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.

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.

Clinical factors affecting prostate-specific antigen levels in prostate cancer patients undergoing radical prostatectomy: a retrospective study.

BACKGROUND: Since prostate-specific antigen (PSA) levels can be influenced by some routinely available clinical factors, a retrospective study was conducted to explore the influence of obesity, smoking habit, heavy drinking and chronic obstructive pulmonary disease on PSA levels in men with histologically confirmed prostate cancer. PATIENTS & METHODS: We reviewed the medical records of 833 prostate cancer patients undergoing radical prostatectomy. RESULTS: Serum PSA levels at the time of surgery were not associated with either BMI or history of chronic obstructive pulmonary disease or heavy drinking. Conversely, PSA levels were associated with smoking status. CONCLUSION: Among the clinical factors explored in this homogeneous population, only tobacco use was associated with PSA levels, which should be considered when using PSA-based screening in male smokers.

Association of NAFLD and Insulin Resistance with Non Metastatic Bladder Cancer Patients: A Cross-Sectional Retrospective Study.

Among risk factors (apart from smoking) likely involved in bladder cancer (BCa), metabolic syndrome (MS), obesity and type 2 diabetes mellitus (T2DM) have been explored with contrasting results. In spite of these studies, there is little data on the association between nonalcoholic fatty liver disease (NAFLD), its main driver, i.e., insulin resistance (IR), and BCa. Implanting a cross-sectional retrospective study we tried to investigate both NAFLD and IR prevalence in a hospital based population of BCa patients. We studied laboratory data from 204 patients with histologically confirmed non metastatic BCa and 50 subjects with no BCa, but with bladder diseases (no Ca BD). We evaluated the presence of NAFLD by the triglycerides/glucose Index (TyG Index), using a cut-off of 0.59 and by the Aspartate Aminotransferase/Alanine Aminotransferase AST/ALT ratio. IR was assessed by the same TyG Index (cut-off 4.68) and the triglycerides/High-Density Lipoprotein HDL ratio (cut-off 2.197). The diagnosis of impaired fasting glucose (IFG), condition of prediabetes, as well as that of T2DM was assessed according to canonical guidelines. The TyG Index predicted NAFLD presence in both groups (p = 0.000), but the BCa group showed a major percentage of NAFLD cases with respect to no Ca BD group (59% versus 40%). A greater proportion of IR (47%) in BCa group than in no Ca BD one (37%) was evidenced by the TyG Index with its median value significantly different (p = 0.0092). This high rate of IR in the BCa group was confirmed by the triglycerides/HDL ratio (p = 0.02). Prediabetes and T2DM were more prevalent in the BCa group than no Ca BD group (p = 0.024). In this study a consistent NAFLD presence was found in BCa patients. This is an important comorbidity factor that deserves further consideration in prospective studies. The higher prevalence of NAFLD, IR, prediabetes and T2DM in the BCa group evidences the need that these disorders should be reckoned as adjunct factors that could impact on this cancerous disease.

Could SCGF-Beta Levels Be Associated with Inflammation Markers and Insulin Resistance in Male Patients Suffering from Obesity-Related NAFLD?

One of the pathologic hallmarks of obesity is macrophage infiltration of adipose tissue that has been confirmed as source of multipotent adult stem cells. Stem cell growth factor-beta (SCGF-ß) shows activity on granulocyte/macrophage progenitor cells in combination with granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). Obesity-associated inflammation induces insulin resistance (IR), which is central to nonalcoholic fatty liver disease (NAFLD) or hepatic steatosis (HS). We searched for relationship between levels of SCGF-ß and those of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-ß (TNF-ß), interleukin-12p40 (IL-12p40), interleukin-10 (IL-10), ferritin, GM-CSF and M-CSF and between SCGF-ß concentrations and IR in obese patients with HS. Eighty obese patients were retrospectively studied. Serum cytokines levels were appreciated by magnetic bead-based multiplex immunoassays. IR was evaluated by homeostatic model assessment (HOMA), HOMA-derived ß-cell function (HOMA-B%), quantitative insulin sensitivity check Index (QUICKI) and single point insulin sensitivity estimator (SPISE). HS and spleen volume were assessed by ultrasonography (US). SCGF-ß and IL-6 levels predicted HOMA values (p = 0.032 and 0.041, respectively) only in males. In male patients, CRP and IL-6 levels (p = 0.007) predicted SCGF-ß concentrations (p = 0.03 and 0.007, respectively), which in turn predicted HS at US, p = 0.037. SCGF-ß levels were linked to IR and HS severity with the mediation role of CRP. IL-10 levels negatively predicted SCGF-ß concentrations (p = 0.033). M-CSF levels predicted serum concentration of both TNF-ß and IL-12p40 (p = 0.00), but did not predict serum IL-10 (p = 0.30). Prediction of HOMA values by SCGF-ß levels, likely mediated by markers of inflammation, characterizes this study, shedding some light on mechanisms inducing/worsening IR of male patients with obesity-related NAFLD.

Gastrointestinal peptides and nonalcoholic fatty liver disease.

PURPOSE OF REVIEW: In this review, authors have selected from literature the most recent and suggestive studies on therapy of nonalcoholic fatty liver disease (NAFLD). The selected interventions regulate the action of gastrointestinal peptides, such as gastric inhibitory polypeptide (GIP), nesfatin, peptide YY, cholecystokinin, and glucagon-like peptide 1 (GLP-1). These hormones have been found frequently modified in obesity and/or type 2 diabetes mellitus, morbidities mostly associated with NAFLD. This disease has a very high prevalence worldwide and could evolve in a more severe form, that is, nonalcoholic steatohepatitis, characterized by inflammation and fibrosis. The findings shown by this article describe the metabolic effects of new drugs, mainly but not only, as well of some old substances. RECENT FINDINGS: Recent approaches, in animal models or in humans, use synthetic GLP-1 receptor agonists, a centrally administered antibody neutralizing GIP receptor, curcumin, compound being active on nesfatin, resveratrol (antiinflammatory agent), and Ginseg, both of them acting on nesfatin, a cholecystokinin receptor analogue, and finally coffee functioning on YY peptide. SUMMARY: The implications of the presented findings, if they are confirmed in larger clinical trials, likely open the door to future application in clinical practice. In fact, nowadays, patients have only diet and article (incl abstract and keywords) exercise as well accepted recommendations. Thus, there are unmet needs to find substances that could really improve the progression of nonalcoholic steatohepatitis toward liver cirrhosis and hepatocellular carcinoma.

Interferon-alpha 2 but not Interferon-gamma serum levels are associated with intramuscular fat in obese patients with nonalcoholic fatty liver disease.

BACKGROUND: Intramuscular triglycerides (IMTGs) represent an important energy supply and a dynamic fat-storage depot that can expand during periods of elevated lipid availability and a fatty acid source. Ultrasonography (US) of human skeletal muscles is a practical and reproducible method to assess both IMTG presence and entity. Although a crosstalk between cytokines in skeletal muscle and adipose tissue has been suggested in obesity, condition leading to hepatic steatosis (HS) or better defined as nonalcoholic fatty liver disease and cancer, there are still questions to be answered about the role of interferons (IFNs), alpha as well as gamma, and IMTG in obesity. We aimed at discovering any correlation between IFNs and IMTG. METHODS: We analysed anthropometric data, metabolic parameters and imaging features of a population of 80 obese subjects with low-prevalence of co-morbidities but HS in relation to IFNs serum levels. A population of 38 healthy subjects (21 males) served as controls. The levels of serum IFNs were detected by a magnetic bead-based multiplex immunoassays. RESULTS: Serum concentrations of IFN-alpha 2 were increased, while serum levels of IFN-gamma were decreased confronted with those of controls; the severity of IMTG, revealed at US as Heckmatt scores, was inversely predicted by IFN-alpha 2 serum concentrations; IMTG scores were not predicted by serum levels of IFN-gamma; IMTG scores were predicted by HS severity, ascertained at US; HS severity was predicted by visceral adipose tissue, assessed by US, but the latter was not instrumental to IMTG. DISCUSSION AND CONCLUSION: This study has added some pieces of observation about the cytokine network regulating the interplay between IMTG and obesity in obese patients with HS.

Suggestive hypothesis on a case report: Patient presenting with cyclical ovarian cysts coupled to increased cholestatic enzymes.

We describe the case of a childbearing-age woman presenting with spontaneous recurrent functional ovarian cysts and, more interestingly, chronic and asymptomatic elevation of cholestatic parameters. The patient showed no history of chronic viral infections, immunological and metabolic disorders, alcohol abuse and environmental toxins exposition. Hepatic ultrasonography and cholangio-pancreatography-magnetic-resonance excluded any morphological and structural abnormalities, while liver biopsy evidenced only minimal and not specific features of inflammation. Cholestasis indices obtained prompt recovery after each cycle of synthetic hormone therapy, implanted to treat functional ovarian cysts. She has continuously experienced the off-therapy asynchronous recurrence of liver laboratory abnormalities and functional ovarian cysts. The favorable effect of the synthetic hormone therapy to obtaining a stable recovery of this unexplained long-lasting cholestatic syndrome could be likely explained by downregulation of an endogenous ovarian overproduction, although estrogen-regulated local intracellular transduction pathways cannot be excluded.

Oleuropein Induces AMPK-Dependent Autophagy in NAFLD Mice, Regardless of the Gender.

Oleuropein (Ole) is one of the most plentiful phenolic compounds with antioxidant, anti-inflammatory, anti-atherogenic, hypoglycemic and hypolipidemic effects. The aim of our study was to establish whether the positive Ole-related effects on liver steatosis could be associated with autophagy. Female and male C57BL/6J mice were fed normal diet (ND) or high-fat diet (HFD) for eight weeks, and Ole was added or not for the following eight weeks. The autophagy-related proteins Akt, mTOR, AMPK, ULK1, Beclin-1, LC3B and p62/Sqstm1 were analyzed. Interestingly, Ole induced a different regulation of the Akt/mTOR pathway in female compared to male mice, but was able to activate the autophagic process in ND and HFD mice through AMPK-dependent phosphorylation of ULK1 at Ser555, regardless of the gender. Our work reveals the ability of Ole to induce, in liver of ND and HFD mice, autophagy independently by gender-specific mTOR activation. We highlight Ole as a novel therapeutic approach to counteract unhealthy diet-related liver steatosis by targeting autophagy.

Hematocrit Values Predict Carotid Intimal-Media Thickness in Obese Patients With Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study.

BACKGROUND: Literature data suggest with some criticism that full-fledged cardiovascular (CV) events (acute or chronic) are likely predicted by blood components, which are reported to be associated with the presence/severity of non-alcoholic fatty liver disease (NAFLD). This study was aimed at determining which marker(s) derived from blood count, such as white blood cells, neutrophils, neutrophil/lymphocyte ratio, platelet count, hemoglobin, mean corpuscular volume, hematocrit values were associated with ear or subclinical atherosclerosis, in obese patients of various classes suffering from NAFLD. METHODS: One hundred consecutive obese patients presenting NAFLD at ultrasound, with low prevalence of co-morbidities and no history or instrumental features of CV diseases, underwent carotid intima-media thickness (IMT) assessment by Doppler ultrasonography. All of them were studied taking into account anthropometric parameters, the metabolic profile, and inflammatory markers. RESULTS: White blood cells and neutrophil count showed no statistical association with IMT, which was predicted by the amount of visceral adiposity, as appreciated by ultrasonography. After adjusting for visceral adiposity and smoking status, only age and hematocrit contextually predicted early atherosclerosis, evaluated as IMT. Visceral adiposity was a confounding factor in foreseeing IMT. CONCLUSION: Hematocrit values along with the patient's age suggest an initial atherosclerosis, evaluated as IMT, and if this finding is confirmed in larger cohorts, could be added to other canonical CV risk factors. Inferences can be enhanced by future prospective studies that aim to identify the relationships between incident cardio-metabolic cases and this hematologic parameter.

Prediction of carotid intima-media thickness in obese patients with low prevalence of comorbidities by serum copper bioavailability.

BACKGROUND AND AIM: Western societies, with growing prevalence, suffer from various metabolic diseases like obesity and hepatic steatosis, better defined as non-alcoholic fatty liver disease, or cardiovascular (CV) diseases that are strictly linked to each other. The association of their occurrence with the altered homeostasis of metals is an intriguing issue. Copper in particular was identified as key player in various metabolic derangements. On these bases, we aimed at investigating the possible association of serum copper levels with an indicator of early CV risk as the intima-media thickness (IMT) of carotid artery and its predictive value in a selected population of obese patients. METHODS: We performed a cross-sectional study recruiting 100 obese patients characterized by a low prevalence of comorbidities. Ultrasound investigation for hepatic steatosis and IMT evaluation were performed. Serum samples were collected and then analyzed through atomic absorption spectrometry to evaluate their copper content. Possible correlations between copper bioavailability and biochemical, clinical, and anthropometric characteristics of patients were sought. RESULTS: Age negatively predicted copper serum levels of patients (P = 0.009). However, the most interesting finding is the negative prediction of IMT by the copper serum levels (t = -2.23, P = 0.028, least absolute deviations regression). Factor analysis confirmed the aforementioned inverse correlation and highlighted the strong inverse correlation between smoking and copper serum levels. CONCLUSION: Our data show that an altered copper bioavailability predicts early atherosclerosis as main CV risk in obese patients with hepatic steatosis detected by ultrasound, shedding some light in this pathological scenario.

Reticulocyte Hemoglobin Content Helps Avoid Iron Overload in Hemodialysis Patients: A Retrospective Observational Study.

BACKGROUND/AIM: Anemia in patients suffering from end-stage renal failure is currently treated with Erythropoiesis-Stimulating Agents (ESA). This treatment needs sufficient iron supplementation to avoid an inadequate dosage of ESA. Nowadays modern analytical instruments allow to accurately calculate the content of Hemoglobin (Hb) in reticulocytes (CHr), that can be used as a guide for prescribing patients with the appropriate amount of iron. PATIENTS AND METHODS: Patients, undergoing hemodialysis, were retrospectively selected from the database and were divided in two groups: group A received intravenous (IV) iron and subcutaneously ESA, and their dosages were adjusted on the basis of the following parameters: Hb, Mean corpuscular haemoglobin (MCH), CHr with consequent MCH/CHr ratio and reticulocyte count determined by the ADVIA 120 Hematology System of Siemens; group B patients were administered IV iron and ESA monitoring iron storage, Hb and ferritin. The aforementioned parameters and the administered amount of iron and ESA were monitored at baseline, four and eight months from the begining of the study. RESULTS: For ESA supplementation, no difference was observed between the groups at the various observed times. Despite similar Hb levels, the patients of group A needed significant lower doses of IV iron (-57.8%) avoiding risks of organ toxicity and obtaining consequent cost saving of nearly 1 €/patient/month. CONCLUSION: The use of CHr and its related parameters allows the avoidance of overdosage of IV iron, which can potentially damage organs, and the reduction of health care direct and indirect costs.

Sublingual administration improves systemic exposure of tacrolimus in kidney transplant recipients: comparison with oral administration.

BACKGROUND: Tacrolimus (TCR) is an immunosuppressive drug used by oral administration. Intravenous (IV) TCR administration is required under conditions of gastrointestinal diseases or abdominal surgery at the onset of paralytic ileus. The infusion formulation needs a large dilution and therefore a careful technical management during continuous infusion by 24 h and may determine anaphylaxis, cardiac arrhythmia, QT prolongation and torsades de pointes. Sublingual (SL) TCR administration was suggested as an alternative route. DESIGN: The aim of this study was to compare in the same kidney transplanted patients the TCR pharmacokinetic profiles by both the routes coupled with the pharmacoeconomic analysis. The study enrolled eight subjects undergoing renal transplantation and treated with TCR and methylprednisolone. TCR was administered by oral route at the scheduled dosage while the 50% of oral dosage was used by SL route, taking into account the absence of liver first pass. RESULTS: Except for AUC, which resulted significantly increased after oral administration, all exposure parameters were not significantly different between the two routes of administration. Analysis of dose-adjusted exposure parameters showed significant increases in AUC and Cmin after SL administration confirming a better bioavailability of the SL route compared with oral route. Cost saving was obtained using the SL rather than the IV route of TCR delivery. CONCLUSION: When oral administration of TCR is not advised, SL delivery represents an attractive option to IV administration.

Successful and Safe Long-Term Standard Antiviral Therapy in a Patient with "Explosive" Immune Response in Course of HCV-Related Liver Cirrhosis.

Hepatitis C virus (HCV) has been recognized to be both a hepato- and lymphotropic virus. HCV lymphotropism represents an essential detail in the pathogenesis of virus-related autoimmune and lymphoproliferative disorders, ranging from clonal expansion of B-cells with organ and non-organ-specific autoantibody production up to overt non-Hodgkin's lymphoma along a continuous step-by-step model of B-cell lymphomagenesis, where the intermediated mixed cryoglobulinemia could be considered as a stage of suppressible antigen-driven lymphoproliferation. The HCV long-lasting extrahepatic replicative state generates an abnormal systemic immunological response, including rheumatoid factor (RF) and cryo- and non-cryoprecipitable immune complexes, as well as clinical manifestations, comprising dermatitis, polyarthralgias and arthritis, pulmonary disease, aplastic anemia, glomerulonephritis and vasculitis. The mechanism of these extra-hepatic disorders is thought of as linked to immune complex disease, but their pathogenesis is poorly clarified. Immune-suppressive treatment could induce high-level hepatitis C viremia and impair hepatic disease. We report a female patient, whose chronic HCV-related liver cirrhosis with associated explosive, but oligosymptomatic lymphoproliferative immune response, i.e., RF beyond three thousand times the upper of normal range (unr), type II cryoglobulinemia with cryocrit 40% and monoclonal gammopathy IgM-k, has been successfully and safely treated by long-lasting (sixty-six months) combined antiviral therapy (pegylated interferon alfa and ribavirin), at moderate and tapering dose regimen, prolonged for nearly 24 months after the first viral suppression. At the last follow-up (fifty-one months), the patient was showing very-long term antiviral response, progressive decline of secondary immune activation and absence of significant side-effects. Further research is required to fully verify the real impact on therapeutic choice/regimen.

Bisphenol-A plasma levels are related to inflammatory markers, visceral obesity and insulin-resistance: a cross-sectional study on adult male population.

BACKGROUND: The current increase of obesity and metabolic syndrome (MS) focuses attention on bisphenol-A (BPA), "obesogen" endocrine disruptor, main plastic component. Aim was to verify the role of BPA in metabolic alterations, insulin resistance, low grade inflammation and visceral obesity. METHODS: A cross-sectional study was performed in 76 out of 139 environmentally exposed adult males, unselected Caucasian subjects, enrolled by routine health survey at the "Federico II" University of Naples outpatient facilities. BPA plasma levels (ELISA), metabolic risk factors, homeostasis model assessment of insulin resistance index, plasma monocyte chemoattractant protein 1, interleukin-6 (IL-6) and tumor necrosis factor-alpha were performed. Clinical and biochemical parameters have been compared with BPA and pro-inflammatory cytokines levels. RESULTS: In total 24 subjects out of 76 (32%) presented with waist circumference (WC) >102 cm, 36 (47%) had impaired fasting glucose and 24 (32%) subjects had insulin resistance [11 out 52 (21%) with WC ≤102 cm and 13 out of 24 with WC >102 cm (54%), χ(2) 6.825, p = 0.009]. BPA and pro-inflammatory cytokine levels were significantly higher in subjects with visceral adiposity (WC > 102 cm). BPA correlated with WC, triglycerides, glucose homeostasis and inflammatory markers. At the multivariate analysis WC and IL-6 remained the main predictors of BPA. CONCLUSIONS: Detectable BPA plasma levels have been found also in our population. The strictly association between BPA and WC, components of MS, and inflammatory markers, further supports the BPA role in visceral obesity-related low grade chronic inflammation.

Could the improvement of obesity-related co-morbidities depend on modified gut hormones secretion?

Obesity and its associated diseases are a worldwide epidemic disease. Usual weight loss cures - as diets, physical activity, behavior therapy and pharmacotherapy - have been continuously implemented but still have relatively poor long-term success and mainly scarce adherence. Bariatric surgery is to date the most effective long term treatment for morbid obesity and it has been proven to reduce obesity-related co-morbidities, among them nonalcoholic fatty liver disease, and mortality. This article summarizes such variations in gut hormones following the current metabolic surgery procedures. The profile of gut hormonal changes after bariatric surgery represents a strategy for the individuation of the most performing surgical procedures to achieve clinical results. About this topic, experts suggest that the individuation of the crosslink among the gut hormones, microbiome, the obesity and the bariatric surgery could lead to new and more specific therapeutic interventions for severe obesity and its co-morbidities, also non surgical.

Is serum Interleukin-17 associated with early atherosclerosis in obese patients?

Atherosclerosis is a chronic inflammatory process of the vessel walls, and CD4+ T-cells are peculiar to both human and murine atherosclerotic lesions. There is a recent line of research favoring hypothetic allergic mechanisms in the genesis of atherosclerosis and, consequently, coronary artery disease (CAD), among which Interleukin (IL)-17 appears to be a key cytokine regulating local tissue inflammation. The objective was to add a piece of information on the role of IL-17 in the genesis of atherosclerosis. Eighty obese patients with normal liver enzyme levels but presenting with ultrasonographic evidence of NAFLD formed the population of this cross-sectional study. Anthropometric measures, data on excess adiposity, metabolic profile, serum concentrations of IL-17, eotaxin-3, IL-8, and CCL4/MIP1ß, C-reactive protein, fibrinogen, ferritin, TNF-α, as well carotid intima-media thickness (IMT), a marker of atherosclerosis, and the main risk factors for CAD, such as blood pressure and smoking status, but also less determinant ones such as degree of NAFLD severity, Intramuscular Triglyceride storage and Resting Metabolic Rate were evaluated. Serum concentrations of Il-17 were detected as related to those of inflammatory cytokines, IL-6, IFN-γ and TNF-α. Furthermore, circulating levels of IL-17 were linked to those mirroring allergic process, IL-8, CCL4/MIP1ß and eotaxin. Early atherosclerosis, evidenced as increased IMT, was not associated with circulating IL-17 levels. At multiple regression,IMT was predicted, other than by age, by the amount of the visceral adiposity, expressed as visceral adipose tissue at ultrasonography, and by serum eotaxin. In conclusion, a strong relationship was found between the IL-17-related chemokine eotaxin and IMT. The association found between the amount of visceral fat and circulating levels of eotaxin on the one hand, and IMT on the other, could reinforce the hypothesis that IL-17, released by the visceral adipose tissue, induces eotaxin secretion via the smooth muscle cells present in the atheromatosus vessels.

Could metabolic syndrome lead to hepatocarcinoma via non-alcoholic fatty liver disease?

It was estimated that from 2002 to 2008 the risk of developing cancer increased a quarter-fold in men and two-fold in women due to excessive BMI. Obesity, metabolic syndrome and type 2 diabetes mellitus are strictly related and are key pathogenetic factors of non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease worldwide. The most important consequence of the "metabolic epidemics" is the probable rise in the incidence of hepatocarcinoma (HCC), and NAFLD is the major causative factor. Adipose tissue is not merely a storage organ where lipids are preserved as an energy source. It is an active organ with important endocrine, paracrine, and autocrine actions in addition to immune functions. Adipocytes produce a wide range of hormones, cytokines, and growth factors that can act locally in the adipose tissue microenvironment and systemically. In this article, the main roles of insulin growth factor (IGF)-1 and IGF-2 are discussed. The role of IGF-2 is not only confined to HCC, but it may also act in early hepato-carcinogenesis, as pre-neoplastic lesions express IGF-2 mRNA. IGF-1 and IGF-2 interact with specific receptors (IGF-1R and IGF-2R). IGF-1R is over-expressed in in vitro and in animal models of HCC and it was demonstrated that IGF ligands exerted their effects on HCC cells through IGF-1R and that it was involved in the degeneration of pre-neoplastic lesions via an increase in their mitotic activity. Both IGF-2R and TGF ß, a growth inhibitor, levels are reduced in human HCC compared with adjacent normal liver tissues. Another key mechanism involves peroxisome proliferator-activated receptor (PPAR)γ. In in vitro studies, PPARγ inhibited various carcinomas including HCC, most probably by regulating apoptosis via the p21, p53 and p27 pathways. Finally, as a clinical consequence, to improve survival, efforts to achieve a "healthier diet" should be promoted by physicians and politicians.