Nonalcoholic fatty liver disease (NAFLD) has been associated with the insulin-resistance syndrome, at present defined as the metabolic syndrome, whose limits were recently set. We assessed the prevalence of the metabolic syndrome in 304 consecutive NAFLD patients without overt diabetes, on the basis of 3 or more criteria out of 5 defined by the U.S. National Institutes of Health (waist circumference, glucose, high-density lipoprotein [HDL]-cholesterol, triglycerides, and arterial pressure). The prevalence of the metabolic syndrome increased with increasing body mass index, from 18% in normal-weight subjects to 67% in obesity. Insulin resistance (Homeostasis Model Assessment method) was significantly associated with the metabolic syndrome (odds ratio [OR], 2.5; 95% CI, 1.5-4.2; P < .001). Liver biopsy was available in 163 cases (54%). A total of 120 patients (73.6%) were classified as having nonalcoholic steatohepatitis (NASH); 88% of them had a metabolic syndrome (vs. 53% of patients with pure fatty liver; P < .0001). Logistic regression analysis confirmed that the presence of metabolic syndrome carried a high risk of NASH among NAFLD subjects (OR, 3.2; 95% CI, 1.2-8.9; P ‫؍‬ .026) after correction for sex, age, and body mass. In particular, the syndrome was associated with a high risk of severe fibrosis (OR, 3.5; 95% CI, 1.1-11.2; P ‫؍‬ .032). In conclusion, the presence of multiple metabolic disorders is associated with a potentially progressive, severe liver disease. The increasing prevalence of obesity, coupled with diabetes, dyslipidemia, hypertension, and ultimately the metabolic syndrome puts a very large population at risk of forthcoming liver failure in the next decades. (HEPATOLOGY 2003;37:917-923.)

Insulin sensitivity (euglycemic clamp, insulin infusion rate: 40 mU ⅐ m ؊2 ⅐ min ؊1) was studied in 30 subjects with biopsy-proven nonalcoholic fatty liver disease (NAFLD), normal glucose tolerance, and a BMI <30 kg/m 2 . Of those 30 subjects, 9 had pure fatty liver and 21 had evidence of steatohepatitis. In addition, 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects were studied. Most NAFLD patients had central fat accumulation, increased triglycerides and uric acid, and low HDL cholesterol, irrespective of BMI. Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, as well as in patients with normal body weight, to an extent similar to that of the type 2 diabetic patients. Basal free fatty acids were increased, whereas insulin-mediated suppression of lipolysis was less effective (؊69% in NAFLD vs. ؊84% in control subjects; P ‫؍‬ 0.003). Postabsorptive hepatic glucose production (HGP), measured by [6,6-2 H 2 ]glucose, was normal. In response to insulin infusion, HGP decreased by only 63% of basal in NAFLD vs. 84% in control subjects (P ‫؍‬ 0.002). Compared with type 2 diabetic patients, NAFLD patients were characterized by lower basal HGP, but with similarly reduced insulinmediated suppression of HGP. There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological, and biochemical data (including insulin sensitivity) were not correlated with iron status. Four subjects were heterozygous for mutation His63Asp of the HFE gene of familiar hemochromatosis. We concluded that NAFLD, in the presence of normoglycemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity. NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance. Diabetes

Metformin treatment is better than a prescriptive diet or vitamin E in the therapy of NAFLD patients receiving nutritional counseling. Limited histological data support an association between improved aminotransferases and biopsy findings, which require confirmation in a double-blind trial with appropriate statistical power based on liver histology.

Plasma levels of adiponectin are decreased in patients with nonalcoholic fatty liver disease (NAFLD), but the relationship among plasma adiponectin, insulin sensitivity, and histological features is unclear. In 174 NAFLD patients and 42 controls, we examined plasma adiponectin concentrations in relation to 1) lipid profile, indices of insulin resistance, and features of the metabolic syndrome (n = 174); 2) hepatic insulin resistance (clamp technique with tracer infusion) (10 patients); and 3) histological features at liver biopsy (n = 116). When the data from all subjects were combined, plasma adiponectin levels were positively associated with increased age, female gender, and plasma high-density lipoprotein levels, and negatively associated with waist circumference, body mass index, triglycerides, indices of insulin resistance, and aminotransferase levels, and also predicted the presence of the metabolic syndrome. In step-wise regression, increased age, female gender, waist circumference, triglyceride levels, and homeostasis model assessment independently associated with adiponectin (adjusted R(2), 0.329). In NAFLD, adiponectin was only associated with increased age, female gender, and triglycerides (adjusted R(2), 0.245). When the measured histological parameters were included in the model, plasma adiponectin levels were also inversely proportional to the percentage of hepatic fat content (adjusted R(2), 0.221), whereas necroinflammation and fibrosis did not fit in the model. Adiponectin was negatively correlated with insulin-suppressed endogenous glucose production during the clamp (P = 0.011). The results demonstrate that decreased levels of circulating adiponectin in NAFLD are related to hepatic insulin sensitivity and to the amount of hepatic fat content. Hypoadiponectinemia in NAFLD is part of a metabolic disturbance characterized by ectopic fat accumulation in the central compartment.

Minimum criteria for the metabolic syndrome are met in most patients with Type 2 diabetes. Correct identification of the syndrome is important for an integrated approach to reduce the high costs and the associated disabilities. The ATPIII proposal more clearly identifies the burden of coronary heart disease associated with the metabolic syndrome.

OBJECTIVE:To measure the effects of cognitive -behavioural therapy on health-related quality of life (HRQL) in obese patients, in relation to binge eating disorder. DESIGN: Longitudinal, clinical intervention study consisting of structured sessions of cognitive -behavioural therapy, preceded by sessions chaired by a psychologist in subjects with binge eating. SUBJECTS: Two groups of obese patients (92 treated by cognitive -behavioural therapy (77 females); 76 untreated controls (67 female), selected from the waiting list (control group)). Of 92 treated patients, 46 had a binge eating disorder at psychometric testing and structured clinical interview. MEASUREMENTS: Health-related quality of life by means of Short-Form 36 questionnaire at baseline and after 3 -5 months. RESULTS: Cognitive -behavioural treatment produced an average weight loss of 9.4 AE 7.5 kg, corresponding to a BMI reduction of 3.48 AE 2.70 kg=m 2 . No changes were observed in the control group. All scales of HRQL improved in treated subjects (by 5 -19%). In obese subjects with binge eating weight loss was lower in comparison to non-bingers (7.7 AE 8.1 vs 11.1 AE 6.6; P ¼ 0.034). However, the improvement in HRQL was on average larger, and significantly so for Role Limitation -Physical (P ¼ 0.006), Role Limitation -Emotional (P ¼ 0.002), Vitality (P ¼ 0.003), Mental Health (P ¼ 0.032) and Social Functioning (P ¼ 0.034). Bodily Pain was the sole scale whose changes paralleled changes in body weight. CONCLUSIONS: The positive effects of cognitive -behavioural therapy, mainly in subjects with binge eating, largely outweigh the effects on body weight, resulting in a significant change in self-perceived health status.

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OBJECTIVE:To determine the influence of body mass index (BMI) on agreement between the American Diabetes Association (ADA) and the new World Health Organization diagnostic criteria for the diagnosis of diabetes mellitus and to investigate the metabolic profile of the resulting subcategories. DESIGN: Cross-sectional study SUBJECTS: A total of 3018 subjects with no previous history of diabetes and fasting glucose < 7.8 mmol=l, with a wide range of BMIs. MEASUREMENTS: (1) Prevalence of impaired glucose regulation (IGR) and diabetes (DM) according to ADA and WHO diagnostic criteria; (2) basal and post-load insulin sensitivity and secretion, calculated on the basis of data derived from an oral glucose tolerance test (OGTT). RESULTS: The diagnosis according to the two classifications was concordant in 2490 subjects, discordant in 528 (452 were identified as impaired glucose tolerance (IGT) and 76 as DM only by means of OGTT). The disagreement increased with increasing BMI, being as high as 25.3% in subjects with BMI ! 35 kg=m 2 . Subjects with isolated fasting hyperglycaemia were mainly characterised by reduced insulin sensitivity and secretion in the basal state, but normal first-phase insulin secretion and moderately reduced insulin sensitivity after glucose challenge. Subjects with isolated 2 h hyperglycaemia were mainly characterised by normal basal insulin secretion and by a marked insulin resistance associated with a blunted first-phase insulin secretion after the glucose load. CONCLUSIONS:The disagreement between ADA and WHO classifications is particularly relevant in obesity, making OGTT mandatory in these subjects. Different pathogenic mechanisms are involved in isolated fasting or post-load hyperglycaemia, possibly related to a different site of insulin resistance (hepatic vs peripheral), and=or to a different disregulation of insulin secretion (basal vs post-load). A correct identification of the underlying mechanism(s) is the rationale for future studies to detect the effectiveness of different pharmacological or behavioural approaches.