Hepatotoxicity fast food dr ludwig kramer


Published on

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Hepatotoxicity fast food dr ludwig kramer

  1. 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. 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. 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
  4. 4. Frozen potatoes replacing fresh in US diet
  5. 5. Fast food is commonly consumed in conjunction with carbonated soda
  6. 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.
  7. 7. David 2011
  8. 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. 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
  10. 10. Evolution of human drinking & beverages
  11. 11. How did we adapt to this evolution? The Independent, 2004
  12. 12. Sugar consumption and obesity, UK & US
  13. 13. Global obesity prevalence 1980-2008
  14. 14. Liver ultrasoundNormal Steatosis / fibrosis
  15. 15. Liver CTNormal Steatosis low HE blood vessels density > liver tissue density
  16. 16. Das et al., Hepatology 2010
  17. 17. JAMA. 2001;286:1195-1200
  18. 18. JAMA. 2001;286:1195-1200
  19. 19. USABrigthness correlates with distance to fast food restaurant
  20. 20. Liver-associated mortality in Great Britain, age 15-44
  21. 21. Liver-associated mortality in Great Britain, age 45-64
  22. 22. Why are UK and US leading the crew?
  23. 23. 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)
  24. 24. 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
  25. 25. NAFLD on histology in general population studies and in selected groups: 3-86%
  26. 26. Not all patients with Fatty Liver have Metabolic syndrome …But most patients with Metabolic Syndrome have Fatty Liver ! Alberti, Circulation, 2009
  27. 27. 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
  28. 28. Abdominal obesity indicates increased liver fat and insulin resistance
  29. 29. „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
  30. 30. Lipotoxicity – current concepts
  31. 31. Causes of hepatic fat storageincreased reduced• Lipid synthesis • Lipid oxidation• Induction of lipogenic and • Lipid export adipogenic transcription • Mitochondrial factors metabolism – PPAR – LXR – SREBP 1c• Transdifferentiation of HSC
  32. 32. 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
  33. 33. 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
  34. 34. High liver fat content parallels reduced insulin sensitivity Stefan, Kantartzis, Häring Endocrine Reviews 2008;29: 939-960
  35. 35. Arch Intern Med. 2008;168(15):1609
  36. 36. Arch Intern Med. 2008;168(15):1609Insulin sensitivity Intima – media thickness Mitochondrial function could be the difference
  37. 37. Fructose – the real cause ofFast-food – related liver damage?
  38. 38. 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
  39. 39. Energy uptake as fructose Other liver diseases NAFLD (age- and BMI – match)356 kcal/d 170 kcal/d J Hepatol, 2008;48:993
  40. 40. Soft drink consumption, metabolic syndrome and fatty liver Alberti, Circulation, 2009
  41. 41. Added sugar, not total energy intake, is associated with NAFLD Alberti, Circulation, 2009
  42. 42. Induction of KHK by fructose Consequences : Increased ATP consumption Increased triglyceride synthesisG G+F G G+F Increased uric acid synthesis
  43. 43. 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
  44. 44. Total vascular resistance in healthy subjectsfollowing soft drinks (500 ml) sweetened by Fructose or о Glucose Brown CM, Int J Obesity (2008)
  45. 45. Fructose and coronary heart disease
  46. 46. 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 .“
  47. 47. HistologyLipid stainingHepatology Oct. 2009
  48. 48. Hepatic INOS- expression: Increased by Fructose consumption In TLR4- wild type, not in TLR- mutation HeJHepatology Oct. 2009
  49. 49. 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
  50. 50. 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
  51. 51. Non-alcoholic steatohepatitis - the main ingredients
  52. 52. 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
  53. 53. 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
  54. 54. Association of Coffee and Caffeine Consumption with Fatty Liver Disease, Non-alcoholicSteatohepatitis, and Degree of Hepatic Fibrosis Molloy Hepatology 2011, in press
  55. 55. Association of Coffee and Caffeine Consumption with Fatty Liver Disease, Non-alcoholicSteatohepatitis, and Degree of Hepatic Fibrosis Molloy Hepatology 2011, in press