Could Adverse Effects of Antibiotics Due to Their Use/Misuse Be Linked to Some Mechanisms Related to Nonalcoholic Fatty Liver Disease?

Nonalcoholic fatty liver disease, recently re-named metabolic dysfunction-associated steatotic fatty liver disease, is considered the most prevalent liver disease worldwide. Its molecular initiation events are multiple and not always well-defined, comprising insulin resistance, chronic low-grade inflammation, gut dysbiosis, and mitochondrial dysfunction, all of them acting on genetic and epigenetic grounds. Nowadays, there is a growing public health threat, which is antibiotic excessive use and misuse. This widespread use of antibiotics not only in humans, but also in animals has led to the presence of residues in derived foods, such as milk and dairy products. Furthermore, antibiotics have been used for many decades to control certain bacterial diseases in high-value fruit and vegetables. Recently, it has been emphasised that antibiotic-induced changes in microbial composition reduce microbial diversity and alter the functional attributes of the microbiota. These antibiotic residues impact human gut flora, setting in motion a chain of events that leads straight to various metabolic alterations that can ultimately contribute to the onset and progression of NAFLD.

What are the common downstream molecular events between alcoholic and nonalcoholic fatty liver?

Liver fat storage, also called hepatic steatosis, is increasingly common and represents a very frequent diagnosis in the medical field. Excess fat is not without consequences. In fact, hepatic steatosis contributes to the progression toward liver fibrosis. There are two main types of fatty liver disease, alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD). Although AFLD and NAFLD are similar in their initial morphological features, both conditions involve the same evolutive forms. Moreover, there are various common mechanisms underlying both diseases, including alcoholic liver disease and NAFLD, which are commonalities. In this Review, the authors explore similar downstream signaling events involved in the onset and progression of the two entities but not completely different entities, predominantly focusing on the gut microbiome. Downstream molecular events, such as the roles of sirtuins, cytokeratins, adipokines and others, should be considered. Finally, to complete the feature, some new tendencies in the therapeutic approach are presented.

Which inflammatory marker, between systemic immune-inflammation index and neutrophil to eosinophil ratio, is associated with Peyronie's disease and are there any implications for a better understanding of its mechanisms?

BACKGROUND: Peyronie's disease affects up to 9% of men and is often accompanied by pain and/or erectile dysfunction. It is characterized by an inflammatory process that is the grassroots of the subsequent fibrosis stage. There is an unmet need to evaluate its onset and progression. Among the newly proposed biomarkers of inflammation, authors developed a novel systemic immune-inflammation index (SII) based on lymphocyte, neutrophil, and platelet counts. Similarly, a recent study reported that a neutrophil-to-eosinophil ratio (NER) represents systemic inflammation. RESULTS: A 49-patient group with Peyronie's disease as confronted with 50 well-matched for age and BMI controls. As laboratory evaluation of inflammation, SII, NER and the eosinophil to neutrophil ratio (ENR) were studied. As a likely risk factor for the presence of Peyronie's disease, a higher prevalence of hypercholesterolemia, hyperglycemia and hypertension was discovered in the patients compared to controls. A significant difference was found in the median values of the NER between the two selected groups, i.e., 32.5 versus 17.3 (p = 0.0021). As expected, also ENR was significantly different. The receiver operating characteristic curves for SII, ENR and NER were 0.55, 0.32 and 0.67, respectively, highlighting the best performance of NER. The cut-off for NER was 12.1, according to the Youden test. CONCLUSIONS: According to our results, any evaluation of circulating eosinophil, evaluated as NER, beyond being a signature of immuno-inflammatory response, help assess tissue homeostasis, since eosinophils are now considered multifunctional leukocytes and give a picture of the inflammatory process and repair process belonging to Peyronie's disease.

RéSUMé: CONTEXTE: La maladie de La Peyronie touche jusqu'à 9% des hommes et s'accompagne souvent de douleurs et/ou de dysfonction érectile. Elle se caractérise par un processus inflammatoire qui est. à la base de l'étape de fibrose ultérieure. Il existe un besoin non satisfait d'en évaluer son apparition et sa progression. Parmi les biomarqueurs de l'inflammation nouvellement proposés, les auteurs ont développé un nouvel indice d'inflammation immunitaire systémique (SII) basé sur le nombre de lymphocytes, de neutrophiles et de plaquettes. De même, une étude récente a rapporté qu'un rapport neutrophiles/éosinophiles (NER) représente une inflammation systémique. RéSULTATS: Un groupe de 49 patients atteints de la maladie de La Peyronie a été confronté à 50 témoins étroitement appariés sur l'âge et l'IMC. Dans le cadre de l'évaluation de l'inflammation au laboratoire, le SII, le NER et le rapport éosinophiles/neutrophiles (ENR) ont été étudiés. En tant que facteur de risque probable de la présence de la maladie de La Peyronie, une prévalence plus élevée d'hypercholestérolémie, d'hyperglycémie et d'hypertension a été découverte chez les patients par rapport aux témoins. Une différence significative a été constatée pour les valeurs médianes du NER entre les deux groupes sélectionnés, c'est-à-dire 32,5 contre 17,3 (p = 0,0021). Comme on pouvait s'y attendre, le ERN était également significativement différent. Les courbes caractéristiques de fonctionnement du récepteur pour le SII, l'ENR et le NER étaient respectivement de 0,55, 0,32 et 0,67, ce qui met en évidence les meilleures performances du NER. Le seuil pour le NER était de 12,1 (test de Youden). CONCLUSIONS: D'après nos résultats, toute évaluation de l'éosinophilie circulante, sous la forme NER, au-delà d'être une signature de la réponse immuno-inflammatoire, permet d'évaluer l'homéostasie tissulaire, puisque les éosinophiles sont maintenant considérés comme étant des leucocytes multifonctionnels, et donne une image du processus inflammatoire et du processus de réparation appartenant à la maladie de La Peyronie. MOTS-CLéS: Maladie de La Peyronie Rapport Neutrophiles/Eosinophiles Rapport Eosinophiles/Neutrophiles Indice d'Inflammation immunitaire systémique Réponse Immuno-inflammatoire.

The Role of Epigenetic Control of Mitochondrial (Dys)Function in MASLD Onset and Progression.

Metabolic dysfunction-associated steatotic fatty liver disease (MASLD), a novel definition for NAFLD, represents one of the most common causes of liver disease, and its incidence is increasing worldwide. It is characterized by a complex etiopathogenesis in which mitochondrial dysfunction exerts a pivotal role together with alteration of lipid metabolism, inflammation, and oxidative stress. Nutrients and bioactive compounds can influence such mechanisms so that changes in diet and lifestyle are regarded as important treatment strategies. Notably, natural compounds can exert their influence through changes of the epigenetic landscape, overall resulting in rewiring of molecular networks involved in cell and tissue homeostasis. Considering such information, the present review aims at providing evidence of epigenetic modifications occurring at mitochondria in response to natural and bioactive compounds in the context of liver (dys)function. For this purpose, recent studies reporting effects of compounds on mitochondria in the context of NAFLD/MASLD, as well as research showing alteration of DNA methylation and non-coding RNAs-related circuits occurring at liver mitochondria, will be illustrated. Overall, the present review will highlight the importance of understanding the bioactive compounds-dependent epigenetic modulation of mitochondria for improving the knowledge of MASLD and identifying biomarkers to be employed for effective preventative strategies or treatment protocols.

Pharmacomicrobiomics of Classical Immunosuppressant Drugs: A Systematic Review.

The clinical response to classical immunosuppressant drugs (cIMDs) is highly variable among individuals. We performed a systematic review of published evidence supporting the hypothesis that gut microorganisms may contribute to this variability by affecting cIMD pharmacokinetics, efficacy or tolerability. The evidence that these drugs affect the composition of intestinal microbiota was also reviewed. The PubMed and Scopus databases were searched using specific keywords without limits of species (human or animal) or time from publication. One thousand and fifty five published papers were retrieved in the initial database search. After screening, 50 papers were selected to be reviewed. Potential effects on cIMD pharmacokinetics, efficacy or tolerability were observed in 17/20 papers evaluating this issue, in particular with tacrolimus, cyclosporine, mycophenolic acid and corticosteroids, whereas evidence was missing for everolimus and sirolimus. Only one of the papers investigating the effect of cIMDs on the gut microbiota reported negative results while all the others showed significant changes in the relative abundance of specific intestinal bacteria. However, no unique pattern of microbiota modification was observed across the different studies. In conclusion, the available evidence supports the hypothesis that intestinal microbiota could contribute to the variability in the response to some cIMDs, whereas data are still missing for others.

Sarcopenia, a condition shared by various diseases: can we alleviate or delay the progression?

Sarcopenia is a severe condition common to various chronic diseases and it is reckoned as a major health problem. It encompasses many different molecular mechanisms that have been for a while discovered but not definitely clarified. Although sarcopenia is a disability status that leads to serious health consequences, the scarcity of suitable animal models has curtailed research addressing this disorder. Another limitation in the field of clinical investigation of sarcopenic patients is the lack of a generally accepted definition coupled with the difficulty of adopting common diagnostic criteria. In fact, both do not permit to clarify the exact prevalence rate and consequently limit physicians to establish any kind of therapeutical approach or, when possible, to adopt preventive measures. Unfortunately, there is no standardized cure, apart from doing more physical activity and embracing a balanced diet, but newly discovered substances start being considered. In this review, authors try to give an overview addressing principal pathways of sarcopenia and offer critical features of various possible interventions.

A Life-Threating Postpartum Atypical Hemolytic-Uremic Syndrome with Multiorgan Involvement.

Atypical Hemolytic Uremic Syndrome is a very rare condition that can be triggered in predisposed patients. It can remain undiagnosed and can result in a life-threatening event or permanent renal failure. We report a case of a 36-year-old pregnant woman who developed atypical hemolytic uremic syndrome postpartum. She underwent an emergency caesarean section due to abruptio placenta, and she developed biochemical alterations suggestive of a thrombotic microangiopathy. Due to worsening of renal function after plasma exchange therapy, we decided to start therapy with eculizumab. Therapy was carried out with a weekly dose of 900 mg IV for five weeks. An improvement of clinical and biochemical parameters was rapidly observed, and her renal function completely recovered. The therapy was continued for six months, with a dose of 1200 mg of eculizumab every two weeks. One year after discontinuation of the therapy, her blood pressure and renal function were still normal. Our case confirms that it is important to promptly identify a pregnancy-related thrombotic microangiopathy and that early therapy can be life-saving for the patient and can preserve renal function, avoiding dialysis.

Could Alcohol Abuse and Dependence on Junk Foods Inducing Obesity and/or Illicit Drug Use Represent Danger to Liver in Young People with Altered Psychological/Relational Spheres or Emotional Problems?

Recent data show that young people, mainly due to the pressure of some risk factors or due to disrupted interpersonal relationships, utilise greater reward value and display greater sensitivity to the reinforcing properties of "pleasurable stimuli", specifically in those situations in which an enhanced dopamine release is present. Alcoholic beverages, foods rich in sugar and fat, and illicit drug use are pleasurable feelings associated with rewards. Research shows that there is a link between substance abuse and obesity in brain functioning. Still, alcohol excess is central in leading to obesity and obesity-related morbidities, such as hepatic steatosis, mainly when associated with illicit drug dependence and negative eating behaviours in young people. It is ascertained that long-term drinking causes mental damage, similarly to drug abuse, but also affects liver function. Indeed, beyond the pharmacokinetic interactions of alcohol with drugs, occurring in the liver due to the same metabolic enzymes, there are also pharmacodynamic interactions of both substances in the CNS. To complicate matters, an important noxious effect of junk foods consists of inducing obesity and obesity-related NAFLD. In this review, we focus on some key mechanisms underlying the impact of these addictions on the liver, as well as those on the CNS.

A Comparative Study of the Triglycerides/HDL Ratio and Pseudocholinesterase Levels in Patients with Bladder Cancer.

BACKGROUND: Lipid alterations may serve as potential tumour biomarkers. The ratio of triglycerides to HDL cholesterol (TG/HDL ratio) is associated with various cancers. Pseudocholinesterase (PChE) activity, involved in TG hydrolysis, plays an important role in the metabolism of lipoprotein. There is scarce data assessing the reliability of both the TG/HDL ratio and PChE levels in correctly classifying patients suffering from bladder cancer. METHODS: Three hundred and ninety-six patients undergoing cystoscopy or transurethral resection of the bladder (TURB), broken into two major groups, i.e., patients with histologically confirmed, non-metastatic bladder cancer (n = 208) and without bladder cancer (no bladder cancer, n = 188), formed the study population. The last group was split into two subgroups consisting of a cohort of patients never suffering from bladder cancer but with other bladder diseases (no CaBD, n = 100) and another cohort formed by patients characterised by eradicated bladder cancer after TURB with no recurrence during a three-month follow-up (previous bladder cancer, n = 88). Pieces of information by both metabolic derangement (the presence of type 2 diabetes mellitus), hypertension and lipid profile were retrieved from patient records upon entry to the study. Sensitivity, specificity, areas under the ROC (AUROC) of the TG/HDL ratio, and PChE levels were used in diagnostic decision making. RESULTS: The TG/HDL ratio as well as PChE concentrations of bladder cancer patients were significantly different when compared to those with previous bladder cancer and the no CaBD patients (p = 0.023 and 0.0004, respectively). There was an independent role of both the TG/HDL ratio and PChE levels in predicting the presence of bladder cancer (OR: 1.22 and 0.99, respectively), but the reliability of the TG/HDL ratio (AUROC: 0.587) was superior to that of PChE levels (AUROC: 0.374). The AUROC of a new parameter resulting from the combination of the TG/HDL ratio with PChE levels showed a further increment in the discriminant power of the bladder cancer presence (0.6298), interestingly with a negative predictive value (89%) according to the Bayesian approach. The cut-off of the TG/HDL ratio, the main marker of the present study that better distinguishes bladder cancer from no bladder cancer patients, was 2.147. DISCUSSION AND CONCLUSIONS: The reliability of the TG/HDL ratio is based on the fact that this parameter likely mirrors the insulin resistance (IR) underlying bladder cancer patients. Furthermore, PChE levels evidence both IR and the associated non-alcoholic fatty liver disease. The TG/HDL ratio and PChE levels as well as their combined use could help physicians to assess/confirm the presence of this very common cancer, where early detection is important to ensure the best therapeutical approach.

Copper-catalyzed dicarbonyl stress in NAFLD mice: protective effects of Oleuropein treatment on liver damage.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) or more appropriately, metabolic associated fatty liver disease (MAFLD), is the hepatic manifestation of metabolic syndrome. An imbalance of copper homeostasis has been described in the progression of NAFLD/MAFLD toward NASH/MASH. We were interested in understanding whether the chelating activity of Oleuropein (Ole) was able to improve the copper accumulation and the related pro-oxidant and glycative damage in the liver of mice fed HFD. METHODS: Twelve C57BL/6J mice fed normal diet (ND) or high-fat diet (HFD) for 16 weeks and then thirty two female and male mice fed ND or HFD for 8 weeks adding Ole for the following 8 weeks were studied. RESULTS: Altered expression of copper-trafficking genes and proteins (CTR1, CTR2, ATP7B, COX17, CCS, and ATOX1) induced imbalance of copper homeostasis combined with an increase in dicarbonyl stress in the liver of HFD fed mice. Interestingly enough, glyoxalase system was improved by Ole administration and the Ole related protective effects differ in the two sexes of mice. CONCLUSIONS: Our study highlights the role of the dicarbonyl stress in the pathogenesis of NAFLD and suggests Ole as a natural copper chelator to prevent the liver damage induced by methyglyoxal pathway derangement.

Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. With no Food and Drug Administration approved drugs, current treatment options include dietary restrictions and lifestyle modification. NAFLD is closely associated with metabolic disorders such as obesity, type 2 diabetes, and dyslipidemia. Hence, clinically various pharmacological approaches using existing drugs such as antidiabetic, anti-obesity, antioxidants, and cytoprotective agents have been considered in the management of NAFLD and nonalcoholic steatohepatitis (NASH). However, several pharmacological therapies aiming to alleviate NAFLD-NASH are currently being examined at various phases of clinical trials. Emerging data from these studies with drugs targeting diverse molecular mechanisms show promising outcomes. This review summarizes the current understanding of the pathogenic mechanisms of NAFLD and provides an insight into the pharmacological targets and emerging therapeutics with specific interventional mechanisms. In addition, we also discuss the importance and utility of new approach methodologies and regulatory perspectives for NAFLD-NASH drug development.

PaO2/FiO2 ratio forecasts COVID-19 patients' outcome regardless of age: a cross-sectional, monocentric study.

We studied the predictive value of the PaO2/FiO2 ratio for classifying COVID-19-positive patients who will develop severe clinical outcomes. One hundred fifty patients were recruited and categorized into two distinct populations ("A" and "B"), according to the indications given by the World Health Organization. Patients belonging the population "A" presented with mild disease not requiring oxygen support, whereas population "B" presented with a severe disease needing oxygen support. The AUC curve of PaO2/FiO2 in the discovery cohort was 0.838 (95% CI 0.771-0.908). The optimal cut-off value for distinguishing population "A" from the "B" one, calculated by Youden's index, with sensitivity of 71.79% and specificity 85.25%, LR+4.866, LR-0.339, was < 274 mmHg. The AUC in the validation cohort of 170 patients overlapped the previous one, i.e., 0.826 (95% CI 0.760-0.891). PaO2/FiO2 ratio < 274 mmHg was a good predictive index test to forecast the development of a severe respiratory failure in SARS-CoV-2-infected patients. Moreover, our work highlights that PaO2/FiO2 ratio, compared to inflammatory scores (hs-CRP, NLR, PLR and LDH) indicated to be useful in clinical managements, results to be the most reliable parameter to identify patients who require closer respiratory monitoring and more aggressive supportive therapies. Clinical trial registration: Prognostic Score in COVID-19, prot. NCT04780373 https://clinicaltrials.gov/ct2/show/NCT04780373 (retrospectively registered).

It Is High Time Physicians Thought of Natural Products for Alleviating NAFLD. Is There Sufficient Evidence to Use Them?

Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease all over the world due to the obesity pandemic; currently, therapeutic options for NAFLD are scarce, except for diet recommendations and physical activity. NAFLD is characterized by excessive accumulation of fat deposits (>5%) in the liver with subsequent inflammation and fibrosis. Studies in the literature show that insulin resistance (IR) may be considered as the key mechanism in the onset and progression of NAFLD. Recently, using natural products as an alternative approach in the treatment of NAFLD has drawn growing attention among physicians. In this review, the authors present the most recent randomized controlled trials (RCTs) and lines of evidence from animal models about the efficacy of nutraceutics in alleviating NAFLD. Among the most studied substances in the literature, the following molecules were chosen because of their presence in the literature of both clinical and preclinical studies: spirulina, oleuropein, garlic, berberine, resveratrol, curcumin, ginseng, glycyrrhizin, coffee, cocoa powder, epigallocatechin-3-gallate, and bromelain.

Steatosis, Steatohepatitis and Cancer Immunotherapy: An Intricate Story.

Immune checkpoint inhibitors represent one of the most significant recent advances in clinical oncology, since they dramatically improved the prognosis of deadly cancers such as melanomas and lung cancer. Treatment with these drugs may be complicated by the occurrence of clinically-relevant adverse drug reactions, most of which are immune-mediated, such as pneumonitis, colitis, endocrinopathies, nephritis, Stevens Johnson syndrome and toxic epidermal necrolysis. Drug-induced steatosis and steatohepatitis are not included among the typical forms of cancer immunotherapy-induced liver toxicity, which, instead, usually occurs as a panlobular hepatitis with prominent lymphocytic infiltrates. Nonetheless, non-alcoholic fatty liver disease is a risk factor for immunotherapy-induced hepatitis, and steatosis and steatohepatitis are frequently observed in this condition. In the present review we discuss how these pathology findings could be explained in the context of current models suggesting immune-mediated pathogenesis for steatohepatitis. We also review evidence suggesting that in patients with hepatocellular carcinoma, the presence of steatosis or steatohepatitis could predict a poor therapeutic response to these agents. How these findings could fit with immune-mediated mechanisms of these liver diseases will also be discussed.

Findings from Studies Are Congruent with Obesity Having a Viral Origin, but What about Obesity-Related NAFLD?

Infection has recently started receiving greater attention as an unusual causative/inducing factor of obesity. Indeed, the biological plausibility of infectobesity includes direct roles of some viruses to reprogram host metabolism toward a more lipogenic and adipogenic status. Furthermore, the probability that humans may exchange microbiota components (virome/virobiota) points out that the altered response of IFN and other cytokines, which surfaces as a central mechanism for adipogenesis and obesity-associated immune suppression, is due to the fact that gut microbiota uphold intrinsic IFN signaling. Last but not least, the adaptation of both host immune and metabolic system under persistent viral infections play a central role in these phenomena. We hereby discuss the possible link between adenovirus and obesity-related nonalcoholic fatty liver disease (NAFLD). The mechanisms of adenovirus-36 (Ad-36) involvement in hepatic steatosis/NAFLD consist in reducing leptin gene expression and insulin sensitivity, augmenting glucose uptake, activating the lipogenic and pro-inflammatory pathways in adipose tissue, and increasing the level of macrophage chemoattractant protein-1, all of these ultimately leading to chronic inflammation and altered lipid metabolism. Moreover, by reducing leptin expression and secretion Ad-36 may have in turn an obesogenic effect through increased food intake or decreased energy expenditure via altered fat metabolism. Finally, Ad-36 is involved in upregulation of cAMP, phosphatidylinositol 3-kinase, and p38 signaling pathways, downregulation of Wnt10b expression, increased expression of CCAAT/enhancer binding protein-beta, and peroxisome proliferator-activated receptor gamma 2 with consequential lipid accumulation.

Age and Interleukin-15 Levels Are Independently Associated With Intima-Media Thickness in Obesity-Related NAFLD Patients.

Common carotid intima-media thickness (IMT) represents a functional and structural marker of early, precocious, and subclinical atherosclerosis, independently from the carotid plaque. Macrophage cells, which have been detected in adipose tissue and atherosclerotic plaques, are regulated by interleukin-15 (IL-15). At the light of the conflicting results concerning the role of IL-15 in atherosclerosis, the aim of the study was to retrospectively evaluate in a population of 80 obese patients, with median age of 46 years (IQR 34-53 years), with a low rate of comorbidities but with non-alcoholic fatty liver disease (NAFLD) or hepatic steatosis (HS), the relationship between IMT and serum concentrations of IL-15. Anthropometric measures, metabolic profile, and serum inflammatory markers, as well as the levels of IL-15, MCP-1, b FGF, and GM-CSF, were analyzed by a bead-based assay. IMT, HS, subcutaneous, and visceral adipose tissues were detected by ultrasonography. The IL-15 levels of the obese patients were increased with respect to those of 44 young healthy subjects, i.e., 2.77 (1.21-4.8) vs. 1.55 (1-2.4) pg/mL (P = 0.002). In the univariate analysis, IL-15 levels were associated to IMT and to those of MCP-1, b FGF, and GM-CSF, without any relation to other inflammatory markers such as CRP and ferritin, except fibrinogen. In the multivariate analysis, after adjusting the HS severity for the extent of visceral adiposity, a dramatic change in prediction of IMT by HS was shown (ß from 0.29 to 0.10, P from 0.008 to 0.37). When the visceral adipose tissue was combined with IL-15, on the one hand, and the well-known coronary artery disease (CAD) risk factors-i.e., age, gender, smoking status, HDL-cholesterol concentrations, triglycerides levels, and HOMA-on the other, only age and IL-15 remained the predictors of IMT (ß = 0.60, P = 0.0001 and ß = 0.25, P = 0.024, respectively). There was no association of IL-15 with various anthropometric parameters nor with body fat distribution and severity of HS, also after adjusting for age. Age is resulted to be the main factor in the prediction of IMT and thus of early atherosclerosis. The prediction of IMT by IL-15 coupled with the lack of prediction by the well-known CAD risks is in agreement with recent data, which emphasizes the main role of the immune system in the onset/worsening of atherosclerosis, even though the role of visceral adiposity should be further deepened. Age and IL-15 levels were both predictors of early atherosclerosis in this population of obese patients with NAFLD, suggesting a possible role of this cytokine in the atherosclerosis process.

Copper concentrations are prevalently associated with antithrombin III, but also with prothrombin time and fibrinogen in patients with liver cirrhosis: A cross-sectional retrospective study.

BACKGROUND: Concerning the link between copper excess and the pathogenesis of chronic liver diseases, its retention is reckoned to develop as a complication of cholestasis. Recently, it has been found that cholestatic liver injury involves largely inflammatory cell-mediated liver cell necrosis, with consequent reduced hepatic mass, more than occurring through direct bile acid-induced apoptosis. On the other hand, interference with protein synthesis could be expected to result, ending in an altered ability of the liver to retain copper. Little is known about the association between serum copper and clotting factors in cirrhotics. We aimed at studying a possible relationship between increased levels of copper and an aspect of the haemostatic process in liver cirrhosis patients, assessing an index of protein synthesis (albumin) and parameters of protein synthesis/coagulation/fibrinolysis, such as prothrombin time (PT), antithrombin (AT) III and fibrinogen. METHODS: Records from 85 patients suffering from liver cirrhosis of various aetiology and different severity were retrospectively examined. Serum concentrations of copper were determined by atomic absorption spectrophotometer. An index of protein synthesis, such as albumin and parameters of both synthesis and coagulation/hypercoagulation such as PT %, AT III%, levels of fibrinogen were taken into account to study possible correlations to serum copper. The severity of cirrhosis was evaluated by the Child-Pugh (C-P) classification. The relationship among variables were studied by linear regression. RESULTS: Copper levels of patients suffering from liver cirrhosis were increased respect to those of controls, 102.7+/-28.7 versus 80.4+/-19.5 mcg/dL, (P = .0009), independently from disease severity, and were positively predicted by PT% (P = 0. 017), fibrinogen (P = 0.007) and AT III% (P = 0.000), at linear regression. Among the previous parameters, to which serum albumin was added, the unique predictor of copper levels was AT III%, at multiple regression (P = 0. 010); AT III% was negatively predicted by the C-P classification (P = 0.000); copper levels, adjusted for C-P classification, were predicted by AT III% (P = 0.020) and fibrinogen concentrations, but not by PT% (P = 0.09). CONCLUSION: The copper concentration is reckoned as responsible for production of the hydroxyl radicals. On the basis that oxidants may enhance the activity of the extrinsic coagulation cascade, ultimately leading to thrombin formation, via their combined effects on stimulation of tissue factor activity and inhibition of fibrinolytic pathways, the positive relationship of copper to coagulation/hypercoagulation parameters (mainly AT III) in our research could find a plausible interpretation.

Liver-spleen axis in nonalcoholic fatty liver disease.

Introduction: NAFLD is often under-diagnosed, even though rates of its co-morbidities such as obesity and type2 diabetes mellitus, prominent statuses of inflammation, are significantly high. The spleen-liver axis is gaining much credit in the last years like other well-known organ axes.Areas covered: PubMed/MEDLINE was searched for relevant articles related to concomitant occurrence of NAFLD and spleen. Areas covered in this review include: (1) updated findings of spleen dimensions at ultrasonography, (2) discussion of current data on pathophysiological connections between obesity-related NAFLD and increased volume of the spleen, and (3) analysis of current immune-mediated mechanisms characterizing the so.called chronic low-grade inflammation leading to insulin resistance.Expert opinion: The advances in explaining mechanisms underlying the spleen involvement in immune regulation, coupled with research about the role of spleen in NAFLD, could impact real world outcomes through establishing better tools for a precocious diagnosis. Using both liver and spleen ultrasonography, technique largely dealt with in this review, could expand the possibility to cover an adequate diagnostic path toward NAFLD, reaching a good sensibility and specificity.

New Avenues for Treatment and Prevention of Drug-Induced Steatosis and Steatohepatitis: Much More Than Antioxidants.

Drug-induced lipid accumulation in the liver may induce two clinically relevant conditions, drug-induced steatosis (DIS) and drug-induced steatohepatitis (DISH). The list of drugs that may cause DIS or DISH is long and heterogeneous and includes therapeutically relevant molecules that cannot be easily replaced by less hepatotoxic medicines, therefore making specific strategies necessary for DIS/DISH prevention or treatment. For years, the only available tools to achieve these goals have been antioxidant drugs and free radical scavengers, which counteract drug-induced mitochondrial dysfunction but, unfortunately, have only limited efficacy. In the present review we illustrate how in vitro preclinical research unraveled new key players in the pathogenesis of specific forms of DISH, and how, in a few cases, proof of concept of the beneficial effects of their pharmacological modulation has been obtained in vivo in animal models of this condition. The key issue emerging from these studies is that, in selected cases, liver toxicity depends on mechanisms unrelated to those responsible for the desired, primary pharmacological effects of the toxic drug and, therefore, specific strategies can be designed to overcome steatogenicity without making the drug ineffective. In particular, the hepatotoxic drug could be given in combination with a second molecule intended to selectively antagonize its liver toxicity whilst, ideally, potentiating its desired pharmacological activity. Although most of the evidence that we discuss is from in vitro or animal models and will need to be further explored and validated in humans, it highlights new avenues to be pursued in order to improve the safety of steatogenic drugs.