Nicola Villanova

A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease.

OBJECTIVES:Metformin proved useful in the treatment of nonalcoholic fatty liver disease (NAFLD), but its superiority over nutritional treatment and antioxidants has never been demonstrated. We aimed to compare the usefulness of metformin versus prescriptive diet or vitamin E.METHODS:In an open label, randomized trial, nondiabetic NAFLD patients were given metformin (2 g/day; n = 55) for 12 months. The control cases were given either vitamin E (800 IU/day; n = 28) or were treated by a prescriptive, weight-reducing diet (n = 27). Outcome measures were liver enzymes, insulin resistance (homeostasis model assessment), parameters of the metabolic syndrome, and histology.RESULTS:Aminotransferase levels improved in all groups, in association with weight loss. The effects in the metformin arm were larger (p < 0.0001), and alanine aminotransferase normalized in 56% of cases (odds ratio (OR) versus. controls, 3.11; 95% confidence interval (CI), 1.56–6.20; p = 0.0013). In multivariate analysis, metformin treatment was associated with higher rates of aminotransferase normalization, after correction for age, gender, basal aminotransferases, and change in body mass index (OR, 5.98; 95% CI, 2.05–17.45). Differences were maintained when the two control groups were separately analyzed. The distribution of positive criteria for the metabolic syndrome was reduced only in the metformin arm (p = 0.001, signed rank test). A control biopsy in 17 metformin-treated cases (14 nonresponders) showed a significant decrease in liver fat (p = 0.0004), necroinflammation, and fibrosis (p = 0.012 for both). No side effects were observed during metformin treatment.CONCLUSIONS: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.

Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is consistently associated with features of the metabolic syndrome, a condition carrying a high risk of cardiovascular events. We measured the vasodilatory response of the brachial artery in response to ischemia (a test of endothelial function) (FMV) as well as cardiovascular risk profile in 52 NAFLD cases and 28 age‐ and sex‐matched controls. The 10‐year risk of coronary events was calculated according to the Framingham equation and the scores derived from the PROCAM study and NCEP‐ATPIII proposals. FMV was 6.33% ± 5.93% in NAFLD versus 12.22% ± 5.05% in controls (P < .0001), and higher in pure fatty liver (9.93%) compared with nonalcoholic steatohepatitis (4.94%) (P = .010). No differences were observed in flow‐independent vasodilation (response to sublingual nitroglycerin). Percent FMV was negatively associated with insulin resistance (homeostasis model assessment) in the whole population (r = −0.243; P = .030). In logistic regression analysis, NAFLD was associated with a percent FMV in the lower tertile (OR, 6.7; 95% CI, 1.26–36.1), after adjustment for age, sex, body mass index, and insulin resistance. Among NAFLD patients, low FMV was associated with nonalcoholic steatohepatitis (adjusted OR, 6.8; 95% CI, 1.2–40.2). The 10‐year probability of cardiovascular events was moderately increased in NAFLD, and particularly in nonalcoholic steatohepatitis. In conclusion, our study provides evidence of endothelial dysfunction and increased risk of cardiovascular events in NAFLD. The risk of advanced liver disease is well recognized in NAFLD patients, but the large majority of cases might experience cardiovascular disease in the long term, indirectly limiting the burden of liver failure. (HEPATOLOGY 2005.)

Gallstone recurrence after successful oral bile acid treatment

Recurrence is a major problem in the medical treatment of gallstones but its extent is still uncertain. The aim of this study was to determine the magnitude of this event and to assess the effectiveness of a postdissolution treatment in preventing it. We evaluated the long-term recurrence rate after 96 confirmed dissolutions observed in 86 subjects (71 women, 15 men) over a 12-yr follow-up period. A low-dose postdissolution treatment (ursodeoxycholic acid, 300 mg/day) was administered to 36 subjects, whereas in the remaining 60 cases no postdissolution treatment was given. By actuarial life-table analysis, the cumulative proportion of gallstone recurrence was 12.5% at the first year, rising to 61% at the 11th year. Postdissolution treatment was effective in reducing the frequency of gallstone recurrence (p = 0.0067), but this was mainly related to its effect on younger subjects (less than or equal to 50 yr old). In older subjects the recurrence rate was unaffected by treatment. The probability of gallstone recurrence was significantly higher in subjects with multiple stones before dissolution treatment than in those who had had solitary stones (p = 0.0091). No other factor predictive of gallstone recurrence could be identified.

Clinical and psychological correlates of health-related quality of life in obese patients

BackgroundHealth-related quality of life (HRQL) is poor in obese subjects and is a relevant outcome in intervention studies. We aimed to determine factors associated with poor HRQL in obese patients seeking weight loss in medical units, outside specific research projects.MethodsHRQL, together with a number of demographic and clinical parameters, was studied with generic (SF-36, PGWB) and disease-specific (ORWELL-97) questionnaires in an unselected sample of 1,886 (1,494 women; 392 men) obese (BMI > 30 kg/m2) patients aged 20-65 years attending 25 medical units scattered throughout Italy. The clinics provide weight loss treatment using different programs. General psychopathology (SCL-90 questionnaire), the presence of binge eating (Binge Eating scale), previous weight cycling and somatic comorbidity (Charlsons index) were also determined. Scores on SF-36 and PGWB were compared with Italian population norms, and their association with putative determinants of HRQL after adjustment for confounders was assessed through logistic regression analysis.ResultsHRQL scores were significantly lower in women than in men. A greater impairment of quality of life was observed in relation to increasing BMI class, concurrent psychopathology, associated somatic diseases, binge eating, and weight cycling. In multivariate analysis, psychopathology (presence of previously-diagnosed mental disorders and/or elevated scores on SCL-90) was associated with lower HRQL scores on both psychosocial and somatic domains; somatic diseases and higher BMI, after adjustment for confounders, were associated with impairment of physical domains, while binge eating and weight cycling appeared to affect psychosocial domains only.ConclusionsPsychopathological disturbances are the most relevant factors associated with poor HRQL in obese patients, affecting not only psychosocial, but also physical domains, largely independent of the severity of obesity. Psychological/psychiatric interventions are essential for a comprehensive treatment of obesity, and to improve treatment outcome and to reduce the burden of disease.

Gallbladder motility and gallstone formation in obese patients following very low calorie diets. Use it (fat) to lose it (well)

OBJECTIVE: Dieting obese subjects are at risk of developing gallstones. A gallbladder motor dysfunction could have a pathogenetic role. The principal aim of this study was to evaluate the long term effects of two very low calorie diets differing in fat content on gallbladder emptying and gallstone formation in obese subjects.DESIGN AND SUBJECTS: Gallbladder emptying in response to meals (breakfast, lunch and dinner) in two different diet regimens (3.0 vs 12.2 g of fat/d) was evaluated by ultrasonography in 32 gallstone-free obese patients on different days, before and during (at 45 d intervals) one or two 6-month weight reduction diets (for the first three months: 2.24 MJ (535.2 kcal), 3.0 g fat/d vs 2.415 MJ (577.0 kcal), 12.2 g fat/d; for the second three months, the same low calorie diet of 4.194 MJ (1002 kcal)/d for both groups). In 10 subjects, bile analysis was also performed.RESULTS: Twenty-two (69%) subjects concluded the study, eleven in each group, and a significant weight loss was achieved by all subjects. Gallstones (asymptomatic) developed in 6/11 (54.5%) (P<0.01) of subjects following the lower fat diet, but in none with the higher fat regimen. In the dieters during the first three months (very low calorie phase) the higher fat meals always induced a significantly greater gallbladder emptying than the lower fat meals. The cholesterol saturation index initially increased significantly and then decreased, without difference between the two groups.CONCLUSION: In the obese during rapid weight loss from a very low calorie diet, a relatively high fat intake could prevent gallstone formation, probably by maintaining an adequate gallbladder emptying, which could counterbalance lithogenic mechanisms acting during weight loss.

A physical activity program to reinforce weight maintenance following a behavior program in overweight/obese subjects

Objective:To investigate the effects of a specific program to implement physical activity (fitness program) on weight loss maintenance, activity level and resting energy expenditure (REE).Design:Observational study of subjects completing a behavioral program.Subjects:In total, 200 overweight/obese subjects (36 males, aged 20–66 years; average BMI, 35.2 kg/m2).Program and measurements:The fitness program consisted of 12 bimonthly sessions, chaired by doctors and dietitians, involving groups of 8–12 subjects. Patients entered the program approximately 9 months after the end of behavioral treatment, during a weight loss maintenance period. The goal was set at a light-to-moderate daily physical activity (brisk walking), quantitatively measured by a pedometer; REE was measured before and after the fitness program by indirect calorimetry in a subset of patients.Results:The fitness program restarted the process of weight loss in over 60% of subjects. At the end of the study, 84% of patients walked at least 5000 steps per day, compared with 24% at the beginning of the study. The probability of losing from 5 to 10% of initial body weight increased by 20% for any 1000 steps/day (OR, 1.20; 95% CI (confidence interval), 1.07–1.35), and that of losing more than 10% by over 30% (OR, 1.33; 95% CI, 1.19–1.49). REE increased significantly by 100 kcal/day (+7.5%), in spite of further weight loss (−1.8%).Conclusion:A specific fitness program in the weight maintenance phase after a behavioral program may significantly improve the long-term control of obesity.

Treatment of chronic sporadic-type non-A, non-B hepatitis with lymphoblastoid interferon: Gamma GT levels predictive for response

The aim of this study was to evaluate the efficacy of human lymphoblastoid interferon-α treatment in chronic sporadic-type non-A, non-B hepatitis. We also aimed to determine if histological or liver function data could predict either response or relapse. Sixty patients with chronic sporadic-type non-A, non-B hepatitis were randomized in two groups of 30. One group was treated with interferon-α (3 MU thrice weekly) for one year; the other group was untreated controls. The treated group was followed for another year after interferon withdrawal. Liver function tests were performed during treatment. Liver biopsy was carried out before and a year after randomization. We evaluated rate of response [normalization of alanine aminotransferase (ALT) levels for at least three consecutive months] and rate of relapse (ALT rebound after therapy suspension). We also looked at possible predictive factors for response and relapse. In the treatment group the rate of response was 55% (16/29). No control patient exhibited ALT normalization. Among the responders, 31% (5/16) relapsed after interferon withdrawal. Low gamma GT and female sex are positive predictive factors of response (P<0.01 andP<0.02 respectively). Presence of portal and periportal inflammation at the second liver biopsy was correlated with relapse (P<0.05). In conclusion, human lyphoblastoid interferon-α treatment for one year is beneficial in patients suffering from chronic sporadic-type non-A, non-B hepatitis. Low pretreatment gamma GT levels and female sex are positive predictors of response in this patient population. Low degrees of portal and periportal inflammation, posttreatment, predict maintenance of response.

Ursodeoxycholic acid administration on bile acid metabolism in patients with early stages of primary biliary cirrhosis.

Ursodeoxycholic acid has been proposed for the treatment of primary biliary cirrhosis. The aim of this study was to evaluate the effect of ursodeoxycholic acid administration on bile acid metabolism in patients with early-stage primary biliary cirrhosis. Biliary bile acid composition, primary bile acid pool sizes, synthesis, and fractional turnover rate were measured before and after four weeks of ursodeoxycholic acid administration (600 mg/day) in nine patients with biopsy-proven primary biliary cirrhosis (stages I-III). Molar percentages of chenodeoxycholic, cholic, and deoxycholic acids in bile were significantly decreased by ursodeoxycholic acid administration, while its biliary concentration increased to 34.2% at the end of the same four-week period. The cholic and chenodeoxycholic acid pools decreased, although not significantly, while the deoxycholic acid pool was reduced by 60% (from 0.7±0.12 to 0.29±0.07 mmol,P<0.002). Primary bile acid synthesis was slightly increased, and fractional turnover rate was significantly increased. The conversion rate of cholic to deoxycholic acid was measured and found to be significantly increased (P<0.05) after ursodeoxycholic acid administration; however, serum levels of both free and conjugated deoxycholic acid were significantly decreased (from 23.2±9.7 to 3.8±1.9 μmol/liter,P<0.001). We conclude that in patients with primary biliary cirrhosis, ursodeoxycholic acid administration replaces endogenous bile acids in the enterophepatic circulation by increasing bile acid fractional turnover rate without significant increments of their hepatic synthesis.

Pilot study on the additive effects of berberine and oral type 2 diabetes agents for patients with suboptimal glycemic control

Background Suboptimal glycemic control is a common situation in diabetes, regardless of the wide range of drugs available to reach glycemic targets. Basic research in diabetes is endeavoring to identify new actives working as insulin savers, use of which could delay the introduction of injectable insulin or reduce the insulin dose needed. Commonly available as a nutraceutical, berberine is a potential candidate. Methods and results Because its low oral bioavailability can be overcome by P-glycoprotein inhibitors like herbal polyphenols, we have tested the nutraceutical combination of Berberis aristata extract and Silybum marianum extract (Berberol®) in type 2 diabetes in terms of its additive effect when combined with a conventional oral regimen for patients with suboptimal glycemic control. After 90 days of treatment, the nutraceutical association had a positive effect on glycemic and lipid parameters, significantly reducing glycosylated hemoglobin, basal insulin, homeostatic model assessment of insulin resistance, total and low-density lipoprotein cholesterol, and triglycerides. A relevant effect was also observed in terms of liver function by measuring aspartate transaminase and alanine transaminase. The product had a good safety profile, with distinctive gastrointestinal side effects likely due to its acarbose-like action. Conclusion Although further studies should be carried out to confirm our data, Berberol could be considered a good candidate as an adjunctive treatment option in diabetes, especially in patients with suboptimal glycemic control.

Effect of ursodeoxycholic acid administration on biliary lipid secretion in primary biliary cirrhosis.

Ursodeoxycholic acid (UDCA) has been reported to improve liver function tests when administered to patients with cholestatic liver diseases, such as primary biliary cirrhosis (PBC). However, its effects on biliary lipid metabolism in patients with PBC are still unknown. In this study we report the effect that UDCA (600 mg/day, for four weeks) had on biliary cholesterol saturation index, biliary bile acid pattern and pool size, and biliary lipid output in seven female patients (ages 34–58 years) with PBC, stages I to III. A significant improvement of liver function tests was observed after four weeks of treatment. Saturation index was significantly decreased from 1.23±0.1 to 0.7±0.08 (P<0.02); this effect was due to the significant decrease of biliary cholesterol concentration from 6.7±0.36 to 3.6±0.37 percent molar (P<0.02). A significant decrease of cholesterol output (from 88±9 to 55±10 μmol/hr, P<0.02) was also observed. The amount of cholic acid, the predominant bile acid in bile, significantly decreased (from 47.3±3.5 to 35.4±2.6 percent molar, P<0.02), as did amounts of chenodeoxycholic and deoxycholic acids, while the amount of UDCA rose from 1.6±1.0 to 34.0±1.3 percent molar (P<0.02). Total bile acid pool size was not affected by UDCA, but the evaluation of individual bile acid pool sizes showed an increased proportion of UDCA relative to the endogenous bile acids. The results of the study confirm the beneficial effect of UDCA on liver function tests in PBC patients and support the hypothesis that the improvement of these measurements may be due to replacement of toxic endogenous bile acids with UDCA.