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Abstracts

Life Extension Magazine January 2012
Abstracts

Liver Efficiency

Treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) comprises benign steatosis and steatohepatitis (NASH) and may lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Its prevalence is estimated to be 20% in the general population and 50-100% in patients with overweight and obesity. In about 15-30% of patients steatosis evolves to NASH which can only be diagnosed by means of a liver biopsy. NAFLD may be described as the hepatic component of the metabolic syndrome and is a consequence of the Western lifestyle. The pathogenesis is multifactorial; oxidative stress plays a crucial role in maintaining inflammation and progressive fibrosis. Lifestyle modification with weight loss and increased physical activity is the cornerstone of the treatment, which should take place in a multidisciplinary setting. To date, no specific registered drug for NAFLD treatment is available. Supportive drug therapy is mainly focused on aspects of the metabolic syndrome and chronic inflammation.

Ned Tijdschr Geneeskd. 2011;155:A3181

Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is associated with cardiovascular risk. The aim of this study was to determine the role of fatty liver in predicting coronary artery disease and clinical outcomes in patients undergoing coronary angiogram. METHODS: This was a prospective cohort study carried out in a University hospital. Consecutive patients who underwent coronary angiogram had ultrasound screening for fatty liver. Significant cardiovascular disease was defined as ≥50% stenosis in at least one coronary artery. The primary outcome was a composite end point comprising cardiovascular deaths, non-fatal myocardial infarction and the need for further coronary intervention during prospective follow-up. RESULTS: Among 612 recruited patients, 356 (58.2%) had fatty liver by ultrasonography, 318 (52.0%) had elevated serum alanine aminotransferase and 465 (76.0%) had significant coronary artery disease. Coronary artery disease occurred in 84.6% of patients with fatty liver and 64.1% of those without fatty liver (p<0.001). After adjusting for demographic and metabolic factors, fatty liver (adjusted OR 2.31; 95% CI 1.46 to 3.64) and alanine aminotransferase level (adjusted OR 1.01; 95% CI 1.00 to 1.02) remained independently associated with coronary artery disease. At a mean follow-up of 87±22 weeks, 30 (10.0%) patients with fatty liver and 18 (11.0%) patients without fatty liver reached the composite clinical end point (p=0.79). CONCLUSIONS: In patients with clinical indications for coronary angiogram, fatty liver is associated with coronary artery disease independently of other metabolic factors. However, fatty liver cannot predict cardiovascular mortality and morbidity in patients with established coronary artery disease.

Gut. 2011 May 20

Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist as they share the pathogenic abnormalities of excess adiposity and insulin resistance. Although type 1 diabetes mellitus (T1DM) is due to a relative lack of insulin, an increased prevalence of obesity and insulin resistance in this population means that NAFLD also commonly coexists with this condition. Both T2DM and NAFLD are associated with adverse outcomes of the other; T2DM is a risk factor for progressive liver disease and liver-related death in patients with NAFLD, whereas NAFLD may be a marker of cardiovascular risk and mortality in individuals with T2DM. Nonalcoholic steatohepatitis-a histological subtype of NAFLD characterized by hepatocyte injury and inflammation-is present in approximately 10% of patients with T2DM and is associated with an increased risk for the development of cirrhosis and liver-related death. Current treatment strategies aim to improve insulin resistance via weight loss and exercise, improve insulin sensitivity by the use of insulin-sensitizing agents (for example, pioglitazone) and reduce oxidative stress by the use of antioxidants, such as vitamin E. Pioglitazone and vitamin E supplementation show the most promise in improving hepatic steatosis and inflammation but have not yet been demonstrated to improve fibrosis, and concern remains regarding the toxicity of long-term use of both of these agents.

Nat Rev Endocrinol. 2011 May 10;7(8):456-65

Full-spectrum antioxidant therapy featuring astaxanthin coupled with lipoprivic strategies and salsalate for management of non-alcoholic fatty liver disease.

Owing to the worldwide epidemic of obesity, and the popularity of diets rich in sugar and saturated fat, nonalcoholic fatty liver disease (NAFLD) is increasingly common; it is usually associated with insulin resistance, and may be considered a component of the metabolic syndrome. The pathologies which can complicate hepatic steatosis—steatohepatitis, cirrhosis, and hepatic cancer--appear to result from an interaction of hepatic lipid overload and hepatic oxidative stress. It is therefore proposed that comprehensive regimens which effectively target each of these precipitating factors should achieve the best therapeutic benefit in NAFLD. Appropriate weight loss, and a diet low in saturated fat, glycemic index, and added sugars, should decrease hepatic lipid load. Measures which enhance adipocyte insulin sensitivity—such as pioglitazone, astaxanthin, and spirulina--may also be helpful in this regard, as may agents that boost hepatocyte capacity for fatty acid oxidation, such as metformin, carnitine, hydroxycitrate, long-chain omega-3 fats, and glycine. Astaxanthin and spirulina appear to have considerable potential for controlling the oxidative stress associated with NAFLD - the former because it may help to prevent the mitochondrial damage that renders mitochondria a key source of superoxide in this syndrome, the latter because it is exceptionally rich in phycocyanobilin, a phytochemical inhibitor of NAPDH oxidase. Other antioxidants which show some promise in this syndrome include high-dose folate, lipoic acid, melatonin, N-acetylcysteine, vitamin E, and taurine. Finally, treatment with salsalate, an inhibitor of IkappaB kinase-beta, has potential for blunting the adverse impact of hepatic steatosis on oxidative stress and inflammation.

Med Hypotheses. 2011 Oct;77(4):550-6

Nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), the most common liver disorder in the Western world, is a clinico-histopathological entity in which excessive triglyceride accumulation in the liver occurs. Non-alcoholic steatohepatitis (NASH) represents the necroinflammatory form, which can lead to advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of NAFLD/NASH is complex but increased visceral adiposity plus insulin resistance with increased free fatty acids release play an initial key role for the onset and perpetuation of liver steatosis. Further events in the liver include oxidative stress and lipid peroxidation, decreased antioxidant defences, early mitochondrial dysfunction, iron accumulation, unbalance of adipose-derived adipokines with a chronic proinflammatory status, and gut-derived microbial adducts. New gene polymorphisms increasing the risk of fatty liver, namely APOC3 and PNPLA3, have been lately identified allowing further insights into the pathogenesis of this condition. In our review pathophysiological, genetic, and essential diagnostic and therapeutic aspects of NAFLD are examined with future trends in this field highlighted.

Best Pract Res Clin Gastroenterol. 2010 Oct;24(5):695-708

Oxidant stress and antioxidant status among patients with nonalcoholic fatty liver disease (NAFLD).

BACKGROUND: One of the major pathogenic mechanisms for progression of nonalcoholic fatty liver disease (NAFLD) is oxidative stress. Recently, many studies have demonstrated the role of oxidative stress in NAFLD however, studies describing the antioxidant status in these patients are lacking. AIM: To study the levels of oxidative stress and antioxidant status among patients with NAFLD. PATIENTS AND METHODS: It was a prospective study in which 29 patients with NAFLD, 25 diseased controls with chronic viral hepatitis, and 23 healthy controls were enrolled. Apart from standard biochemical parameters, lipid peroxidation products were measured as thiobarbituric acid reactive substances. As measures of antioxidant capacity, superoxide dismutase, vitamin C levels and ferric reducing ability of plasma were measured. RESULTS: Level of thiobarbituric acid reactive substances was significantly higher among NAFLD patients as compared with diseased [4.7 nmol/mL (1.0 to 10.2) vs. 2.4 nmol/mL (0.8 to 10.7); P=0.02] or healthy controls [4.7 nmol/mL (1.0 to 10.2) vs. 1.8 nmol/mL (0.5 to 4.1); P=0.0001]. FRAP was found to be significantly higher in patients with NAFLD as compared with healthy controls [450.3 (197.6 to 733.3) vs. 340.8 (141.6 to 697.5) mumol Fe liberated; P=0.04], even though it was similar between NAFLD and diseased controls. Among NAFLD patients, there was no significant correlation between histological grading or staging and levels of pro and antioxidants. CONCLUSIONSProducts of lipid peroxidation are significantly increased among patients with NAFLD as compared with chronic viral hepatitis or healthy controls. Larger studies and newer markers of oxidative stress are required to clarify the association between oxidative stress and histological severity in NAFLD.

J Clin Gastroenterol. 2006 Nov-Dec;40(10): 930-5

Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease in the world. It encompasses a histological spectrum, ranging from simple, nonprogressive steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. While liver-related complications are confined to NASH, emerging evidence suggests both simple steatosis and NASH predispose to type 2 diabetes and cardiovascular disease. The pathogenesis of NAFLD is currently unknown, but accumulating data suggest that oxidative stress and altered redox balance play a crucial role in the pathogenesis of steatosis, steatohepatitis, and fibrosis. We will examine intracellular mechanisms, including mitochondrial dysfunction and impaired oxidative free fatty acid metabolism, leading to reactive oxygen species generation; additionally, the potential pathogenetic role of extracellular sources of reactive oxygen species in NAFLD, including increased myeloperoxidase activity and oxidized low density lipoprotein accumulation, will be reviewed. We will discuss how these mechanisms converge to determine the whole pathophysiological spectrum of NAFLD, including hepatocyte triglyceride accumulation, hepatocyte apoptosis, hepatic inflammation, hepatic stellate cell activation, and fibrogenesis. Finally, available animal and human data on treatment opportunities with older and newer antioxidant will be presented.

Antioxid Redox Signal. 2011 Sep 1;15(5):1325-65

Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model.

BACKGROUND & AIMS: In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model. METHODS: OLETF rats and their non-hyperphagic control Long-Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n=6-8 per group). RESULTS: At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p<0.01) hepatic mitochondrial dysfunction as measured by reduced hepatic carnitine palmitoyl-CoA transferase-1 activity, fatty acid oxidation, and cytochrome c protein content compared with LETO rats. Hepatic TG levels were significantly elevated by 8 weeks of age, and insulin resistance developed by 13 weeks in the OLETF rats. NAFLD progressively worsened to include hepatocyte ballooning, perivenular fibrosis, 2.5-fold increase in serum ALT, hepatic mitochondrial ultrastructural abnormalities, and increased hepatic oxidative stress in the OLETF animals at later ages. Measures of hepatic mitochondrial content and function including beta-hydroxyacyl-CoA dehydrogenase activity, citrate synthase activity, and immunofluorescence staining for mitochondrial carbamoyl phosphate synthetase-1, progressively worsened and were significantly reduced at 40 weeks in OLETF rats compared to LETO animals. CONCLUSIONS: Our study documents that hepatic mitochondrial dysfunction precedes the development of NAFLD and insulin resistance in the OLETF rats. This evidence suggests that progressive mitochondrial dysfunction contributes to the natural history of obesity-associated NAFLD.

J Hepatol. 2010 May;52(5):727-36

Effectiveness of the analogue of natural Schisandrin C (HpPro) in treatment of liver diseases: an experience in Indonesian patients.

OBJECTIVE: To determine the effect of dimethyl-4,4’-dimethoxy-5,6, 5’,6-dimethylene dioxy- biphenyl-2,2’-dicarboxylate (HpPro) on patients with acute and chronic liver diseases. METHODS: An open trial and a prospective randomized and controlled study were performed. The open trial consisted of 56 cases (16 cases of acute hepatitis, 20 cases of chronic hepatitis, 14 cases of liver cirrhosis and 6 cases of fatty liver). Controlled study consisted of 20 cases of Child A chronic hepatitis which were randomly treated with either HpPro or a mixture of known drugs which used as a liver protective agent in Indonesia as control for one week. The patients were then crossed over those two drugs in the next week. RESULTS: In the open trial, after 4 weeks’ treatment with HpPro 7.5 mg orally three times daily, acute hepatitis, chronic hepatitis and fatty liver cases showed rapid decrease of SGOT and SGPT. In the liver cirrhosis cases, SGOT and SGPT were decreased slowly. In the controlled trial, nine patients received HpPro 7.5 mg three times daily orally and eleven were treated with a mixture of known drugs as the controls. After one week treatment, HpPro group clinically showed significant decrease of SGPT and SGOT levels compared to control group (P = 0.035). At the second week, HpPro group showed significant decrease of SGOT compared to control group (P = 0.038) but the decrease of SGPT was not significant (P = 0.096). CONCLUSION: Treatment with HpPro is effective to reduce liver impairment in acute and chronic liver diseases on Indonesian patients. No side effect of HpPro was observed.

Chin Med J (Engl). 1998 Mar;111(3):248-51

A melon pulp concentrate rich in superoxide dismutase reduces stress proteins along the gastrointestinal tract of pigs.

OBJECTIVE: A melon (Cucumis melo LC.) pulp concentrate (MPC) rich in superoxide dismutase (SOD) activity was tested for its ability to decrease stress protein expressions along the gastrointestinal tract in a swine model. METHODS: Pig sextuplets weaned at 21 d of age were selected from among six litters (n = 36). After a 2-d fasting period, the pigs were fed at similar levels of intake of the control, MPC1, and MPC2 diets, which provided 0, 12.5, and 50 IU of added SOD per kilogram of food, respectively. One triplet of pigs per litter was slaughtered at 7 d and the second triplet at 14 d after weaning. SOD, catalase, and digestive enzymes were determined enzymatically and stress protein expressions by western blotting. RESULTS: Plasma SOD increased with MPC dose at day 14 (P < 0.05). Mucosal weights in the proximal and mid small intestine were lower at day 14 (P < 0.05), cecum tissue weight was greater (P < 0.05), and sucrase-specific activity in mid and distal small intestine mucosa was lower (P = 0.05) in the MPC2 group than in the control group. MPC supplementation essentially decreased (P < 0.05 to P < 0.001) stress proteins in the stomach (all), the mid small intestine (heat-shock protein-27, neuronal nitric oxide synthase) and the colon (heat-shock protein-70, neuronal nitric oxide synthase). CONCLUSION: A SOD-rich MPC provided at the dose of 50 IU/kg of food for up to 12 d was effective in lowering the level of stress proteins along the gastrointestinal tract of pigs after weaning.

Nutrition. 2011 Mar;27(3):358-63

Associations between liver histology and cortisol secretion in subjects with nonalcoholic fatty liver disease.

OBJECTIVES: To assess associations between the activity of hypothalamo-pituitary-adrenal (HPA) axis and liver histology in patients with nonalcoholic fatty liver disease (NAFLD). DESIGN AND PATIENTS: In a cross-sectional study, we enrolled 50 consecutive, overweight, NAFLD patients and 40 control subjects who were comparable for age, sex and body mass index (BMI). MEASUREMENTS: NAFLD (by liver biopsy), HPA axis activity (by 24-hour urinary free cortisol [UFC] excretion and serum cortisol levels after 1 mg dexamethasone), insulin resistance (by homeostasis model assessment: HOMA-IR), and metabolic syndrome (MetS) features. RESULTS: NAFLD patients had markedly higher (P < 0.001) 24-h UFC (149 +/- 24 vs. 90 +/- 16 nmol/day) and postdex suppression cortisol concentrations (32 +/- 10 vs. 16 +/- 7 nmol/l) than controls. The MetS and its individual components were more frequent among NAFLD patients. The marked differences in urinary/serum cortisol concentrations that were observed between the groups were little affected by adjustment for age, sex, BMI, waist circumference, systolic blood pressure, triglycerides, homeostasis model assessment for insulin resistance score and presence of diabetes. Importantly, 24-h UFC and postdex cortisol concentrations strongly correlated to hepatic necroinflammatory grade (P < 0.01) and fibrosis stage (P < 0.001) among NAFLD patients. By logistic regression analysis, 24-h UFC (odds ratio (OR) 1.80, 95%CI 1.3-2.8) or postdex cortisol concentrations (OR 1.95, 95%CI 1.4-3.1) independently predicted the severity of hepatic fibrosis, but not necroinflammation, after adjustment for potential confounders. CONCLUSIONS: These results suggest that NAFLD patients have a subtle, chronic overactivity in the HPA axis (that is closely associated with the severity of liver histopathology) leading to subclinical hypercortisolism that might be implicated in the development of NAFLD.

Clin Endocrinol (Oxf). 2006 Mar;64(3):337-41

Evaluation of blood oxidative stress-related parameters in alcoholic liver disease and non-alcoholic fatty liver disease.

Oxidative stress is implicated in the pathogenesis of liver disease. We investigated oxidative stress-related parameters and correlated with clinical findings in 35 non-alcoholic fatty liver disease (NAFLD) patients, 38 alcoholic liver disease (ALD) patients and 38 normal subjects. NAFLD patients showed significantly higher body mass index, cholesterol, LDL-cholesterol, VLDL-cholesterol levels and transaminase activities compared to the other two groups. Haematological parameters were significantly altered in ALD patients and were reported only in male subjects. Glutathione content, catalase activity, glutathione reductase activity and glutathione peroxidase activity in NAFLD patients were reduced by 10.7 %, 18.5%, 8.1% and 16.8%, respectively, and in ALD patients by 21.8%, 29.6%, 24.3% and 45.3%, respectively, compared to the normal group. However, thiobarbituric acid reactive substance content, superoxide dismutase activity and glutathione s-transferase activity were increased by 35.2%, 31.6% and 5.4%, respectively, in NAFLD patients, and in ALD patients by 75.2%, 72.7% and 32.4%, respectively, compared to the normal group. Oxidative stress is associated with collagen production and leads to fibrosis. Type IV collagen level in NAFLD patients (190.6 +/- 83 ng/mL) was significantly higher than in the normal group (124.5 +/- 14.5 ng/mL) and lower than in ALD patients (373.4 +/- 170 ng/mL). While type IV collagen level of >124 ng/mL was a predictor of NAFLD patients from normal subjects, elevated ALT (>40 IU/L) activity could discriminate either of the liver disease patients from normal subjects.

Scand J Clin Lab Invest. 2008;68(4):323-34