Rebecca Marzocchi

Nonalcoholic fatty liver disease and the metabolic syndrome.

Purpose of review Clinical, epidemiological and biochemical data strongly support the concept that nonalcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome. Insulin resistance is the common factor connecting obesity, diabetes, hypertension and dyslipidemia with fatty liver and the progression of hepatic disease to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. Recent findings The association of nonalcoholic fatty liver disease with the features of the metabolic syndrome has been confirmed in several epidemiological studies. The diagnostic and clinical significance of raised liver enzymes has been questioned; advanced hepatic disease may also be present in individuals with ultrasonographically detected steatosis and normal aminotransferase levels. The role of adipokines (leptin, adiponectin) and cytokines (tumor necrosis factor-α, interleukin-6, transforming growth factor-β) in disease progression is probably pivotal, mediated by oxidative stress. The importance of iron accumulation in this process has not been confirmed. Treatments aimed at weight loss remain a primary option; among pharmacological interventions, insulin sensitizers (glitazones and metformin) have confirmed beneficial effects on both biochemical and histological data, but new treatments are on the horizon. Summary Nonalcoholic fatty liver disease prevalence in Western countries is high and there is a trend towards a further increase, with millions of people at risk of advanced liver disease. The epidemiological evidence, the lifestyle origin of the disease and the cost of pharmacotherapy make prevention a primary goal, and will contribute to making behavior therapy the background treatment. We need specific programs and carefully controlled, randomized studies to tackle simultaneously all the components of the metabolic syndrome.

Metabolic syndrome in liver transplantation: Relation to etiology and immunosuppression

Excessive weight gain, hypertension, hyperlipidemia, and diabetes are frequently observed in patients having undergone liver transplantation (LTx). These alterations are probably multifactorial in origin, and cluster to generate a metabolic syndrome (MS), increasing the risk of cardiovascular events. We assessed the prevalence of MS (National Cholesterol Education Program‐Adult Treatment Panel III criteria) in 296 LTx patients in the course of regular follow‐up, at least 6 months after transplantation (median, 38 months). Several pre‐LTx and post‐LTx data were collected to identify the factors associated with the presence of MS. In a subset of 99 patients, insulin resistance was measured by the homeostasis model assessment. High blood pressure was present in 53% of cases, hyperlipidemia in 51%, high glucose in 37%, and enlarged waist circumference in 32%. Overall, MS (defined as 3 or more of the above features) was present in 44.5% of cases. Insulin resistance (homeostasis model assessment > 2.7) was observed in 41% of cases. Hypertension and hyperlipidemia were more frequent in subjects on cyclosporine than in tacrolimus‐treated cases, whereas the type of immunosuppressive drug had no effect on the prevalence of diabetes, enlarged waist, and MS. In a logistic regression analysis, only pre‐LTx body mass index (odds ratio, 1.20), body mass index increase (odds ratio, 1.18), and pre‐LTx diabetes (odds ratio, 2.36) predicted MS; age, gender, etiology of liver disease, time from LTx, type of immunosuppressive drug, and previous hepatocellular carcinoma were removed from the model. Disorders related to MS are frequent in LTx patients, and are related to both pre‐LTx conditions and to weight gain. Weight control is mandatory in LTx patients to prevent risk factors of premature atherosclerosis. Liver Transpl 14: 1648–1654, 2008.

Branched-Chain Amino Acid Supplementation in Patients with Liver Diseases

Because of their peculiar role in whole-body nitrogen metabolism and the competitive action on amino acid transport across the blood-brain barrier, branched-chain amino acids (BCAAs) have been extensively used in subjects with liver disease to preserve or to restore muscle mass and to improve hepatic encephalopathy. There are no data regarding safe limits of BCAA administration; the results appear to be better when BCAA-enriched formulas or BCAA-supplemented diets are preferred to pure BCAA formulas. Improved nitrogen retention might ameliorate the nutritional status, a prognostic index of long-term survival in cirrhosis and of short-term survival in patients undergoing surgical procedures. The effects on nutrition and ultimately on prognosis of patients with advanced cirrhosis were confirmed in a large multicenter, long-term trial where oral BCAA supplements were compared with equicaloric or equinitrogenous-equicaloric supplements (maltodextrin or lactoalbumin). Similarly, BCAA treatment improved the prognosis of patients with hepatocellular carcinoma, treated by surgical resection or chemoembolization, and of liver transplant patients. The mechanism(s) for the beneficial effects of BCAAs might be mediated by their stimulating activity on hepatocyte growth factor, favoring liver regeneration. The debate regarding the potential effectiveness of BCAAs dates back to the early 1980s. The number of patients who cannot tolerate dietary proteins in amounts sufficient to meet the higher catabolism of advanced liver disease is probably low, but BCAAs remain the sole treatment of proved efficacy in this specific setting.

Vascular Risk in Young Women With Polycystic Ovary and Polycystic Ovary Syndrome

OBJECTIVE: To estimate if young polycystic ovary syndrome (PCOS) patients have subclinical risks of vascular disease compared with eumenorrheic polycystic ovary (PCO) women and healthy controls. METHODS: Twenty-eight PCOS patients, 17 eumenorrheic PCO women, and 15 healthy eumenorrheic volunteers underwent medical examination; blood measurement of nitrites/nitrates, biochemical and hormonal parameters; uteroovarian ultrasonographic analysis and color Doppler evaluation of uterine, stromal ovarian, and ophthalmic arteries; brachial artery flow–mediated vasodilatation; 24-hour ambulatory blood pressure monitoring. An oral glucose tolerance test was performed to analyze glucose, insulin, and C-peptide. RESULTS: Doppler analysis revealed a significantly higher uterine pulsatility index in the PCOS group compared with controls. The lowest vascular resistances in the ovaries were found in PCOS and PCO compared with controls. The ophthalmic artery back pressure was significantly higher in women with PCOS than in controls. The brachial artery diameter, at baseline, was similar in all the participants. After the reactive hyperemia, a greater vasodilatation was observed in controls and PCO patients in comparison with PCOS women. Total cholesterol, triglycerides, and the atherogenic plasma index were significantly higher in PCOS than PCO and controls. Leukocytes and homocysteine were slightly higher in PCOS. The nitrites/nitrates plasma levels were lower in PCOS and PCO patients compared with controls. The insulin and C-peptide plasma values were higher in PCOS patients than controls. In PCOS patients the different estimates of insulin sensitivity and pancreatic β-cell function were higher compared with PCO and controls. CONCLUSION: Polycystic ovary syndrome is a condition associated with an increased vascular risk. LEVEL OF EVIDENCE: II

The Effect of Lifestyle Changes in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a clinical/biochemical condition associated with the metabolic syndrome. As the disease stems from excess calorie intake and lack of physical activity, the correction of unhealthy lifestyles is the background of any prevention and treatment strategy; drugs should remain a second-line treatment. Several studies have shown that weight loss and physical activity, the cornerstones of a healthy lifestyle, have a specific therapeutic role in NAFLD, preventing disease progression and reducing the burden of disease. Prescriptive diets have a limited long-term efficacy; after a short period, most patients resume their old habits and weight regain is the rule. Physical activity, usually in combination with diet, but also independent of weight loss, improves liver enzymes and reduces liver fat, with uncertain results on hepatic necroinflammation; however, making patients increase their physical activity is very difficult. Only a behavioral approach may give patients the practical instruments to achieve their eating and exercise goals, incorporate them into lifestyle, and maintain the results for a long period, thereby possibly guaranteeing long-term durability of change. Cognitive-behavior treatment should be provided to patients at risk of advanced liver disease, and this action should be coupled with prevention strategies at the population level. Only a synergistic approach and a global societal response might be effective in reducing the burden of advanced liver disease and premature death due to NAFLD/NASH (non-alcoholic steatohepatitis).

Major factors for facilitating change in behavioral strategies to reduce obesity.

It is very unlikely that our obesity-promoting environment will change in the near future. It is therefore mandatory to improve our knowledge of the main factors associated with successful adoption of obesity-reducing behaviors. This may help design more powerful procedures and strategies to facilitate the adoption of healthy lifestyles in a “toxic” environment favoring the development of a positive energy balance. The aim of this review is to describe the main factors associated with successful adoption of obesity-reducing behaviors and to describe the most recent development, limits, and outcomes of lifestyle modification programs. The evidence regarding predictors of weight loss and weight loss maintenance remains largely incomplete. It is necessary to develop strategies matching treatments to patients’ needs to improve successful weight loss and its maintenance. How to detect and how to address these needs is a continuous, challenging, research problem.

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.

Update on nutritional supplementation with branched-chain amino acids

Purpose of reviewBranched-chain amino acids (BCAAs) have a peculiar role in whole-body nitrogen metabolism. BCAAs are not only a substrate for protein synthesis, but also modulate several components of the synthetic machinery and help to conserve muscle mass; accordingly, several conditions, characterized by protein loss and catabolic status, are likely to benefit from amino acid administration. In addition, the competitive action of BCAAs on amino acid transport across the blood-brain barrier may ultimately alter the synthesis of brain neurotransmitters, involved in neurological diseases. Recent findingsBoth putative actions of BCAAs have been tested in controlled clinical studies in the last few years. The beneficial effects on nutrition were reported to improve muscle performance, reduce protein loss during bed-rest, favor weight loss in obesity, reduce catabolism in trauma patients and improve clinical outcomes in patients with advanced cirrhosis. In this last area, the effects on nutrition might be coupled with the effects on hepatic encephalopathy mediated by improved neurotransmission, successfully tested in mania, tardive dyskinesia and spinocerebellar degeneration. SummaryAfter 30 years of investigation with BCAAs, new studies each year provide further evidence supporting their beneficial effect in a variety of diseases. There is a need for long-term, randomized clinical studies, both in the prevention and in the treatment of various pathological conditions.

Lifestyle modification in the management of the metabolic syndrome: achievements and challenges

Lifestyle modification based on behavior therapy is the most important and effective strategy to manage the metabolic syndrome. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioral and cognitive strategies. The intervention may be delivered face-to-face or in groups, or in groups combined with individual sessions. The main challenge of treatment is helping patients maintain healthy behavior changes in the long term. In the last few years, several strategies have been evaluated to improve the long-term effect of lifestyle modification. Promising results have been achieved by combining lifestyle modification with pharmacotherapy, using meals replacement, setting higher physical activity goals, and long-term care. The key role of cognitive processes in the success/failure of weight loss and maintenance suggests that new cognitive procedures and strategies should be included in the traditional lifestyle modification interventions, in order to help patients build a mind-set favoring long-term lifestyle changes. These new strategies raise optimistic expectations for an effective treatment of metabolic syndrome with lifestyle modifications, provided public health programs to change the environment where patients live support them.

Update on branched-chain amino acid supplementation in liver diseases

Purpose of review Branched-chain amino acids (BCAAs) have a peculiar role in whole-body nitrogen metabolism. BCAAs are a substrate for protein synthesis, and have been used to conserve or restore muscle mass in advanced liver disease. In addition, the competitive action of BCAAs on amino acid transport across the blood-brain barrier may improve hepatic encephalopathy. Recent findings The effects of branched-chain amino acids on nutrition and ultimately on prognosis of patients with advanced cirrhosis have been confirmed in a large multicenter, long-term trial. Similarly, BCAA treatment improved the prognosis of patients with hepatocellular carcinoma, treated by chemoembolization. The mechanism for the beneficial effects of BCAA is likely to depend on the stimulating activity of BCAA on hepatocyte growth factor, favoring liver regeneration. Summary After an experience of 25 years with branched-chain amino acids, new data supports their beneficial effect in liver diseases. Although the number of patients who cannot tolerate dietary proteins in amounts sufficient to meet their increased catabolism is probably low, in this specific setting BCAAs remain the sole treatment of proved efficacy.