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.

Pathogenic role of oxidative and nitrosative stress in primary biliary cirrhosis

Primary biliary cirrhosis is a multifactor autoimmune disease characterized by hepatic and systemic manifestations,with immune system dysregulation and abnormalities in the hepatic metabolism of bile salts,lipids,and nutrients,as well as destruction of membrane lipids and mitochondrial dysfunction.Both oxidative and nitrosative stress are associated with ongoing manifestations of the disease.In particular,abnormalities in nitric oxide metabolism and thiol oxidation already occur at early stages,thus leading to the hypothesis that these biochemical events play a pathogenic role in primary biliary cirrhosis.Moreover,the association of these metabolic abnormalities with the progression of the disease may indicate some biochemical parameters as early diagnostic markers of disease evolution,and may open up the potential for pharmacological intervention to inhibit intra-and extra-cellular stress events for resuming hepatocellular functions.The following paragraphs summarize the current knowledge by outlining molecular mechanisms of the disease related to these stress events.

Relationships between emissions of toxic airborne molecules and type 1 diabetes incidence in children:An ecologic study

BACKGROUND Type 1 diabetes originates from gene-environment interactions,with increasing incidence over time.AIM To identify correlates of childhood type 1 diabetes in European countries using an ecological approach.Several environmental variables potentially influencing the onset of type 1 diabetes have been previously evaluated.However,the relationships between epidemiologic data and exposure to toxic airborne molecules are scarcely studied.METHODS We employed an ecological model to explore,in a wide time period(1990-2018),associations between type 1 diabetes incidence in 19 European countries(systematic literature review)and the nationwide production of five widely diffused air pollutants:particulate matter<10μm(PM10),nitrogen oxides(NO),non-methane volatile organic compounds(VOCs),sulphur oxide(SO2),and ammonia.RESULTS Data confirm a raising incidence of type 1 diabetes in 18 out of 19 explored countries.The average difference(last vs first report,all countries)was+6.9×100000/year,with values ranging from-1.4(Germany)to+16.6(Sweden)per 100000/year.Although the overall production of pollutants decreased progressively from 1990 to 2018,type 1 diabetes incidence was positively associated with the nationwide emissions of PM10,VOCs,and NO but not with those of SO2 and ammonia.Type 1 diabetes incidence was significantly higher in countries with high emissions than in those with low emissions of PM10(27.5±2.4 vs 14.6±2.4×100000 residents,respectively),VOCs(24.5±4.4 vs 13.2±1.7×100000 residents,respectively),and NO(26.6±3 vs 13.4±2.4×100000 residents,respectively),but not of SO2 or ammonia.CONCLUSION Evidence justify further studies to explore better links between long-term air quality and type 1 diabetes onset at the individual level,which should include exposures during pregnancy.In this respect,type 1 diabetes could be,at least in part,a preventable condition.Thus,primary prevention policies acting through a marked abatement of pollutant emissions might attenuate future type 1 diabetes incidence throughout Europe.

Childhood obesity, cardiovascular and liver health: a growing epidemic with age

Background The frequency of childhood obesity has increased over the last 3 decades,and the trend constitutes a worrisome epidemic worldwide.With the raising obesity risk,key aspects to consider are accurate body mass index classification,as well as metabolic and cardiovascular,and hepatic consequences.Data sources The authors performed a systematic literature search in PubMed and EMBASE,using selected key words(obesity,childhood,cardiovascular,liver health).In particular,they focused their search on papers evaluating the impact of obesity on cardiovascular and liver health.Results We evaluated the current literature dealing with the impact of excessive body fat accumulation in childhood and across adulthood,as a predisposing factor to cardiovascular and hepatic alterations.We also evaluated the impact of physical and dietary behaviors starting from childhood on cardio-metabolic consequences.Conclusions The epidemic of obesity and obesity-related comorbidities worldwide raises concerns about the impact of early abnormalities during childhood and adolescence.Two key abnormalities in this context include cardiovascular diseases,and non-alcoholic fatty liver disease.Appropriate metabolic screenings and associated comorbidities should start as early as possible in obese children and adolescents.Nevertheless,improving dietary intake and increasing physical activity performance are to date the best therapeutic tools in children to weaken the onset of obesity,cardiovascular diseases,and diabetes risk during adulthood.