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Salvatore Sutti, Frank Tacke
Drug-induced liver injury (DILI) remains a clinical challenge due to the poorly predictable outcomes. Accordingly, considerable efforts have been devoted to unravel the risk factors responsible for DILI worsening toward acute liver failure (ALF), liver transplantation (LT), and/or death. From a pathogenic point of view, exhaustion of drug metabolizing pathways, cell death mechanisms, activation of local immune cells, such as Kupffer cells, and recruitment of inflammatory leukocytes including monocytes and lymphocytes are key drivers of DILI progression...
March 15, 2018: Clinical Science (1979-)
Jia-Bo Wang, Yun Zhu, Zhao-Fang Bai, Fu-Sheng Wang, Xiu-Hui Li, Xiao-He Xiao
Herb-induced liver injury (HILI) is a type of adverse drug reactions related to using Chinese medicine (CM) or herbal medicine (HM), and is now a growing segment of drug-induced liver injury (DILI) worldwide. Owing to the complicated compositions and miscellaneous risk factors associated with the clinical usage of CM or HM, it is more challenging to diagnose and manage HILI than DILI. In the present guideline issued by the China Association of Chinese Medicine (CACM), the authors present an evidence chain-based workflow with 9 structured judgment criteria for diagnosing HILI...
March 15, 2018: Chinese Journal of Integrative Medicine
David Noiva Perdigoto, Pedro Amaro, Manuela Ferreira, Luis Tomé
A patient is admitted with complaints of recent onset nausea, discomfort, jaundice and blood tests that reveal severe hepatitis. At the time, she had been taking medication with Hypericum perforatum (St John's wort) for 6 months, and 6 weeks before this event, she took flupirtine maleate. A few days after being admitted, she developed encephalopathy progressing to acute liver failure (ALF) requiring unsuccessful liver transplantation. The patient was ultimately diagnosed with drug-induced liver injury (DILI)...
March 9, 2018: BMJ Case Reports
Hella Wobser, Tanja Paur, Elisabeth Schnoy, Janine Hartl, Gabriele I Kirchner
Background: Several years ago the International Autoimmune Hepatitis Group simplified the previous revised original scoring system for diagnosis of autoimmune hepatitis (AIH) into a scoring system based on only four instead of 13 parameters. Objective: We aimed to evaluate the suitability of the simplified AIH score for diagnosis of AIH in a German cohort with chronic liver diseases. Methods: In this retrospective single-center study, we compared the accuracy of both AIH scores in 70 patients with AIH and 211 patients with chronic liver diseases (PBC ( n  = 52), PSC ( n  = 27), NASH ( n  = 67), DILI ( n  = 15), CHB/C ( n  = 50))...
March 2018: United European Gastroenterology Journal
Shiho Makabe, Toshio Mochizuki, Michihiro Mitobe, Yumi Aoyama, Hiroshi Kataoka, Ken Tsuchiya, Kosaku Nitta
BACKGROUND: In 2014, tolvaptan, a vasopressin receptor antagonist, was approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD) in Japan. Clinical trials of tolvaptan revealed frequent occurrence of the liver function abnormality. According to the package insert in Japan, liver function tests should be performed once a month in patients receiving tolvaptan. Furthermore, immediate discontinuation of tolvaptan is recommended in the appearance of liver function abnormalities...
March 5, 2018: Clinical and Experimental Nephrology
Henrik Cordes, Christoph Thiel, Vanessa Baier, Lars M Blank, Lars Kuepfer
Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism...
2018: NPJ Systems Biology and Applications
Gaby Danan, Rolf Teschke
Launched in 1993 and partially based on the results of an international consensus meeting organized under the auspices of the Council of International Organizations of Medical Sciences (CIOMS), the Roussel Uclaf Causality Assessment Method (RUCAM) is the most used causality assessment tool worldwide for the diagnosis of drug-induced liver injury (DILI) and herb-induced liver injury (HILI) in a large number of epidemiological studies, case reports, and case series. The 25-year experience of RUCAM use confirmed that the success was due to its objective, standardized, and liver-injury-specific approach structured with defined key elements derived from a series of DILI cases with positive rechallenge...
March 3, 2018: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
Steven Wink, Steven W Hiemstra, Suzanne Huppelschoten, Janna E Klip, Bob van de Water
Drug-induced liver injury remains a concern during drug treatment and development. There is an urgent need for improved mechanistic understanding and prediction of DILI liabilities using in vitro approaches. We have established and characterized a panel of liver cell models containing mechanism-based fluorescent protein toxicity pathway reporters to quantitatively assess the dynamics of cellular stress response pathway activation at the single cell level using automated live cell imaging. We have systematically evaluated the application of four key adaptive stress pathway reporters for the prediction of DILI liability: SRXN1-GFP (oxidative stress), CHOP-GFP (ER stress/UPR response), p21 (p53-mediated DNA damage-related response) and ICAM1 (NF-κB-mediated inflammatory signaling)...
March 3, 2018: Archives of Toxicology
Julia C Dettinger, Stephen Kamau, Kimberly Calkins, Susanna R Cohen, John Cranmer, Minnie Kibore, Onesmus Gachuno, Dilys Walker
As the proportion of facility-based births increases, so does the need to ensure that mothers and their newborns receive quality care. Developing facility-oriented obstetric and neonatal training programs grounded in principles of teamwork utilizing simulation-based training for emergency response is an important strategy for improving the quality care. This study uses 3 dimensions of the Kirkpatrick Model to measure the impact of PRONTO International (PRONTO) simulation-based training as part of the Linda Afya ya Mama na Mtoto (LAMMP, Protect the Health of mother and child) in Kenya...
February 2018: Maternal & Child Nutrition
Eita Sasaki, Tsuyoshi Yokoi
Several drugs have been withdrawn from the market or restricted to avoid unexpected adverse outcomes. Drug-induced liver injury (DILI) is a serious issue for drug development. Among DILIs, idiosyncratic DILIs have been a serious problem in drug development and clinical uses. Idiosyncratic DILI is most often unrelated to pharmacological effects or the dosing amount of a drug. The number of drugs that cause idiosyncratic DILI continue to grow in part because no practical preclinical tests have emerged that can identify drug candidates with the potential for developing idiosyncratic DILIs...
2018: Journal of Toxicological Sciences
Preeti Chavan-Gautam, Alka Rani, Dilys J Freeman
Maternal fatty acid and lipid metabolism undergoes changes during pregnancy to facilitate fetal growth and development. Different types of fatty acids have different roles in maintaining a successful pregnancy and they are incorporated into different forms of lipids for the purpose of storage and transport. This chapter aims to provide an understanding of the distribution and metabolism of fatty acids and lipids in the maternal, placental, and fetal compartments. We further describe how this distribution is altered in maternal obesity, preterm birth, and pregnancy complications such as gestational diabetes mellitus, preeclampsia, and intrauterine growth restriction...
2018: Advances in Clinical Chemistry
Cyriac Abby Philips, Rajaguru Paramaguru, Adarsh K Joy, K L Antony, Philip Augustine
INTRODUCTION: Ayurvedic and herbal medicines (AHM) are known to cause varying degrees of drug-induced liver injury (DILI). Clinical, biochemical, histological spectrum and outcomes of AHM linked to severe DILI are not well studied. METHODS: Out of 1440 liver disease patients, 94 were found to have a severe liver injury and associated AHM intake. Thirty-three patients were suspected to have AHM-DILI on Roussel Uclaf Causality Assessment Scoring Method. Forty-seven and 30 of retrieved AHM samples were analyzed for heavy metals and hepatotoxic volatile organic compounds (hVOCs), respectively...
February 24, 2018: Indian Journal of Gastroenterology: Official Journal of the Indian Society of Gastroenterology
John N Cranmer, Julia Dettinger, Kimberly Calkins, Minnie Kibore, Onesmus Gachuno, Dilys Walker
BACKGROUND: Globally, the rate of reduction in delivery-associated maternal and perinatal mortality has been slow compared to improvements in post-delivery mortality in children under five. Improving clinical readiness for basic obstetric emergencies is crucial for reducing facility-based maternal deaths. Emergency readiness is commonly assessed using tracers derived from the maternal signal functions model. OBJECTIVE-METHOD: We compare emergency readiness using the signal functions model and a novel clinical cascade...
2018: PloS One
W A Tol, S J Rees, A K Tay, N Tam, A da Costa Saldanha Segurado, Z M da Costa, E S da Costa Soares, A da Costa Alves, N Martins, D M Silove
No abstract text is available yet for this article.
February 1, 2018: International Journal of Epidemiology
Jennifer Ryan, Ryan E Morgan, Yuan Chen, Laurie Volak, Robert T Dunn, Kenneth W Dunn
The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it mediates the elimination of monovalent bile salts into the bile. Inhibition of BSEP is considered a susceptibility factor for drug-induced liver injury (DILI) that often goes undetected during non-clinical testing. Although in vitro assays exist for screening BSEP inhibition, a reliable and specific method for confirming Bsep inhibition in vivo would be a valuable follow-up to a BSEP screening strategy, helping to put a translatable context around in vitro inhibition data, incorporating processes such as metabolism, protein binding, and other exposure properties that are lacking in most in vitro BSEP models...
February 21, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Amish Asthana, Charles McRae White, Megan Douglass, William S Kisaalita
The lack of prediction accuracy during drug development and screening risks complications during human trials, such as drug-induced liver injury (DILI), and has led to a demand for robust, human cell-based, in vitro assays for drug discovery. Microporous polymer-based scaffolds offer an alternative to the gold standard flat tissue culture plastic (2D TCPS) and other 3D cell culture platforms as the porous material entraps cells, making it advantageous for automated liquid handlers and high-throughput screening (HTS)...
February 21, 2018: Biotechnology Progress
Laurène Leclair-Visonneau, Laurent Magy, Christelle Volteau, Thomas Clairembault, Séverine Le Dily, Cécile Préterre, Arnaud Peyre, Philippe Damier, Michel Neunlist, Yann Péréon, Pascal Derkinderen
Dysautonomic symptoms are frequent non-motor complaints in patients with Parkinson's disease. Numerous neuropathological studies have shown that Lewy bodies and neurites, the pathological hallmarks of Parkinson's disease, are widely distributed throughout the peripheral autonomic nervous systems and across end organs. However, few investigations integrally explored the symptoms and physiology of dysautonomia in Parkinson's disease. We, therefore, performed a comprehensive evaluation of the autonomic function in a prospective group of 45 patients with idiopathic Parkinson's disease...
February 20, 2018: Journal of Neurology
Abigail Zabron, Alberto Quaglia, Evangelia Fatourou, Praveen Peddu, Dylan Lewis, Michael Heneghan, Christopher Willars, Georg Auzinger, Nigel Heaton, Julia Wendon, Pauline Kane, John Karani, William Bernal
BACKGROUND: Liver volume (LV) can be non-invasively determined from analysis of computed tomography (CT) images, and in patients with Acute liver injury (ALI) or failure (ALF) reflect the balance of structural collapse with hepatic regeneration. We examined its relation to cause of liver injury, measures of liver function and histopathological findings, and utility in prediction of complications and mortality. METHODS: 273 patients with ALF/ALI admitted to a specialist intensive care unit were studied...
February 20, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
Jun Cao, Yijun Mi, Cuilin Shi, Yicong Bian, Chenrong Huang, Zhijian Ye, Linsheng Liu, Liyan Miao
Tuberculosis (TB) has become a global public health and social threat. As clinical first-line drugs, rifampicin and isoniazid used in combination with pyrazinamide and ethambutol (the HRZE regimen) usually induce hepatotoxicity. However, the mechanisms underlying this phenomenon remain unclear, and studying the metabolic impact of co-treating TB patients with the HRZE regimen can provide new hepatotoxicity evidence. In this study, urine metabolites from TB patients were profiled using a high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) platform...
February 15, 2018: Biochemical and Biophysical Research Communications
Kathleen M Gura, Andrew E Mulberg, Paul D Mitchell, John Yap, Clara Y Kim, Minjun Chen, Alexis Potemkin, Mark Puder
BACKGROUND: Intestinal failure-associated liver disease (IFALD) is complex and diagnosed by concurrent use of parenteral nutrition, clinical presentation, and alterations in hepatic biomarkers exclusive of other causes of liver disease. In comparison with individual measures, composite biomarkers may provide a more effective means for assessing disease progression and response to treatment than single parameters. Since IFALD is considered by some to be a type of drug-induced liver injury (DILI), those diagnostic criteria could potentially be used in this population...
February 2018: JPEN. Journal of Parenteral and Enteral Nutrition
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