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Final seminar 1 oct 13


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Dr. Pooja G

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Final seminar 1 oct 13

  1. 1. Effect of Alcohol on Pancreas Pooja Goswami AI.I.M.S. New Delhi
  2. 2. Point to be covered • Pancreas normal physiology and anatomy • Exocrine & endocrine function of pancreas • Epidemiology • Different hypothesis for pancreatitis • Effect of alcohol on pancreas • Effect of alcohol on PSCs • Role of PSCs in fibrosis or cancer progression
  3. 3. Pancreas • Anatomy – Endocrine • Pancreatic islets produce insulin and glucagon – Exocrine • Acini produce digestive enzymes – Regions: Head, body, tail
  4. 4. Normal Pancreas • The pancreatic gland contains three major types of cells. • The ductular cells make up about 10% of the pancreas and secrete solutions rich in bicarbonate. • The acinar cells comprise over 80% of the pancreas and they synthesize and secrete pancreatic enzymes. • The islet cells make up about 10% of the pancreas and form the endocrine portion of the pancreas. These cells secrete the hormones insulin, glucagon, somatostatin, and pancreatic polypeptide.
  5. 5. Islet cells – Alpha cells secrete glucagon-elevates blood glucose concentrations – Beta cells secrete insulin-reduces blood glucose concentrations – Delta cells secrete somatostatin- slows the rate of food absorption and digestive enzyme secretion
  6. 6. Pancreatic enzyme
  7. 7. Exocrine & Endocrine function of Pancreas Exocrine Endocrine 1. Occurs in the islets of Langerhans 2. Beta cells secrete insulin 3. Alpha cells secrete glucagon 4. Delta cells secrete somatostatin 1. The acinar cells secrete amylase, proteases, and lipases, enzymes responsible for the digestion of 3 food types: carbohydrate, protein, and fat. 2. Trypsin is the most abundant enzyme 3. Stored in its inactive form, trypsinogen; activated by enterokinase
  8. 8. Alcohol & Pancreatitis • Alcohol abuse accounts for 38-94% CP • Daily 80g/day for 13-21 years to develop alcohol induced pancreatitis • Only 10 % of heavy drinker develop pancreatic inflammation • Black ppl are 3-4 times more chances to develop pancreatitis • Patient get diagnosed at age of 35-40 years of age
  9. 9. Ductal obstruction hypothesis • Chronic alcohol use • acinar and ductal cell • protein rich pancreatic juice, low in volume and HCO3 • formation of protein precipitates – plug • calcification of ppt – ductal stone formation • ductule obstruction • parenchymal damage • Pancreatic ductal stone are seen in alcoholic, tropical, hereditary, idiopathic • Histologic changes of CP may be seen with out ductal obstruction
  10. 10. Toxic metabolic hypothesis • (alcohol) Direct injurious effect on acinar and ductal cells • Increased membrane lipid peroxidation (oxidative stress), free radical production • Increase acinar cell sensitivity to pathogenic stimuli • Activation of pancreatic stellate cells (alcohol, cytokines) – produce proteins of extracellular matrix
  11. 11. Necrosis fibrosis hypothesis • Repeated episodes of acute pancreatitis with cellular necrosis or apoptosis, healing replaces necrotic tissue with fibrosis • Evidence from natural history studies - more severe and frequent attacks • More evidence from hereditary pancreatitis and animal models • But some have evidence of chronic pancreatitis at time of first clinical acute attack
  12. 12. Genetics Basis of CP Autosomal dominant disorder Cationic Trypsinogen gene mutation….PRSS1(R122H) Autosomal Recessive….CFTR mutation Susceptabilty gene….SPINK1 Course Modifiers…..various polymorphisms (ADH2,ADH3,ALDH2,CYP2E1 ETC.)
  13. 13. Distribution of ALDH genotypes with age at onset of Alcoholic Pancreatitis 41 40 39 38 37 36 35 34 38.5 ± 3 Allele Type Mean Age (in years) 40.76 ± 8 34.71 ± 10 2-1 2-1 2-1 2-2 2-2 2-2 It appears that  When genotype 2-2/is conferring risk ( double dose of Lys; allele 2-2 *)  But when genotype 2-1/2-2 (heterozygous) is conferring risk (single dose of Lys; allele 2-2 *)  When genotype 2-1/2-1 is present (absence of allele 2-2 *)  onset of pancreatitis is slightly delayed  onset of pancreatitis is significantly delayed  onset of pancreatitis occurs at younger age
  14. 14. Alcohol and Pancreas • Incompletely understood and intensely studied. • Why 10% heavy alcoholics develop chronic pancreatitis and the rest not, or limited to asymptomatic pancreatic fibrosis
  15. 15. How alcohol affect pancreas • Earlier theories suggested pancreatic duct is the central organ to develop alcohol induced pancreatitis • New theory evolved, alcohol have direct effect on acinar cell as well as PSCs
  16. 16. Mechanism of ethanol induced Pancreas dysfunction • Ethanol & other factors combined affect – Pancreatic blood flow – Pancreatic exocrine secretion – Pancreatic duct permeability – Zymogen activation – Intracellular signaling – Oxidative stress generation – Interaction of ethanol and its metabolite
  17. 17. Spasm in sphincter of oddi causes • The sphincter of Oddi separates the common bile duct & pancreatic duct from the small intestine. So by relaxing it, bile and pancreatic juices can be dumped into the small intestine. • Digestive enzyme of pancreas instead of entering to intestine to digest food, “ digest” pancreatic cell • Backflow of bile or duodenum content back into the pancreatic duct lead
  18. 18. Effect of alcohol on small duct • Small pancreatic duct begins at the acini and drain into large pancreatic duct • Small duct blocked by protein plug formation • Protein plug get enlarge and calcify, which may be a cause or effect of disease Freedman at al 1993
  19. 19. Protein plug: pancreatic digestive enzyme and lithostathine & GP2 • Pancreatic Lithostathine – Form 5-10% protein of pancreatic secretion – Inhibit the deposition of ca+ from pancreatic juice, therfore its ↓ level promote calcification of protein (Bernard et al 1992) – Convert lithostathine into lithostathine S1( to initiate plug formation – Long term alcohol consumption leads to ↑ conc. of lithostathine in juice, which promotes protein deposition in ducts (Apte et al 1996) • Pancreatic GP2 – Help in protein precipitation from pancreatic juice – Alcohol consumption lead to ↑ conc. of GP2, favor plug formation
  20. 20. Effect of protein plug formation on pancreas • Protein plug formation or stone in small duct lead to ulceration, scarring further obstruction & finally atrophy and fibrosis via – Reduces pancreatic secretion – Increased viscosity of secretion – Decrease citrate conc. In pancreatic juice, a predisposing factor for crystal formation – Producing protein to increase stone formation Protein plug known to be a player in progression of disease if not initiation
  21. 21. Direct effect of alcohol on acinar cell • A single acinar cell can synthesize 10 million enzyme mol/day • They protect themselves by synthesizing most digestive enzymes (trypsin) as inactive precursor i.e. zymogen granule • Any disruption could lead to premature activation of zymogen & causes auto-digestion of pancreatic acinar cells whitcomb et al 1996
  22. 22. Effect of alcohol on fragility of zymogen & lysosome • Long term alcohol consumption premature activation of zymogen enzyme • Alcohol ↑ the synthesis of digestive enzyme • Alcohol consumption lead to↑ in fragility of lysosome & zymogen granule allowing zymogen leakage to the cell Wilson et al 1992, Apte et al 1995
  23. 23. How fragility start auto-digestion of pancreas • Alcoholic metabolites makes fragile zymogen granule & lysosomal membrane • Trypsin can not be degrade by protective enzyme of acinar cell • So due to fragile membrane lysosomal enzyme (cathepsin B) will active trypsin to trypsinogen which further lead to activate other enzyme & start the cascade of event or autodigestion of pancrease L Z Trypsinogen Trypsin Cathepsin B Activate other enzyme and strat autodigestion of pancreas
  24. 24. Ethanol Metabolism Ethanol Metabolism Non-oxidative Pathway Oxidative Pathway Rate is 21 fold higher Alcohol dehydrogenase Cytochrome P-4502E1 (CYP2E1) Catalse FAEE synthases Acetaldehyde ROS FAEE Induces morphological Alteration in pancreas Harmful to cell membrane, intracellular protein & DNA lysosomal fragility
  25. 25. Alcohol induced oxidative stress in pancreas • The cell is normally protected from the disruptive effect of free radicals by antioxidant system, which releases during normal metabolism of alcohol via CYP2E1 • Oxidative stress is the imbalance between production of ROS & defense mechanism (Antioxidant glutathione, peroxidase, superoxide mutase & catalase) • This imbalance may be a due to – ROS release during ethanol oxidation via CYP2E1 – Depletion of ROS scavenger gluthathione • As a result oxidative stress destabilizes zymogen & lysosome granules lead to auto digestion of pancreas via acinar cell activation • Altomare et al 1996
  26. 26. Effect of alcohol metabolism on pancreas • Acetaldehyde induces the stellate cells & lead to fibrosis • FAEE induces the acinar cell & lead to necrosis and continuous insult lead to fibrosis
  27. 27. Alcoholic Chronic Pancreatitis ALCOHOL Oxidative pathway Acetaldehyde Non-oxidative pathway Fatty acid ethyl esters (FAEEs) Pancreatic Stellate Cell Activation
  28. 28. Pancreatic stellate cells (PSCs) • PSCs are 4% cell of total pancreatic cell • Vit A containing lipid droplets • On activation loose vitamin A – Maintained matrix turn over – Protective immune function as phagocytic cell – Work as progenitor cell (in acute injury secrte insulin after differentiation) – CCK (Cholecystokinin ) induced pancreatic exocrine function
  29. 29. Stellate cells Quiscent PSc Active PSc Vitamin A lipid droplets Present Absent a Smooth muscle actin Absent Present Proliferation Limited Increased Migration Limited Increased ECM Limited Increased MMPs and TIMPs Maintain normal ECM turnover Change in types of MMPs and TIMPs to facilitate ECM deposition Production of cytokines Limited Increased ((PDGF, TGFb, CTGF, IL1, IL6, IL15) Capacity for phagocytosis Absent Present
  30. 30. Stellate cells formation, proliferation & Active PSc migration PDGF induced Proliferation mediated by ERK & JAK/STAT •PDGF induced migration mediated by PI3K •Migration also mediated by hedgehog pathway Quiscent PSc TGFB mediated LPS receptor (TLR 2 &4) SMA positve
  31. 31. PSCs Activation • PSCs are activated via paracrine pathways by exogenous factors such as cytokines, oxidant stress, ethanol and its metabolites • Activated PSCs secrete cytokines which act on PSC in autocrine way • These remain active PSCs even in the absence if the initial trigger factors, leading to excessive ECM production and eventually causing pancreatic fibrosis Active PSC Quiescent PSC Cytokine autocrine effect Pancreatic fibrosis
  32. 32. Activated PSCs leads to fibrosis Active PSC Quiescent PSC Cell proliferation SMA expression ECM protein synthesis Matrix degradation via Vit. A loss (Altered retinol metabolism) Imbalance MMP/TIMP Cell migration Contractility Pancreatic fibrosis Ethanol insult & Endotoxin Mainly acetaldehyde LPS ↑ in blood of alcoholics
  33. 33. PSC in Chronic Pancreatitis: Animal studies • Fibrosis has been produced in rat model via (1) trinitrobenzene sulfonic acid (TNBS) injection into the pancreatic duct (Haber et al., 1999) (2) intravenous injection of an organotin compound dubutyltin chloride (DBTC) (Emmrich et al., 2000) (3) spontaneous chronic pancreatitis in WBN/Kob rats (Ohashi et al., 1990) (4) severe hyperstimula- tion obstructive pancreatitis (SHOP), involving intraperitoneal (IP) injections of supramaximal doses of caerulein (a synthetic analogue of CCK, a major pancreatic secretagogue) + bile- pancreatic duct ligation (Murayama et al., 1999) (5) repeated IP injections of a superoxide dismutase inhibitor (Matsumura et al., 2001)
  34. 34. Continued.. • (6) intragastric high dose alcohol administration + repeated caerulein injections (Tsukamoto et al., 1988; Uesugi et al., 2004) • (7) chronic alcohol administration (liquid diet) with repeated cyclosporin and caerulein injections (Gukovsky et al., 2008) • (8) chronic alcohol administration with repeated endo- toxin LPS, injections (Vonlaufen et al., 2007b). •Rat model produced by chronic alcohol administration and repeated endotoxin exposuren that is based on a well recognized clinical phenomenon, namely endo- toxinaemia (secondary to increased gut mucosal permeability) in alcoholics (Bode et al., 1993; Parlesak, 2005). •Thus, the alcohol feeding, LPS challenge model possibly represents the most physiologically relevant model of chronic alcoholic pancreatitis described to date.
  35. 35. Pancreatic fibrosis Lost vitamin A
  36. 36. Inflammation towards PDAC