Veronique Chachay

Resveratrol Does Not Benefit Patients With Nonalcoholic Fatty Liver Disease

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD. METHODS Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were randomly assigned to groups given 3000 mg resveratrol (n = 10) or placebo (n = 10) daily for 8 weeks. Outcomes included insulin resistance (assessed by the euglycemic-hyperinsulinemic clamp), hepatic steatosis, and abdominal fat distribution (assessed by magnetic resonance spectroscopy and imaging). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured; transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed. RESULTS Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1, PTP1B, IL6, or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated. CONCLUSIONS Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.

Resveratrol - pills to replace a healthy diet?

Nutrapharmacology, or the use of bioactive food compounds at pharmacological doses is emerging as a therapeutic approach to target the complex metabolic dysregulations in ageing and obesity-related chronic disease. Resveratrol, a polyphenol found in the skin of grapes, and other edible plants and related food products, has received extensive attention through the link with the French paradox, and later with its chemopreventive activity demonstrated in vitro and in animal cancer models. A plethora of laboratory investigations has provided evidence for the multi-faceted properties of resveratrol and suggests that resveratrol may target ageing and obesity-related chronic disease by regulating inflammation and oxidative stress. A number of obstacles stand in the path to clinical usage however, not least the lack of clinical evidence to date, and the myriad of doses and formulations available. Further, data on the effects of resveratrol consumption in a capsule vs. food form is conflicting, and there are uncertain effects of long term dosing. The review will summarize the human pharmacokinetic and pharmacodynamic published data, and the topics for research if resveratrol is to become a multi-target therapeutic agent addressing chronic disease.

A Pilot Randomised Study of the Metabolic and Histological Effects of Exercise in Non-alcoholic Steatohepatitis

Aims: Type 2 diabetes is a risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). Lifestyle intervention is the principal treatment for NAFLD however the effects of exercise alone on the histological and metabolic severity of NAFLD are unclear. This study assessed the effects of 6 months exercise training and diet-induced weight loss on insulin resistance and liver histologyin overweight patients with NAFLD. Methods: 21 patients were randomised to circuit exercise (EX) training (60 min×3/week) or dietary induced weight loss (DIWL) (-500 kcal/d). Insulin sensitivity (euglycaemic-hyperinsulinemic clamp with tracer), adiposity (CT scan) and histology (liver biopsy) were assessed at 0 and 6 months. Results: Weight decreased by 9.7 ± 4.6% (-6.7 ± 6.3 kg p=0.02) with DIWL but was unchanged after EX. Both groups equivalently reduced visceral fat (DIWL -22 ± 24% p=0.06 and EX -18 ± 18% p<0.05) while only EX increased lean mass (+3% p<0.01). DIWL markedly reduced steatosis (73 ± 36% to 23 ± 32%, p<0.05) and NAFLD activity score NAS (median (range) 5 (1-7) to 1 (0-5), p<0.05). After EX, there was no change in steatosis or NAS. A decrease in steatosis was associated with weight loss (r s =0.82, p<0.0001). An improvement in fibrosis was associated with a decrease in steatosis (r s =0.64, p=0.02). Small improvements in fasting hepatic insulin resistance were similar in both groups while changes in muscle insulin resistance were not significant. Conclusions: Circuit exercise is safe and efficacious for improving cardiometabolic risk factors in patients with NAFLD, however this dose of circuit training, without concomitant weight loss, was insufficient for histological improvements in NAFLD. The pilot study outcomes should stimulate further development of different exercise protocols (type, frequency and intensity) to address disease-specific conditions in those with severe insulin resistance.

Optimising care of patients with chronic disease: patient-oriented education may improve disease knowledge and self-management

Many patients with chronic disease do not possess the knowledge and skills required to access and interpret appropriate health information. A pilot study in people with liver cirrhosis (n = 50) identified that only 54% of patients could recall being given written information by a clinician and 64% had self‐sought information, most commonly using the Internet. Many patients reported difficulties understanding the material and the majority wanted more accessible information. A pilot chronic disease educational booklet was well received by the study participants with 85% reporting it was helpful and 78% using it in between clinic appointments.

Independent effects of diet and exercise training on fat oxidation in non-alcoholic fatty liver disease

AIM To investigate the independent effects of 6-mo of dietary energy restriction or exercise training on whole-body and hepatic fat oxidation of patients with non-alcoholic fatty liver disease (NAFLD). METHODS Participants were randomised into either circuit exercise training (EX; n = 13; 3 h/wk without changes in dietary habits), or dietary energy restriction (ER) without changes in structured physical activity (ER; n = 8). Respiratory quotient (RQ) and whole-body fat oxidation rates (Fatox) were determined by indirect calorimetry under basal, insulin-stimulated and exercise conditions. Severity of disease and steatosis was determined by liver histology; hepatic Fatox was estimated from plasma β-hydroxybutyrate concentrations; cardiorespiratory fitness was expressed as VO2peak. Complete-case analysis was performed (EX: n = 10; ER: n = 6). RESULTS Hepatic steatosis and NAFLD activity score decreased with ER but not with EX. β-hydroxybutyrate concentrations increased significantly in response to ER (0.08 ± 0.02 mmol/L vs 0.12 ± 0.04 mmol/L, P = 0.03) but remained unchanged in response to EX (0.10 ± 0.03 mmol/L vs 0.11 ± 0.07 mmol/L, P = 0.39). Basal RQ decreased (P = 0.05) in response to EX, while this change was not significant after ER (P = 0.38). VO2peak (P < 0.001) and maximal Fatox during aerobic exercise (P = 0.03) improved with EX but not with ER (P > 0.05). The increase in β-hydroxybutyrate concentrations was correlated with the reduction in hepatic steatosis (r = -0.56, P = 0.04). CONCLUSION ER and EX lead to specific benefits on fat metabolism of patients with NAFLD. Increased hepatic Fatox in response to ER could be one mechanism through which the ER group achieved reduction in steatosis.

Discrepancies in the use of medications in patients with cirrhosis

Individuals with decompensated cirrhosis and ascites requiring paracentesis utilize exceptionally high levels of hospital resources. Consequently, potential modifications to existing models of healthcare to assist patients in the management of their liver disease and reduce the need for hospital encounters have potential to improve patients’ health and reduce demand on acute hospital services. However, there is a paucity of data examining how much healthcare resources could be re-directed to interventions that prevent hospitalizations without net annual budgetary disadvantage (from the hospital’s perspective). The purpose of this study was to probabilistically examine how much healthcare resourcing could be saved per hospital presentation avoided among this clinical population.