criteria of the DILI Expert Working Group were used for the diagnosis of DILI, and the RUCAM (Roussel Uclaf Causality AssessmentMethod) for the causality analysis. The specific association between DILI and antitubercular drugs was established by drug rechallenge or discontinuation and recovery. Results: Seven cases of MDR-TB and DILI are described in this research. The mean age (standard deviation) was 39.10 (3.30) years.Mean DILI occurred 30.40 (27.70) days after starting the treatment. Three (43.00 %) patients presented jaundice. Regarding the type of injury, four (57.00 %) had hepatocellular injury and three (43.00 %) cholestatic injury. Four patients showed mild DILI andthree moderate DILI. All the patients had taken pyrazinamide (pyrazinamide alone: four patients; pyrazinamide and ethionamide: one patient; pyrazinamide, rifampin and isoniazid: one patient; pyrazinamide and rifampicin: one patient). The mean hospital stay was 48.10 (48.70) days. The mean serum alkaline phosphatase (AP), alanine aminotransferase (ALT) and gamma-glutamyltranspeptidase (GGT) were 2.40 (1.10), 7.90 (7.10) and 5.60 (3.70) times the upper limit of normal (ULN), respectively. The meantotal bilirubin was 2.30 (2.00), with a range of 0.50 to 6.40 mg/dl. As part of the discharge plan, quinolones were given to seven patients (levofloxacin: six patients; ofloxacin: one patient) and amoxicillin/clavulanic acid was added to one patient. Conclusions: MDR-TB patients may develop DILI after the first month of treatment. Hepatocellular injury was the mostcommon type of liver injury, and pyrazinamide was the most frequently used antimycobacterial.Objetivo: Describir las características clínicas de la injuria hepática inducida por antituberculosos (IHIA) en pacientes con tuberculosis multirresistente (MDR-TB).Materiales y métodos: Estudio retrospectivo de pacientes hospitalizados con TB-MDR e IHIA. Se utilizó los criterios de laDILI-Expert Working Group, y el instrumento de análisis de causalidad fue el RUCAM (Roussel Uclaf Causality AssessmentMethod). La asociación específica de la IHIA con un antituberculoso fue por un proceso de reexposición o suspensión y recuperación. Resultados: Reportamos 7 casos de MDR-TB e IHIA; la edad media (desviación estándar) fue de 39,1 (3,3) años. La media de la IHIAapareció después de 30,4 (27,70) días de iniciar el tratamiento. Tres (43,00 %) pacientes presentaron ictericia. En cuanto al patrón, en 4 (57,00 %) fue hepatocelular y en 3 (43,00 %), colestásico. En 4 pacientes, la IHIA fue leve, y moderada en 3. En todos los casos estuvo involucrada la pirazinamida (pirazinamida sola, 4; pirazinamida y etionamida, 1; pirazinamida, rifampicina e isoniazida, 1;pirazinamida y rifampicina, 1). La estancia hospitalaria media fue de 48,10 (48,70) días. Los promedios de fosfatasa alcalina (FA), alanina aminotransferasa (ALT) y gamma-glutamiltranspeptidasa (GGT) sérica fueron 2,40 (1,10), 7,9 (7,10) y 5,60 (3,70) veces el límite superior normal (NUL), respectivamente. La bilirrubina total media fue 2,30 (2,10), rango de 0,50 a 6,40 mg/dl. Como parte del esquema de alta del paciente, se administraron quinolonas a 7 pacientes (levofloxacino, 6; ofloxacino,1), y en un paciente se agregó ácido amoxicilina/ácido clavulánico.Conclusiones: La IHIA en pacientes con TB-MDR puede aparecer después del primer mes de tratamiento. El patrón de lesión común fue hepatocelular, y la pirazinamida fue el antimicobacteriano involucrado con mayor frecuencia

Hepatite aguda secundária ao abuso de cocaína, associada a severa rabdomiólise

A cocaína é uma droga com notória capacidade de afetar adversamente quase todos os órgãos do corpo e pode causar uma infinidade de anormalidades multisistêmicas secundárias. No presente estudo, relatamos três casos de insuficiência hepática aguda complicada por rabdomiólise e lesão renal aguda após consumo de cocaína e álcool. O início da doença, as manifestações clínicas, os dados laboratoriais, o diagnóstico e a terapêutica de cada paciente foram registrados. Nota-se a presença de causas multifatoriais para a ocorrência de Insuficiência Hepática e Rabdomiólise nos três casos relatados. Os testes laboratoriais revelaram que a concentração sérica de transaminases, bem como os de creatinafosfoquinase (CPK) aumentaram e que os sintomas de insuficiência renal aguda estavam presentes, o que forneceu um diagnóstico exato de insuficiência hepática aguda complicada por grave rabdomiólise e lesão renal aguda dialítica. Rabdomiólise é uma condição de hipermioglobinúria, sendo uma dos principais fatores que fomentam uma piora da função renal. A terapia da fase inicial envolveu suporte a ressuscitação volêmica associada a terapia dialítica com rigoroso controle da função renal. Os três pacientes desenvolveram comprometimento de múltiplos órgãos, mas apenas um foi a óbito devido a gravidade do quadro. Considerando os três casos apresentados, concluímos que a insuficiência hepática, complicada por rabdomiólise, secundária ao uso de cocaína e álcool pode ter mau prognóstico clínico, a depender de vários fatores. E os médicos devem estar cientes dos potenciais efeitos causados pela cocaína, a fim de gerir as múltiplas complicações associadas ao abuso destas substâncias.Cocaine is a drug with a noticeable ability to adversely affect almost every organ in the body and can cause a multitude of secondary multisystem abnormalities. In the present study, we report three cases of acute liver failure complicated by rhabdomyolysis and acute kidney injury following cocaine and alcohol use. The disease onset, clinical manifestations, laboratory data, diagnosis and treatment of each patient were recorded. Note the presence of multifactorial causes for the occurrence of liver failure and rhabdomyolysis in the three reported cases. Laboratory tests revealed that serum trasaminases as well as creatine phosphokinase (CPK) concentrations increased, and symptoms of acute renal failure were present, which provided an accurate diagnosis of acute liver failure complicated by severe rhabdomyolysis and acute renal injury. dialytic rhabdomyolysis is a condition of hypermyoglobinuria, being one of the main factors that promote a deterioration of renal function. Early phase therapy involved support for volume resuscitation associated with dialysis therapy with strict control of renal function. All three patients developed multiple organ involvement, but only one died due to the severity of the condition. Considering the three cases presented, we conclude that liver failure, complicated by rhabdomyolysis, secondary to cocaine and alcohol use may have a poor clinical prognosis, depending on several factors. And doctors should be aware of the potential effects caused by cocaine in order to manage the multiple complications associated with substance abuse

Liver Multiacinar Regenerative Nodules: Imaging Findings and Clinical Implications

Introduction: Multiacinar regenerative nodules are benign hepatocellular nodules related to vascular disturbances of the liver. They strongly resemble conventional focal nodular hyperplasia but are connected to different clinical settings, typically chronic liver disease. The purpose of the present study was to describe the key imaging features of these lesions and compare them with a control arm of focal nodular hyperplasia. Material and Methods: A blinded consensus review of liver magnetic resonance consisting of 26 cases of multiacinar regenerative nodules and 25 cases of focal nodular hyperplasia was performed. Lesion size, shape, margins, structure, T1 and T2 signal intensity, diffusion and contrast-enhanced features (including hepatobiliary phase), presence of a central scar and of a peripheral hypointense rim were compared between the two groups. Results: Significant differences between multiacinar regenerative nodules and focal nodular hyperplasia included size (median 2.35 cm, IQR: 2.13, vs 6.00 cm, IQR: 5.20, respectively, p < 0.001), presence of a peripheral hypointense rim after contrast (n = 9 vs n = 2 cases, p = 0.038) and of a central scar (n = 9 vs n = 20, p = 0.002). There were no other significant differences. Discussion: Overall multiacinar regenerative nodules and focal nodular hyperplasia have very similar imaging features but lack of a central scar and presence of a hypointense rim should suggest a diagnosis of multiacinar regenerative nodules. Conclusions: Recognition of the imaging findings of multiacinar regenerative nodules can explain some atypical cases of focal nodular hyperplasia, avoiding unnecessary biopsies. They may also be the trigger to investigate an unsuspected underlying liver vascular abnormality

Carnitine in Alleviation of Complications Caused by Acute Valproic Acid Toxicity; an Exprimental Study on Mice

Introduction: Hyperammonemia and hepatotoxicity are well-known complications of valproic acid (VPA) poisoning. The objective of this study is to evaluate the potential role of carnitine in mitigating the adverse effects of acute VPA toxicity in mice. Methods: 54 male mice (25-30 g) were randomly assigned to one of three categories, including acute, sub-acute, and chronic poisoning. Each category contained 3 groups, each consisting of 6 mice (Group 1: control, Group 2: VPA treated, and Group 3: VPA + carnitine treated). The animals were sacrificed 24 hours after the initial injection, and their blood, liver, and brain samples were compared between groups of each category regarding liver function biomarkers, oxidative stress markers, ammonia level, and liver histopathologic changes using one-way ANOVA followed by Tukey’s multiple comparison test. Results: The administration of VPA increased the serum level of aspartate aminotransferase (AST) (p=0.003) and alanine aminotransferase (ALT) (p=0.001), as well as serum, and brain level of ammonia (p=0.0001 for both) in the intervention group. Elevated levels of lipid peroxidation and oxidative stress (p=0.0001 for both) in the liver tissue, decreased liver glutathione (p=0.0001) and ferric ion-reducing antioxidant power (FRAP) (p=0.0001), and histopathologic changes in the form of moderate to severe inflammation were observed. Administration of VPA + carnitine reduced AST (p=0.05) and ALT (p=0.01), increased the FRAP, reduced free oxygen radicals and liver lipid peroxidation (p=0.0001 for all), and decreased tissue damage in the form of moderate inflammation. The administration of carnitine was ineffective in reducing brain or plasma ammonia levels in acute VPA-treated animals (p = 0.0115). Conclusions: Although the administration of carnitine has been suggested as a protective remedy in cases of VPA toxicity, according to the present study, it did not have an antidotal effect and did not prevent encephalopathy or liver injury in acute VPA toxicity

TRADUÇÃO E VALIDAÇÃO DE ALGORITMO PARA IDENTIFICAÇÃO DE LESÃO HEPÁTICA INDUZIDA POR MEDICAMENTOS

A lesão hepática induzida por medicamentos é um tipo de reação adversa a medicamento (RAM), cuja ocorrência é a causa de falha hepática fulminante em 13% a 30% dos casos. O Russel Uclaf Causality Assessment Method (RUCAM) é um algoritmo específico para a determinação de lesão hepática induzida por medicamentos. O objetivo deste trabalho é traduzir e validar o algoritmo RUCAM para o português. Método: Foi realizada a tradução e tradução inversa do algoritmo. A validação de conteúdo foi verificada pela aplicação do algoritmo traduzido a um caso real, por um grupo de médicos, farmacêuticos e enfermeiros. Resultados: Foram obtidas 41 aplicações do algoritmo. O tempo médio de aplicação foi de 17 + 10 minutos. O escore médio foi de 7,58 + 3,48 (provável relação de causalidade). As diferenças do escore para as diferentes categorias profissionais não foi estatisticamente significativa (p=0,800). Discussão: O algoritmo RUCAM possui sete domínios: tempo de início da doença hepática, duração da doença, fatores de risco, uso concomitante de medicamentos, exclusão de causas alternativas, história prévia do medicamento suspeito e resposta à reexposição ao medicamento. Tais informações permitem maior acurária na confirmação da suspeita da RAM, favorecendo a identificação dos medicamentos com potencial hepatotóxico. Conclusão: O algoritmo RUCAM traduzido para o português se mostrou uma ferramenta útil para a investigação de causalidade entre a lesão hepática e medicamentos, que pode ser aplicado por médicos, enfermeiros e farmacêuticos

Risk assessment of melatonin. Opinion of the Norwegian Scientific Committee for Food and Environment

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