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.

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.

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.

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.

[Chronic kidney disease prevalence and trends (1998-2008) in an area of southern Italy. The data of the VIP project]. / Prevalenza e trend (1998-2008) dell'insufficienza renale cronica in un'area dell'Italia meridionale: i dati del progetto VIP.

Chronic kidney disease (CKD) is a common disorder whose prevalence is increasing worldwide. In Italy the prevalence of CKD, especially the early stages, is still not exactly known. Our study examines the prevalence and trends in ten years (1200 subjects in 1998-1999 and 1200 subjects in 2008-2009) of the estimated glomerular filtration rate (eGFR) in a population of southern Italy. We analyzed, within the VIP project, the prevalence of CKD (eGFR <60) in our area and its relationship to diabetes and hypertension as well as the trend between the years 1998-1999 and 2008-2009. The estimate of the GFR was obtained with the Cockcroft-Gault formula corrected for body surface area. The prevalence of CKD, stratified by the population of Campania, was about 5.9% in males and 3.9% in females in the years 1998-1999; ten years later (2008-2009) it had increased to 6.2% in males and 4.5% in females. The differences between males and females and between the two decades are not statistically significant although the trend shows a clear increase in subjects affected by CKD among both sexes. Among the male population the prevalence of CKD in persons with hypertension or diabetes, in those with both diseases, and in those free from these diseases was 11.2%, 12%, 13.8% and 6.3% (p=0.018), respectively. The same groups among females showed a CKD prevalence of 8%, 9.2%, 9.7% and 4.4%, respectively (p=0.042). Our work provides a picture of the prevalence of CKD in an area of southern Italy. It highlights the increase in CKD and calls upon a greater use of renal function tests in clinical practice, so that individuals at increased risk of developing cardiovascular complications may be detected as early as possible.

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.

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.

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.

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.

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.

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.

Troponin Levels Relate to CRP Concentrations in Patients With NAFLD on Maintenance Haemodialysis: A Retrospective Study.

INTRODUCTION: Several studies have shown that high sensitivity cardiac troponin (hs-cTnT) levels are elevated in patients suffering from end-stage renal disease (ESRD), even in the absence of clinical signs and instrumental features of symptomatic acute coronary syndrome (ACS). In patients undergoing haemodialysis because of ESRD, nephrologists bear witness to this increase, whose origin and clinical impact are not yet well defined. METHODS: By a retrospective study, we evaluated data from records of 70 patients with ESRD on haemodialysis, all of them with a history of NAFLD, not suffering for at least 3 months from symptomatic angina and without a history of ischemic heart disease in the same period. RESULTS: Hs-cTnT and C-reactive protein (CRP) levels both increased and were correlated, rho = 0.34, P = 0.004. The correlation coefficient between troponin and age was significant, rho = 0.47, P = 0.0001. Serum concentrations of hs-cTnT for the whole population were positively predicted by CRP levels, P = 0.004. On separation of the population by gender, significant correlation between hs-cTnT and CRP was not found in women and was only present in men, P = 0.66 and P = 0.000, respectively. DISCUSSION: The assessment of hs-cTnT levels could represent a biological marker in particular subgroups of haemodialysis patients, especially for male patients with higher CRP, those at greater risk of silent myocardial ischemia and future major adverse cardiac events. CONCLUSIONS: The evaluation of hs-cTnT in haemodialysed patients with NAFLD could indicate that men with higher CRP should undergo close monitoring in order to adopt specific therapy.

Blood ammonia levels in liver cirrhosis: a clue for the presence of portosystemic collateral veins.

BACKGROUND: Portal hypertension leads to the formation of portosystemic collateral veins in liver cirrhosis. The resulting shunting is responsible for the development of portosystemic encephalopathy. Although ammonia plays a certain role in determining portosystemic encephalopathy, the venous ammonia level has not been found to correlate with the presence or severity of this entity. So, it has become partially obsolete. Realizing the need for non-invasive markers mirroring the presence of esophageal varices in order to reduce the number of endoscopy screening, we came back to determine whether there was a correlation between blood ammonia concentrations and the detection of portosystemic collateral veins, also evaluating splenomegaly, hypersplenism (thrombocytopenia) and the severity of liver cirrhosis. METHODS: One hundred and fifty three consecutive patients with hepatic cirrhosis of various etiologies were recruited to participate in endoscopic and ultrasonography screening for the presence of portosystemic collaterals mostly esophageal varices, but also portal hypertensive gastropathy and large spontaneous shunts. RESULTS: Based on Child-Pugh classification, the median level of blood ammonia was 45 mcM/L in 64 patients belonging to class A, 66 mcM/L in 66 patients of class B and 108 mcM/L in 23 patients of class C respectively (p < 0.001).The grade of esophageal varices was concordant with venous ammonia levels (rho 0.43, p < 0.001). The best area under the curve was given by ammonia concentrations, i, e., 0.78, when comparing areas of ammonia levels, platelet count and spleen longitudinal diameter at ultrasonography. Ammonia levels predicted hepatic decompensation and ascites presence (Odds Ratio 1.018, p < 0.001). CONCLUSION: Identifying cirrhotic patients with high blood ammonia concentrations could be clinically useful, as high levels would lead to suspicion of being in presence of collaterals, in clinical practice of esophageal varices, and pinpoint those patients requiring closer follow-up and endoscopic screening.

What are the implications of the spontaneous spleno-renal shunts in liver cirrhosis?

BACKGROUND: Although significant advances are expected to be made in the assessment of the portal hypertension-related complications, the prognostic role of spleno-renal shunts has not been fully explored so far. Clarifying this aspect could help tackle the life-treating events occurring in patients suffering from liver cirrhosis. The aim of the study was to analyze the relationships between the spleno-renal shunts presence at doppler ultrasound and the liver cirrhosis complications. DESIGN: eighty one patients out of 129 formed the study population (35 females). Chronic liver damage in these patients was caused by HCV (66), HBV (2), alcohol abuse (2) or unknown etiology, likely non-alcoholic steatohepatitis (11). SETTING: two Liver Units of university/primary hospitals in Southern Italy. MAIN OUTCOME MEASURES: grading of esofageal varices; detection of ascites: assessment of hepatic encephalopathy; evaluation of liver cirrhosis severity; tracking hepatocellular carcinoma; doppler features of spleno-renal shunts and splenic flow velocity; spleen longitudinal diameter at sonography. RESULTS: The prevalence of spleno-renal shunts was 18.5%, without no difference concerning the etiology (HCV versus non-HCV, p = 0.870); the prevalence of hepatocellular carcinoma in patients with spleno-renal shunts was superior to that of patients without them (Pearson Chi-square, p = 0.006, power of sample size 74%), also after adjustment for liver decompensation (p = 0.024). The median score of hepatic encephalopathy in patients with and without spleno-renal shunts was similar, i.e., 0 (range, 0-2) versus 0 (0 - 3), p = 0.67. The median splenic vein flow velocity in patients with spleno-renal shunts was significantly inferior to that of patients without them, i.e., 13 cm/sec (95% confidence intervals, 6-18) versus 21 cm/sec (17-24), p < 0.0001. By far the largest percentage of large esophageal varices was in patients without spleno-renal shunts (p = 0.005). In contrast, the frequency of ascites and hepatic encephalopathy severity was overlapping in the two groups. BMI values but not Child-Pugh's classification predicted spleno-renal shunts (Ors = 1.84, 95% confidence intervals = 1.28-2.64, p = 0.001 and 1.145, 95% confidence intervals = 0.77-1.51, p = 0.66). CONCLUSION: Taking into consideration the relatively small sample size, patients with spleno-renal shunts are burdened by an increased incidence of hepatocellular carcinoma. BMI predicted the spleno-renal shunts presence.

Nonalcoholic Fatty Liver Disease: A Challenge from Mechanisms to Therapy.

Focusing on previously published mechanisms of non-alcoholic fatty liver disease (NAFLD), their uncertainty does not always permit a clear elucidation of the grassroot alterations that are at the basis of the wide-spread illness, and thus curing it is still a challenge. There is somehow exceptional progress, but many controversies persist in NAFLD research and clinical investigation. It is likely that hidden mechanisms will be brought to light in the near future. Hereby, the authors present, with some criticism, classical mechanisms that stand at the basis of NAFLD, and consider contextually different emerging processes. Without ascertaining these complex interactions, investigators have a long way left ahead before finding an effective therapy for NAFLD beyond diet and exercise.

Is There a Link between Basal Metabolic Rate, Spleen Volume and Hepatic Growth Factor Levels in Patients with Obesity-Related NAFLD?

BACKGROUND: Recent pieces of research point to a link between basal metabolic rate (BMR) and non-alcoholic fatty liver disease (NAFLD) or hepatic steatosis (HS). The spleen in obese patients is associated with the cardiovascular system. Enlargement of the spleen is suggestive of nonalcoholic steatohepatitis (NASH). Patients with NASH present an increase in growth factor (HGF) as well as those with advanced heart failure. Interleukin-16 and interleukin-12p40 levels were found to correlate significantly with BMI, and waist circumference. AIM: We tried to find a relationship between BMR, spleen length and HGF. METHODS: We analysed retrospective data from 80 obese patients with NAFLD. We evaluated indices of indirect calorimetry by the bioimpendance analysis; carotid intima-media thickness (IMT), spleen length (SLD) and HS by ultrasonography; serum HGF, IL-16, IL-12p40 and IL-6 concentrations by a magnetic bead-based multiplex immunoassays and the severity of NAFLD by BARD score > 2. RESULTS: HGF levels of the obese were higher than those of controls, p < 0.001. At linear regression, BMR was foreseen by spleen length (p < 0.001), which was predicted by HGF (p = 0.04). BMR was predicted by IL-16 (p = 0.005), which predicted HGF, p = 0.034. Only fat mass, among other factors, predicted early atherosclerosis, p = 0.017; IL-12p40 did not predict IMT, HGF and BMR (p = 0.57, 0.09 and 0.59, respectively). The BARD score > 2 was negatively predicted by BMR and FFM (p =0.032 and 0.031, respectively), at the logistic regression. Interesting findings at the extended regression (mediation effect) were: IL-16 was likely causal in predicting BMR by HGF levels; HGF was influential in predicting BMR by SLD level. HS was predicted by SLD in males (p = 0.014), of advanced age (p < 0.001) and by BMR (p < 0.001). IL-6 concentrations, but not BMR were influential in the prediction of HS by SLD. CONCLUSION: These data reinforce the concept that the immune system is a sensor of the metabolic state, showing a link between HGF levels and BMR, which is mediated by IL-16 (cytokine inducing a cascade of inflammatory factors), and ascertaining the influential effect of the spleen, as main immune organ.

Do Transferrin Levels Predict Haemodialysis Adequacy in Patients with End-Stage Renal Disease?

BACKGROUND: Since haemodialysis is a lifesaving therapy, adequate control measures are necessary to evaluate its adequacy and to constantly adjust the dose to reduce hospitalisation and prolong patient survival. Malnutrition is common in haemodialysis patients and closely related to morbidity and mortality. Patients undergoing haemodialysis have a high prevalence of protein-energy malnutrition and inflammation, along with abnormal iron status. The haemodialysis dose delivered is an important predictor of patient outcome. AIM: To evaluate through haemodialysis adequacy, which parameter(s), if any, better predict Kt/V, among those used to assess nutritional status, inflammation response, and iron status. METHODS: We retrospectively studied 78 patients undergoing haemodialysis due to end-stage renal disease. As parameters of nutritional status, geriatric nutritional risk index (GNRI), transferrin levels, lymphocyte count, and albumin concentration were analysed. As signs of inflammation, C reactive protein (CRP) levels and ferritin concentrations were studied as well. Iron status was evaluated by both transferrin and ferritin levels, as well as by haemoglobin (Hb) concentration. RESULTS: The core finding of our retrospective study is that transferrin levels predict the adequacy of haemodialysis expressed as Kt/V; the latter is the only predictor (P = 0.001) when adjusting for CRP concentrations, a solid marker of inflammation, and for ferritin levels considered an iron-storage protein, but also a parameter of inflammatory response. DISCUSSION AND CONCLUSION: In keeping with the results of this study, we underline that the use of transferrin levels to assess haemodialysis quality combine into a single test the evaluation of the three most important factors of protein-energy wasting.

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.