Exploration of the common bileduct

https://www.cghjournal.org/article/S1542-3565(15)00841-1/pdf

The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond

The liver is a key organ that plays a pivotal role in metabolism and ensures a variety of functions in the body, including homeostasis, synthesis of essential components, nutrient storage, and detoxification. As the centre of metabolism for exogenous molecules, the liver is continuously exposed to a wide range of compounds, such as drugs, pesticides, and environmental pollutants. Most of these compounds can cause hepatotoxicity and lead to severe and irreversible liver damage. To study the effects of chemicals and drugs on the liver, most commonly, animal models or in vitro 2D cell cultures are used. However, data obtained from animal models lose their relevance when extrapolated to the human metabolic situation and pose ethical concerns, while 2D static cultures are poorly predictive of human in vivo metabolism and toxicity. As a result, there is a widespread need to develop relevant in vitro liver models for toxicology studies. In recent years, progress in tissue engineering, biomaterials, microfabrication, and cell biology has created opportunities for more relevant in vitro models for toxicology studies. Of these models, the liver organ-on-chip (OoC) has shown promising results by reproducing the in vivo behaviour of the cell/organ or a group of organs, the controlled physiological micro-environment, and in vivo cellular metabolic responses. In this review, we discuss the development of liver organ-on-chip technology and its use in toxicity studies. First, we introduce the physiology of the liver and summarize the traditional experimental models for toxicity studies. We then present liver OoC technology, including the general concept, materials used, cell sources, and different approaches. We review the prominent liver OoC and multi-OoC integrating the liver for drug and chemical toxicity studies. Finally, we conclude with the future challenges and directions for developing or improving liver OoC models.

Liver organ-on-chip models for toxicity studies and risk assessment.

https://www.liver.theclinics.com/article/S1089-3261(13)00037-8/pdf

Hepatotoxicity of Antibiotics: A Review and Update for the Clinician

The safety of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (statins) remains very much in the news, with recent regulatory alerts issued about the potential for effects on memory loss, an increased risk of type 2 diabetes, myopathy, and possible drug interactions involving HIV and hepatitis C protease inhibitors [1–3]. Although the US Food and Drug Administration (FDA) currently considers serious statinrelated liver injury to be a rare and unpredictable event [1], it nevertheless remains an important concern among physicians and patients alike. Moreover, the risk of adverse hepatic events receives renewed emphasis with each new case series that appears in the literature. Indeed, the proportion of patients who are not being prescribed statins because of the potential for adverse hepatic events, but who might otherwise benefit from their cardioprotective effects, is substantial [4]. A reading of the recent published literature contains a not so subtle war of words over the risk and magnitude of statin-related hepatotoxicity [5–14]. It almost appears as if each new case series of statin-associated hepatic injury [5, 6, 15] can be matched with or accompanied by editorial comments to place the risk into perspective [11–13]. As a case in point, the authors of a recent Icelandic case series of statin-associated liver injury appearing in Digestive Diseases and Sciences suggest that the risk of jaundice seen with statins is substantially higher than has been previously estimated, and call for increased vigilance when statins are prescribed, while they chide the author of a number of editorials who has opined that statin-induced hepatotoxicity is no more than a ‘‘myth’’ [5]. In his editorial retorts [11–13], Bader’s choice of words regarding the safety of statins is based on the fact that asymptomatic aminotransferase elevations are not an accurate reflection of hepatic injury, as similar elevations have also been noted in placebo recipients. This is also echoed by a recent safety update by FDA which finds that the ‘‘routine periodic monitoring of serum ALT does not appear to detect or prevent serious liver injury in association with statins’’ [1]. Bader’s opinions are bolstered by evidence arguing against a significant incidence of severe hepatotoxicity from statins, including the report of an expert panel of hepatologists who concluded that abnormal liver-associated enzymes (LAEs) associated with statins are not evidence for hepatic dysfunction [14], and that no consistent histologic picture has emerged. Furthermore, Bader contends that given the extensive usage of statins worldwide for more than two decades, if there were one or more patterns of hepatotoxicity that could be definitively linked to statins, they would certainly have been identified long before now [11]. In an accompanying editorial to the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study [16], Bader reiterates his opinion that statins have only very rarely been implicated in causing liver injury, and he bemoans the fact that most clinicians still base their concern about statin-associated liver injury on the warnings in their prescribing information [12]. Indeed, as recently as 2005, many physicians were still reluctant to prescribe a statin to patients with only minimal ALT elevations [4]. Bader infers that a few isolated published reports are still capable of perpetuating the ‘‘myth of statin-induced hepatotoxicity.’’ To the casual reader, such contrasting views may be a source of confusion and even consternation. Is statin J. H. Lewis (&) Georgetown University Medical Center, Washington, DC, USA e-mail: LEWISJH@gunet.georgetown.edu

Clinical perspective: statins and the liver--harmful or helpful?

13 – Hepatic injury due to drugs, herbal compounds, chemicals and toxins

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13 – Hepatic injury due to drugs, herbal compounds, chemicals and toxins