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.

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.

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.

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.

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.

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.

Nutrition, inflammation and liver-spleen axis.

Chronic low-grade systemic inflammation represents a mechanism common to many diseases linked to atherosclerosis-related pathways. There is a growing body of evidence indicating that the combination of food quantity and quality along with genetic susceptibility are able to induce the aberrant activation of innate immune signalling, which initially contributes to chronic low-grade inflammation. Liver represents the central player to inflammatory response. Dietary/metabolic factors contribute to the pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD), the main causes of liver disease in the Western world. Enlargement of the spleen, central organ in regulating the inflammation-related immune response, is commonly seen in patients with of NAFLD, depicting the so called "liver-spleen axis." The aim of this review was to provide an at-a-glance overview of the possible bi-directional mechanisms linking nutrition and inflammation, particularly pinpointing the inflammatory effects stemmed by nutrition on "liver-spleen axis." In particular, the role of unhealthy diet, healthy dietary patterns, such as the Mediterranean diet style, dietary vitamins and micronutrients, such as vitamin D or Magnesium, and Glucagon-Like Peptide-1, a well-known incretin released in response to meal intake, will be discussed. The highly variability of the inflammatory response highlights the role of expert nutritionists in refining methodologies apt to assess nutritional epidemiology and to apply appropriate dietary intervention to counteract diet-induced inflammation mechanisms.

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.

Comparison of the everolimus concentrations measured in whole blood with everolimus QMS or sirolimus CMIA.

Few years ago, it was proposed that everolimus blood levels could be determined with the commercially available sirolimus chemiluminescence magnetic microparticle immunoassay (CMIA). More recently, a highly specific microsphere system (QMS) has been approved by FDA for therapeutic drug monitoring in humans. Aim of the present study was to compare the results of everolimus assay performed with everolimus QMS and with sirolimus CMIA. The two methods were compared with Passing-Bablok regression and Bland-Altman plot analysis. The Passing-Bablok regression analysis showed that although the results obtained with the two techniques were significantly correlated, CMIA-measured differed from QMS-measured everolimus concentrations by both a systematic and a proportional error. Specifically, at blood levels lower than 5 ng/mL CMIA were lower than QMS-measured everolimus concentrations. On the opposite, at everolimus blood concentrations higher than 10 ng/mL CMIA-estimated values became progressively higher than QMS-measured everolimus concentrations. The analysis of the Bland Altman plot showed a less than optimal agreement of the two tests (5.59% of the data point outside the ±1.96 SD interval). Moreover, the relationship between the difference between EveroQMS and EveroCMIA and their average was clearly concentration dependent with positive and negative values at concentration values lower and higher than 5 ng/mL respectively. In conclusion, our finding showed that the values of everolimus concentrations measured with sirolimus CMIA differ from those detected with the FDA-approved everolimus QMS further suggesting that sirolimus CMIA should not be used anymore for everolimus therapeutic drug monitoring.

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.

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.

Serum levels of Lp(a) are related to waist circumference in NAFLD patients with low prevalence of co-morbidities.

BACKGROUND: Novel evidence suggests a relationship between circulating Lp(a) levels and the presence of cardiovascular events independently from the cardio-metabolic profile. METHODS AND RESULTS: The purpose of this study was to investigate serum Lp(a) concentrations in relation to carotid intima-media thickness (IMT), anthropometric measures, lipid profile, assessment of insulin resistance, and other parameters conventionally used to predict CVD risk, in obese patients suffering from hepatic steatosis (HS), the well-known nonalcoholic fatty liver disease (NAFLD). Evidencing the key-points of this research, firstly, serum Lp(a) concentrations were not associated with carotid IMT in this selected population or, consequently, with early atherosclerosis, at least as evaluated by IMT. Secondly, carotid IMT was not predicted by HS severity, as evaluated by ultrasound. Finally, in the adjusted model, Lp(a) was positively predicted by waist circumference (WC) (ß = 0.25, t = 2.3, p = 0.02) and negatively by central adiposity, assessed as visceral adipose tissue at US (ß = -0.33, t = -3.0, p = 0.003). CONCLUSION: Serum Lp(a) values may not play a direct role in increasing IMT, albeit associated with WC.

Nutrition: a key environmental dietary factor in clinical severity and cardio-metabolic risk in psoriatic male patients evaluated by 7-day food-frequency questionnaire.

BACKGROUND: Western dietary pattern is included among the environmental dietary factors involved in the pathogenesis of psoriasis. Nutritional data collection methods and gender differences might affect the association between diet and psoriasis. The 7-day food records is considered the "gold standard" of self-administered food frequency questionnaires. In this study, we evaluated the differences in the dietary intake, anthropometric measurements and cardio-metabolic risk profile in a group of psoriatic patients compared with an age and Body Mass Index (BMI)-matched control group. In addition, in the group of psoriatic patients we investigated the association between the dietary intake and clinical severity of psoriasis. METHODS: Cross-sectional case control observational study. A total of 82 adult males, 41 treatment-naïve patients with psoriasis and 41 healthy subjects matched for age and BMI were included in the study. The clinical severity of psoriasis was by assessed by Psoriasis Area and Severity Index (PASI) score. The dietary interview data were collected by a 7-day food records. Anthropometric measures, glucose and lipid profile, liver function tests and C-reactive protein levels were measured. Homeostasis Model Assessment of Insulin Resistance (HoMA-IR), Visceral Adiposity Index (VAI) and the Fatty Liver Index (FLI) were calculated. RESULTS: Psoriatic patients consumed a higher percentage of total and simple carbohydrates, total fat, polyunsaturated fatty acid (PUFA) and n-6/n-3 PUFAs ratio, and cholesterol, while the consumption of protein, complex carbohydrates, monounsaturated fatty acid (MUFA), n-3 PUFA and fiber was lower than in the control group. In addition, psoriatic patients presented altered anthropometric measurements, glucose and lipid profile, liver function tests, and elevated values of HoMA-IR, VAI and FLI. PASI score well correlated with anthropometric measures, glucose and lipid profile, liver function tests, cardio-metabolic indices, and the dietary components, except for protein and total carbohydrates. At logistic regression analysis between PASI score and MUFA, MetS presence was well predicted only by higher PASI score (OR = 1.794; p = 0.002; CI 1.242-2.591). At multiple regression analysis, MUFA was the best predictor of PASI score (r(2) = 0.387, ß = -0.635, t = -5.127, p < 0.001). CONCLUSION: Differences in dietary intake were observed in adult male psoriatic patients compared with the controls. These differences were associated to the severity of the psoriasis and cardio-metabolic risk. FLI represented an early indicator of the cardio-metabolic risk profile in psoriatic patients, and dietary MUFA were major predictor of the clinical severity of psoriasis, while the association between psoriasis and metabolic syndrome appeared to be independent of MUFA intake. The low MUFA consumption might act as a possible adjunctive mechanism in increasing the inflammation milieu of psoriatic patients.

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.

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.

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.

Noninvasive assessment of liver fibrosis in patients with chronic hepatitis C (and congenital bleeding disorders): where do we stand?

The assessment and monitoring of liver fibrosis (LF) is a key issue in the management and definition of prognosis of patients with chronic hepatitis C (CHC). In this respect, despite recognized limitations (invasive nature, sampling errors, interobserver variability, nondynamic evaluation of LF), liver biopsy is traditionally considered the reference standard. These limitations stimulated the search for noninvasive approaches for the assessment of LF, particularly attractive in patients with hemophilia and other congenital bleeding disorders (CBD). In patients with congenital bleeding disorders (CBD), who often suffer from CHC because of the past use of nonvirally inactivated plasma-derived products, the risk of bleeding hamper to routinely obtain histological data for LF staging. A variety of methods have been proposed and, in some cases, validated in patients with CHC and other liver diseases, including biomarkers directly or indirectly associated with LF, often combined in scores or algorithms, and the more recently developed physical approaches, evaluating the properties of the liver parenchyma with instrumental techniques studying the propagation of specific signals, that is, transient elastography (TE), acoustic radiation force impulse imaging elastography, and magnetic resonance elastography. This review will describe the available strategies for noninvasive assessment of LF, with more details on the latter promising instrumental approaches. Moreover, although lacking of validation against liver biopsy, recent studies extending the use of noninvasive methods (particularly TE) in the setting of patients with CBD will be discussed.

Bisphenol A in polycystic ovary syndrome and its association with liver-spleen axis.

CONTEXT: Bisphenol A, one of the highest-volume chemicals currently available, is known to act as endocrine disruptor and alters several metabolic functions, including inflammatory pathways. Elevated serum levels of bisphenol A have been found in women with polycystic ovary syndrome (PCOS) and a role of low-grade chronic inflammation has been recently reported in the pathogenesis of this syndrome. Increased spleen volume, a reliable and stable index of chronic inflammation, was strictly associated with the severity of hepatic steatosis (HS) in obese subjects, determining the so-called liver-spleen axis. OBJECTIVE: To evaluate the contribution of increased serum bisphenol A levels to low-grade chronic inflammation, HS and hyperandrogenism in women with PCOS. DESIGN, SETTING AND PARTICIPANTS: Forty lean and overweight/obese premenopausal women with PCOS and 20 healthy age-matched women were consecutively enrolled in a cross-sectional study from 2009 to 2011 at the Federico II University Hospital in Naples. MEASUREMENTS: Bisphenol A, homoeostasis model assessment of insulin resistance (HoMA-IR), laboratory liver tests, testosterone, sex hormone-binding globulin, free androgen index (FAI), C-reactive protein, interleukin-6, and the ultrasound quantification of HS and spleen longitudinal diameter. RESULTS: Independently of body weight, higher bisphenol A levels in PCOS women were associated with higher grades of insulin resistance, HS, FAI and inflammation, spleen size showing the best correlation. At multivariate analysis, spleen size and FAI were the best predictors of bisphenol A (ß coefficients 0.379, P = 0.007 and 0.343, P = 0.014, respectively). CONCLUSIONS: In premenopausal women with PCOS, we evidenced an association of serum bisphenol A levels with HS and markers of low-grade inflammation, in particular with spleen size, unravelling the presence of the liver-spleen axis in this syndrome.