Dietary supplementation in treating non-alcoholic fatty liver disease Dr. Ahmad Saedi Associate Professor School of Nutritional Sciences and Dietetics Tehran University of Medical Sciences Honorary Academic Appointee of Western Sydney University, Australia 1
Introduction Non-alcoholic fatty liver disease (NAFLD) encompasses a range of conditions caused by fatty infiltration of the hepatocytes without significant amounts of alcohol use, that can be originated from multiple factors. 2
Natural History of NAFLD fatty liver steatohepatitis steatohepatitis + fibrosis steatohepatitis + cirrhosis cryptogenic cirrhosis 3
Fatty liver Normal liver 4
Pathogenesis The two-hit hypothesis of NASH, originally explained by Day and James. Lipid Accumulation 1 st HIT Oxidative Stress Cytokine Activation 2 nd HIT 5
Pathogenesis Genetics, epigenetic mechanisms, as well as environmental elements, appear to promote hepatocyte fat deposition and insulin resistance. Both of which further lead to the secondary pathologic event such as oxidative stress, lipid peroxidation, increased inflammatory responses, hepatic fibrosis and apoptosis. 6
NAFLD NAFLD is a spectrum of disease which includes Fatty liver disease and NASH, but only NASH is known to progress to cirrhosis. Fatty Liver 2 nd hit NASH Cirrhosis Obese BMI>28 Centipetal (apple) Bright liver on USS Insulin Resistance Normal ALT Obese BMI>28 Bright liver on USS Abnormal ALT Features of metabolic syndrome Dyslipidaemia DM HBP 7 Bright/ small liver on USS + splenomegaly Abnormal ALT Thrombocytopenia Obesity Poorly controlled DM Poorly controlled lipids Hypertension
NAFLD: risk factors Middle age Female gender Over-weight or obese Viral hepatitis Iron overload Medications Rapid weight loss Starvation/refeeding syndrome Auto-immune disease Malnutrition Abetalipoproteinemia Overgrowth of bacteria in small intestines TPN Acute fatty liver of pregnancy Hispanic ethnicity Hereditary 8
Risk factors: Established association Obesity Type 2 DM: insulin resistance (IR) Dyslipidemia Metabolic syndrome (MS) 9
Diagnostic methods for NAFLD Liver biopsies are considered gold standard Magnetic Resonance Imaging (MRI), computed tomography (CT) and ultrasonography (U.S) Other clinical diagnostic : Increased serum levels of bilirubin, AST, ALT, AP, 10
Grading and Staging of NAFLD Grading NAFLD Grade 0: None Grade 1: Grade 2: Grade 3: 11
Epidemiology One third of the population is affected The prevalence of fatty liver in Iran general population is 2% It increases with age 12
Epidemiology NAFLD affects 40%-75% of patients with T2DM, 33%-76% of obese and 90% of morbidly obese people About 20%-25% of adults with NASH have been reported to develop liver cirrhosis. 13
Management of NAFLD The only proven strategy for NAFLD management is lifestyle modification techniques such as weight loss through a healthy diet and exercise. 14
Management of NAFLD Weight loss strategies in presence of overweight/obesity. Weight loss results in improved lipid and carbohydrate metabolism. Weight loss must be slow. Rapid weight loss results in worsening liver function tests and hepatomegaly. Rapid weight loss may promote or worsen NAFLD, NASH and may result in liver failure. 15
Management of NAFLD Normal weight subjects: dietary and pharmacological treatment of altered lipid and /or carbohydrate metabolism. In overweight individuals with elevated aminotransferase levels weight loss of 10% or more corrects aminotransferase levels and decreases hepatomegaly. 16
Management of NAFLD Moreover, a wide range of drugs and supplements : Metformin Antioxidants Anti-inflammations Insulin sensitizers Lipid lowering agents 17
Dietary supplementation in the treatment of NAFLD 18
1-Antioxidants agents 19
Vitamin E and vitamin C Oxidative stress is one of the factors involved in the pathogenesis of NAFLD. Vitamin E is only recommended in adults with NASH who do not have diabetes or cirrhosis, or an aggressive histology. Improvement in fatty liver disease when you take vitamin E with vitamin C. 20
Resveratrol Resveratrol is found in the skin of red grapes. Anti-oxidative Anti-inflammatory Anti-cancer Anti-obesity Anti-diabetic Anti-aging 21
Anthocyanin Decrease hepatic lipid accumulation Counteract oxidative stress Decrease hepatic inflammation 22
Green tea extract Main important green tea polyphenol is epigallocatechin-3-gallate (EGCG). EGCG is thought to have antioxidant and antiinflammatory characteristics. 23
Epigallocatechin gallate (EGCG) Reduce dietary absorption of lipids and carbohydrates. Inhibit de novo lipogenesis Improve insulin sensitivity Stimulate of β-oxidation and thermogenesis 24
Milk thistle Silymarin, the active ingredient in milk thistle. As an antioxidant, repairs damage to the liver One very effective combination is silymarin plus vitamin E and phospholipids. Quicken the rate of liver cell regeneration Inhibit liver fibrosis 25
Garlic S-allylmercaptocysteine derived from garlic. Therapeutic role in diabetes and nonalcoholic fatty liver Regulation of lipogenesis and glucose metabolism Decrease the liver injury Decrease fat build-up Decrease collagen formation 26
Ginger Increasing insulin sensitivity Activation of peroxisome proliferator-activated receptor gamma Induce adiponectin and down-regulates pro-inflammatory cytokines Antidyslipidemic properties Reduce hepatic triglyceride 27
Lecithin (phosphatidylcholine) Phosphatidylcholine increases sensitivity to insulin and reduces fatty liver in mice. It is believed that it may provide a treatment for pre-diabetic patients. 28
Spirulina Hypoglycemic and hypolipidemic effects Spirulina significantly decreases serum glucose and improve insulin sensitivity Decrease weight, ALT, AST and TG levels in NAFLD patients. 29
2-Anti-inflammatory agents 30
n-3 PUFAs Promote weight loss Reduce hepatic triglyceride accumulation Improve insulin sensitivity Reduce steatosis 31
Curcumin Reduce serum lipid levels and liver steatosis Prevents fatty liver progression to steatohepatitis Reduce the expression of lipogenic genes in the liver and adipose tissue Enhance the antioxidant defense system 32
Probiotics It has been reported that NAFLD might be linked to small intestinal bacterial overgrowth by gut-derived lipopolysaccharides (LPS) and TNF- α production. Gut microbiota increases the liver s exposure to endotoxins. Thus, it seems that the manipulation of enteric flora may be a novel therapeutic strategy in the management of NAFLD. 33
Probiotics Can modulate the gut flora and influence the gut-liver axis Promote the intestinal mucosal barrier function and mucosal recovery during a pathological condition Prevent fat from accumulating in the liver 34
3-Insulin sensitizers and lipid lowering agents 35
Cinnamon Inhibit pancreatic enzymes such as α-amylase and α-glucosidase Stimulate cellular glucose Stimulate insulin release and glycogen synthesis Inhibit gluconeogenesis 36
Carnitin Abnormalities in the mitochondria have been found to play an important role in NAFLD and NASH development. 37
Conclusion It is critically important to find dietary approaches to the prevention, or reversal of hepatic steatosis, and its progression to steatohepatitis. As insulin resistance, oxidative stress, and inflammation are involved in pathogenesis of NAFLD, it seems that dietary supplements that can modulate these pathologies could be useful in the treatment of NAFLD. 38