1. 1. Jayaprakash Sreenarasimhaiah, MD Associate Professor of Medicine Division of Digestive and Liver Disease March 11th, 2015
2. 2. Pancreatic function Exocrine acinar and ductal cells Endocrine Alpha cells regulation of glucagon Beta cells regulation of insulin PP cells pancreatic polypeptide Delta cells - somatostatin 80% of pancreas is exocrine pancreatic acini 2% is endocrine cells of the islets of Langerhans Inorganic constituents of pancreatic secretion - water, Na, K, HCO3 Secretion of 2.5L daily - secretin
3. 3. Pancreatic function Inorganic Digestive enzymes Amylase - pancreas and saliva; digests starch /glycogen Lipase - small amount also from stomach and saliva hydrolysis of TG into 2 FA + 1 MG Phospholipase A2 hydrolyzes FA into FFA Proteases - trypsin, chymotrypsin, elastase Trypsinogen converted to trypsin by enterokinase Maximal activity of lipase at pH 7 At pH 4, lipase is irreversibly inactivated Neutralization of gastric acid delivered to duodenum required for normal fat digestion
4. 4. Pathophysiology Inflammation of the exocrine pancreas with variable involvement of peripancreatic tissues and remote organ systems Autodigestive process with premature activation of zymogens within acinar cells Impaired microcirculation of blood in pancreas Release of cytokines (IL-1, TNF, PAF, NO) Trypsin stimulates complement and kinin systems Leukocyte chemoattraction/bacterial translocation
5. 5. Pathophysiology Mutation in human cationic trypsinogen gene (aka protease, serine 1, or PRSS 1) Inherited pancreatitis Mutation in gene for pancreatic secretor trypsin inhibitor (aka serine protease inhibitor, Kazal-type 1, or SPINK 1) Acute and chronic pancreatitis Causes pancreatitis when combined with other genetic and environmental factors
6. 6. Etiology of acute pancreatitis Gallstones Biliary sludge Alcohol Hypertriglyceridemia Hypercalcemia Drugs Infections/toxins Trauma Vascular disease Post-operative states Post-ERCP Hereditary pancreatitis Structural abnormalities Duodenum/ampulla Bile duct Pancreatic duct SOD Malignancy Autoimmune Idiopathic
7. 7. Etiology Alcohol 30% of acute pancreatitis 70-90% of chronic pancreatitis Only 10% of all alcoholics Acute becomes chronic after 10 to 20 years of alcohol abuse Commonly underlying pancreatic disease exists SOD relaxation, bile reflux into pancreas, increase of enzyme activity, direct injury to acinar cells, increased fragility of lysozymes and zymogen granules
8. 8. Etiology Gallstones and biliary sludge 1/3 of acute pancreatitis in US; rarely chronic Incidence is higher in women; RR is higher in men Impaction of stones at papilla (mostly 1000mg/dl (as little as 500) Hyperchylomicronemia in inherited type I or V lipid disorders FFA damages pancreatic acinar cells TG can also be increased by alcohol in a dose-dependent manner Hypercalcemia Deposition in PD Activation of trypsinogen Most commonly part of a multifactorial process
9. 11. Etiology Drugs (acute) AIDS treatment didanosine, pentamidine NSAID salicylates, sulindac Antimicrobials metronidazole, sulfonamides, TCN, INH, nitrofurantoin, erythromycin Diuretics furosemide, thiazides IBD sulfasalazine, mesalamine Immunosuppressants Azathioprine, 6-MP Others valproic acid, calcium, estrogens, tamoxifen, ACE-I
10. 12. Etiology of acute pancreatitis Drugs (confirmed by rechallenge) Alpha methyldopa Azathioprine Cannabis Carbimazole Clomiphene Codeine Enalapril Ethinyl estradiol Furosemide Hydrocortisone Isoniazid Lamuvidine Mesalamine 6-mercaptopurine Methimazole Metronidazole Omeprazole Pentamidine Pravastatin Procainamide Simvastatin Sulfamethoxazole Sulindac Tetracycline Trimethoprin-sulfa Valproic acid
11. 13. Etiology Infections/toxins Ascariasis, clonorchiasis, mumps, CMV, TB, MAI Organophosphate insecticides, scorpion venom Vascular disease Ischemia, atherosclerotic emboli Vasculitis (PAN, SLE, TTP, HSP) Duodenal disease PUD, periampullary diverticulum, Crohns Ampullary or duodenal neoplasm Pancreatic disease Pancreatic/ampullary tumors, lymphoma
12. 14. Etiology Tropical pancreatitis Most common cause of chronic disease in certain parts of India, Africa, Southeast Asia, and Brazil (30 latitude from equator) Mean onset at age 24 Abdominal pain, severe malnutrition, exocrine insufficiency Endocrine insufficiency (diabetes) is inevitable Pancreatic calculi in over 90% Pathophysiology unknown Possibly related cassava (tapioca) ingestion Mutations in pancreatic secretory trypsinogen inhibitor gene SPINK-1 in subset of patients Risk of pancreatic cancer is 25%
13. 15. Etiology Hereditary pancreatitis (familial) Rare, 1% of all cases AD with 80% penetrance and variable expression 60% have mutations in cationic trypsinogen gene on chromosome 7 (PRSS1) Onset of between infancy and 4th or 5th decade Median onset is age 10 Clinical presentation is same as other pancreatitis 50% develop chronic pancreatitis 40% cumulative risk of developing cancer by age 70
14. 16. Etiology Autoimmune pancreatitis Rare; presence of autoantibodies, elevated serum IgG4 Enlarged pancreas (diffuse or focal) Mass-like appearance dense lymphoplasmacytic infiltrate; IgG4 immunostaining In 60%, association with other autoimmune diseases such as Sjgrens, PSC, PBC, AIH Responsive to glucocorticoid therapy
15. 17. Etiology Cystic fibrosis Mutations in CF transmembrane conductance regulator (CFTR) 85% of CF has exocrine pancreatic dysfunction 30 to 75% have endocrine insufficiency (glucose intolerance) Fat and protein maldigestion Pancreatitis is worse in older patients
16. 18. Etiology Idiopathic pancreatitis (10 30%) Occurs in 2 forms early onset at age 20 and late onset at age 50 CFTR mutations without diagnostic features of CF in a subset Pancreatic divisum controversial cause of acute pancreatitis 5 to 7% of general population duct of Santorini drains larger portion of gland (dorsal) through accessory papilla and does not fuse with duct of Wirsung draining smaller portion (ventral) through major papilla
17. 19. Pancreas divisum
18. 20. Clinical presentation Local Inflammatory mass (phlegmon) Peripancreatic effusion/ascites or pleural effusion Bile duct obstruction Ileus Necrosis/abscess Systemic CV hypovolemia, hypotensive shock, capillary leak Pulm hypoxia, pleural effusion, ARDS Renal oliguria, azotemia Metabolic hypoalbuminemia, hypocalcemia, hyperglycemia, hypertriglyceridemia, metabolic acidosis Hematologic vascular thrombosis; DIC Hemorrhagic stress gastritis, ulcers, pseudoaneurysms, gastric varices Cullens sign and Grey-Turners
19. 21. Clinical presentation Biliary pancreatitis Stones usually 5mm or less in size Transient in most cases with stone passage within 48hrs Sudden rise in pain decline in transaminases >50% or dec in pain suggests stone passage ERCP only if ongoing pancreatitis >24 48hrs, cholangitis, or complications such as necrosis EUS prior to ERCP can image bile duct with less invasive method
20. 22. EUS
21. 23. Laboratory diagnosis Amylase Rises within 6 12 hrs of onset; half-life of 10 hrs Elevated for 3 to 5 days; most have 3-fold elevation May be normal in TG-induced pancreatitis Exclude other causes of hyperamylasemia Salivary gland stones, mumps, cholecystitis, CBD obstruction, gastrointestinal perforation, intestinal obstruction or ischemia, appendicitis, renal insufficiency, DKA, ovarian cysts, acute salpingitis, ovarian cancer, lung cancer, macroamylasemia Lipase Similar sensitivity to amylase but higher specificity Almost entirely pancreatic origin; remains elevated for 8 14 days In renal failure without pancreatitis, lipase elevation is < 2-fold Nonpancreatic sources duodenum/sb; gastric; adipose tissue; leukocytes; lung
22. 24. Severity of acute pancreatitis Ransons criteria On admission to hospital: Age > 70 y; wbc > 18,000; glucose > 220; LDH > 400; AST > 250 Within 48 hours of admission: Decreased Hct > 10 pts; increase in BUN > 2; calcium < 8; base deficit > 5; fluid deficit > 4 Mild disease has < 2 criteria (mortality 3 criteria (mortality of 10%) 6 or more criteria (mortality > 60%) Best used to exclude severe disease; poor sensitivity and specificity for mild to moderate disease
23. 25. Severity of acute pancreatitis APACHE-II More accurate and continuous assessment but more complex Assignment of points to 12 physiologic variables: HR, RR, MAP, PaO2, pH, K+, Na+, creatinine, Hct, wbc, and Glascow Coma Scale Most patients survive if scores are 13 has high mortality Low sensitivity at admission (34 70%) but specificity of almost 100% At 48 hours, no better than other scoring systems
24. 26. Severity of acute pancreatitis BISAP Score and Mortality in acute pancreatitis Measurement within 24 hrs points BISAP score Mortality BUN >25 1 0 1 60 1 4 12 19% Pleural effusion 1 5 22-27% BUN > 25 increases risk of mortality by 5-fold Steady increase in mortality with increasing number of points
25. 27. Diagnostic imaging Acute pancreatitis with peri-pancreatic Chronic pancreatitis with atrophic mesenteric stranding fibrotic pancreas
26. 28. Acute pancreatitis - management Mild pancreatitis Excellent prognosis, supportive care, NPO, IV fluids Pain control with Demerol or Dilaudid NG suction not beneficial unless ileus or intractable nausea/emesis PPI and H2-receptor blockers not beneficial Prophylactic antibiotics not indicated
27. 29. Acute pancreatitis - management Severe pancreatitis Vigorous IV volume resuscitation (may require 5-10 L NS daily) May require ICU monitoring for pulmonary, renal and hepatobiliary function SG ARDS occurs between day 2-7 and requires mechanical ventilation; no specific treatment will prevent or affect this condition Hyperglycemia; cautious insulin use because of variable blood glucose Cautious correction of serum calcium and magnesium Bacterial infection in 30% of severe disease with necrosis or phlegmon E. Coli, Pseudomonas, Klebsiella,Enterococcus
28. 30. Nutrition Early enteral feeding; prevents bacterial overgrowth and translocation In severe disease, feedings with nasojejunal tube as soon as ileus subsides In prolonged disease, consider endoscopic or radiologic placement of jejunal feeding tube High-protein, low fat regimen Parenteral nutrition if enteral feedings not tolerated In mild disease, start feeds when pain resolved
29. 31. Pseudocysts Occurs in 10% Persistent elevation of enzymes is a clue US, CT, MRI, EUS Treat if symptomatic, > 6cm, and more than 6 wks Surgical decompression highly successful Percutaneous and endoscopic drainage
30. 32. Pancreatic necrosis 20% of acute cases contrast-enhanced CT if organ dysfunction or systemic toxicity Necrosum dead tissue- irreversible Definition confused with fluid collections, abscess, duct disruption, etc. Leukocytosis >20,000; fever
31. 33. Pancreatic necrosis Percutaneous CT-guided v endoscopic aspiration if infection suspected Prophylactic antibiotics Surgical debridement if infection confirmed Often, surgical debridement requires percutaneous large bore drains for weeks with exchanges If sterile necrosis, 4 6 weeks of medical therapy
32. 34. Endoscopic necrosectomy
33. 35. Endoscopic necrosectomy Several studies showing that endo v surgical necrosectomy reduces hospital stay from average of 10 to 5 days Nasocystic drain left for irrigation Multiple sessions required Stenting Hydrogen peroxide irrigation
34. 36. Chronic pancreatitis Recurrent episodes of pancreatitis Chronic abdominal pain Endocrine and exocrine insufficiency Calcifications Pancreatic duct strictures and upstream dilation Bile duct strictures 5% will develop pancreas cancer over 20 years - higher in tropical and familial pancreatitis >50%
35. 37. Calcifications Dilated pancreas duct
36. 38. Chronic pancreatitis Pain control Narcotics, pain specialist, nerve block, antioxidants Endoscopic therapy for strictures Surgical decompression of duct Maldigestion Pancreatic enzymes given with PPI to prevent premature breakdown in gastric acid; >20,000 u of lipase give at least 2 caps with each meal and 1 with snacks Screen for cancer No good guidelines; Low threshhold for weight loss, worsening pain Encourage cessation of tobacco/etoh
37. 39. Epidemiology 4th leading cause of cancer death Lifetime risk of 1.5% at age 85 in caucasians Highest in African-Americans and lowest in Asian-Americans Risk factors >80% are due to sporadic mutations and not familial but inc with age Cigarette smoking, pipe, and smokeless tobacco = 2X risk Obesity = 20% increase risk Age >65 Men have 30% more risk than women Long-term diabetes has 2 3X risk Chronic pancreatitis 4X
38. 40. Epidemiology Genetic risks (10% of all panc adenocarcinoma) Hereditary pancreatitis PRSS1 75X BRCA2 (hereditary breast and ovarian) 10X Familial atypical multiple melanoma (FAMM) p16/CDKN2A has 20-35X Familial pancreatic cancer BRCA2 10X HNPCC MLH1, MSH2 - undefined Peutz-Jeghers STK11 100X ABO blood group 25X Neuroendocrine tumor VHL, NF1, MEN1
39. 41. Diagnostics Rare early diagnosis 80%), mean age 55 Predominantly in body and tail of pancreas Macroseptated Larger cysts >3cm have increased malignant likelihood Solid or mural nodules Rarely communicate with pancreatic duct on ERCP Viscous mucous material
40. 48. Radiographic diagnosis Mucinous cystic neoplasms Large cyst with large cystic spaces, unilocular or multilocular Multiple contrast- enhancing septations and solid intramural nodules Peripheral calcification in 10 to 25% ( distinct from serous central calcification)
41. 49. Serous cystadenomas Second most common cystic tumor Women (80%), mean age 63 years Occur in body or tail (50 to 70%) Microseptation Association with von Hippel-Lindau disease Similar in character to simple pancreatic cyst, acellular in some
42. 50. Radiographic diagnosis Serous cystadenoma Central stellate scar with calcification sometimes seen Honeycombed appearance Sometimes appears as solid mass depending on number of microcysts and amount of fibrous tissue
43. 51. IPMN Intraductal papillary mucinous neoplasm Initially described 1982 Cystic dilation of main and/or side branch of PD Papillary neoplasms within the main PD Mucin hypersecretion Premalignant histology may range from hyperplasia to carcinoma in different sites of same pancreas men > women; 6th to 7th decade 75% are symptomatic abdominal pain and weight loss Malignant IPMN more likely in older patients with new onset DM and jaundice Mutations in K-ras-2 and tumor suppressor gene p53
44. 52. Radiographic diagnosis IPMN Main duct, branch duct or combined dilation CT detects dilated duct MRCP detects communication of abnormal cystic region with main duct
45. 53. EUS imaging - IPMN Ductal dilation is very prominent Patulous ampulla extruding mucus Thick fluid aspirate ERCP shows dilated PD and side-branch ectasia without ductal stricture Associated cysts may be complex always communicate with main duct
46. 54. Radiographic diagnosis Determination of pseudocyst v. nonpseudocyst Pseudocyst features CT fluid collection with barely perceptible wall or thick wall with contrast enhancement Peripancreatic changes of prior pancreatitis Contrast-enhancement may suggest hemorrhage within cyst
47. 55. EUS images of cysts Pseudocyst Large fluid collections with defined wall Lack of septations Layering debris
48. 56. Cyst fluid analysis WR Brugge, et al Gastroenterol 2004 68 mucinous cystic neoplasms CEA > 192 ng/mL MCN; accuracy of 79% CEA >800 highly diagnostic; CEA 50% pancreatic necrosis with multiple fluid collections around pancreas. He requires mechanical ventilation. By day 7, his clinical status has improved and he is extubated and tolerating NJ feeds. On day 10, he develops fever and hypotension. Investigations show a new leukocytosis, worsening serum Cr, normal LFTs, and worsening abdominal tenderness but no guarding or rigidity What is the next appropriate step?
49. 60. Question #1 A. Urgent ERCP should be performed B. Urgent pancreatic necrosectomy is indicated to reduce mortality C. Antifungal medications should be started D. A CT-guided FNA of pancreas is indicated to rule out infected pancreatic necrosis.
50. 61. Question #1 A. Urgent ERCP should be performed B. Urgent pancreatic necrosectomy is indicated to reduce mortality C. Antifungal medications should be started D. A CT-guided FNA of pancreas is indicated to rule out infected pancreatic necrosis.
51. 62. Questions #2 A 65 y.o. man is admitted with severe abdominal pain, fever, nausea, and vomiting. On examination, he is febrile with stable VS. Upper abdomen is diffusely tender with rebound an dabsent bowel sounds. Serum amylase and lipase are elvated. Left flank ecchymosis is present. After aggressive fluid resuscitation, a contrast CT scan on day 2 shows edematous pancreas with non-enhancement of 30% of the gland and multiple peri-pancreatic fluid collections. In terms of management, which of the following is correct? A. TPN and enteral nutrition result in similar metabolic complications B. Nutrion support is indicated in mild pancreatitis to reduce complications C. TPN is associated with mortality reduction in acute pancreatitis D. Enteral nutrition is preferred for patients with severe acute pancreatitis
52. 63. Questions #2 A 65 y.o. man is admitted with severe abdominal pain, fever, nausea, and vomiting. On examination, he is febrile with stable VS. Upper abdomen is diffusely tender with rebound an dabsent bowel sounds. Serum amylase and lipase are elvated. Left flank ecchymosis is present. After aggressive fluid resuscitation, a contrast CT scan on day 2 shows edematous pancreas with non-enhancement of 30% of the gland and multiple peri-pancreatic fluid collections. In terms of management, which of the following is correct? A. TPN and enteral nutrition result in similar metabolic complications B. Nutrion support is indicated in mild pancreatitis to reduce complications C. TPN is associated with mortality reduction in acute pancreatitis D. Enteral nutrition is preferred for patients with severe acute pancreatitis
53. 64. Questions #3 A 42 y.o. woman is admitted with severe epigastric pain, nausea and vomiting. On exam, she is afebrile with a HR of 126 and BP of 86/45. Her abdomen is diffusely tender with rebound and no bowel sounds. Wbc 15K, Hct 47, BUN 28, Cr 1, normal LFTs, amylase 5200 (