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
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
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
Frozen potatoes replacing fresh in US diet
Fast food is commonly consumed in conjunction with carbonated soda
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.
David 2011
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)
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
Evolution of human drinking & beverages
How did we adapt to this evolution?
The Independent, 2004
Sugar consumption and obesity, UK & US
Global obesity prevalence 1980-2008
Normal Steatosis / fibrosis
Liver ultrasound
Normal Steatosis low HE
blood vessels density
> liver tissue density
Liver CT
Das et al., Hepatology 2010
JAMA. 2001;286:1195-1200
JAMA. 2001;286:1195-1200
USA Brigthness correlates with distance to fast food restaurant
Liver-associated mortality in Great Britain, age 15-44
Liver-associated mortality in Great Britain, age 45-64
Why are UK and US leading the crew?
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)
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
NAFLD on histology in general population studies and in selected groups: 3-86%
Not all patients with Fatty Liver have Metabolic syndrome … But most patients with Metabolic Syndrome have Fatty Liver !
Alberti, Circulation, 2009
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
Abdominal obesity indicates increased liver fat and insulin resistance
„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
Lipotoxicity – current concepts
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
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
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
High liver fat content parallels reduced insulin sensitivity
Stefan, Kantartzis, Häring
Endocrine Reviews 2008;29: 939-960
Arch Intern Med. 2008;168(15):1609
Arch Intern Med. 2008;168(15):1609
Insulin sensitivity Intima – media thickness
Mitochondrial function could be the difference
Fructose – the real cause of Fast-food – related liver damage?
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
NAFLD 356 kcal/d
Energy uptake as fructose
Other liver diseases (age- and BMI – match)
170 kcal/d
J Hepatol, 2008;48:993
Soft drink consumption, metabolic syndrome and fatty liver
Alberti, Circulation, 2009
Added sugar, not total energy intake, is associated with NAFLD
Alberti, Circulation, 2009
Induction of KHK by fructose Consequences : Increased ATP consumption Increased triglyceride synthesis Increased uric acid synthesis
G G+F G G+F
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
Total vascular resistance in healthy subjects following soft drinks (500 ml) sweetened by
Fructose or
о Glucose
Brown CM, Int J Obesity (2008)
Fructose and coronary heart disease
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 .“
Lipid staining
Histology
Hepatology Oct. 2009
Hepatic INOS- expression: Increased by Fructose consumption In TLR4- wild type, not in TLR- mutation HeJ
Hepatology Oct. 2009
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
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
Non-alcoholic steatohepatitis - the main ingredients
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
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
Association of Coffee and Caffeine Consumption with Fatty Liver Disease, Non-alcoholic
Steatohepatitis, and Degree of Hepatic Fibrosis
Molloy Hepatology 2011, in press
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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