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Hepatotoxicity fast food dr ludwig kramer
1. Hepatotoxicity of Fast Food
Fernando Botero Mona Lisa
Ludwig Kramer
I. Med. Dept. Hospital Hietzing, Vienna, Austria
ludwig.kramer@wienkav.at
DAYS OF THE SERBIAN MEDICAL DIASPORA 2011
Beograd Oct 14, 2011
2. 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
3. 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
5. Fast food is commonly consumed in
conjunction with carbonated soda
6. 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.
8. 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)
9. 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
24. 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)
25. 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
26. NAFLD on histology in general population
studies and in selected groups: 3-86%
27. Not all patients with Fatty Liver have Metabolic syndrome …
But most patients with Metabolic Syndrome have Fatty Liver !
Alberti, Circulation, 2009
28. NASH – Pathophysiology
• Metabolic Syndrome / diabetes & insulin resistance
• oxidative stress
• portal endotoxinemia
• mitochondriopathy
– Role of hypoxia
– ATP depletion by fructose
• Cytokines -> TNFa
• Drugs and toxins
• Steatosis, inflammation, fibrosis, apoptosis
– „Second hit“ concept
– lipotoxicity
30. „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
32. Causes of hepatic fat storage
increased reduced
• Lipid synthesis • Lipid oxidation
• Induction of lipogenic and • Lipid export
adipogenic transcription • Mitochondrial
factors metabolism
– PPAR
– LXR
– SREBP 1c
• Transdifferentiation of HSC
33. 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
34.
35.
36. MRS as „metabolic window“
liver fat vs insulin sensitivity
„favorable“ fat distribution Normal insulin sensitivity
„infavorable“ fat distribution Reduced insulin sensitivity
Stefan, Kantartzis, Häring
Endocrine Reviews 2008;29: 939-960
44. Added sugar, not total energy intake,
is associated with NAFLD
Alberti, Circulation, 2009
45. Induction of KHK by fructose
Consequences :
Increased ATP consumption
Increased triglyceride synthesis
G G+F G G+F
Increased uric acid synthesis
46. 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
47. Total vascular resistance in healthy subjects
following soft drinks (500 ml) sweetened by
Fructose or
о Glucose
Brown CM, Int J Obesity (2008)
49. 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 .“
51. Hepatic INOS-
expression:
Increased by
Fructose consumption
In TLR4- wild type,
not in TLR- mutation
HeJ
Hepatology Oct. 2009
52. 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
53. 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
56. 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
57. 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
58.
59. Association of Coffee and Caffeine Consumption
with Fatty Liver Disease, Non-alcoholic
Steatohepatitis, and Degree of Hepatic Fibrosis
Molloy Hepatology 2011, in press
60. Association of Coffee and Caffeine Consumption
with Fatty Liver Disease, Non-alcoholic
Steatohepatitis, and Degree of Hepatic Fibrosis
Molloy Hepatology 2011, in press
