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Hepatotoxicity of Fast Food
Ludwig Kramer I. Med. Dept. Hospital Hietzing, Vienna, Austria
DAYS OF THE SERBIAN MEDICAL DIASPORA 2011
Beograd Oct 14, 2011
Fernando Botero Mona Lisa
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Definition of Fast Food
• „Fast Food“ – any food which may be cooked easily and sold to be eaten quickly or taken away. – Fast food has been available over centuries in all countries
Ancient fast food joint Pompei, Thermopolium
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Fast Food – fast changes …
• Changes in the dietary pattern of the last decades have made fast food a relevant component of „Western“ diets
• Highly industrialized production – Distribution center services 300-400 individual „restaurants“
– Complex storage / freezing logistics
– Ready – made, heated / fried
– Contains preservatives, colours, stabilisers …
• Usually sold in disposable containers
• High content of flour, sugar, processed fat & meat » Notorious health concerns
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Frozen potatoes replacing fresh in US diet
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Fast food is commonly consumed in conjunction with carbonated soda
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Development of daily caloric intake in industrialized nations
• Over the past decades, daily caloric intake has been increasing by 150 to 300 kcal (differing by age and sex)
• about 50% of the increased calories have come from calorically sweetened beverages
Popkin BM, Armstrong LE, Bray GM, Am J Clin Nutr 2006, 83(3):529–542.
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David 2011
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Fast food and liquid carbohydrate consumption are positively associated
• Deleterious effects of fast food have been largely attributed to its increased fat content.
• The available evidence, however, suggests a major role of rapidly absorbed carbohydrates
• Dietary recommendations favoring carbohydrate over fat ingestion tend to increase this problem – Less satiety
– Increased uric acid and triglyceride synthesis
– GIT discomfort by fructose
• Fructose malabsorption
• Bacterial overgrowth
• Irritable bowel syndrome (IBS)
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Carbohydrate release from solid vs. liquid / processed food
• Monosaccharides: water- soluble – Fruits, vegetables:
• Cell matrix – Sugar stored in cytosol/vacuole
– Gradual release upon cell digestion
– Juice, HFCS-sweetened sodas: • Immediate delivery of monocaccharides
• rapid gastric passage – Early absorption
– Reduced satiety (less or no insulin, leptin secretion)
– Increased total energy consumption
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Evolution of human drinking & beverages
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How did we adapt to this evolution?
The Independent, 2004
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Sugar consumption and obesity, UK & US
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Global obesity prevalence 1980-2008
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Normal Steatosis / fibrosis
Liver ultrasound
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Normal Steatosis low HE
blood vessels density
> liver tissue density
Liver CT
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Das et al., Hepatology 2010
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JAMA. 2001;286:1195-1200
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JAMA. 2001;286:1195-1200
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USA Brigthness correlates with distance to fast food restaurant
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Liver-associated mortality in Great Britain, age 15-44
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Liver-associated mortality in Great Britain, age 45-64
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Why are UK and US leading the crew?
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In these countries, dietary habits have changed most significantly over the past decades
• Introduction of high fructose corn syrup (HFCS)
US: rapid increase in HFCS consumption (kg/yr)
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The incidence of non-alcoholic steatohepatitis (NASH) is rapidly increasing at a global scale
• Until very recently, NASH was virtually unknown – First description in 19th century Vienna (Rokitansky 1846)
• Ultra-rare, doctors forgot about it
– First description of liver damage in diabetics around 1920
• Use of sucrose syrup as sweetener in British diet
– First description of „non-alcoholic steatohepatitis“ (NASH ) by Ludwig (Mayo Clinic) in 1980
• No apparent cause other than obesity identified at that time
• Things worsened in subsequent years
– NASH is now main reason for elevated liver enzymes in industrialized countries
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NAFLD on histology in general population studies and in selected groups: 3-86%
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Not all patients with Fatty Liver have Metabolic syndrome … But most patients with Metabolic Syndrome have Fatty Liver !
Alberti, Circulation, 2009
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NASH – Pathophysiology
• Metabolic Syndrome / diabetes & insulin resistance
• oxidative stress
• portal endotoxinemia
• mitochondriopathy – Role of hypoxia
– ATP depletion by fructose
• Cytokines ->
• Drugs and toxins
• Steatosis, inflammation, fibrosis, apoptosis – „Second hit“ concept
– lipotoxicity
TNFa
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Abdominal obesity indicates increased liver fat and insulin resistance
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„Lipotoxicity“
• Excessive storage of triglycerides outside of fat tissue
• Characteristic cell damage, not necessarily pathophysiologically related – Apoptosis
– Insulin resistance
• „low-grade inflammation“ of white adipose tissue secondary to chronic activation of unspecific immune system – Fat becomes „motor“ of systemic inflammation
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Lipotoxicity – current concepts
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Causes of hepatic fat storage
increased
• Lipid synthesis
• Induction of lipogenic and adipogenic transcription factors
– PPAR
– LXR
– SREBP 1c
• Transdifferentiation of HSC
reduced
• Lipid oxidation
• Lipid export
• Mitochondrial metabolism
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Aigner et al; Gastroenterology 2008
• Patients with low hepatic and plasma- copper -conzentration had NASH – related disturbance of hepatic iron metabolism
• Lack of copper-dependent ferroxidase caeruloplasmin could be a mechanism of hepatic iron storage.
• Copper depletion – a further possible co- factor in NASH? – Pivotal role of Cu++ in mitochondrial function
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MRS as „metabolic window“ liver fat vs insulin sensitivity
Stefan, Kantartzis, Häring
Endocrine Reviews 2008;29: 939-960
„favorable“ fat distribution
„infavorable“ fat distribution
Normal insulin sensitivity
Reduced insulin sensitivity
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High liver fat content parallels reduced insulin sensitivity
Stefan, Kantartzis, Häring
Endocrine Reviews 2008;29: 939-960
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Arch Intern Med. 2008;168(15):1609
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Arch Intern Med. 2008;168(15):1609
Insulin sensitivity Intima – media thickness
Mitochondrial function could be the difference
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Fructose – the real cause of Fast-food – related liver damage?
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Facts on fructose …
• Passive absorption in small gut • (GLUT-5, GLUT2 - transporter)
• Glucose favors enterocyte transport
– Relative lack of glucose (HFCS):
– Increased fructose delivery to colon
– (bacterial cleavage!)
– Endotoxin release
• Fructose is metabolized by
•Hepatocytes Liver ketohexokinase (KHK)
• Kidney, fat tissue, endothelium ...
– Energy depletion by ATP consumption
– Uric acid release
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NAFLD 356 kcal/d
Energy uptake as fructose
Other liver diseases (age- and BMI – match)
170 kcal/d
J Hepatol, 2008;48:993
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Soft drink consumption, metabolic syndrome and fatty liver
Alberti, Circulation, 2009
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Added sugar, not total energy intake, is associated with NAFLD
Alberti, Circulation, 2009
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Induction of KHK by fructose Consequences : Increased ATP consumption Increased triglyceride synthesis Increased uric acid synthesis
G G+F G G+F
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The metabolic fate of fructose
• GLUT-2 in enterocytes and
• hepatic fructokinase (Ketohexokinase) » Both up-regulated by fructose
» positive feedback loop
» Perfusion studies:
» Almost unlimited (up to 40 kg/d) fructose absorption
» Fructose metabolism not controlled by insulin secretion
» Uric acid increase of up to 2 mg/dl following fructose drink
» UA is a vasoconstrictor
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Total vascular resistance in healthy subjects following soft drinks (500 ml) sweetened by
Fructose or
о Glucose
Brown CM, Int J Obesity (2008)
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Fructose and coronary heart disease
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Fructose and renal damage Ketohexokinase-Dependent Metabolism of Fructose Induces Proinflammatory
Mediators in Proximal Tubular Cells
J. Am. Soc. Nephrol., March 1, 2009; 20(3): 545 - 553.
„this study shows direct and potentially deleterious changes by
fructose on cultivated proximal tubular cells .“
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Lipid staining
Histology
Hepatology Oct. 2009
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Hepatic INOS- expression: Increased by Fructose consumption In TLR4- wild type, not in TLR- mutation HeJ
Hepatology Oct. 2009
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Hepatic and plasma TNFa concentration are massively increased in TLR-4 wild type, not in TLR-4 mutation HeJ Role for endotoxin? Hepatology Oct. 2009
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TNF-a impairs gut integrity in in vitro
• zona occludens - protein staining in colonic ell cultures
normal TNF-a TNF-a + natural antagonist
(Curcumin)
Ma et al., AJP-Gastrointest Liver Physiol • VOL 286 • MARCH 2004
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Non-alcoholic steatohepatitis - the main ingredients
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Summary
• The unparalleled rise of Fructose and HFCS ingestion due to carbonated soda consumption in late 20th century appears to be the major cause of hepatic damage induced by Fast Food.
• Pathogenesis of fast – food related hepatotoxicity is complex – Lipotoxicity
– Insulin resistance
– Metallotoxicity (Fe, Cu)
– Mitochondriopathy
– hypoxia
– Endotoxin
– Cytokines
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NASH - drug therapy
• Anti-diabetic medication
– Works in diabetics, almost no effect in non-diabetics
– Promising drugs (glitazones) hampered by
• Weight increase, bladder cancer, cardiovascular morbidity
– Additional Metformin, losartan: no benefit in liver histology
• Torres, Hepatology 2011
• Vitamin E 800U/day: better than pioglitazone • Sanyal, NEJM 2009
• Weight loss (>6%) equals best medication
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Association of Coffee and Caffeine Consumption with Fatty Liver Disease, Non-alcoholic
Steatohepatitis, and Degree of Hepatic Fibrosis
Molloy Hepatology 2011, in press
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Association of Coffee and Caffeine Consumption with Fatty Liver Disease, Non-alcoholic
Steatohepatitis, and Degree of Hepatic Fibrosis
Molloy Hepatology 2011, in press