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Aims Adults affected by obesity are at higher risk of premature mortality. Medications can help to lose weight and to maintain weight loss. Aim of this meta-analysis was to assess whether anti-obesity medications affect all-cause mortality, mortality due to cardiovascular events, cardiovascular risk factors and body weight. Data synthesis A Medline search was performed to identify randomized controlled trials (RCTs) of anti-obesity medications in adults with overweight or obesity reporting data on all-cause mortality, cardiovascular mortality or non-fatal cardiovascular events, with a follow-up of at least 6 months. We identified 28 RCTs with 50,106 participants. The median follow-up was 52 weeks. Evidence did not show superiority of anti-obesity medications over placebo in reducing all-cause mortality (risk ratio 1.03, 95%Confidence Interval [CI] 0.87 to 1.21) or cardiovascular mortality (risk ratio 0.92, 95%CI 0.72 to 1.18). All-cause mortality rate was positively associated with weight loss (β = 0.0007; p = 0.045); hence, for each kg of body weight lost there was a 0.07% decrease of all-cause mortality. The pharmacological treatment reduced total-cholesterol (7.15 mg/dl; 95%CI 1.46–12.85), LDL-cholesterol (5.06 mg/dl; 95%CI 1.12–9.00), and triglycerides levels (9.88 mg/dl; 95%CI 5.02–14.75), while it increased HDL-cholesterol (1.37 mg/dl; 95%CI 0.17–2.57). Systolic blood pressure decreased (0.90 mmHg; 95%CI 0.15–1.64). Conclusions Although we were unable to demonstrate a superiority of anti-obesity medications over placebo on mortality, metaregression showed that even a small weight reduction tends to reduce all-cause mortality in obesity. Our data support public health measures to reduce the obesity burden by including the use of anti-obesity medications. Registration number (PROSPERO) CRD42020210329.

AIMS To compare different treatments for non-alcoholic steatohepatitis (NASH) and to determine an effectiveness hierarchy. MATERIALS AND METHODS We conducted a systematic review and Bayesian network meta-analysis including randomized controlled trials or prospective trials with at least 6 months' follow-up and histologically proven NASH in adult participants. Monte Carlo simulations were performed, each generating 10 000 data points, and results are reported as medians and 95% credibility intervals (CrIs). A meta-regression was conducted to find the effects of body mass index (BMI) decrement or reduction of homeostatic model assessment of insulin resistance (HOMA-IR) index on non-alcoholic fatty liver disease activity score (NAS) change. RESULTS The review identified 48 eligible trials comprising 2356 adults (55.6% men). Data were pooled using a random-effects model. The most effective treatments in terms of NAS reduction per semester were pioglitazone and Roux-en-Y gastric bypass (RYGB; -1.50 [95% CrI -2.08, -1.00] for pioglitazione and -1.00 [95% CrI -1.70, -0.32] for RYGB). Pioglitazone was also the best therapy for steatosis and lobular inflammation reduction. RYGB was the best treatment for hepatocellular ballooning reduction, whereas antioxidants appeared to be best for fibrosis improvement. For each 1% decrement in BMI, NAS was reduced by 1.3% (β = 1.28%, P = 0.01). Conversely, a 1% reduction of HOMA-IR index reduced NAS by 0.3% (β = 0.31%, P

Aims/hypothesis The small intestine plays an important role in hepatic and whole-body insulin sensitivity, as shown by bariatric surgery. Our goal was to study whether routes and dose of glucose administration have an acute impact on insulin sensitivity. The primary endpoint of this proof-of-concept study was the difference in insulin-mediated metabolic clearance rate (MCR/I) of glucose between the oral and intravenous routes of glucose administration. Secondary endpoints were differences in insulin effect on proteolysis, ketogenesis, lipolysis and glucagon levels. Methods In this parallel cohort study, we administered multiple oral glucose loads to 23 participants (aged between 18 and 65 years) with morbid obesity and with normal or impaired glucose tolerance or type 2 diabetes. In a different session, we administered isoglycaemic intravenous glucose infusions (IGIVI) to match the plasma glucose levels observed during the oral challenges. Glucose rate of appearance (Ra) and disappearance (Rd) and endogenous glucose production (EGP) were calculated by infusing [6,6-2H2]glucose with or without oral [U-13C6]glucose. Plasma small polar metabolites were measured by gas chromatography and time-of-flight mass spectrometry. Lipids were measured by ultra-HPLC and quadrupole mass spectrometry. Glucagon-like peptide-1, insulin, C-peptide and glucagon were also measured. Participants, caregivers, people doing measurements or examinations, and people assessing the outcomes were unblinded to group assignment. Results Glucose MCR/I was significantly higher during IGIVI than during oral glucose administration, independently of glycaemic status (12 ± 6 for IGIVI vs 7.4 ± 3 ml min−1 kg−1 per nmol/l for oral, pt test). Insulin secretion was higher during oral administration than during IGIVI (p−1 kg−1 (nmol/l)−1 pmol/min; p = 0.005). Insulin clearance was significantly higher when glucose was infused rather than ingested (2.53 ± 0.82 vs 2.16 ± 0.49 l/min in intravenous and oral procedure, respectively, p = 0.006). The efficacy of insulin in inhibiting lipolysis and proteolysis was decreased after oral glucose loads. A heat map diagram showed a different pattern for the metabolites between the two routes of glucose administration. Conclusions/interpretation Our study shows that insulin sensitivity depends on the route of glucose administration, the oral route leading to increased insulin secretion and compensatory insulin resistance compared with the intravenous route. The efficacy of insulin in blocking lipolysis and protein breakdown is lower after oral glucose loads vs the intravenous route. Our findings suggest that, while the glucose-mediated incretin release is followed by an increase in insulin release, the effect of the released insulin is limited by an increase in insulin resistance. Trial registration ClinicalTrials.gov NCT03223129.

Purpose: Bariatric surgery (BS) is considered the most efficient treatment for severe obesity. International guidelines recommend multidisciplinary approach to BS (general practitioners, endocrinologists, surgeons, psychologists, or psychiatrists), and access to BS should be the final part of a protocol of treatment of obesity. However, there are indications that general practitioners (GPs) are not fully aware of the possible benefits of BS, that specialty physicians are reluctant to refer their patients to surgeons, and that patients with obesity choose self-management of their own obesity, including internet-based choices. There are no data on the pathways chosen by physicians and patients to undergo BS in the real world in Italy. Methods: An exploratory exam was performed for 6 months in three pilot regions (Lombardy, Lazio, Campania) in twenty-three tertiary centers for the treatment of morbid obesity, to describe the real pathways to BS in Italy. Results: Charts of 2686 patients (788 men and 1895 women, 75.5% in the age range 30–59 years) were evaluated by physicians and surgeons of the participating centers. A chronic condition of obesity was evident for the majority of patients, as indicated by duration of obesity, by presence of several associated medical problems, and by frequency of previous dietary attempts to weight loss. The vast majority (75.8%) patients were self-presenting or referred by bariatric surgeons, 24.2% patients referred by GPs and other specialists. Self-presenting patients were younger, more educated, more professional, and more mobile than patients referred by other physicians. Patients above the age of 40 years or with a duration of obesity greater than 10 years had a higher prevalence of all associated medical problems. Conclusions: The majority of patients referred to a tertiary center for the treatment of morbid obesity have a valid indication for BS. Most patients self-refer to the centers, with a minority referred by a GP or by specialists. Self-presenting patients are younger, more educated, more professional, and more mobile than patients referred by other physicians. Older patients and with a longer duration of obesity are probably representative of the conservative approach to BS, often regarded as the last resort in an endless story. Graphical abstract: [Figure not available: see fulltext.]

Purpose Patients with functional hypothalamic amenorrhea (FHA) could commonly have bone damage, often preceded by metabolic alterations due to a relative energy deficit state. To date, there are no markers capable of predicting osteopenia before it is manifested on DXA. Irisin is a myokine that promotes the differentiation of osteoblastic cells and appears to be inversely correlated with the incidence of bone fragility and fractures in postmenopausal women. The aim of this study was to measure irisin levels in FHA patients and to correlate it with bone density parameters. Methods Thirty-two patients with FHA and 19 matched controls underwent the same clinical and laboratory evaluation. Results Irisin and body mass index (BMI) were significantly lower in the case group than in healthy controls (2.03 ± 0.12 vs. 2.42 ± 0.09 p p 2) was significantly lower in the case group than in the healthy controls (1.09 ± 0.08 vs. 1.14 ± 0.05, p Conclusions The FHA group showed lower irisin levels associated with significantly reduced BMD parameters that did not reach the severity of osteopenia. Therefore, we could speculate that irisin could predict DXA results in assessing modifications of body composition parameters. Future research is warranted to study these parameters in a larger population to confirm our results, so that irisin could be used as a predictor and screening method for bone deprivation. Furthermore, irisin is strictly related to energy metabolism and could be an indirect marker of nutritional status in FHA patients, identifying earlier states of energy deficit.

To investigate the prevalence of biopsy-proven non-alcoholic steatohepatitis (NASH) in a cohort of patients with morbid obesity and with or without type 2 diabetes (T2D) and to find non-invasive predictors of NASH severity.We evaluated a cohort of 412 subjects (age 19-67 years, body mass index-BMI: 44.98 kg/mThe prevalence of biopsy-proven NASH was 63% and 78% in subjects with obesity and without or with T2D, respectively. T2D doubled the risk of NASH [OR 2.079 (95% IC=1.31-3.29)]. The prevalence of NAFL increased with the increase of BMI, while there was an inverse correlation between BMI and NASH (r=-0.145 p=0.003). Only mild liver fibrosis was observed. HOMA-IR was positively associated with hepatocyte ballooning (r=0.208, p0.0001) and fibrosis (r=0.159, p=0.008). The NNA highlighted a specificity of 77.3% using HDL-cholesterol, BMI, and HOMA-IR as main determinants of NASH.Our data show a higher prevalence of NASH in patients with morbid obesity than reported in the literature and the pivotal role of T2D among the risk factors for NASH development. However, the inverse correlation observed between BMI and biopsy-proven NASH suggests that over a certain threshold adiposity can be somewhat protective against liver damage. Our model predicts NASH presence with high specificity, thus helping identifying subjects who should promptly undergo liver biopsy.

The lifetime risk of developing symptomatic knee osteoarthritis is 60% in subjects with obesity. It is unclear which is the best weight loss interventions leading to a meaningful improvement of osteoarthritis symptoms and clinical conditions in subjects with obesity. Our network meta-analysis compares different weight loss interventions on the improvement of osteoarthritis symptoms and clinical conditions in subjects affected by obesity. PubMed, Embase, and Cochrane databases were systematically searched for eligible studies until November 2020. Thirty eligible studies comprising 4651 adults (74.6% women) were included. The most effective interventions reducing pain were bariatric surgery, low-calorie diet and exercise, and intensive weight loss and exercise (-62.7 [95% CrI: -74.6, -50.6]; -34.4 [95% CrI: -48.1, -19.5]; -27.1 [95% CrI: -40.4, -13.6] respectively). For every 1% weight loss Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain, function, and stiffness scores decreased by about 2% points. In conclusion, our meta-analysis shows that a substantial weight loss is necessary to reduce significantly knee pain and joint stiffness and to improve physical function: 25% weight reduction from baseline is necessary to obtain a 50% reduction of each subscale of the WOMAC score. However, performing physical exercise is essential to preserve the lean body mass and to avoid sarcopenia. Our results apply to a large spectrum of body mass index (BMI), from overweight to severe obesity.

Background: No data from randomised controlled trials of metabolic surgery for diabetes are available beyond 5 years of follow-up. We aimed to assess 10-year follow-up after surgery compared with medical therapy for the treatment of type 2 diabetes. Methods: We did a 10-year follow-up study of an open-label, single-centre (tertiary hospital in Rome, Italy), randomised controlled trial, in which patients with type 2 diabetes (baseline duration >5 years; glycated haemoglobin [HbA] >7·0%, and body-mass index >=35 kg/m) were randomly assigned (1:1:1) to medical therapy, Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD) by a computerised system. The primary endpoint of the study was diabetes remission at 2 years (HbA

Background: The need to rapidly immunize the population against SARS-CoV-2 to obtain herd immunity together with shortage of vaccine supplies suggest to vaccinate the largest number of people with a single dose of vaccine delaying the second dose. Methods: The primary outcomes of our meta-analysis were the efficacy of one or both doses of vaccines in preventing COVID-19 and their safety. In addition, using a differential equation model taking into account the effects of lockdown and vaccination, we sought to study the effectiveness of one or both doses of vaccines in preventing new cases of COVID-19 in UK and Israel. These countries, where a large portion of the population is already vaccinated, have different vaccination strategies, 3 vs. 12 weeks delay between first and second dose. Findings: The first vaccine dose averted infection in 71% of participants, while the booster dose cumulatively prevented COVID-19 in 87% of participants. The pooled treatment effects in two age subgroups (

Background/Objectives As only 1% of clinically eligible subjects choose to undergo surgical treatment for obesity, other options should be investigated. This study aimed to assess the effects of intensive lifestyle modification (ILM) with or without 3-mg liraglutide daily vs sleeve gastrectomy (SG) on BMI after 1 year. Subjects/Methods In this study performed at an Italian university hospital, non-diabetic patients eligible for bariatric surgery were recruited from a weight-loss clinic and had the option to choose from three possible weight-loss programmes up to an allocation of 25 subjects in each arm matched by BMI and age. ILM consisted in 813 kcal of a very low-calorie diet (VLCD) for 1 month, followed by a diet of 12 kcal/kg body weight of high protein and high fat for 11 months plus 30 min of brisk walking daily and at least 3 h of aerobic exercise weekly. SG patients followed a VLCD for 1 month and a free diet thereafter. Patients were evaluated at baseline and at 1, 3, 6, 9 and 12 months. Results A total of 75 patients were enrolled; retention was 100% in the SG and 85% in the two medical arms. SG reduced BMI by 32% (P < 0.001 vs medical arm), while ILM + liraglutide and ILM led to BMI reductions of 24% and 14%, respectively (P < 0.001). More women allocated themselves to the ILM + liraglutide group. Weight loss was 43 kg with SG, 26 kg with ILM + liraglutide and 15 kg with ILM alone. Lean body mass reductions were − 11.6 kg with SG, − 6.3 kg with ILM and − 8.3 kg with ILM + liraglutide. Prevalence of prediabetes was significantly lower with ILM + liraglutide, and insulin resistance was reduced by about 70% by both ILM + liraglutide and SG vs 39% by ILM alone. Cardiometabolic risk factors were greatly reduced in all three groups. Discussion At least in the short-term, liraglutide 3.0 mg once daily associated with drastic calorie-intake restriction and intensive physical activity promoted a 24% weight loss, which was almost two times greater than ILM alone and only about 25% less than with SG, while preserving lean body mass. Although this study was non-randomized, it was designed to explore the efficacy of medical treatments for obesity in everyday clinical practice.

Context We compared the incidence of hypoglycemia after Roux-en-Y gastric bypass (RYGB) vs sleeve gastrectomy (SG). Design, Setting, and Main Outcome Measures Randomized, open-label trial conducted at the outpatient obesity clinic in a university hospital in Rome, Italy. The primary aim was the incidence of reactive hypoglycemia (

Background The prevalence and degree of obesity is rising worldwide, increases cardiovascular risk, modifies body composition and organ function, and potentially affects the pharmacokinetics and/or pharmacodynamics of drugs. Objectives To investigate the pharmacodynamics of once-daily low-dose aspirin in healthy obese subjects, and to assess whether body weight (BW) and body mass index (BMI) affect the pharmacology of aspirin. Patients/methods Otherwise healthy, obese (BMI > 30 kg/m2 ) subjects were studied before and after 3-4 weeks of 100-mg once-daily aspirin intake. Aspirin pharmacodynamics were assessed according to serum thromboxane (TX) B2 levels measured at 4 hours, 24 hours (i.e., posologic interval) and 48 hours after the last witnessed intake; age-matched and sex-matched non-obese controls were included. A previously calibrated pharmacokinetic/pharmacodynamic in silico model of aspirin was used to fit serum TXB2 data from obese subjects. At baseline, the major urinary TXA2 and prostacyclin metabolites, urinary isoprostane and plasma inflammatory biomarkers were measured. Results In 16 obese subjects (aged 47 ± 11 years; BMI of 39.4 ± 5.1 kg/m2 ), residual serum TXB2 values between 4 and 48 hours after aspirin intake were increased 3- to 5-fold as compared with controls. At 24 hours, the residual serum TXB2 level was log-linearly associated with body size over a wide range of BMI and BW values, without any apparent threshold. The in silico model predicted that reduced aspirin bioavailability would be inversely related to body size and rescued by 200 mg of aspirin once daily or 85 mg twice daily. Baseline urinary TXA2 metabolite, isoprostane and plasma C-reactive protein levels were significantly increased in obese subjects. Conclusions Obesity is associated with impaired aspirin responsiveness, largely because of body size. Impaired inhibition of platelet activation by conventional low-dose aspirin may affect antithrombotic efficacy.

No data have been reported regarding the risk of hyperinsulinemic response and reactive hypoglycemia after single anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S). Furthermore, comparative studies with other bariatric procedures are lacking.To compare response to oral glucose tolerance test (OGTT) in patients who underwent SADI-S, Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and biliopancreatic diversion (BPD).Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome.Consenting, nondiabetic patients matched for age, sex, and preoperative body mass index, who underwent SADI-S, RYGB, SG, and BPD, were recruited. A 75 g OGTT was performed pre and postoperatively. Plasma insulin and glucose (pGlu-mg/dL) were measured at baseline, and at +30, +60, +90, +120, +150, and +180 minutes. Severe hypoglycemia was defined as pGlu concentration55 mg/dL.Thirty-five patients were recruited: 9 SADI-S, 11 RYGB, 7 SG, and 8 BPD. Comparing preoperative and postoperative responses to OGTT, all procedures improved the glycemic control with better early results after SADI-S and BPD compared with RYGB and SG. No patients showed severe hypoglycemia. Significantly more patients who underwent RYGB and SG showed asymptomatic pGlu70 mg/dL during OGTT compared with SADI-S and BPD (63.6% and 57.1% vs 22.2% and 12.5%, respectively, P.05).Similar to BPD, SADI-S seems to be associated to insulin sensitivity and glucose homeostasis improvement, together with a reduced risk of hyperinsulinemia and, consequently, to hypoglycemia, often associated with RYGB and SG.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that impairs patients’ quality of life. Various psychiatric or psychological conditions have been associated with HS, however, no data are available on alexithymia, a psychological construct characterized by the inability to express, describe, and recognize feelings. To assess the presence of alexithymia in HS patients. Demographic and clinical data from patients with HS were collected. Alexithymiawas assessed using the Toronto Alexithymia Scale (TAS)-20 questionnaire to define non-alexithymic subjects (scoring 20-50), borderline (possible) alexithymia subjects (scoring 51-60), and alexithymic subjects (scoring≥61). The alexithymic personality trait is identified based on TAS-20 score≥51. This multicentre study included 86 HS patients, 100 obese individuals, and 85 healthy control subjects. The mean TAS-20 score was significantly higher in the HS patient cohort (55.37 ±13.42) than in the control group (40.96±10.47) (p

BACKGROUND/OBJECTIVE Normal weight obesity (NWO) is associated with increased risk of metabolic syndrome, cardiovascular- and all-cause mortality. However, no data have been reported on the relationship between adiposity and cognitive performance in NWO. We therefore studied the association between cognitive function and body fat percentage (BF%) in NWO, using a representative sample of the United States population. METHODS A cross-sectional study was performed using the nationwide 1988 to 1994 data set from the Third National Health and Nutrition Examination Survey. Cognitive function was measured by three validated cognitive tests: simple reaction time test (SRTT), symbol digit substitution test (SDST), and serial digit learning test (SDLT). The association between BF% and cognitive performance was evaluated in 2,039 adults aged 20-59 years and with a body mass index ranging from 18.5 to 24.9 kg/m2. Linear regression modeling was used to adjust for potential confounders. RESULTS Increased BF% was significantly associated with poorer performance on SDLT in the entire study sample (coefficient [95% CI]: 0.15 [0.01, 0.29]) and with poorer performance on SDST in the age group 20-29 years (coefficient [95% CI]: 0.30 [0.10, 0.49]). Increased BF% did not significantly predict poorer performance on SRTT. CONCLUSION Higher BF% is significantly associated with poorer cognitive function in a nationally representative sample of US adults with NWO. The identification of possible complications associated with increased adipose tissue underlines the need to measure body fat content in NWO individuals, whose metabolic and cognitive dysfunction could go undetected for years due to their young age and normal body weight.

The purpose of this study was to examine the contribution of nonesterified fatty acids (NEFA) and incretin to insulin resistance and diabetes amelioration after malabsorptive metabolic surgery that induces steatorrhea. In fact, NEFA infusion reduces glucose-stimulated insulin secretion, and high-fat diets predict diabetes development. Six healthy controls, 11 obese subjects, and 10 type 2 diabetic (T2D) subjects were studied before and 1 mo after biliopancreatic diversion (BPD). Twenty-four-hour plasma glucose, NEFA, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) time courses were obtained and analyzed by Granger causality and graph analyses. Insulin sensitivity and secretion were computed by the oral glucose minimal model. Before metabolic surgery, NEFA levels had the strongest influence on the other variables in both obese and T2D subjects. After surgery, GLP-1 and C-peptide levels controlled the system in obese and T2D subjects. Twenty-four-hour GIP levels were markedly reduced after BPD. Finally, not only did GLP-1 levels play a central role, but also insulin and C-peptide levels had a comparable relevance in the network of healthy controls. After BPD, insulin sensitivity was completely normalized in both obese and T2D individuals. Increased 24-h GLP-1 circulating levels positively influenced glucose homeostasis in both obese and T2D subjects who underwent a malabsorptive bariatric operation. In the latter, the reduction of plasma GIP levels also contributed to the improvement of glucose metabolism. It is possible that the combination of a pharmaceutical treatment reducing GIP and increasing GLP-1 plasma levels will contribute to better glycemic control in T2D. The application of Granger causality and graph analyses sheds new light on the pathophysiology of metabolic surgery.

Intestinal nutrients stimulate insulin secretion more potently than intravenous (IV) glucose administration under similar plasma glucose levels (incretin effect). According to the anti-incretin theory, intestinal nutrients should also cause a reduction of insulin sensitivity and/or secretion (anti-incretin effect) to defend against hyperinsulinemia-hypoglycemia. An exaggerated anti-incretin effect could contribute to insulin resistance/type 2 diabetes, whereas reduction of anti-incretin signals might explain diabetes improvement after bariatric surgery. In this study, we tested some of the predictions made by the anti-incretin theory. Eight healthy volunteers and eight severely obese subjects with insulin resistance were studied. Insulin secretion, insulin sensitivity, Ra, and disposition index were measured after oral glucose tolerance test and isoglycemic IV glucose injection (IGIV). Obese subjects were studied before and after intestinal bypass surgery (biliopancreatic diversion [BPD]). The d-xylose test and lactulose-to-rhamnose ratio were used to test for possible malabsorption of glucose after surgery. Monte Carlo mathematical simulations were used to test whether insulin secretion induced by oral glucose could cause hypoglycemia when coupled with the levels of insulin sensitivity measured during IGIV. Despite isoglycemic conditions, insulin sensitivity was lower during oral than during IV glucose administration. This difference was amplified in obese subjects and reduced to normal after BPD. No evidence of glucose malabsorption was found. Mathematical simulations showed that hypoglycemia would occur if insulin sensitivity were not reduced by oral glucose stimulation. This study demonstrates an anti-incretin effect of intestinal glucose stimulation, which downregulates insulin sensitivity. The findings support a new model for how foodborne factors can induce insulin-resistance and provide a possible explanation for the improvement of insulin resistance/diabetes after gastrointestinal bypass surgery.

A large body of literature indicates the rapidity with which Roux-en-Y gastric bypass (RYGB) improves glycemic control. However, the underlying physiologic mechanisms are still a matter of debate.Catholic University, School of Medicine, Rome, Italy.Ten morbidly obese patients, before and 4 weeks after RYGB, and 10 healthy controls were studied. We measured insulin sensitivity as the homeostasis model assessment-estimated insulin resistance (HOMA-IR) and by the euglycemic hyperinsulinemic clamp, and phosphorylation of protein kinase B (Akt) on Ser473 and Thr308 and of GSK3 α-β on Ser 9 and Ser21 in skeletal muscle biopsy specimens by Western blot analysis.Obese patients before RYGB displayed reduced insulin sensitivity (M value) and clearance and increased fasting Akt phosphorylation on Ser473 compared with controls. M significantly increased after surgery (from 2.6 ± 0.6 to 2.8 ± 0.7 mg/kg fat free mass/min, P = .026) but remained far below the values in controls (10.0 ± 3.8 mg/kg fat free mass/min, P.001). Insulin clearance increased from 453.5 ± 117.5 to 555.2 ± 61.6 (P = .00076), becoming similar to that of controls 582.2 ± 59.0 mU/m(2)/min. HOMA-IR decreased from 4.1 ± 0.07 to 2.3 ± 0.5 (P = .004), becoming comparable with controls (2.2 ± 0.9). The hyperphosphorylation of Akt on Ser473 observed at fasting before RYGB was significantly reduced thereafter, becoming similar to that of healthy controls; the other phosphorylation states remained unchanged.Following RYGB, we found a prompt improvement of hepatic insulin resistance with normalization of hepatic insulin clearance and a small amelioration of whole-body insulin sensitivity. The supranormal levels of Akt Ser473 observed at fast in the skeletal muscle tissue at baseline were normalized after RYGB, and their changes correlated with those of both hepatic and peripheral insulin resistance. Although other mechanisms of action, such as the effect of weight loss and reduced food intake, cannot be excluded, the reduction of muscle Akt hyperphosphorylation on the serine residue can play a role in the early improvement of insulin sensitivity.

Low high-density lipoprotein-cholesterol (HDL-C) concentration correlates with increased cardiovascular risk. A great prevalence of celiac disease (CD) was reported among patients with low HDL-C concentration, and gluten-free diet (GFD) treatment seems to normalize lipid profile. We evaluated blood lipids and body composition in 26 CD patients with low HDL-C level (1.0 mmol/L) at diagnosis and after GFD.A case-control study.The diagnosis was based on histologic evidence of subtotal or total duodenal villous atrophy. Patients were studied before and after GFD treatment (14.2+/-1.4 mo) with biopsy-proven return to normal of the duodenal mucosa. HDL-C was enzymatically assessed after precipitation of very low-density lipoprotein and low-density lipoprotein with heparin-magnesium. Apolipoprotein (Apo)-AI level was assessed by immunoturbidimetric assay; triglycerides by an enzymatic colorimetric method. Body composition was assessed by dual-energy x-ray absorptiometry.Body composition improved after GFD, with increasing body weight (P0.05) essentially owing to increased fat mass (FM) (P0.01), rather than fat-free mass (P=0.064). Total cholesterol and HDL-C were lower in untreated compared with treated patients (P0.001 and P0.0001). Apo-AI level increased significantly after GFD (1.20+/-0.22 vs. 1.46+/-0.17 g/L; P0.0001). Apo-AI, sex, and FM were all significant determinants of HDL-C level; a positive correlation (R=0.68; P0.0001) was found between increase in HDL-C level and in FM after GFD treatment.Restoration of lipid profile in CD patients after GFD treatment may be explained by an increase in both Apo-AI secretion by intestinal cells and body fat stores.

Aims: Subjects with chronic alcohol abuse can present several metabolic and nutritional alterations. The hypothalamic-pituitary-adrenal (HPA) axis may play a role in these nutritional and metabolic disorders. The goal of this study was to investigate if there is any relationship between HP-hormones and metabolic and nutritional parameters in alcoholic subjects. Methods: Sixteen alcoholics were considered before and after 3 months of total alcohol abstinence. HP-related hormones were determined. Nutritional and metabolic parameters were assessed by dual-energy X-ray absorptiometry (DXA) and indirect calorimetry. Results: At baseline, a significant negative correlation was found between fat mass (FM) and cortisol ( r = −0.54, P = 0.03). During abstinence, a significant increase of both body mass index (BMI) ( P < 0.0001) and FM ( P < 0.0001) was found at 12 weeks compared to baseline. A significant decrease of both plasma cortisol ( P = 0.044) and aldosterone ( P = 0.023) was found at 12 weeks compared to baseline. At 12 weeks, the significant correlation between cortisol and FM disappeared. Conclusions: A higher HPA-axis activation—reflected by higher cortisol levels—was associated with a lower FM in alcoholics. Conversely, during total abstinence a reduced HPA-axis activity can play a role in the parallel nutritional recovery. The present results suggest a role of the HPA axis throughout cortisol both in the etiology of the alcohol-related nutritional alterations and in their recovery after a period of total alcohol abstinence.

Background: A relationship between some hypothalamic–pituitary–related hormones and craving for alcohol has been suggested, leading to hypothesize a role of some hormones in the neurobiology of alcohol dependence. Investigating this association in alcohol-dependent (AD) patients was the aim of this preliminary and exploratory study. Methods: Cortisol, adrenocorticotropic hormone, prolactin, thyroid-stimulating hormone (TSH), free T3, free T4, growth hormone, follicle-stimulating hormone, luteinizing hormone as well as administering the Obsessive-Compulsive Drinking Scale (OCDS) and Penn Alcohol Craving Scale (PACS) were assessed at baseline and after 12 weeks in 25 current AD patients. Patients were treated with baclofen (10 mg t.i.d.) for these 12 weeks. Sixteen patients remained totally abstinent for 12 weeks. Results: At baseline, a significant inverse correlation was found between TSH and PACS (r = −0.46; p = 0.022) and OCDS scores (r = −0.53; p = 0.007). A significant direct correlation was found between free T3 and OCDS score (r = 0.44; p = 0.026). In the 16 abstinent patients, craving scores were significantly decreased at 12 weeks (p

SUMMARY Objectives: To evaluate state and trait form of anxiety and current depression in patients affected by gastrointestinal diseases. Methods: We studied 1641 outpatients with gastrointestinal disorders, consecutively referred to our Internal Medicine outpatients from 1997 to 2005. State and trait anxiety were assessed by the State and Trait Anxiety Inventory. Current depression was assessed by the Zung self-rating depression scale. Results: Among patients, 1379 (84.1%) showed state anxiety, 1098 (67%) showed trait anxiety and 442 (27%) showed current depression. The number of gastrointestinal diseases was directly correlated to state anxiety (p < 0.001) and trait anxiety (p = 0.04). Females showed higher levels of anxiety and depression than males (p < 0.001). State anxiety was related to food allergies (p < 0.001), small intestinal bacterial overgrowth (SIBO) (p = 0.001), Hp infection (p = 0.01) and ulcerative colitis in active phase (p = 0.03). Trait anxiety was related to irritable bowel syndrome (IBS) (p < 0.001), Helicobacter pylori (Hp) infection (p = 0.001), food allergies (p = 0.001) and SIBO (p = 0.001). Current depression was related to IBS (p < 0.001) and coeliac disease (p = 0.01), SIBO (p = 0.02). A predicted probability of 0.77 ± 0.16 to have state anxiety, of 0.66 ± 0.12 to have trait anxiety and of 0.39 ± 0.14 to have depression was found in these patients. Conclusions: Most of the patients who seek medical consultation for gastrointestinal problems show an associated affective disorder. These patients should be managed by a team including gastroenterologists, psychologists and ⁄ or psychiatrists, or by a gastroenterologist having expertise in the treatment of psychological disorders. What’s known Anxiety and depression represent a common feature in patients affected by gastrointestinal diseases. These affective disorders can be present as a personality trait or in a reactive form. What’s new The study supports that the approach to patients affected by gastrointestinal diseases should be managed by a team including gastroenterologists, psychologists and ⁄ or psychiatrists, or alternatively they should be managed by gastroenterologist having expertise in the treatment of psychological disorders. 1

Objective: The objective was to evaluate ghrelin and growth hormone (GH) interactions and responses to a growth hormone-releasing hormone (GHRH)/arginine test in severe obesity before and after surgically-induced weight loss. Research Methods and Procedures: Our study population included 11 severely obese women 39 ± 12 years of age, with a mean BMI of 48.6 ± 2.4 kg/m2, re-studied in a phase of stabilized body weight, with a BMI of 33.4 ± 1.2 kg/m2, 18 months after having successfully undergone biliopancreatic diversion (BPD). A GHRH/arginine test was performed before and 18 months after BPD to evaluate ghrelin and GH interactions. Active ghrelin, measured by radioimmunoassay (RIA), and GH, measured by chemiluminescence assay, were assayed before and after the GHRH/arginine test. Results: Fasting serum GH levels and GH area under the curve (AUC) significantly increased from 0.2 ± 0.05 ng/mL to 1 ± 0.3 ng/mL (p < 0.05) and from 514.76 ± 98.7 ng/mL for 120 minutes to 1957.3 ± 665.1 ng/mL for 120 minutes after bariatric surgery (p < 0.05), respectively. Although no significant change in fasting ghrelin levels was observed (573 ± 77.9 before BPD vs. 574.1 ± 32.7 after BPD), ghrelin AUC significantly increased from −3253.9 ± 2180.9 pg/mL for 120 minutes to 1142.3 ± 916.4 pg/mL for 120 minutes after BPD (p < 0.05). Fasting serum insulin-like growth factor (IGF)-1 concentration did not change significantly (133.6 ± 9.9 ng/mL before vs. 153.3 ± 25.2 ng/mL after BPD). Discussion: Our study demonstrates that the mechanisms involved in ghrelin and GH secretion after the secretagogue stimulus (GHRH/arginine) are consistent with patterns observed in other populations.

Wilson disease, an autosomal recessive disorder due to mutations of the ATP7B gene, is characterized by copper accumulation and toxicity in the liver and subsequently in other organs, mainly the brain and cornea. A new missense mutation (T1288R) of the ATP7B gene has recently been discovered in a Wilson disease patient in our laboratory. The aim of the present study was to analyze clinical and genetic features of more generations of the family of the patient in which the new mutation T1288R was discovered. A total of 19 subjects were studied; in particular, four generations of the patient's family were analyzed. The ATP7B gene was analyzed by single-strand conformational polymorphism followed by direct sequencing. Two brothers presented a clinical diagnosis of Wilson disease with an hepatic phenotype and a genotype characterized by the homozygotic mutation T1288R. The heterozygotic mutation T1288R was found in seven subjects belonging to all four generations. The present study represents the first screening for a Wilson disease mutation through four generations of a nonconsanguineous family. All the patients with the homozygotic T1288R mutation in the present pedigree presented an hepatic phenotype without a neurological presentation. Consequently, a genotype-phenotype correlation could be hypothesized, although further studies are necessary to clarify this topic.

To investigate energy expenditure and glucose metabolism after a standard oral glucose load (75 g) in 8 normal weight bulimic women and 8 normal weight control women and to evaluate the relative endocrine implication.Serum glucose and insulin were measured both in basal conditions and after the glucose load; a basal endocrine assessment and body composition was evaluated and glucose induced thermogenesis (GIT) was calculated during 300 min following the glucose load.Serum glucose levels were significantly lower in bulimics both in fasting and in post-prandial state. Insulin levels were similar in bulimic and control women before and after the glucose load. FSH, leptin and free urinary cortisol (FUC) were all within the normal ranges, but significantly lower in bulimic patients compared with controls (p0.001). Fat mass (FM) and Fat-free mass (FFM) were reduced in bulimic patients, even if they normalized after correction per body weight. Resting energy expenditure (REE) was similar in the two groups even after FFM normalization, while GIT was lower in bulimic patients and it was strongly related to free urinary chortisol. Glucose oxidation was higher in fasting state and post glucose load, while lipid oxidation was strongly reduced.An energy preservation mechanism seems to be the key element for normal-weight bulimic patients' metabolism, consisting in leptin levels and GIT reduction, and lipid oxidation inhibition.

SUMMARY Background: Anxiety and depression are common features of coeliac disease. Depression is cause of noncompliance to treatment in chronic illness. Aim: To evaluate the useful of psychological support counselling to improve affective disorders and glutenfree diet adherence in coeliac disease with anxiety and depression. Methods: A total of 66 coeliac disease patients with state anxiety and current depression were enrolled. Patients were randomized in two groups: in group A psychological support was started at the beginning of gluten-free diet, while group B was free of psychological support. Both groups were followed every 2 weeks for 6 months. State and Trait Anxiety Inventory test Y-1 and the modified Zung self-rating depression scale were administered before (T0) and after 6 months of glutenfree diet (T1). Results: At T1 no difference was found between groups in the percentage of state anxiety, while a significant lower percentage of depressed subjects was found in group A with respect to group B (15.1% vs. 78.8%; P ¼ 0.001). In the follow-up period, a significant lower compliance to gluten-free diet was found in group B with respect to group A (39.4% vs. 9.1%; P ¼ 0.02). Conclusions: In coeliac disease patients with affective disorders psychological support seems to be able to reduce depression and to increase gluten-free diet compliance.

Background: Several skin disorders are present in patients affected by coeliac disease (CD) – among them, psoriasis has been described. However, at present the relationship between CD and psoriasis remains controversial since there are few and contrasting data on this topic. Method: Here we describe a case of psoriasis in a CD patient not responding to specific therapies for psoriasis. Result: The regression of skin lesions after gluten-free diet (GFD) was evident in a short time. Conclusion: The present case supports the association between CD and psoriasis and the concept that psoriasis in CD patients can be improved by GFD. Future studies are needed to clarify the possible mechanisms involved in this association.

Background Our aim was to investigate the regulation of the gene expression of leptin in subcutaneous adipose tissue biopsies in morbid obesity before and after biliopancreatic diversion (BPD). Methods Longitudinal study in morbidly obese subjects investigated twice: before and 6 months after BPD. Fourteen morbidly obese women, 37±13 years old and with a body mass index of 51.6±8.2 kg/m2, were studied before and 6 months after BPD (40.6±8.0 kg/m2). Using reverse transcriptase polymerase chain reaction analysis, the mRNA expression of leptin was investigated in adipose tissue. Plasma leptin was measured by radioimmunoassay; plasma insulin was measured by microparticle enzyme immunoassay. Free fatty acids (FFA) were measured using a colorimetric kit. Results A significant decrease in leptin mRNA level was observed in comparison with pretreatment in BPD patients (59±34 vs 143±85 arbitrary units, P 2=0.80, P 2=0.86, P 2=0.65, P 2=0.92, P 2=0.64, P 2=0.88, P 2=0.83, P Conclusion These data demonstrate a high correlation between leptin mRNA expression in adipose tissue and plasma leptin in postobese subjects after BPD. The significant relationship between both leptin mRNA and plasma leptin with insulin suggests that circulating insulin might regulate leptin expression. It might be hypothesized that plasma FFA concentration can act on the insulin secretion and subsequently on the leptin secretory pathway.

Conventional bioimpedance analysis (BIA) methods now simplify the representation of lower limb geometry and electrical properties for body composition estimation. In the present study, a three-dimensional model of the lower limb was assembled by segmentation of magnetic resonance cross-sectional images (MRI) for adipose tissue, skeletal muscle, and bone. An electrical network was then associated with this model. BIA and MRI measurements were made in six lean subjects (3 men and 3 women, age 32.2 ± 6.9 yr). Assuming 0.85 S/m for the longitudinal conductivity of the muscle, the model predicted in the examined subjects an impedance profile that conformed well to the BIA impedance profile; predicted and measured resistances were similar (261.3 ± 7.7 vs. 249 ± 9 Ω; P = not significant). The resistance profile provided, through a simpler model, muscle area estimates along the lower limb and total leg muscle volume (mean 4,534 cm3 for men and 4,071 cm3 for women) with a mean of the absolute value of relative error with respect to MRI of 6.2 ± 3.9. The new approach suggests that BIA can reasonably estimate the distribution and volume of muscles in the lower extremities of lean subjects.

Alcohol withdrawal syndrome is a distressing and at times life-threatening condition in alcohol-dependent patients (1). Usually, symptoms develop within 6 –24 hours after the last drink (2). Early symptoms include raised blood pressure and pulse rate, tremor, hyperreflexia, and anxiety with increased irritability. Clinical management is aimed at symptom relief, prevention of seizures and delirium, and a smooth transition to a treatment program to maintain long-term abstinence from alcohol (3). Benzodiazepines are presently the drug of choice (4). We recently found that baclofen, a -aminobutyric acid (GABA)B receptor agonist used to control spasticity (5), reduced voluntary alcohol intake in alcohol-preferring rats (6), as well as alcohol craving and intake, up to complete alcohol abstinence, in alcohol-dependent patients (7). Furthermore, baclofen suppressed the intensity of alcohol withdrawal syndrome in rats who were physically dependent on alcohol (6). We therefore studied the effects of oral administration of baclofen in patients with severe alcohol withdrawal syndrome.

RATIONALE Hashimoto's thyroiditis is a chronic inflammatory condition often associated with changes in appetite and body composition. Ghrelin is an orexigenic peptide involved in the regulation of appetite and food intake. A possible role of ghrelin in mediating inflammation has been suggested. A few contrasting published data are available on the relationship between thyroid status and circulating ghrelin in patients affected by Hashimoto's thyroiditis. The aim of the present case-control study was to provide additional evidence on the relationship between thyroid status and plasma ghrelin levels in post-treatment euthyroid female patients with Hashimoto's thyroiditis, compared to healthy controls. METHODS 25 women [age 46.6±10.6 years; Body Mass Index 26.3±3.8 kg/m²] affected by overt hypothyroidism due to Hashimoto's thyroiditis were studied after thyroid hormones and body weight were already normalized for at least 2 months following L-thyroxine replacement. 25 healthy women (age 40.2±6.4 years; Body Mass Index 26.2±4.0 kg/m²) served as the control group. Blood levels of thyroid hormones, thyroid peroxidase antibodies, thyroglobulin antibodies and ghrelin were determined. Fat mass, fat-free mass and high-density lipoprotein cholesterol were also assessed. RESULTS Circulating ghrelin levels were significantly higher in patients vs. control subjects (p

Celiac disease (CD) is a chronic disease causing the inflammation of the proximal small intestine, in genetically predisposed individuals. This is triggered by the consumption of the gluten protein and the side effects of the disease are mitigated by a lifelong gluten-free diet (GFD) treatment. The predominant consequence of CD is malnutrition due to malabsorption (with diarrhea, weight loss, nutritional deficiencies, and altered blood parameters), especially in patients who do not show strict adherence to GFD treatment. Recent evidence shows that, despite a lifelong GFD, some functional disorders persist, such as compromised gallbladder function and motility, exocrine pancreatic insufficiency, increased gut permeability, small-intestinal bowel overgrowth, nonalcoholic fatty liver disease (NAFLD), lactose intolerance, and milk allergy. These abnormalities may predispose to the occurrence of overweight and obesity even in CD patients. This review focuses on the principal functional and metabolic disorders in both treated and untreated CD, ranging from alterations of the gastrointestinal system to impaired glucose and lipid metabolism and insulin secretion with the aim of providing new implications beyond a GFD, for an ad hoc nutrition treatment in these patients.

A high prevalence of anxiety and depression has been reported in untreated coeliac disease (CD) patients. At present, the role of a gluten-free diet (GFD) on psychological disorders is still poorly known. The aim of this study was to evaluate state and trait anxiety and depression in adult CD patients before and after 1 year of GFD.A total of 35 CD patients were studied before and after 1 year of GFD. A total of 59 healthy subjects matched for gender, age and socio-economic status were studied as a control group. State and trait anxiety were assessed with the STAI test; depression was assessed using the modified version of the SDS Zung self-rating depression scale (M-SDS). The tests were administered before (TO) and after 1 year of GFD (T1).At T0, CD patients showed high levels of state anxiety in a significantly higher percentage compared to controls (71.4% versus 23.7%; P0.0001), while there was no significant difference in trait anxiety between groups (25.7% versus 15.2%; P:ns); the percentage of subjects with depression was significantly higher in the CD group than in the control group (57.1% versus 9.6%; P0.0001). At T1, a significant decrease in the percentage of state anxiety was found in CD patients (T0: 71.4% versus T1: 25.7%; P0.001), while there were no significant changes in the percentage of trait anxiety (T0: 25.7% versus T1: 17.1%; P:ns) or depression (T0: 57.1.% versus T1: 45.7%; P:ns), which was still present in a significantly higher percentage in treated CD compared to controls (P0.0001).In CD patients anxiety is present in a predominantly reactive form and it decreases after GFD. Depression is present in a higher percentage in CD patients and 1 year of GFD fails significantly to affect depressive symptoms. The presence of depression after GFD could be related to the reduction in quality of life in CD patients. The non-regression of depression after GFD could suggest that these patients need psychological support.

The main objective in alcoholism therapy is to achieve and maintain abstinence and to prevent relapse. Pharmacotherapy may be necessary in treating persons who are not helped by group or psychosocial support alone. Among the substances experimented with in the past few years, gamma-hydroxybutyric acid has been effective in preventing alcohol withdrawal syndrome and in inducing a reduction in craving and an increase in the abstinence rate in treated alcoholics, in view of the alcohol-mimicking effects of the drug on the central nervous system. However, a possible development of craving for the drug and the risk of abuse and physical dependence have been reported in subjects who used gamma-hydroxybutyric acid for different reasons, including alcoholism therapy. The present review updates the existing differences in drug abuse behavior, side effects, and poisoning in the use of gamma-hydroxybutyric acid in a treatment alcoholism program and in self nonclinical illicit use.

Objective Since malnutrition and lactose intolerance are frequently reported in Crohn's disease (CD), we evaluated the differences in terms of compliance-to-treatment and nutritional status in inactive CD patients after two different treatments using either a standard polymeric diet or a vegetable-protein-rich and lactose-free diet. Study design A case-control study. Subjects Forty CD patients with inactive disease were randomly divided into two groups. Group A (10 men; aged 33.9 ± 7.2 years; BMI, 21.8 ± 1.7 kg/m 2 ) received a conventional polymeric enteral diet, while group B (10 men; aged 35.6 ± 6.8 years; BMI, 21.4 ± 1.8 kg/m 2 ) was administered a soy-rich and lactose-free polymeric diet, over a 4-week period. Methods All the patients had a clinical and laboratory examination. Body composition was assessed by isotopic dilution and resting metabolic rate (RMR), and substrate oxidation rates were measured by indirect calorimetry. Results Body weight significantly increased after treatment in both groups (A, P

Dicarboxylic acids (DA) are alternate lipid substrates recently proposed in parenteral nutrition. Two new derivatives of DA, a triglyceride of sebacic (TGC10) and one of dodecanedioic (TGC12) acid have been synthesised in order to reduce the amount of sodium given with the unesterified forms. The present paper describes a rapid and direct high-performance liquid chromatographic method (HPLC) for the analysis of these substances in both plasma and urine. Thirty-six male Wistar rats were rapidly injected with 64 mg of TGC10 or 53 mg of TGC12. The triglycerides and their products of hydrolysis were measured in plasma samples taken at different times. For the dose of 500 ng the intra-assay variations ranged from 6. 80+/-0.35% for TGC10 to 18.6+/-3.20% for TGC12 and the inter-assay variations were from 4.44+/-2.21% for TGC10 to 15.0+/-6.72% for TGC12. The detection limit for both triglycerides was 5 ng. This rapid and direct HPLC method could have practical implications in monitoring the concentration of both triglycerides and free forms of DA in biological samples of patients who might benefit from the administration of these substances during parenteral nutrition regimens.

Background: At present few data are available on the total body water (TBW) content and in particular on the distribution of water in the intra- and extracellular compartments (ICW and ECW) of alcoholics. The aim of this study was to evaluate TBW, ICW, and ECW in chronic alcoholic patients. Methods: Thirty-six alcoholics meeting DSM-III-R criteria for diagnosis (20 men, 16 women; body mass index [BMI] 22.3 ± 2.57 kg/m 2 ) were enrolled. Fifty-four healthy social drinkers (31 men, 23 women; BMI 23.7 ± 1.68 kg/m 2 ) matched for age and height were used as controls. Systolic and diastolic blood pressure was measured for all cases. All patients were assessed using specific anthropometric measurements. The waist-to-hip ratio (WHR) was used as an indicator of body fat distribution. TBW was measured by isotopic dilution by giving 100 μCi of tritiated water. ICW and ECW were assessed by multifrequence bioelectric impedance analysis (BIA). Basal metabolic rate (BMR) was measured by indirect calorimetry. Results: Body weight was lower in the alcoholics than in the controls (61.9 ± 5.5 kg vs. 65.8 ± 5.2 kg;p < 0.01), essentially due to a reduction in fat mass. Significantly higher WHR values were found in both male (p < 0.001) and female (p < 0.001) alcoholics than in healthy subjects. A higher ECW/TBW ratio was found in the alcoholics compared with the controls, both as a whole (0.53 ± 0.04 vs. 0.41 ± 0.03; p < 0.0001) and separated by gender (p < 0.001). Conclusions: The increased ECW could derive from an increase in cellular permeability related to endothelial damage linked to the vasoconstriction present in the alcoholics and/or to a direct toxic effect of ethanol on cellular membranes. In addition, because the high ECW volumes correlated positively with WHR in the alcoholics, a potential association of these two factors in determining an increased risk of liver disease, hypertension, and cardiovascular disease may exist. Finally, the lower TBW characteristic of women may be one of the reasons for the observed greater rate of toxic effects of ethanol that occur in women.