High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice

Macroautophagy (referred to as autophagy hereafter) is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles. Previous studies showed that autophagy protects against acetaminophen (APAP)-induced injury (AILI) via selective removal of damaged mitochondria and APAP protein adducts. The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes. In the present study, we showed that transcription factor EB (TFEB), a master transcription factor for lysosomal biogenesis, was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers. Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI, respectively. Mechanistically, overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2 (NRF2) activation to protect against AILI. We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists. Among these agonists, salinomycin, an anticoccidial and antibacterial agent, activated TFEB and protected against AILI in mice. In conclusion, genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.

Clinician's dilemma: Naproxen-induced liver injury

Naproxen is a widely used nonsteroidal anti-inflammatory drug (NSAID) in pediatric population, used for mild-to-moderate pains, arthritis, and other immune-mediated disorders. It rarely causes clinically apparent liver injury in the adult population taking high doses of the drug over a prolonged period and is reported even rarer in pediatric population. We present a case of drug-induced liver injury (DILI) in a 13-year-old girl taking naproxen in therapeutic doses for juvenile rheumatoid arthritis. There was a complete recovery of liver function following discontinuation of naproxen therapy.

Drug-induced liver injury after anti tuberculosis drugs administration, how to diagnose? a case report

Drug-induced liver injury (DILI) is a liver injury caused by various drugs, herbs, or other xenobiotics, which causes abnormalities in liver tests or liver dysfunction in the absence of other causes of liver damage. The most common causative drugs are antituberculosis drugs (ATDs), anti-infective drugs, and natural herbal medicines. The diagnosis of DILI can be difficult due to the lack of specific signs, symptoms and tests and is partly a diagnosis based on exclusion. In this case report, we will discuss how to diagnosis DILI TB and causative assessment using RUCAM score. A male, 64 years old, has complained of weakness since 1 week ago and worsened since 1 day ago. The patient also felt persistent nausea for 1 week, so his eating and drinking decreased. Besides, he complained getting abdominal pain, especially in the upper right region and heartburn. The patient has been on first category of TB treatment since 20 days ago. Chest X-ray showed Lung TB with infiltrate inmultiple cavities. Abdominal ultrasound showed no abnormality. The patient was discharged from our hospital after 6 days of hospitalization. DILI remains a diagnosis of exclusion based primarily on a detailed history and judicious use of blood tests, hepatobiliary imaging, and liver biopsy. TheRoussel Uclaf causality assessment method (RUCAM)system is an assigning point for clinical, biochemical, serologic and radiologic features of liver injury. We use RUCAM score to make an assessment that show the likelihood of the hepatic injury due to a specific medication.

Cholestatic drug induced liver injury in active pulmonary tuberculosis patient: a case report

Drug induced liver injury (DILI) has been a long-standing concern in the treatment of tuberculosis. Anti-tuberculosis therapy (ATT) is known to have hepatotoxicity effect. DILI is diagnosed clinically using liver biochemical test, such as alanine transaminase (ALT), alkaline phosphatase (ALP), and total bilirubin. Calculating ratio (R) of ALT over ALP, is useful to classify types of injury pattern in DILI. Roussel Uclaf causality assessment method (RUCAM)scaleserves as a method to assess the causality agents for DILI. Here we report a case of 59 years old male who developed cholestatic DILI on fourth weeks of ATT. Patient came in with loss of consciousness, jaundice, nausea, pruritus, and abdominal tenderness. Patient抯 ALT level was normal, but ALP and total bilirubin was significantly elevated, with R values less than 2, indicating a cholestatic type of injury. Patient sputum was positive for tuberculosis bacteria, showing an active infection. Patient was admitted and ATT was discontinued. Patient showed improvement, but eventually fall into sepsis and developed respiratory distress on sixth day of admission despite adequate treatment and close monitoring. Despite most of the cases resolves spontaneously upon cessation of the toxic agents, in the severe form, it may fall into chronic liver injury, acute liver failure, and eventually death. Preventing DILI is readily important by educating, screening for risk factors, and routine evaluation of liver enzymes in patient under ATT. Early diagnosis and prompt treatment are needed to avoid poor prognosis in the course of the disease.

Research progress on liver transplantation for drug-induced liver injury / 器官移植

Drug-induced liver injury (DILI) is a type of necrotizing and inflammatory liver disease caused by certain commonly-used drugs, Chinese herbal medicines or dietary supplements. In severe cases, it may lead to acute liver failure. Without liver transplantation, the fatality could reach up to 80%. It is of significance to master the indications of liver transplantation. Several prognostic scoring systems have been developed to help clinicians to decide which patients need urgent liver transplantation, such as King's College criteria (KCC) and model for end-stage liver disease (MELD) scoring systems. However, these scoring methods have been developed for a long period of time and lack of modifications. Therefore, scholars have proposed several new scoring systems, such as acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) and sequential organ failure assessment (SOFA) scoring systems, which provide novel ideas for the evaluation of liver transplantation. As an important treatment measure for drug-induced acute liver failure, urgent liver transplantation has greatly improved the survival rate of patients. In this article, the classification, clinical diagnosis, liver transplantation evaluation and prognosis of DILI were summarized, aiming to provide reference for the treatment of DILI by liver transplantation.

Hepatotoxicity reports in the FDA adverse event reporting system database: A comparison of drugs that cause injury

Drug-induced liver injury (DILI) is a leading reason for preclinical safety attrition and post-market drug withdrawals. Drug-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI, especially in idiosyncratic liver injury. This study examined liver injury reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for drugs associated with hepatotoxicity

Mechanisms of immune checkpoint inhibitor-mediated liver injury

The immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1/ligand-1 (PD-1/PD-L1) are vital contributors to immune regulation and tolerance. Recently immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, they come with the cost of immune related adverse events involving multiple organs such as the liver. Due to its constant exposure to foreign antigens, the liver has evolved a high capacity for immune tolerance, therefore, blockade of the immune checkpoints can result in aberrant immune activation affecting the liver in up to 20% of patients depending on the agent(s) used and underlying factors. This type of hepatotoxicity is termed immune mediated liver injury from checkpoint inhibitors (ILICI) and is more common when CTLA4 and PD-1/PD-L1 are used in combination. The underlying mechanisms of this unique type of hepatotoxicity are not fully understood; however, the contribution of CD8

Drug-Induced Fatty Liver

Drug-induced fatty liver disease is defined as the accumulation of fat in the liver due to exposure to some drugs. This condition is callednon-alcoholic fatty liver disease (NAFLD). Fatty liver can be progressed to inflammation called non-alcoholic steatohepatitis or NASH,which can be progressed into fibrosis and eventually liver failure. This condition is frequently associated with long-term intake of thepotentially harmful drug. Differents mechanisms have been postulated to illustrate how these drugs could induce fatty liver. Due to currentlifestyle, the fatty liver rate is increasing, however, some drugs can induce this condition even in non-obese persons. This review focuses ondrug-induced fatty liver and the possible role for some antioxidants in reversing this condition.

Hepatotoxicidad colestásica asociada al uso de quimioterapia en esquema con lomustina: reporte de un caso y revisión de la literatura / Colestasic hepatotoxicity associated with the use of chemotherapy in scheme with lomustine: case report and literature review

Drug-induced liver injury (DILI) is a rare entity associated with high morbidity and mortality. It includes a broad spectrum of clinical patterns, from acute hepatitis to cirrhosis. Among the common associated drugs are antimicrobial like anti-TBC, antineoplastic, CNS agents and non-steroidal anti-inflammatory drugs. Establishing causality between DILI and a certain drug is a challenge. Some scoring systems have been evaluated, considering RUCAM score as the gold standard. We present the case of a 35-year-old woman with a history of a high-grade glioma treated with surgery and chemotherapy with lomustine, procarbazine and vincristine. She evolved with altered liver tests, predominantly cholestatic pattern, but asymptomatic. Etiologic study negative and abdominal imaging were normal. The liver biopsy was compatible with 40% ductopenia, without inflammatory elements. We consider DILI associated with the use of lomustine, with RUCAM score suggesting. After discontinuing chemotherapy and using ursodeoxycholic acid for the treatment of cholestasis there was an improvement in liver tests. There is limited evidence in the literature regarding hepatotoxicity associated with lomustine, mainly in experimental animal models. Cases of cholestatic hepatotoxicity have been described with the use of other similar nitrosureas. In relation to procarbazine and vincristine, DILI is reported mainly reversible and predominantly with hepatocellular pattern, not consistent with our case. We find it interesting to communicate with review of the literature about it.

El daño hepático inducido por drogas (DILI) es una entidad poco frecuente, con alta morbimortalidad asociada. Incluye un amplio espectro de patrones clínicos, desde hepatitis aguda a cirrosis. Dentro de los fármacos frecuentemente asociados se encuentran antibióticos como anti-TBC, agentes antineoplásicos, de acción en el SNC y anti-inflamatorios no esteroidales. Establecer una causalidad entre DILI y una determinada droga constituye un desafío. Para ello, se han evaluado diversos sistemas de puntuación, considerándose gold estándar el RUCAM score. Se presenta el caso de una mujer de 35 años de edad con antecedentes de glioma de alto grado operado y en quimioterapia con lomustina, procarbazina y vincristina. En su evolución presenta alteración de pruebas hepáticas de predominio colestásico de manera asintomática, con estudio etiológico causal negativo e imagenológico normal. La biopsia hepática fue compatible con ductopenia de 40% sin elementos inflamatorios. Se plantea DILI asociado al uso de lomustina con un score de RUCAM sugerente, decidiéndose interrumpir sus ciclos de quimioterapia e inicia tratamiento con ácido ursodesoxicólico, presentando mejoría progresiva de pruebas hepáticas. Existe evidencia limitada en la literatura en relación a hepatotoxicidad asociada a este fármaco, principalmente en modelos experimentales, y con el uso de otras nitrosureas similares se han descrito casos de hepatotoxicidad de predominio colestásico. En relación con procarbazina y vincristina existen reportes de DILI principalmente reversible y con patrón de predominio hepatocelular, lo que no es concordante con nuestro caso, por lo cual nos parece de interés comunicarlo con revisión de la literatura al respecto.

Guidelines for clinical diagnosis and treatment of herb-induced liver injury / 中国中药杂志

In recent years, the issues related to herb-induced liver injury (HILI) have received much concern. Its clinical diagnosis is much difficult than that of Western medicine-induced liver injury due to its complicated drug combination and multiple constituents. Moreover, it is also correlated with physiques, inheritance and basic diseases. China Association of Chinese Medicine has released the first standards for HILI diagnosis and treatment technology in 2016, namely Guidelines for clinical diagnosis of herb-induced liver injury (hereinafter referred to as the Guidelines). The diagnostic processes with different diagnostic results were explained in this paper to help clinicians, particularly liver specialists, in diagnosing liver diseases by applying the operation of the Guidelines.

Hepatotoxicidad por isoniazida en un paciente con enfermedad de Crohn: Reporte de caso y revisión de la literatura / Hepatotoxicity due to Isoniazide in a Patient with Crohn’s Disease: Case Report and Literature Review

La isoniazida se utiliza para el tratamiento o profilaxis de la tuberculosis; sin embargo, su uso puede asociarse con reacciones hepáticas adversas. La hepatitis clínicamente manifiesta sucede en 0,5%-1% de los pacientes que reciben isoniazida como monoterapia. En este artículo se describe el caso de un paciente con enfermedad de Crohn que cursó con hepatotoxicidad grave por isoniazida, y se hace una revisión de la literatura al respecto

Isoniazid is used for treatment or prophylaxis of tuberculosis but may be associated with adverse hepatic reactions. Clinically manifest hepatitis occurs in 0.5%-1% of patients who receive isoniazid as monotherapy. This article describes the case of a patient with Crohn’s disease who experienced severe hepatotoxicity due to isoniazid. It also reviews the literature.

Clinical analysis of two diagnosis methods for herb-induced liver injury / 中国中药杂志

To compare the consistency and difference of herb-induced liver injury between two methods in guidelines for clinical diagnosis and treatment of liver injury related to Chinese herbal medicine in China (2016) and guidelines for the diagnosis and treatment of drug-induced liver injury in China(2015). This retrospective analysis included 390 patients with herb-induced liver injury who had a history of suspicious Chinese herbal medicines or patent medicines; the patients with integrative Chinese and western medicines were excluded from this study. The results indicated that there were 14(4%) extremely probable patients (>8 points), 185(47%) highly probable patients (6-8 points) and 191(49%) probable patients(3-5 points) in 390 cases with guidelines for diagnosis and treatment of drug-induced liver injury of China (2015). While when guidelines for clinical diagnosis and treatment of liver injury related to Chinese herbal medicine in China (2016) was used for 390 patients, the results indicated that there were 5 (1%) cases with proven diagnosis, 163(42%) cases with clinical diagnosis, and 222(57%) cases with suspected diagnosis. Statistics showed that two methods had a consistency of 43% and difference of 14%. The research results showed that Guidelines for clinical diagnosis and treatment of liver injury related to Chinese herbal medicine in China(2016) was more suitable for the diagnosis of herb-induced liver injury. Due to the limitations of retrospective case study, further more prospective studies would be needed.

Drug-induced liver injury:metabolic and genetic basis / 中国药理学通报

Drug-induced liver injury ( DILI) is a significant rea-son of acute liver failure and is the main cause of therapeutic drugs withdrawal from the market .Multiple mechanisms can cul-minate in DILI , but metabolism and genetics play distinct roles in this process .This review will cover papers we consider have addressed these mechanisms of DILI in commonly used medica-tions for adults , and discuss the hot issues .The aim is to gener-ate discussion about the potential clinical significance among these researchs and point out the key areas for further study of DILI.

Progress in influence factors on drug induced liver injury / 中国药学杂志

Drug-induced liver injury (DILI) is a hot topic for clinicians, academia, drug companies and regulators. It is essential to understand risk factors of idiosyncratic DILI in order to accurately predict and prevent this problem. However, the role of factors on the pathogenesis of DILI is poorly understood. Indeed, both drug properties and host factors are likely interact at multiple levels to determine individual risks and clinical outcome of DILI. In this review, cross-disciplinary view over drug characteristics associated with hepatotoxicity is provided, and various host factors influencing individuals' DILI risks at updating the current knowledge to stimulate future investigation are discussed.

Drug-induced liver injury caused by iodine-131

Iodine-131 is a radioisotope that is routinely used for the treatment of differentiated thyroid cancer after total or near-total thyroidectomy. However, there is some evidence that iodine-131 can induce liver injury . Here we report a rare case of drug-induced liver injury (DILI) caused by iodine-131 in a patient with regional lymph node metastasis after total thyroidectomy. A 47-year-old woman was admitted with elevated liver enzymes and symptoms of general weakness and nausea. Ten weeks earlier she had undergone a total thyroidectomy for papillary thyroid carcinoma and had subsequently been prescribed levothyroxine to reduce the level of thyroid-stimulating hormone. Eight weeks after surgery she underwent iodine-131 ablative therapy at a dose of 100 millicuries, and subsequently presented with acute hepatitis after 10 days. To rule out all possible causative factors, abdominal ultrasonography, endoscopic ultrasonography (on the biliary tree and gall bladder), and a liver biopsy were performed. DILI caused by iodine-131 was suspected. Oral prednisolone was started at 30 mg/day, to which the patient responded well.

Risk Assessment for Groundwater Resources in Dili, The Capital City of Timor-Leste.

As a newly independent nation-state, Timor-Leste is in the process of developing itself to achieve better condition to meet and provide the needs of its citizens. However, Timor-Leste is still facing challenges in many areas including lack of clean water supply from groundwater resources. Dili, the capital city of Timor-Leste, is an emerging urban city that makes water availability is crucial. High birth rate and continuing rural-urban migration to Dili signifies that population in Dili is likely to increase, and this has put more pressure on water resources. For the groundwater resource in Dili - deforestation, lack of waste management, and unsafe boreholes and unmanaged domestic wells - are the main issues that need to be addressed because they can greatly affect groundwater in terms of reducing the quantity and potential hazards for contamination. This paper highlights thatassessing the risk to groundwater resources is vital for the sustainable management of water supply in Dili.This paper can definitely serve as an effort to raise awareness about the groundwater issue in the country that should be considered by the government of Timor-Leste.

Amoxycillin Clavulanic Acid Induced Hepatotoxicity.

Drug-related hepatotoxicity is a serious health problem, with broad implications for patients, healthcare providers, the pharmaceutical industry and governmental regulatory agencies. Herein we report a rare case of amoxycillinclavulanic acid combination induced liver injury of cholestatic pattern in 40 years old, well educated male patient. Patient gave history that though other drugs were given to him by his physician for fever with chills & rigors, malaise, bodyache, except amoxycillin-clavulanic acid combination all other drugs were well tolerated previously by the patient, without appearance of jaundice. So jaundice in this patient was most probably due to amoxycillinclavulanic acid combination. Though severe liver injury is rare, proper history should be taken while prescribing amoxycillin-clavulanic acid combination. Attention must be paid to potential side-effects of the drugs and close follow-up with patients is a medical necessity to evaluate adverse reactions, especially in case of amoxycillinclavulanic acid combination.

Factors affecting drug-induced liver injury: antithyroid drugs as instances

Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.

Albendazole-induced liver injury: a case report / Lesión hepática inducida por albendazol: reporte de un caso

We report a case of a 47-year-old male, who was referred to the clinical hepatology services at Pablo Tobón Uribe Hospital for evaluation of a jaundice syndrome. After undergoing several exams, we diagnosed hepatic hydatidosis and the patient was treated with albendazole; however, after five months of uninterrupted treatment the patient again consulted and his liver test showed marked hepatocellular damage. This time, the patient was diagnosed with drug-induced liver injury due to albendazole, based on information from the clinical record, history of drug consumption, clinical and laboratory tests improved after discontinuing the medication and after discarding other possible causes; this diagnosis was supported by the CIOMS/RUCAM scale, which showed a "likely" correlation between hepatocellular damage and drug toxicity etiology.

Presentamos el caso de un paciente masculino de 47 años de edad, quien fue remitido al servicio de hepatología clínica del Hospital Pablo Tobón Uribe para el estudio de un síndrome ictérico. Tras realizársele varios análisis, se le diagnosticó hidatidosis hepática y recibió albendazol como terapia, sin embargo, después de cinco meses de tratamiento ininterrumpido consultó nuevamente y su perfil hepático mostró marcado daño hepatocelular. Se le diagnosticó entonces una hepatitis toxica inducida por albendazol basados en la información de la historia clínica, el antecedente de consumo del fármaco, la mejoría clínica y en las pruebas de laboratorio tras suspender el medicamento y después de descartar las otras causas posibles; este diagnóstico fue respaldado por la escala CIOMS/RUCAM, que mostró una correlación probable entre el daño hepatocelular y la etiología toxica farmacológica.

Frecuencia y factores asociados a daño hepático inducido por medicamentos en tratamiento antituberculosis / Frequency and factors associated with DILI in antituberculosis treatment

Introduction: Potentially hepatotoxic drugs are used in tuberculosis treatment. The incidence range of drug-induced liver injury (DILI) varies from 0.6 to 33 percent. Adverse reactions can be asymptomatic; therefore periodical liver tests are required. Multiple risk factors are described, such as age and HIV infection, among others. Objective: To determine risk factors associated to DILI and secondary lethality in patients receiving anti-tuberculosis drugs. Materials and Methods: The database from the Servicio de Salud Metropolitano Central de Chile was used. 1,249 patients were analyzed from 2003 to 2008 to determine DILI’s frequency and time of appearance. Multivariate binominal regression was used to study possible risks associated to hepatotoxicity. Results: 2,8 percent of our patients presented DILI (n = 35), three of them died from this cause (8.5 percent). Association between DILI and HIV infection and extrapulmonary tuberculosis was observed (p < 0.01). DILI was present in 50 percent of our patients before the 23rd day. Conclusions: We propose a more exhaustive control of the liver function in patients with DILI risk factors, including HIV carriers and extrapulmonary tuberculosis.

Introducción: El tratamiento antituberculosis incluye drogas hepatotóxicas, estimándose una incidencia de daño hepático inducido por medicamentos (DHIM) entre 0,6 y 33 por ciento. Puede ser asintomático, debiendo evaluarse periódicamente con perfil hepático. Se han descrito múltiples factores de riesgo, como mayor edad e infección por VIH, entre otros. Objetivo: Determinar factores asociados al desarrollo de DHIM y letalidad secundaria a tratamiento antituberculosis. Materiales y Métodos: Base de datos del Programa de Tratamiento antituberculosis del Servicio de Salud Metropolitano Central de Chile. Se analizaron 1.249 pacientes entre 2003 y 2008. Se determinó frecuencia y tiempo de aparición de DHIM. Se estudiaron posibles factores asociados a hepatotoxicidad mediante regresión binomial. Resultados: se diagnosticó DHIM en 2,8 por ciento de los pacientes (n = 35), falleciendo 3 de ellos por esta causa (8,5 por ciento). Se observó asociación entre DHIM con ser portador de VIH (+) y tuberculosis extrapulmonar (p < 0,01). Aparición de DHIM antes del día 23 en 50 por ciento de los casos. Conclusión: Sugerimos un control más exhaustivo del perfil hepático en pacientes con factores de riesgo, entre los cuales deben considerarse los portadores de VIH y tuberculosis extrapulmonar.