Biochemical mechanisms in drug-induced liver injury:Certainties and doubts

Drug-induced liver injury is a significant and still unresolved clinical problem.Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development.Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites.Aging,preexisting liver disease,enzyme induction or inhibition,genetic variances,local O2 supply and,above all,the intrinsic molecular properties of the drug may affect this process.Necrotic death follows antioxidant consumption and oxidation of intracellular proteins,which determine increased permeability of mitochondrial membranes,loss of potential,decreased ATP synthesis,inhibition of Ca2+-dependent ATPase,reduced capability to sequester Ca2+ within mitochondria,and membrane bleb formation.Conversely,activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis.Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage.Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis,in which different HLA genotypes might play a major role.This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage.Future perspectives including new frontiers for research are discussed.

Therapy of gallstone disease:What it was,what it is,what it will be

Cholesterol gallstone disease is a common clinical condition influenced by genetic factors,increasing age,female gender,and metabolic factors.Although laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones,new perspectives regarding medical therapy of cholelithiasis are currently under discussion,also taking into account the pathogenesis of gallstones,the natural history of the disease and the analysis of the overall costs of therapy.A careful selection of patients may lead to successful nonsurgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent stones.The classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations,suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe),or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis,might be proposed as additional approaches for treating cholesterol gallstones.In this review we discuss old,recent and future perspectives on medical treatment of cholesterol cholelithiasis.

Management of liver cirrhosis between primary care and specialists

This article discusses a practical, evidence-based approach to the diagnosis and management of liver cirrhosis by focusing on etiology, severity, presence of complications, and potential home-managed treatments. Relevant literature from 1985 to 2010 (PubMed) was reviewed. The search criteria were peer-reviewed full papers published in English using the following MESH headings alone or in combination: "ascites", "liver fibrosis", "cirrhosis", "chronic hepatitis", "chronic liver disease", "decompensated cirrhosis", "hepatic encephalopathy", "hypertransaminasemia", "liver transplantation" and "portal hypertension". Forty-nine papers were selected based on the highest quality of evidence for each section and type (original, randomized controlled trial, guideline, and review article), with respect to specialist setting (Gastroenterology, Hepatology, and Internal Medicine) and primary care. Liver cirrhosis from any cause represents an emerging health issue due to the increasing prevalence of the disease and its complications worldwide. Primary care physicians play a key role in early identification of risk factors, in the management of patients for improving quality and length of life, and for preventing complications. Specialists, by contrast, should guide specific treatments, especially in the case of complications and for selecting patient candidates for liver transplantation. An integrated approach between specialists and primary care physicians is essential for providing better outcomes and appropriate home care for patients with liver cirrhosis.

Dynamic carbon 13 breath tests for the study of liver function and gastric emptying

In gastroenterological practice,breath tests(BTs)are diagnostic tools used for indirect,non-invasive assessment of several pathophysiological metabolic processes,by monitoring the appearance in breath of a metabolite of a specific substrate.Labelled substrates originally employed radioactive carbon 14(^(14)C)and,more recently,the stable carbon 13 isotope(^(13)C)has been introduced to label specific substrates.The ingested^(13)C-substrate is metabolized,and exhaled^(13)CO_(2)is measured by mass spectrometry or infrared spectroscopy.Some^(13)C-BTs evaluate specific(microsomal,cytosolic,and mitochondrial)hepatic metabolic pathways and can be employed in liver diseases(i.e.simple liver steatosis,non-alcoholic steato-hepatitis,liver fibrosis,cirrhosis,hepatocellular carcinoma,drug and alcohol effects).Another field of clinical application for^(13)C-BTs is the assessment of gastric emptying kinetics in response to liquids(^(13)C-acetate)or solids(^(13)C-octanoic acid in egg yolk or in a pre-packed muffin or the^(13)C-Spirulina platensis given with a meal or a biscuit).Studies have shown that^(13)C-BTs,used for gastric emptying studies,yield results that are comparable to scintigraphy and can be useful in detecting either delayed-(gastroparesis)or accelerated gastric emptying or changes of gastric kinetics due to pharmacological effects.Thus,^(13)C-BTs represent an indirect,cost-effective and easy method of evaluating dynamic liver function and gastric kinetics in health and disease,and several other potential applications are being studied.

肠易激综合征与饮食干预

肠易激综合征(IBS)系胃肠道慢性功能性疾病,是最常见的胃肠疾病之一。由于IBS患病率高、治疗效果欠佳、经济负担显著,其对一般人群的影响甚大。IBS的病理生理十分复杂,其治疗主要是对症治疗。对于IBS最常采用的治疗方式包括教育和安抚、生活方式的调整(尤其是营养干预)、外周药物(一般是针对肠道动力)、中枢药物(针对内脏高敏性和疼痛)及心理干预(旨在减少应激和症状引起的焦虑)。有效的饮食调节可能包括以下措施:低FODMAPs(发酵的低聚糖、单糖、二糖及多元醇)饮食,限制或禁食产气食物和/或乳糖和麸类食物,补充纤维素。一些新的治疗药物,如某些保健品,也可以作为IBS患者的一项治疗选择。本文重点探讨IBS的饮食干预,对基于营养的饮食治疗的循证医学证据进行了综述。

The pros and cons of biological effects of herbs and herb-derived compounds on liver tumorigenesis

Consumption of natural products such as herbs,spices,plant-derived compounds,and foods is on the rise globally.The use of these substances is widely recognized as an integral part of culture and tradition,with the philosophy being“no benefit is no harm”.The utility of medicinal plants and extracts is under scrutiny,and the scientific community needs to clarify many conceptual gaps.Medicinal plants are rich in bioactive phytochemicals that produce chemopreventive effects at different levels,including cellular,animal,and clinical.The ultimate translational value is often missing,and some studies suggest that botanicals may contain toxic compounds that cause acute or chronic toxicity.In this regard,the liver is the center,and herbal products can show protective effects or induce hepatotoxicity,thereby promoting liver cancer.In this review article,we examine a range of herbal products implicated in hepatocarcinogenesis and extend the discussion to herbal products that may be potentially involved in the prevention and treatment of liver carcinoma.