What about non-alcoholic fatty liver disease as a new criterion to define metabolic syndrome?

Non-alcoholic fatty liver disease (NAFLD) is currently not a component of the diagnostic criteria for metabolic syndrome (MetS); however, the development of NAFLD has some common mechanisms with the development of MetS, as they share the pathophysiologic basis of insulin resistance. It is also recognized that NAFLD is the hepatic manifestation of MetS. To define MetS, the presence of at least three of the proposed criteria is required, and sometimes it is sufficient to have only one laboratory value, modified by diet or drugs, for the classification of MetS. Ultrasonographically-detected NAFLD (US-NAFLD) is more stable, only changing during the middleto long-term. Although controversies over MetS continue, and considering that abdominal ultrasonography for diagnosing NAFLD has high specificity and guidelines to modify the natural course of NAFLD by diet composition or lifestyle have not yet been established, why should we not introduce US-NAFLD as a new criterion to define MetS?

What is the role of adiponectin in obesity related non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries.Insulin resistance is a key factor in the pathogenesis of NAFLD,the latter being considered as the hepatic component of insulin resistance or obesity.Adiponectin is the most abundant adipose-specific adipokine.There is evidence that adiponectin decreases hepatic and systematic insulin resistance,and attenuates liver inflammation and fibrosis.Adiponectin generally predicts steatosis grade and the severity of NAFLD;however,to what extent this is a direct effect or related to the presence of more severe insulin resistance or obesity remains to be addressed.Although there is no proven pharmacotherapy for the treatment of NAFLD,recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications.In this adiponectin-focused review,the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are analyzed systematically.

Drug-induced liver injury:Is it somehow foreseeable?

The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neosubstances that react abnormally), mainly by cytochromes P-450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.

Pathogenesis of hepatic steatosis:The link between hypercortisolism and non-alcoholic fatty liver disease

Based on the available literature,non alcoholic fatty liver disease or generally speaking,hepatic steatosis,is more frequent among people with diabetes and obesity,and is almost universally present amongst morbidly obese diabetic patients.Non alcoholic fatty liver disease is being increasingly recognized as a common liver condition in the developed world,with non alcoholic steatohepatitis projected to be the leading cause of liver transplantation.Previous data report that only 20%of patients with Cushing’s syndrome have hepatic steatosis.Aiming at clarifying the reasons whereby patients suffering from Cushing’s syndrome-a condition characterized by profound metabolic changes-present low prevalence of hepatic steatosis,the Authors reviewed the current concepts on the link between hypercortisolism and obesity/metabolic syndrome.They hypothesize that this low prevalence of fat accumulation in the liver of patients with Cushing’s syndrome could result from the inhibition of the so-called low-grade chronicinflammation,mainly mediated by Interleukin 6,due to an excess of cortisol,a hormone characterized by an anti-inflammatory effect.The Cushing’s syndrome,speculatively considered as an in vivo model of the hepatic steatosis,could also help clarify the mechanisms of non alcoholic fatty liver disease.

Hepatic steatosis,low-grade chronic inflammation and hormone/growth factor/adipokine imbalance

Non-alcoholic fatty liver disease (NAFLD), a further expression of metabolic syndrome, strictly linked to obesity and diabetes mellitus, is characterized by insulin resistance (IR), elevated serum levels of free fatty acids and fatty infi ltration of the liver, which is known as hepatic steatosis. Hepatocyte apoptosis is a key feature of this disease and correlates with its severity. Free-fatty-acidinduced toxicity represents one of mechanisms for the pathogenesis of NAFLD and hormones, growth factors and adipokines influence also play a key role. This review highlights the various pathways that contribute to the development of hepatic steatosis. Circulating concentrations of inflammatory cytokines are reckoned to be the most important factor in causing and maintaining IR. Low-grade chronic inflammation is fundamental in the progression of NAFLD toward higher risk cirrhotic states.

Should nonalcoholic fatty liver disease be regarded as a hepatic illness only?

The highly increasing prevalence of obesity and type 2 diabetes mellitus in the general population makes nonalcoholic fatty liver disease the most common diagnosis in every-day practices. Lifestyle changes （mainly exercise withdrawal and weight gain） have probably heightened the prevalence of nonalcoholic fatty liver disease. Mortality in patients with Nonalcoholic Fatty Liver Disease is significantly higher when compared with that of the same age-gender general population. Hepatologists claim to bear a new burden, being Nonalcoholic Fatty Liver Disease strongly linked to systemic diseases.

Liver-spleen axis: Intersection between immunity, infections and metabolism

Spleen has been considered a neglected organ so far, even though is strictly linked to liver. The spleen plays an important role in the modulation of the immune system and in the maintenance of peripheral tolerance via the clearance of circulating apoptotic cells, the differentiation and activation of T and B cells and production of antibodies in the white pulp. Moreover, splenic macrophages are able to remove bacteria from the blood and protect from sepsis during systemic infections. We review the spleen function and its assessment in humans starting from the description of spleen diseases, ranging from the congenital asplenia to secondary hyposplenism. From the literature data it is clear that obesity in humans affects different compartments of immune system, even thought there are still few data available on the implicated mechamisms. The intent is to enable clinicians to evaluate the newly recognized role of metabolic and endocrine functions of the spleen with special emphasis to obesity and nonalcoholic fatty liver disease in the context of the available literature.Moreover, understanding the spleen function could be important to develop appropriate prevention strategies in order to counteract the pandemia of obesity. In this direction, we suggest spleen longitudinal diameter at ultrasonography, as simple, cheap and largely available tool, be used as new marker for assessing splenic function, in the context of the so-called liver-spleen axis.

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 β, 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.

JNKs,insulin resistance and inflammation:A possible link between NAFLD and coronary artery disease

The incidence of obesity has dramatically increased in recent years.Consequently,obesity and associated disorders such as nonalcoholic fatty liver disease constitute a serious problem.Therefore,the contribution of adipose tissue to metabolic homeostasis has become a focus of interest.In this review,we discuss the latest discoveries that support the role of lipids in nonalcoholic fatty liver disease.We describe the common mechanisms(cJun aminoterminal kinases,endoplasmic reticulum stress,unfolded protein response,ceramide,lowgrade chronic inflammation)by which lipids and their derivatives impair insulin responsiveness and contribute to inflammatory liver and promote plaque instability in the arterial wall.Presenting the molecular mechanism of lipid activation of proinflammatory pathways,we attempt to find a link between nonalcoholic fatty liver disease,metabolic syndrome and cardiovascular diseases.Describing the common mechanisms by which lipid derivatives,through modulation of macrophage function,promote plaque instability in the arterial wall,impair insulin responsiveness and contribute to inflammatory liver and discussing the molecular mechanism of lipid activation of proinflammatory pathways,the key roles played by the proliferatoractivated receptor and liver X receptorα,nuclear receptorslipid sensors that link lipid metabolism and inflammation,should be emphasized.Further studies are warranted of antiinflammatory drugs such as aspirin,antiinterleukin6 receptors,immunemodulators(calcineurin inhibitors),substances enhancing the expression of heat shock proteins(which protect cells from endoplasmic reticulum stressinduced apoptosis),and anticJun aminoterminal kinases in welldesigned trials to try to minimize the high impact of these illnesses,and the different expressions of the diseases,on the whole population.

Exposure to ambient air particulate matter and non-alcoholic fatty liver disease

The present study was designed to alert the public opinion and policy makers on the supposed enhancing effects of exposure to ambient air particulate matter with aerodynamic diameters < 2.5 mm (PM 2.5 ) on non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western countries. For far too long literature data have been fixated on pulmonary diseases and/or cardiovascular disease, as consequence of particulate exposure, ignoring the link between the explosion of obesity with related syndromes such as NAFLD and air pollution, the worst characteristics of nowadays civilization. In order to delineate a clear picture of this major health problem, further studies should investigate whether and at what extent cigarette smoking and exposure to ambient air PM 2.5 impact the natural history of patients with obesity-related NAFLD,i.e. , development of non alcoholic steatohepatitis, disease characterized by a worse prognosis due its progression towards fibrosis and hepatocarcinoma.

Could quantitative liver function tests gain wide acceptance among hepatologists?

It has been emphasized that the assessment of residual liver function is of paramount importance to determine the following： severity of acute or chronic liver diseases independent of etiology; long-term prognosis; step-bystep disease progression; surgical risk; and efficacy of antiviral treatment. The most frequently used tools are the galactose elimination capacity to asses hepatocyte cytosol activity, plasma clearance of indocyanine green to assess excretory function, and antipyrine clearance to estimate microsomal activity. However, a widely accepted liver test （not necessarily a laboratory one） to assess quantitative functional hepatic reserve still needs to be established, although there have been various proposals. Furthermore, who are the operators that should order these tests？ Advances in analytic methods are expected to allow quantitative liver function tests to be used in clinical practice.

Serum Bcl-2 concentrations in overweight-obese subjects with nonalcoholic fatty liver disease

AIM： To shed some light on the relationship between anti-apoptotic serum Bcl-2 concentrations and metabolic status, anthropometric parameters, inflammation indi- ces, and non-alcoholic fatty liver disease severity were investigated in 43 young individuals with fatty liver （FL） and 41 with nonalcoholic steatohepatitis （NASH）. METHODS： Circulating levels of Bcl-2 were detected in 84 patients with ultrasonographic findings of ＂bright liver＂ and/or hyper-transaminasemia of unknown origin and/or increase in T-glutamyl-transpeptidase （T-GT） strictly in the absence of other acute or chronic liver disease, whose age was not advanced, who gave consent to liver biopsy and were then divided on the basis of the histological results into two groups （43 with FL and 41 with NASH）. Twenty lean subjects, apparently healthy and young, were chosen as controls.RESULTS： Serum Bcl-2 concentrations were significantly higher in the FL group than in the NASH group. Insulin resistance and γ-GT activity were significantly higher in NASH subjects. Apoptotic hepatocytes were significantly more numerous in NASH patients. NASH patients presented with larger spleens and augmented C-reactive protein （CRP） concentrations than healthy subjects. Steatosis grade at histology was similar in both NASH and FL populations. The number of apoptotic cells was significantly related to anti-apoptotic Bcl-2 protein values in FL patients. Bcl-2 serum levels positively correlated to body mass index （BMI） values （P ~ 0.0001） but not to age of the population. Triglycerides/HDL ratio correlated well to waist circumference in males （P = 0.0008）. γ-GT activity was associated with homeostatic metabolic assessment （HOMA） （P = 0.0003） and with serum ferritin （P = 0.02）. Bcl-2 concentrations were not related to either spleen size or CRP values. NASH patients pre- sented a weak negative correlation between Iobular inflammation and Bcl-2 levels. A prediction by low values of serum Bcl-2 towards a greater presence of metabolically unhealthy overweight/obese patients （MUOs） was evidenced. HOMA, BMI and uric acid, in that sequence, best predicted serum Bcl-2 concentrations. CONCLUSION： IvlUOs could be detected by Bcl-2 levels. By favoring the life span of hepatocytes, and enhancing triglyceride formation, the anti-apoptotic process inhibits free fatty acids toxicity in FL.

High prevalence of nonalcoholic fatty liver in patients with idiopathic venous thromboembolism

AIM:To assess the prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with idiopathic venous thromboembolism (VTE). METHODS:In a case-control study,after excluding subjects with well-consolidated risk factors for VTE,idiopathic VTE was documented in 138 consecutive patients who were referred to our department. Two hundred and seventy-six healthy sex/age/body-massindex-matched subjects,without any clinical/instrumental evidence of VTE,served as controls. All underwent a clinical/laboratory/ultrasound assessment for the presence of metabolic syndrome and NAFLD. RESULTS:NAFLD was detected in 112/138 cases (81%) and in 84/276 controls (30%) [risk ratio:2.7,95% confidence interval (CI):2.2-3.2,P < 0.0001]. Metabolic syndrome and smoking habit were more prevalent in patients with idiopathic VTE. The high prevalence of NAFLD in VTE was also confirmed after adjustment for inherited thrombophilia. NAFLD was clearly predicted by VTE (odds ratio:1.8,95% CI:1.2-2.7,P < 0.0001).

What does irritable bowel syndrome share with non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease(NAFLD)and irritable bowel syndrome(IBS)are two very common diseases in the general population.To date,there are no studies that highlight a direct link between NAFLD and IBS,but some recent reports have found an interesting correlation between obesity and IBS.A systematic PubMed database search was conducted highlighting that common mechanisms are involved in many of the local and systemic manifestations of NAFLD,leading to an increased cardiovascular risk,and IBS,leading to microbial dysbiosis,impaired intestinal barrier and altered intestinal motility.It is not known when considering local and systemic inflammation/immune system activation,which one has greater importance in NAFLD and IBS pathogenesis.Also,the nervous system is implicated.In fact,inflammation participates in the development of mood disorders,such as anxiety and depression,characteristics of obesity and consequently of NAFLD and,on the other hand,in intestinal hypersensitivity and dysmotility.

Hepatitis C virus lymphotropism and peculiar immunological phenotype:Effects on natural history and antiviral therapy

Hepatitis C virus （HCV） has been recognized to be both a hepato- and lymphotropic virus. HCV lymphotropism represents an essential lap 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. HCV infection of lymphoid ceils could set up privileged reservoirs able to interfere with the host viral clearance efficiency and may be implicated in viral recurrence after apparently successful antiviral therapy. The HCV long-lasting extrahepatic replicative state generates an abnormal systemic immunological response, easily detectable by searching simple laboratory and clinical parameters, mainly represented by vasculitis-like skin features and hypocomplementemia.The presence or absence of this hypersensitivity pattern seems to correlate with the antiviral response and could be identified as a novel immunological cofactor. Further research is required to fully verify the real impact on therapeutic choice/regimen.

Hepatic steatosis in overweight/obese females: New screening method for those at risk

AIM: To identify which parameters could help to distinguish the "metabolically benign obesity", which is not accompanied by insulin resistance (IR) and early atherosclerosis.METHODS: Eighty two of 124 overweight/obese females formed the study population, which was divided into two groups (52 and 30 subjects, respectively) with and without IR according to a HO meostatic Metabolic Assessment (HOMA) cut-off of 2, and were studied in a cross-sectional manner. The main outcome measures were waist circumference, serum uric acid, high-density lipoprotein-cholesterol and triglycerides, alanine amino-transferase, blood pressure and the two imaging para-meters, hepatic steatosis and longitudinal diameter of the spleen, which were measured in relation to the presence/absence of IR. RESULTS: A variable grade of visceral obesity was observed in all subjects with the exception of three.Obesity of a severe grade was represented more in the group of IR individuals (P = 0.01). Hepatic steatosis, revealed at ultrasound, was more pronounced in IR than in non-IR subjects (P = 0.005). The two groups also demonstrated a clear difference in longitudinal spleen diameter and blood pressure, with raised and signif icant values in the IR group. Metabolic syndrome was frequent in the IR group, and was not modified when adjusted for menopause (P = 0.001). At linear regression, the β values of waist circumference and body mass index predicting HOMA were 0.295, P = 0.007 and 0.41, P = 0.0001, respectively. Measures of spleen longitudinal diameter were well predicted by body mass index (BMI) values, β = 0.35, P = 0.01, and by HOMA, β = 0.41, P = 0.0001. Blood pressure was predicted by HOMA values, β = 0.39, P = 0.0001). HOMA and hepatic steatosis were highly associated (rho = 0.34, P = 0.002). Interestingly, IR patients were almost twice as likely to have hepatic steatosis as non-IR patients. Among the MS criteria, blood pressure was very accurate in identifying the presence of IR (AUROC for systolic blood pressure 0.66, cut-off 125 mm of Hg, sensibility 64%, specif icity 75%; AUROC for diastolic blood pressure 0.70, cut-off 85 mm of Hg, sensibility 54.5%, specif icity 75%). CONCLUSION: As health care costs are skyrocketing, reliable and mainly inexpensive tools are advisable to better defi ne subjects who really need to lose weight.

Omega-3 fatty acids for the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease （NAFLD） has been recognized as a major health burden. It is the most important cause of chronic liver disease and a major in- dependent cardiovascular risk factor. Lacking a definite treatment for NAFLD, a specific diet and an increase in physical activity represent the most commonly used therapeutic approaches. In this review, major literature data about the use of omega-3 polyunsaturated fatty ac- ids （n-3 PUFAs） as a potential treatment of NAFLD have been described, n-3 PUFAs, besides having a beneficial impact on most of the cardio-metabolic risk factors （hy- pertension, hyperlipidemia, endothelial dysfunction and atherosclerosis） by regulating gene transcription factors [i.e., peroxisome proliferator-activated receptor （PPAR） cz, PPARy, sterol regulatory element-binding protein-i, carbohydrate responsive element-binding protein], im- pacts both lipid metabolism and on insulin sensitivity. In addition to an enhancement of hepatic beta oxidation and a decrease of the endogenous lipid production, n-3 PUFAs are able to determine a significant reduction of the expression of pro-inflammatory molecules （tumor necrosis factor-~ and interleukin-6） and of oxygen reac- tive species. Further strengthening the results of the in vitro studies, both animal models and human interven- tion trials, showed a beneficial effect of n-3 PUFAs on the severity of NAFLD as expressed by laboratory pa- rameters and imaging measurements. Despite available results provided encouraging data about the efficacy of n-3 PUFAs as a treatment of NAFLD in humans, well- designed randomized controlled trials of adequate size and duration, with histological endpoints, are needed to assess the long-term safety and efficacy of PUFA, as well as other therapies, for the treatment of NAFLD and non-alcoholic steatohepatitis patients. It is worthwhile to consider that n-3 PUFAs cannot be synthesized by the human body and must be derived from exogenous sources （fish oil, flaxseeds, olive oil） which are typical foods of the Mediterranean diet, known for its beneficial effects in preventing obesity, diabetes and, in turn, cardiovascular events. According to these data, it is important to consider that most of the beneficial effects of n-3 PUFAs can also be obtained by an equilibrate nutrition program.

Nonalcoholic fatty liver disease, spleen and psoriasis:New aspects of low-grade chronic inflammation

AIM: To investigate spleen status in psoriasis and itsrelationship with hepatic steatosis, Psoriasis Area and Severity Index, and insulin resistance.METHODS: Seventy-nine psoriatic patients who were not suffering from any chronic inflammatory disease were retrospectively selected for inclusion in this study,and their complete medical records were accessed.An age- and sex-matched group of 80 non-psoriatic,obese patients was included as a control. The following relevant data were collected: age, sex, weight, height,body mass index, waist circumference, blood pressure,insulin resistance status, age at psoriasis onset, and severity of psoriasis. Abdominal ultrasonography was performed to determine spleen longitudinal diameter(SLD), and hepatic steatosis grade.RESULTS: The SLD of control obese patients was greater than that of psoriatic subjects(P = 0.013),but body mass index predicted the size of the spleen in psoriatic patients(P < 0.001). The SLD of psoriatic patients with normal weight was significantly reduced with respect to the overweight/obese psoriatic patients(P = 0.002). A multiple regression analysis revealed that body mass index was a unique predictor of the spleen size(P < 0.001). Finally, the disease duration predicted the spleen size in psoriatic subjects(P =0.038).CONCLUSION: This study shows a correlation between the SLD and the duration of psoriasis.

NAFLD or MAFLD:That is the conundrum

Where do we stand and where are we going? This question is of paramount importance in the light of the necessity of shedding light on the novel, controversial issue that is changing the acronym of nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD).

Spleen:A new role ffoorr an old player?

The spleen could be considered a neglected organ.To date,it has been deemed an ancillary organ in portal hypertension or an organ localization in lymphoproliferative diseases,even though it has had significant attention in infectious diseases for some time.Now,it is thought to be central in regulating the immune system,a metabolic asset and involved in endocrine function with regard to nonalcoholic fatty liver disease.The main mechanisms involved in this complex network will be critically discussed in this article.