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Background and aims: In the present population-based study, we aimed to describe the per patient annual healthcare cost of people with diabetes in 2007-2012, to assess the relative burden of diabetes complications and other potential determinants on healthcare costs in the 2012 cohort, and to describe and analyse the determinants of the cost of incident cases diagnosed in 2012. Methods and results: We analysed data from a retrospective cohort of residents in four Italian areas that were served by Local Health Units participating in the ARNO Observatory. Per patient annual healthcare costs (Euros) were estimated as the sum of all the resources supplied during that year (drugs, outpatient care, and hospitalisations). The mean per patient annual healthcare cost increased from €2752 in 2007 to €3191 in 2010, before decreasing to €2791 in 2012. The largest component of these costs was represented by hospitalisations (around €1550, on average; 51.7% of total cost), followed by outpatient care (€422; 14.6%) and drugs (€973; 33.7%). In 2012, the most relevant cost determinants were chronic diabetes complications, with an additional cost due to nephropathy/end stage renal disease (€4683), amputations (€5042), lower extremity revascularization (€4808), and cerebrovascular diseases (€3861). Costs associated with incidence cases were higher than those associated with prevalent. Conclusion: The present study provides evidence on the excess of healthcare costs due to diabetes complications in both prevalent and incident cases.

The construct of trait Emotional Intelligence (trait EI) takes into account the subjective aspects of human’s emotional experience, as it conceptualizes EI as a set of self-perceived emotional abilities. Although several studies have shown the importance of trait EI over individual’s health and wellbeing, there’s currently no literature studying its role in the context of eating disorders. Given the well-known association between obesity and emotional difficulties, this study attempts to provide new insights into the potential application of trait EI. A sample of 164 obese patients was recruited between May 2014 and June 2016. Each patient completed a set of self-report questionnaires including the Trait Emotional Intelligence Questionnaire, the Emotion Regulation Questionnaire, the Beck Depression Inventory, the State-Trait Anxiety Inventory and the Binge Eating Scale. Independent assessments were performed at three time points (baseline, after three months, and after six months) at the S. Orsola Malpighi Hospital (Bologna). At each time point body weight and other medical were measured. A sample of normally-weighted adults was also recruited through an online software. Correlations, ANOVAs and mediation analysis were used as analytic strategies. Our results show differences in trait EI between case and control. Additionally, data show that trait EI has different functions over BMI depending on the predictor being considered. More detailed results will be presented at the conference. These results suggest once more the importance of emotional difficulties in obese patients and underline that trait EI may play an important role both as risk and as protective factor in the development of overweight and obesity.

The role of nonalcoholic fatty liver disease, namely nonalcoholic steatohepatitis (NASH), as risk factor for liver- and non-liver-related morbidity and mortality has been extensively reported. In addition to lifestyle changes, capable of removing the metabolic factors driving disease progression, there is an urgent need for drugs able to reduce hepatic necroinflammation without worsening of fibrosis. This goal is considered by regulatory agencies as surrogate marker to define the effectiveness in pharmacological compounds in NASH, and fast-track approval was granted by the Food and Drug Administration in consideration of disease severity and unmet medical needs. Several compounds are in the pipeline of pharmaceutical industries and are being studied in phase II trials, but only a few (obeticholic acid, elafibranor) have started phase III trials. This concise review is intended to offer a systematic analysis of the most promising therapeutic intervention in NASH. In conclusion, there is reasonable expectation that drug may help curb the burden of NASH, and we look forward to obtaining solid data on their long-term safety and effectiveness. However, we should not forget that behavioral interventions remain a mandatory background treatment, able to stop disease progression in compliant overweight/ obese patients, with results that compare favorably with - and add to - the beneficial effects of drug treatment.

Introduction: Trait Emotional Intelligence (trait EI) is a construct which takes into account the subjective aspect of human’s emotional experience. Current literature has shown an association between trait EI and health behaviors, with little evidence suggesting that it may be relevant in the context of eating disorders, including obesity. The present study expands these preliminary results, by investigating whether the levels of trait EI impact the outcome (i.e., short and long-term weight change) of a weight-loss psychoeducational intervention for obese patients. Method: A sample of 164 obese patients undergoing an in-hospital psychoeducational group intervention was recruited between May 2014 and January 2016. Each patient completed a set of self-report questionnaires including the Trait Emotional Intelligence Questionnaire, the Emotion Regulation Questionnaire, the Beck Depression Inventory, the State-Trait Anxiety Inventory and the Binge Eating Scale. Independent assessments were performed pre-treatment and post-treatment at 2- and 12-week follow-ups at the S. Orsola Malpighi Hospital (Bologna). At each time point body weight and other medical were also measured. Correlations and ANOVAs will be used as analytic strategy. Results: Our results show that EI is a significant predictor of body-weight loss in obese patients even at three months after the end of the treatment. Additional results will be presented at the conference. Conclusion: We assume that, along with weight changes, affect-related psychological variables may be related to treatment success. For such reason, EI should be taken into account in developing effective interventions targeting obesity.

Night eating syndrome is an eating disorder characterized by a delay in the circadian timing of food intake, which is remarkably reduced during the first part of the day and greatly increased after dinner, frequently with awakenings characterized by nocturnal food ingestion and morning anorexia. In the absence of standard diagnostic criteria, its prevalence is difficult to estimate. According to the most agreed criteria, the disorder affects approximately 1.5% of the general population, it is more common among obese persons and the prevalence increases with increasing adiposity. Longitudinal studies with adequate follow-up are needed to determine whether night eating contributes to weight gain and the development of obesity. The research should also aim to assess the interaction of genetic and environmental processes in the pathogenesis and in the maintenance of the disorder. There is no satisfactory treatment of night eating. Limited information is available on drug treatment (sertraline, topiramate). Lifestyle modifications aimed at weight loss are standard treatment whenever night eating is associated with obesity and have demonstrated a favorable effect, but more research is needed also in this area to optimize the protocols.

SUMMARY. Soluble CD36 (sCD36) plasma levels, a known marker of cardiometabolic disorders, are associated with surrogate markers of steatosis, while experimental and human studies show a link between CD36 expression in the liver and steatosis. In a cohort of patients with genotype 1 chronic hepatitis C (G1 CHC), we tested the association of sCD36 plasma levels with host and viral factors and sustained virological response (SVR). One hundred and seventy-five consecutive biopsy-proven patients were studied. sCD36 plasma levels were assessed by an in-house ELISA. All biopsies were scored by one pathologist for staging and grading (Scheuer) and graded for steatosis, which was considered moderate–severe if ‡20%. Patients underwent standard of care therapy with pegylated interferon and ribavirin. The severity of steatosis progressively increased according to sCD36 quartiles (P = 0.02); total and low-density lipoprotein (LDL) cholesterol levels were significantly higher in patients in the lower quartile compared to all the others. Gamma-glutamyl transferase (P = 0.02), homoeostasis model assessment (HOMA) score (P = 0.002) and sCD36 (P = 0.04) were independently associated with the severity of steatosis as continuous variable. Multivariate logistic regression analysis showed that HOMA (OR 1.243, 95% CI 1.04–1.484, P = 0.01) and sCD36 (OR 1.445, 95%CI 1.135–1.839, P = 0.003) were independently linked to steatosis ‡20%. No association was found between sCD36 and SVR. CD36 is linked to steatosis and insulin resistance in patients with G1 CHC, but does not predict response to treatment. The potential of sCD36 as a surrogate marker of steatosis should be further investigated.

The impact of diabetes mellitus (DM) on public health is growing worldwide due to its increasing prevalence and the severity of complications. According to the ARNO observational study, a population-oriented database containing 20 years of medical prescriptions for over 10 million Italians in 30 Local Health Districts of 7 regions, the prevalence of pharmacologically treated DM increased from 3% to over 5% from 1997 to 2008; the associated direct costs may be estimated to be 54% higher per population unit compared to similar patients without DM. Over the years, pharmacological treatment has been modified according to the results of recent trials (metformin as initial treatment, larger use of cholesterol and blood pressure lowering drugs), but drug use remains far below the standards proposed by guidelines, and clinical targets are not systematically reached. More aggressive treatment based on both standard and innovative pharmacological approaches would be needed to reduce the clinical burden of the disease, but such a policy would increase the total cost of DM to levels largely incompatible with economic resources in an era of financial crisis. A policy that promotes primary prevention, involving decision makers at different levels, even outside the National Health System, is urgently needed.

L’epidemia di diabete di tipo 2 nel mondo non più solo occidentale trova le sue origini anche dalla combinazione di comportamenti non salutari e potrebbe largamente essere corretta da un’educazione a uno stile di vita più sano. Terminata la stagione dei grandi trial di prevenzione, si sta affermando la stagione dell’intervento nella popolazione con diabete, con tutte le difficoltà prevedibili considerando il numero delle persone sulle quali intervenire e le difficoltà nelle quali operano già le strutture diabetologiche. Così come in altri Paesi, anche dalla realtà italiana sono state pubblicate esperienze positive sia attraverso programmi specifici sia attraverso l’utilizzazione di sussidi che favoriscono la motivazione al cambiamento. Analogamente a quanto dimostrato nella terapia dell’obesità, la dieta prescrittiva può essere ormai considerata una metodologia obsoleta, non garantendo alcuna aderenza e risultato nel lungo termine. Occorre oggi ripensare l’organizzazione dei servizi di diabetologia e dei team diabetologici per fornire ai pazienti una cura più efficace. In questo lavoro vengono passate in rassegna le principali esperienze pubblicate, documentandone gli effetti favorevoli e le difficoltà che ancora si frappongono alla loro diffusione. SUMMARY Lifestyle interventions in diabetes – where are we now? The epidemics of type 2 diabetes, no longer involving exclusively western countries, is largely due to a combination of unhealthy lifestyles and might be corrected by healthy diet and physical activity. Following the results of the large intervention trials on diabetes prevention, the focus is now on diabetes treatment. Here, the very large number of cases to be treated and the paucity of resources may be an insurmountable limit for most diabetes unit. As well as in different Countries, also in Italy we do have successful experiences published in the literature. They have been carried out either by in-house developed programs or by the use of tools favoring behavior changes. The use of prescriptive diet, as also observed in the treatment of obesity, does not guarantee long-term adherence and weight loss maintenance. We need to reconsider the organization of the diabetes Unit and diabetes team, in order to provide more effective treatment. We review the most important experiences in the behavior treatment of diabetes, underlining the favorable effects and the limits totheir full implementation.

The restoration of a normal body weight is a key strategy in the treatment of eating disorders, in order to eliminate the adverse effects of starvation on health and on the eating disorder psychopathology. Unfortunately, weight regain is frequently hindered by changes in body shape, in particular a protrusion of the abdomen, which may lead underweight patients to stop their nutritional rehabilitation program. In adult patients with underweight eating disorders, studies using dual-energy X-ray absorptiometry, skinfold thickness, dual photon absorptiometry and circumference measurements found a preferential accumulation of body fat in the central regions rather than the extremities during the process of weight regain. These data, however, were not confirmed in adolescents and in young adults with eating disorders. To date, the mechanism(s) implicated in the preferential accumulation of abdominal fat (e.g., low level of estrogens, fast rate of weight regain) have not been settled by experimental research, nor is it settled whether the preferential accumulation is a transient phenomenon or it persists after complete and stable weight restoration. Available data indicate that weight regain produces an increase in bone mineral density, initially greater in the hip than in the spine, but in the long-term bone recovery is never complete, especially whenever the eating disorder starts during adolescence and peak bone mass has not been attained. As lack of exercising may contribute to decrease bone mass, to increase the risk for atherosclerosis and to decrease compliance with the program, clinicians tend to incorporate healthy and social exercising in the nutritional rehabilitation. Preliminary findings indicate that this procedure helps patients get out of the isolation of their disease, overcome the urge to exercise, accept weight gain and changes in shape, and increase lean body mass, while it does not reduce the short-term gain of body fat or BMI.

A marked variability has been documented in the therapeutic approaches to diabetes by various countries, suggesting that the level of care currently delivered may not produce the expected health-related gains. We investigated quality of care indicators in a large, representative multiregional population-based cohort of people (the ARNO Observatory) living in four Italian regions (2 million inhabitants), assessing process indicators and hospital admissions as outcome indicators. Diabetic individuals were identified in 2010 through record linkage among prescriptions, hospital admissions, and local diabetes registries. The guidelines of the Italian scientific societies recommend that risk factors such as lipids and microalbuminuria should be tested at least once a year in all patients with type 2 diabetes, and HbA1c should be tested at least twice a year, even in people with stable glycemic control over time and more frequently in insulin-treated and -complicated people. Of 126,163 diabetic individuals (prevalence of diabetes 5.8%, mean age 71 years), as many as 42% did not have their HbA1c measured for over a year. Even considering only insulin-treated people, this frequency remains disappointingly high (35%). The proportion of people having at least two annual tests for HbA1c was low (32.7%; 43.1% among insulin-treated patients).

Introduction: Non-alcoholic fatty liver disease (NAFLD) is becoming one of the most common causes of chronic liver disease worldwide. The economic and social cost of disease is very high and there is a need for effective treatments. Areas covered: The available and potential future treatments for NAFLD are reviewed. Expert opinion: Weight loss remains the cornerstone of treatment of hepatic steatosis, but difficult to pursue. A pragmatic approach relies on generic recommendations for weight loss and physical activity in the whole population and limiting interventions to subject at risk of disease progression, but the type of preferred treatment remains a matter of debate. The large number and mechanistic diversity of drugs that have so far been investigated bear testimony to the lack of a specific, effective agent. Insulin resistance remains the pivotal alteration responsible for liver disease and its progression and insulin sensitizers are regarded as the treatment of choice. Several ongoing studies are testing the effectiveness of new approaches on histological outcomes and new metabolic pathways are under scrutiny.

Introduction: In September 2010, FDA announced the ongoing investigation on a possible association between long-term use of pioglitazone and bladder cancer. The aim of our study was to provide the contribution of spontaneous adverse event reporting analysis on causality assessment between bladder cancer and pioglitazone. Methods: Association between antidiabetic drugs and bladder cancer was analyzed by the case/non reports recorded in FDA_AERS (Adverse Event Reporting System) between 2004 and 2009. Cases were represented by the reports of reactions included in the MedDRA high-level term ‘Bladder neoplasms’ for a given drug; non-cases were all the reports of other reactions associated to the same drug. For each drug, the association between such drug and bladder cancer was calculated by using the ADR reporting odds ratio (ROR). To weight the influence on ROR of male and older age, well known risk factors for bladder cancer, stratified analyses were performed. Furthermore, to consider the possible effect of notoriety bias a year-by-year analysis was performed. Results: Overall, 93 reports of bladder cancer were retrieved, Corresponding to 138 drug reaction pairs, with 31 concerning pioglitazone, 29 insulin, 25 metformin, 13 glimepiride, 8 exenatide; 22 others. ROR was significantly >1 for pioglitazione (4.30; 95%CI 2.82–6.52, P < 0.001), gliclazide (3.56; 1.42–8.39, P = 0.001) and acarbose (5.12; 1.61–14.33, P < 0.001), although for the last two drugs only a few cases were reported (6 and 4, respectively). Concerning pioglitazone, ROR resulted statistically significant both in female (5.19; 2.15–12.11) and male (3.86; 2.37–6.26), but only in older patients (>65 years); moreover the stratified year-by-year analysis showed a statistically significant ROR for 2004, 2006, 2007 and 2008. Conclusions: We found a definite signal for bladder cancer associated with pioglitazone use. The demographic characteristics of the selected cases were consistent with bladder cancer epidemiology (male gender, old age). A weaker signal was also associated with gliclazide and a much weaker signal with acarbose. Of note, the occurrence of >5 events, although resulting in a statistically significant ROR, may be considered clinically meaningless because too much open to reporting biases. The presence of a signal for pioglitazone also before main relevant publications (PROactive 2005) supports the importance of this safety issue despite its notoriety among clinicians. This safety signal should stimulate more specific studies to confirm or reject the causality relationship between pioglitazone and bladder cancer, and to quantify the magnitude of the hazard.

All over the world obesity represents a social and medical emergency. The obesity epidemic is particularly alarming in young age, as overweight or obese children and teen-agers are likely to become obese adults. Overweight and obesity in childhood and in adolescence can be ascribed to genetic factors as well as to socio-environmental factors peculiar to the principal contexts of life. All over the world, public institutions are taking action to break this vicious circle. Also in Italy, national, regional and local projects have been developed to favor healthy lifestyles in children, following a prevention model integrating ‘macro’ actions (of political and social nature) with educational interventions directed to the ‘micro’ environment of individual subjects. In this report, we revise the literature in the area of healthy life-style promotion in childhood, focusing on the results of a few Italian programs on the nutritional and physical habits of children. The main purpose was to demonstrate whether interventions aimed at increasing physical activity could produce significant changes in children’s behavior, as well as awareness about the needs of healthy choices in the family.

Aims/hypothesis: To estimate the prevalence and the direct cost of pharmacologically-treated diabetes in Italy. Methods: The ARNO observatory database, containing the 20-year medical prescriptions of over 10 million Italian people, was used. Ten-year longitudinal data were available in 22 Local Health Districts (LHD). Subjects were classified as having diabetes when prescribed glucose-lowering drugs (oral agents or insulin) (311,979 individuals in 2006). The direct cost was calculated as the sum of drug use, financial compensation by LHD for the inpatient (hospital DRG) and outpatient activities (consultations, laboratory tests, radiology, etc.), all regulated by government contracts. Individuals with diabetes were compared with pharmacologically-treated subjects without diabetes, pair-matched for age, sex and general practitioner. Results: In the 10-year period, the prevalence of pharmacologically-treated diabetes increased from 3.08% to 4.45% (P for trend

Gli incretino-mimetici (exenatide) e gli inibitori della dipeptidil-peptidasi (DDP-4) (sitagliptin e vildagliptin) sono nuovi farmaci, attualmente disponibili in Italia, sviluppati per il controllo della glicemia in pazienti con diabete tipo 2. Un sistema di monitoraggio è stato attivato dall’AIFA per valutare i reali vantaggi in termini di efficacia e di sicurezza di questi farmaci altamente innovativi. L’analisi dei dati raccolti dal monitoraggio ha sostanzialmente confermato ciò che è emerso dagli studi pre-registrativi. L’exenatide si è dimostrata in grado di migliorare il compenso metabolico e di indurre un calo ponderale in soggetti con diabete tipo 2. E’ risultato essere un farmaco sicuro con effetti collaterali di lieve entità principalmente a carico dell’apparato gatro-intestinale e tendenti a scomparire con il protrarsi della terapia. L’ipoglicemia è risultata un evento molto raro, osservato quando l’exenatide era usata in terapia di associazione con sulfaniluree. Gli inibitori della DDP-4 hanno dimostrato una riduzione significativa dell’Hb-glicata (lievemente inferiore rispetto all’exenatide) ed un effetto complessivamente neutro sul peso corporeo. Si sono dimostrati farmaci ben tollerati, anche in soggetti in età avanzata, con bassissimo rischio di ipoglicemia. Dato anche l’alto costo saranno necessari ulteriori approfondimenti per definire meglio la tipologia del paziente che può usufruire di questi farmaci e i possibili effetti di queste molecole sui fattori di rischio cardiovascolare e sulle complicanze micro- e macro-angiopatiche. Interessante sarà confermare in vivo le capacità rigenerative e proliferative di queste molecole sulla beta-cellula.

La steatosi epatica non alcolica (Nonalcoholic fatty Liver Disease, NAFLD), manifestazione epatica della sindrome metabolica, strettamente associata ad obesità e diabete, è patologia epatica che riconosce come meccanismo patogenetico l’insulino-resistenza, sia a livello dell’intero organismo, sia più specificamente epatica. La steatosi, definita per un accumulo di trigliceridi nel fegato superiore al 5-10% del suo peso, è variamente associata a fibrosi e necroinfiammazione, realizzando il quadro della steatoepatite non-alcolica (Non-Alcoholic Steatohepatitis, NASH), la fibrosi e la cirrosi. Attraverso questa via metabolica una percentuale non irrilevanti di pazienti giunge all’insufficienza epatica terminale; circa il 10-15% dei soggetti in lista di trapianto di fegato nella varie strutture potrebbero essere giunti ad una insufficienza epatica terminale attraverso questo via. Il riconoscimento di questa patologia come problema importante di salute ha condotto a verificare la possibilità che, accanto agli effetti negativi dell’eccesso ponderale, la progressione della patologia potesse essere sostenuta da errati comportamenti alimentari e/o dalla sedentarietà. Per quanto riguarda l’apporto alimentare, i soggetti con NAFLD si caratterizzano per un eccessivo apporto di grassi saturi e sopratutto di carboidrati raffinati, che vengono convertiti a trigliceridi all’interno del fegato. Una serie di studi condotti da un gruppo di ricerca finlandese ha estesamente dimostrato l’esistenza di fattori genetici che possono condizionare gradi diversi di steatosi in presenza di simile eccesso ponderale, un effetto diretto di una dieta sperimentale ricca di grassi sul contenuto in trigliceridi del fegato, sul quadro di insulino-resistenza globale ed epatica, ed infine sul profilo biochimico.

Introduzione Il diabete mellito tipo 2 presenta un’alta prevalenza nella popolazione, non più solo limitata ai Paesi occidentali, ed in progressivo aumento in rapporto all’epidemia di obesità. In Italia vi è poi un’alta prevalenza di malattie epatiche, il rapporto ad una notevole diffusione del virus dell’epatite C ed a problemi alcol-correlati. Questo rende ragione della frequente associazione delle due patologie, semplicemente legata al caso. Tuttavia, un’analisi attenta del fenomeno documenta una prevalenza maggiore di quanto atteso, a significare un’associazione non soltanto legata al caso, ma con precise implicazioni patogenetiche. Il diabete si associa ad un ampio spettro di patologie epatiche che vedono in primo luogo la steatosi epatica non alcolica (Non-Alcoholic Fatty Liver Disease, NAFLD) nelle sue varie forme di progressione, dalla steatoepatite non alcolica (Non-Alcoholic Steato Hepatitis, NASH), alla cirrosi epatica criptogenetica, fino al carcinoma epatico. In questo caso, i fattori determinanti sono comuni e da ricondursi all’obesità, alla sedentarietà, e all’insulino-resistenza, sia generale, sia specificamente epatica. Questo meccanismo è alla base della sindrome metabolica (SM), un cluster di patologie che comprende l’obesità viscerale, il diabete tipo 2, l’ipertensione arteriosa, la dislipidemia, ed ha come manifestazione epatica la steatosi. Meccanismi in parte diversi sono invece alla base della steatosi presente nelle amlattie epatiche da virus, particolarmente da virus C, ove un meccanismo virale diretto si somma ai problemi metabolici. D’altra parte, il fegato ha un ruolo importante nel metabolismo dei carboidrati poiché regola il valore della glicemia plasmatica attraverso la gliconeogenesi e la glicogenolisi, favorendo così lo sviluppo di insulino-resistenza, di alterata glicemia a digiuno, e di diabete franco in ogni condizione di danno epatico, di qualunque eziologia (un tempo noto come “diabete epatogeno”), fino a problemi specifici in alcune condizioni nella quali fegato e cellule beta-pancreatiche possono essere contemporaneamente interessate (es. emocromatosi familiare). Infine, per la sua posizione a cavaliere tra la circolazione generale e la circolazione portale, per la sua azione di clearance dell’insulina, per il metabolismo epatico delle lipoproteine che consente al fegato di regolare i livelli plasmatici di colesterolo e trigliceridi, la malattia epatica finisce per produrre effetti sui livelli circolanti di insulina, sulla sensibilità insulinica e sulla regolazione generale del metabolismo dei carboidrati. Tutto questo comporta importanti riflessi terapeutici, anche per il fatto che molti farmaci, per il loro metabolismo epatico, trovano difficile impiego nelle patologie epatiche avanzate. Nella gestione del paziente diabetico tipo 2 con malattia epatica è quindi sempre necessario un non-facile compromesso tra il controllo ottimale dell’assetto glico-metabolico e la preservazione/miglioramento del quadro epatico.

Introduzione. Il profilo di sicurezza dei glitazoni, rosiglitazone e pioglitazone, è attualmente sotto indagine da parte delle agenzie regolatorie internazionali, FDA ed EMA. Diversi studi successivi alla loro commercializzazione hanno fatto emergere possibili associazioni tra questi farmaci e reazioni avverse gravi. Nel giugno 2007 Nissen ha pubblicato una metanalisi che evidenziava un aumento di eventi cardiovascolari per il rosiglitazone, rischio confermato da studi successivi. Altri studi clinici suggeriscono possibili associazioni anche con danni oculari e ossei. Il presente studio ha l'obiettivo di delineare il profilo di sicurezza dei glitazoni per ciò che riguarda l'infarto miocardico, l'edema maculare e il rischio di fratture, mediante l'analisi delle segnalazioni spontanee presenti nel database FDA_AERS (Adverse Event Reporting System). Metodi. Sono state raccolte tutte le segnalazioni spontanee di reazioni avverse (Adverse Drug Reaction - ADR) da farmaci antidiabetici presenti nel database FDA_AERS da gennaio 2005 a dicembre 2008. I dati sono stati sottoposti a procedure di data cleaning semiautomatiche, per eliminare i duplicati e i record multipli. L'associazione farmaco-reazione è stata analizzata mediante il metodo del caso/non-caso. I casi sono rappresentati dalle segnalazioni in cui i glitazoni sono associati alla specifica reazione, classificata secondo la terminologia MedDRA, mentre i non-casi sono costituiti dalle segnalazioni della stessa reazione associata a farmaci antidiabetici diversi dai glitazoni. L'associazione farmaco-razione è stata analizzata calcolando il Reporting Odds Ratio (ROR) che identifica una disproporzionalità tra il farmaco oggetto dell'analisi e gli altri farmaci antidiabetici. L'analisi è stata eseguita sia per classi di farmaci antidiabetici, sia per singolo principio attivo. Infine, allo scopo di valutare il possibile pubblication bias sull'incidenza di segnalazione l'analisi è stata effettuata anche per singolo trimestre. Risultati. Sono state raccolte 77.669 segnalazioni di ADR da antidiabetici, corrispondenti a 301.950 coppie farmaco-reazione. Queste riguardavano principalmente biguanidi (26%), seguite da sulfaniluree (22%), exenatide (18%) e glitazoni (16%). I glitazoni hanno mostrato una disproporzionalità significativa per l'infarto miocardico (ROR 4,71 IC95% 4,40-5,05), per l'edema maculare (3,88; 2,79-5,39) e per le fratture (1,73; 1,53-1,96). Considerando i due glitazoni separatamente, il solo rosiglitazone è risultato associato all'infarto del miocardio (7,86; 7,34-8,34) e all'edema maculare (5,55; 3,94-7,79), mentre il pioglitazone al rischio di fratture (2,00; 1,70-2,35) in particolare al livello degli arti e del bacino. L'analisi del trend temporale per l'ROR dell'infarto miocardico evidenzia che già nel periodo gennaio-marzo2005 il valore di ROR era statisticamente significativo (3,13; 2,38-4,10), per poi raggiungere un picco nel periodo ottobre-dicembre 2007 (8,71; 6,02-12,90). Conclusioni. Lo studio ha confermato, tramite l'analisi delle segnalazioni spontanee, il rischio di infarto miocardico, di edema maculare e di fratture per il glitazoni rispetto agli altri farmaci antidiabetici. Inoltre, è stata evidenziata un'ampia differenza tra rosiglitazone e pioglitazone, il primo associato a infarto miocardico ed edema maculare, mentre il secondo al rischio di fratture. L'analisi del trend temporale mostra come l'impiego dei dati di segnalazioni spontanee può generare segnali di farmacovigilanza precoci, in quanto l'infarto miocardico presentava un segnale di disproporzionalità ben prima della pubblicazione della metanalisi di Nissen del 2007. I risultati del presente studio contribuiscono a delineare il profilo di rischio dei glitazoni e a sottolineare le differenze esistenti tra i due principi attivi; informazioni fondamentali per consentire alle agenzie regolatorie di rivalutare il rapporto rischio/beneficio di questi farmaci.

This paper is an Italian Expert Consensus Document on multidimensional treatment of obesity and eating disorders. The Document is based on a wide survey of expert opinion. It presents, in particular, considerations regarding how clinicians go about choosing the most appropriate site of treatment for a given patient suffering from obesity and/or eating disorders: outpatient, partial hospitalization, residential rehabilitation centre, inpatient hospitalization. In a majority of instances obesity and eating disorders are long-term diseases and require a multiprofessional team-approach. In determining an initial level of care or a change to a different level of care, it is essential to consider together the overall physical condition, medical complications, disabilities, psychiatric comorbidity, psychology, behaviour, family, social resources, environment, and available services. We first created a review manuscript, a skeleton algorithm and two rating scales, based on the published guidelines and the existing research literature. As the second point we highlighted a number of clinical questions that had to be addressed in the specific context of our National Health Service and available specialized care units. Then we submitted eleven progressive revisions of the Document to the experts up to the final synthesis that was approved by the group. Of course, from point to point, some of the individual experts would differ with the consensus view. The document can be viewed as an expert consultation and the clinical judgement must always be tailored to the particular needs of each clinical situation. We will continue to revise the Document periodically based on new research information and on reassessment of expert opinion to keep it up-to-date. The Document was not financially sponsored.

La terapia dell'obesità è un dilemma: a volte i risultati sono troppo facili, anche in assenza di qualsiasi razionale o professionalità. Qualsiasi individuo può perdere peso da solo e chiunque può mettersi a fare la professione, anche senza alcuna competenza. A volte, ed è quasi la regola, la situazione è talmente problematica che i pazienti obesi (e i loro medici) annoverano una tale successione di fallimenti da abbassare il livello dell'autoefficacia e quindi dell'autostima ("self-efficacy": processo cognitivo della percezione della propria competenza e abilità nel compiere una determinata azione). Si deve pertanto attivare un rapporto relazionale terapeutico a triangolo paziente-medico-malattia e ogni lato deve trovare la sua giusta dimensione e interazione. Risultati troppo facili generano eccessivi entusiasmi che non permettono alcuna riproduicibilità; il successo è destinato al fallimento per la ripresa del peso perduto. Le fortune commerciali della "diet industry" non hanno limite: in America si calcola che vengano spesi, ogni anno, 30 bilioni di dollari per il controllo del peso. Se i risultati sonmo problematici i pazienti sono obbligati a ricercare terapie aggressive, cruente e prescrittive e spesso si abbandonano alle frodi ed alle mistificazioni. Il risultato non è mai quello desiderato: ottenere, cioè, una migliore qualità della vita ed una migliore aspettativa per la riduzione del rischio di mortalità. La lezione della storia non è ancora definita. Pochi l'hanno imparata e poco viene insegnata dall'Accademia.

Lifestyle changes are considered first line treatment in type 2 diabetes, but very few data are available in the “real world” of diabetes units. We aimed to measure the effectiveness of moderate and high intensity interventions on weight loss, metabolic control and insulin use We report a prospective cohort study, carried out in 822 consecutive subjects with type 2 diabetes, first seen in a 4-year period in a diabetes unit of an academy hospital. Subjects were either treated with a sole prescriptive diet (Diet), or received an additional short-course Elementary Nutritional Education (4 group sessions - ENE) or an intensive Cognitive Behavioral Therapy (12-15 group sessions - CBT). The results were adjusted for the propensity score to be assigned different treatments, derived from logistic regression on the basis of age, gender, BMI, HbA1C, diabetes duration and insulin use at baseline. Main outcome measures were weight loss and weight loss maintenance, metabolic control, secondary failure to insulin use. Both structured programs produced a larger weight loss, and the adjusted probability of achieving the 7% weight loss target was increased. Similarly, both programs favoured metabolic control, irrespective of insulin use. After adjustment for propensity score, both ENE (hazard ratio, 0.48; 95% CI, 0.27-0.84) and CBT (hazard ratio, 0.36; 95% CI, 0.16-0.83) were associated with a reduced risk of de novo insulin treatment. We conclude that structured behavioural programs aimed at lifestyle changes are feasible and effective in the “real world” setting of a diabetes unit for the treatment of type 2 diabetes.

Nonalcoholic fatty liver disease has long been neglected by healthcare professionals unless cirrhosis develops; however, this disesae has now been shown to be a cause of poor health-related quality of life. The association of nonalcoholic fatty liver disease with chronic metabolic diseases and cardiovascular complications, however, makes it difficult to define a specific role for liver damage in the poor perceived health status of these patients.

La NAFLD è una malattia epatica di sempre più frequente rilievo in individui di tutte le età e di ogni razza, senza distinzione di sesso; rappresenta oggi la principale causa di malattia cronica epatica in molti Paesi. È generalmente associata ad obesità, diabete e dislipidemia, ma può presentarsi anche in soggetti magri e con normale tolleranza glucidica. Nella maggior parte dei casi è associata ad insulino-resistenza, che favorisce il deposito di lipidi anche al di fuori del tessuto adiposo. Alla sua patogenesi concorrono numerosi fattori: una possibile base genetica, stili di vita a rischio, lo stress ossidativo, la produzione di citochine. L’assenza di una franca sintomatologia porta alla diagnosi in modo occasionale per transaminasi alterate o fegato brillante all’ecografia, ma la conferma e la stadiazione della malattia si basano esclusivamente sulla biopsia epatica.

Indirect methods for predicting the presence of esophageal varices (EV) in cirrhotic patients are not sensitive enough to be used as a surrogate for endoscopy. We tested the effectiveness of liver stiffness measurement (LSM) by transient elastography (TE) and the presence of insulin resistance (IR), a marker associated with fibrosis progression, in the non-invasive prediction of portal hypertension. One hundred and four consecutive patients with newly diagnosed Child A HCV cirrhosis underwent upper GI endoscopy to search for EV. Clinical, anthropometric, biochemical, ultrasonographic and metabolic features, including IR by the homeostasis model assessment (HOMA), and LSM by TE, were recorded at the time of endoscopy. EV were detected in 63 of 104 patients (60%). In 10 patients (16%) the EV were medium-large (≥ F2). By multivariate analysis presence of EV was independently associated with a low platelet count/spleen diameter ratio (OR 0.998; 95% CI; 0.996-0.999) and with a high HOMA score (OR 1.296; 95%CI; 1.018-1.649) but not with LSM (OR 1.009; 95%CI; 0.951-1.070). It is noteworthy that 9/10 patients with medium-large EV had a platelet/spleen ratio of < 792 and/or a HOMA of > 3.5. The independent association between low platelet/spleen ratio (OR 0.998; 95%CI; 0.996-1.000), high HOMA score (OR 1.373; 95%CI; 1.014-1.859) and presence of EV was confirmed in the sub-group of 77 non-diabetic subjects. Conclusions: In patients with Child A HCV cirrhosis, a low platelet/spleen ratio and a high HOMA score, regardless of diabetes, are the strongest independent predictors of the presence of EV. In this specific setting LSM seems not contribute to the diagnosis of portal hypertension.

OBJECTIVES: Metabolic factors may affect the course of chronic hepatitis C (CHC). Insulin resistance (IR) determines steatosis, but its direct role in affecting progression of hepatic fibrosis is less clear. We aimed to assess whether increasing degrees of IR, up to overt diabetes, are linked to steatosis and higher stages of fibrosis in patients with CHC resulting from genotype 1 HCV (G1-HCV). METHODS: Two hundred one consecutive patients with G1-HCV infection were evaluated by liver biopsy and anthropometric and metabolic measurements, including IR, by the homeostasis model assessment (HOMA). Nondiabetic patients were defined as insulin resistant if HOMA-IR was >2.7. All biopsies were scored by one pathologist for staging and grading (Scheuer), and graded for steatosis. RESULTS: Ninety-six patients were noninsulin resistant (group 1), 76 were insulin resistant without diabetes (group 2), and 29 were diabetic (group 3). At multivariate analysis, fibrosis of >/=3 was independently associated with high necroinflammatory activity (odds ratio [OR] 2.994, 95% confidence interval [CI] 1.422-6.098), low platelets (OR 0.994, 95% CI 0.981-0.999), low cholesterol (OR 0.987, 95% CI 0.976-0.998), high ferritin (OR 1.002, 95% CI 1.001-1.004), and a high prevalence of IR (OR 2.692, 95% CI 1.463-4.954). Diabetic patients were twice as likely to have severe fibrosis (60%) than those with IR but no diabetes (30%) (P= 0.006). The degree of steatosis and that of fibrosis were weakly associated with each other (P= 0.42). CONCLUSIONS: In subjects with CHC resulting from G1-HCV, IR and overt diabetes are major determinants of advanced fibrosis, regardless of the degree of steatosis, mainly in the presence of severe necroinflammation.

Per molto tempo la malattia epatica ad origine metabolica è stata sottovalutata come condizione di scarsa rilevanza clinica. Solo oggi si sta prendendo coscienza dell’importanza della patologia, in termini epidemiologici e clinici, anche in rapporto all’epidemia di obesità e diabete del mondo occidentale. L’importanza della NAFLD rimane comunque sottovalutata, se si considera come la presenza di una patologia epatica complichi spesso anche le malattie epatiche di altra eziologia (virus B e C, emocromatosi, malattie autoimmuni ed alcoliche), peggiorandone significativamente la prognosi e riducendo le prospettive terapeutiche. Vi è l’esigenza di trasferire percorsi strutturati di terapia cognitivo-comportamentale, specifici per il diabete e l’obesità, verso il trattamento multidisciplinare dei soggetti NAFLD (68). Vi è l’esigenza di attivare protocolli di sorveglianza epatologica in soggetti con NAFLD evoluta a fibrosi avanzata, per ridurre il rischio di giungere troppo tardivamente alla diagnosi delle complicanze più severe della malattia.

Retinol-binding protein 4 (RBP4) is an adipocytokine associated with insulin resistance. We tested serum levels of RB4 to assess its link with steatosis in patients with genotype 1 (G1) chronic hepatitis C (CHC) or non-alcoholic fatty liver disease (NAFLD). Non-diabetic patients with CHC (n=143) or NAFLD (n=37) were evaluated by liver biopsy and anthropometric and metabolic measurements, including insulin resistance by the homeostasis model assessment (HOMA). Biopsies were scored by Scheuer classification for CHC, and Kleiner for NAFLD. Steatosis was tested as a continuous variable and graded as absent-mild

Background: There is no consensus on the treatment of pediatric nonalcoholic fatty liver disease (NAFLD). However, in a small pilot study conducted in 10 children, metformin has been proposed to be effective. Objective: We aimed to determine the effect of metformin in addition to lifestyle intervention/modification in children with NAFLD. Methods: Overweight or obese children aged 9 to 18 years with biopsy-proven NAFLD or nonalcoholic steatohepatitis were enrolled in an observational pilot study, initially planned for 12 months, which aimed to estimate the effect of metformin on liver enzymes. The study was extended to 24 months to estimate outcomes on liver histology. All subjects received lifestyle intervention (nutritional counseling and a physical exercise regimen) and metformin 1.5 g/d (MET group). To serve as the control in this study, we selected a control group from a separate but parallel study (N = 30) that had identical inclusion criteria on the use of antioxidants in NAFLD. End points were changes in liver enzymes and histology. Insulin resistance (IR) was estimated by the Homeostasis Model Assessment of IR (HOMA-IR) and liver biopsy was determined by the NAFLD activity score (NAS). Results: Sixty patients were assessed for inclusion in this study. However, 2 patients in the MET group dropped out of the study during the first year because they relocated abroad, and 1 patient in the control group refused follow-up after 12 months. Thus, study data is based on the findings in the 57 remaining patients. Alanine aminotransferase significantly improved from baseline with decreasing body weight in both groups (MET: 35 [range, 21–43] to 32 [20–46] U/L; control: 66 [28–121] to 33 [14–45] U/L; P ≤ 0.01). HOMA-IR significantly improved in both groups from baseline with decreasing body weight as well (MET: 1.4 [range, 0.5–5.11] to 1.3 [0.13–4.21]; control: 2.29 [0.86–5.76] to 1.5 [0.70–4.23]; P ≤ 0.01). Steatosis was reduced in both the MET (P = 0.02) and control (P = 0.02) groups as well as ballooning (both, P = 0.008). Lobular inflammation improved from baseline in the MET group (P = 0.003). The NAS score decreased from baseline (both, P = 0.001), but no significant changes in fibrosis were detected. Conclusion: In this small, 24-month observational study, metformin did not appear more effective than lifestyle intervention in ameliorating levels of aminotransferases, steatosis, and liver histology in these children with NAFLD.

Background It is uncertain whether patients with nonalcoholic fatty liver disease (NAFLD) and normal alanine aminotransferase (ALT) have a milder disease and should undergo liver biopsy. Materials & Methods We reviewed the histological data of 458 Italian patients with NAFLD in whom liver biopsy was indicated because of altered liver enzymes (395 cases, 86%) or persistently elevated ferritin or long-lasting severe steatosis in (63 cases). Factors associated with nonalcoholic steatohepatitis (NASH) and fibrosis ≥ 2 were identified by logistic regression analysis. Results Patients with normal ALT were significantly older, had lower body mass index, fasting triglycerides, insulin resistance (homeostasis model assessment – HOMA), ALT and gamma-glutamyltransferase (GGT), but a higher prevalence of hypertension. NASH was diagnosed in 59% and 74% patients with normal and increased ALT, respectively (p=0.01). In the overall series of patients, NASH was independently predicted by ALT (Odd Ratio (OR), 1.11; 95% confidence interval (CI), 1.04-1.19 per 10 IU/mL increase) and diabetes (OR, 1.5; 95% CI 1.1-2.0). The same variables were selected in patients with increased ALT, whereas in those with normal ALT, HOMA-IR and ALT were independent predictors. Severe fibrosis was independently predicted by serum ferritin (OR, 1.04; 95%CI 1.001-1.08 per 50 ng/mL increase), ALT (OR, 1.07; 95% CI1.02-1.14), and diabetes (OR, 1.8; 95%CI 1.4-2.3) in the overall series, serum ferritin and diabetes in those with increased ALT, and only HOMA-IR (OR, 1.97;95% CI 1.2-3.7) in patients with normal ALT. Conclusion Alterations in glucose metabolism and insulin resistance should be considered in the selection of NAFLD cases for the histological assessment of disease severity and progression, also in subjects with normal ALT.

In the dictionary, fast food is defined as any food which may be cooked easily, and is sold by restaurants to be eaten quickly or taken away. Changes in the dietary pattern of the last decades have made fast food a relevant component of western diet, but a diet largely based on fast food has detrimental effects on health, which have been a matter of discussion for 20 years.1 Two potential mechanisms have been suggested: a) fast feeding does not suppress appetite, leading to increased calorie consumption; b) fast food is usually richer in fats and saturated fats (and thus richer in calories), as well as in other components which may cause harm to several organs, namely widespread cardiovascular disease. Both mechanisms are likely to promote obesity, but is there evidence for a direct hepatotoxicity? The issue came to public attention in the movie “Super Size Me”. After consuming three meals a day in a fast food restaurant for one month, Morgan Spurlock increased by nearly 10 kg, and liver enzymes peaked at 290 U/L (alanine aminotransferase - ALT) from baseline values of 20 U/L, accompanied by increased total cholesterol, uric acid and the onset of clinical features of the metabolic syndrome. No doubt that elevated aminotransferase levels are a marker of hepatic dysfunction, but are they related to any specific dietary component of fast food-based diet, or simply to weight gain and obesity-associated non-alcoholic fatty liver disease (NAFLD)?

• Liver biopsy remains the only diagnostic tool to stage NAFLD and to assess disease progression; clinical/biochemical parameters may be used as surrogate markers, but their accuracy is limited • The presence of multiple features of the metabolic syndrome is associated with more advanced and more progressive disease • Obesity and diabetes are associated with more aggressive liver disease, but their effect on final outcome is uncertain • Cardiovascular risk may compete with liver disease-related risk in dictating the final outcome • Longitudinal studies based on liver biopsy data are needed to define the natural history of disease

La NAFLD (Non-Alcoholic Fatty Liver Disease – Steatosi epatica non alcolica) è una condizione clinica di comune riscontro che comprende un ampio spettro di patologie epatiche che vanno dalla semplice steatosi, a prognosi generalmente benigna, a quadri più avanzati come la steatoepatite (NASH, Non-Alcoholic Steatohepatitis), caratterizzata da necroinfiammazione e fibrosi di vario grado, fino ad arrivare alla cirrosi criptogenetica ed al carcinoma epato-cellulare. Dal punto di vista anatomo-patologico, si caratterizza per una quadro simile alla steatosi alcol-indotta, ma si sviluppa in soggetti il cui consumo di alcol è nulla o molto modesto (il limite è arbitrariamente fissato a 20-30 g di alcol al giorno).

Nonalcoholic fatty liver disease (NAFLD) defines the most of common liver diseases encompassing alcohol-like hepatic histologic lesions seen in the non-alcoholic insulin resistant patient. NAFLD, deemed to be the hepatic counterpart of the metabolic syndrome, represents a multifactorial condition spanning the widespectrum from steatosis through non-alcoholic steatohepatitis (NASH) with or without (cryptogenic) cirrhosis. End-stage liver failure and hepatocellular carcinoma are observed in a yet undetermined proportion of individuals. Along with insulin resistance, additional endocrine and vascular changes play a prominent role in the development and progression of NAFLD. Genetic factors underlying NAFLD are being unravelled. Their understanding will further our understanding of pathogenesis and will also probably enhance non-invasive diagnosis. Diet and physical exercise represent, with the correction of predisposing metabolic changes, the mainstay of treatment. Insulin sensitizing drugs should better be used only in selected patients, preferably in the context of controlled clinical trials. Non-invasive evaluation of risk for cardiovascular events is recommended in all individuals presenting with NAFLD and conversely, the presence of NAFLD should be always looked for in subjects with features belonging to the metabolic syndrome.

Riassunto Ogni tentativo di misurare l’apporto calorico è necessariamente approssimativo, qualora non si giunga alla registrazione e pesatura meticolosa degli alimenti, peraltro gravata da errori. Abbiamo sviluppato un questionario autosomministrato, basato su 20 gruppi di alimenti. Per ognuno, il paziente deve indicare la frequenza settimanale e la porzione su una scala a 5 punti. Le calorie delle porzioni sono conteggiate per multipli di 50. Attraverso un semplice calcolo si giunge alla definizione delle calorie medie giornaliere su base settimanale. Dopo un periodo di taratura, per approssimazioni successive, siamo giunti ad una versione definitiva, testata su 123 soggetti consecutivi nei confronti dell’intervista semistrutturata condotta dalla dietista. L’apporto calorico stimato dal questionario (2388 ± SD 798 kcal/die in 100 questionari validi per l’analisi) non risulta significativamente diverso da quello misurato nell’inchiesta (2317 ± 676; P = 0.191; t appaiata) ed esiste tra le due misurazioni una buona correlazione (r 2 = 0.585; P< 0.0001), in un range calorico misurato dall’intervista compreso tra 946 e 5080 kcal/die. Il questionario sovrastima l’apporto calorico nel primo quintile dell’intervista (range 900 – 1833 kcal/die; ? = +163 ± SD 343 kcal/die; P = 0.047), ma mantiene una buona correlazione tra 1500 e 3000 kcal/die (? = 65 kcal/die), nel quale si colloca l’83% dei casi analizzati. Lo strumento può essere utile per indagini epidemiologiche in soggetti motivati a perdere peso, o come ausilio ai medici di medicina generale in assenza di dietisti in una politica di controllo dell’obesità. English Summary Any attempt to measure calorie intake is approximate when foods are not registered and weighted, and several biases may be introduced. We developed a self-administered questionnaire, based on 20 items, their weekly intake and the average portion on a Likert scale. Portions are given a score as multiple of 50 calories, allowing a simple calculation of the daily intake on a weekly basis. The test was adjusted during the years and its final version was tested in 123 consecutive subjects against a semi-structured interview carried out by a dietitian. Calorie intake measured by the questionnaire (2388 ± SD 798 kcal/day in 100 questionnaires valid for analysis) does not differ from values calculated by interview (2317 ± 676; P = 0.191; paired t), and a good correlation exists between the two measurements (r 2 = 0.585; P< 0.0001) in a calorie range measured by the interview between 946 and 5080 kcal/day. The questionnaire overestimates calorie intake in the first quintile of interview (range, 900 – 1833 kcal/day; ? = +163 ± SD 343 kcal/die; P = 0.047), but maintains a good correlation between 1500 and 3000 kcal/day (? = 65 kcal/day), a range comprising 83% of tested cases. The self-administered instrument may be useful in epidemiological surveys in subjects seeking a weight-losing treatment, or as support to general practitioner in the absence of dietitians.

Negli ultimi 15 anni si è progressivamente affermato il concetto che vede nella steatosi epatica il momento iniziale di un danno epatico potenzialmente progressivo. La steatosi epatica nonalcolica (NAFLD) ha assunto quindi una notevole importanza, configurandosi come una via metabolica alla cirrosi ed al carcinoma epatocellulare. Altri agenti eziologici, in particolare il virus C dell’epatite, possono interagire con la malattia metabolica attraverso vie non interamente chiarite. Il diabete tipo 2, l’obesità e la dislipidemia rimangono i principali fattori di rischio della NAFLD, che viene ad essere considerata come l’espressione epatica della Sindrome Metabolica (SM). Una serie importante di studi ha messo in luce i rapporti tra NAFLD e SM, il rischio di malattia epatica associato alle varie condizioni che caratterizzano la SM, l’importanza dell’insulino resistenza come denominatore comune. Resta da chiarire il meccanismo di progressione del danno epatico dalla semplice steatosi alla steatoepatite ed infine alla cirrosi, e la ragione per la quale si giunge solo in alcuni casi alla malattia epatica terminale, in altri (la grande maggioranza) agli eventi cardiovascolari. L’epidemia di obesità e diabete del mondo occidentale prospetta un aumento significativo dei casi di malattia epatica su base metabolica per i prossimi anni. Progetti di prevenzione e di intervento basati sullo stile di vita divengono quindi particolarmente urgenti anche per quanto riguarda la epatopatia metabolica. Riassunto In the last 15 years evidence has been accumulating suggesting that hepatic steatosis may be the starting point for a progressive liver disease. Nonalcoholic steatohepatitis (NAFLD) is now considered a metabolic pathway to advanced liver disease, cirrhosis and hepatocellular carcinoma. Liver disease of other etiology, namely hepatitis C virus, may interact with NAFLD, although the underlying mechanism(s) have not been fully elucidated. Type 2 diabetes mellitus, obesity and dyslipidemia are the principal factors associated with NAFLD, which is now considered the hepatic expression of Metabolic Syndrome (MS). Several studies have dealt with the relationship of NAFLD and MS, the risk of liver disease associated with the classical features of MS, the importance of insulin resistance as the common soil of different diseases. We still need to clarify the mechanism(s) responsible for liver disease progression from pure fatty liver, to steatohepatitis and to cirrhosis, and the reason(s) why only a few NAFLD cases progress to terminal liver failure while others (the majority) will have a cardiovascular outcome. The epidemics of obesity and diabetes of Western countries is expected to produce a significant increase of metabolic liver disease in the next years. Prevention and intervention programs based on lifestyle are therefore mandatory to reduce the burden of metabolic liver disease.