Benign Pancreatic disorders

1. Benign Pancreatic disorders RaikaJamali M.D. Gastroenterologist and Hepatologist Sina Hospital Tehran University of Medical Sciences

3. Regulation of Pancreatic Secretion • Gastric acidis the stimulus for the release of secretin from the duodenum, which stimulates the secretion of water and electrolytes from pancreatic ductal cells. • Release of cholecystokinin (CCK) from the duodenum and proximal jejunum is largely triggered by long-chain fatty acids, certain essential amino acids (tryptophan, phenylalanine, valine, methionine), and gastric acid itself. CCK evokes an enzyme-rich secretion from acinar cells in the pancreas.

4. The parasympathetic nervous system(via the vagus nerve) exerts significant control over pancreatic secretion. • Secretion evoked by secretin and CCK depends on permissive roles of vagal afferent and efferent pathways. • Also, vagal stimulation effects the release of vasoactive intestinal peptide (VIP), a secretin agonist.

5. Pancreatic exocrine secretion is influenced by inhibitory neuropeptides: • somatostatin, • pancreatic polypeptide, • peptide YY, • neuropeptide Y, • calcitonin gene–related peptides, • Although pancreatic polypeptide and peptide YY may act primarily on nerves outside the pancreas, somatostatin acts at multiple sites. • The mechanism of action of these various factors has not been fully defined. • pancreastatin, • enkephalin, • glucagon, • galanin.

6. The ductal cells secrete bicarbonate, derived from plasma (93%) and intracellular metabolism (7%). • Bicarbonate enters through the sodium bicarbonate cotransporter with depolarization caused by chloride efflux through the cystic fibrosis transmembrane conductance regulator (CFTR). • Secretin and VIP, both of which increase intracellular cyclic AMP, act on the ductal cells opening the CFTR in promoting secretion.

7. CCK potentiates the stimulatory effects of secretin. • Acetylcholine also plays an important role in ductal cell secretion. • Bicarbonate helps neutralize gastric acid and creates the appropriate pH for the activity of pancreatic enzyme. • All pancreatic enzymes have pH optima in the alkaline range.

8. The acinar cell is concerned with the secretion of pancreatic enzymes. • Proteins synthesized by the endoplasmic reticulum are processed in the Golgi and then targeted to the appropriate site, whether that be zymogen granules, lysosomes, or other cell compartments. • The pancreas secretes amylolytic, lipolytic, and proteolytic enzymes.

9. Amylolytic enzymessuch as amylase, hydrolyze starch to oligosaccharides and to the disaccharide maltose. • Lipolytic enzymesinclude: • lipase, • phospholipase A2, • cholesterol esterase. • Bile salts inhibit lipase in isolation, but colipase, another constituent of pancreatic secretion, binds to lipase and prevents this inhibition. • Bile salts activate phospholipase A and cholesterol esterase.

10. Proteolytic enzymes include: • endopeptidases (trypsin, chymotrypsin), which act on internal peptide bonds of proteins; • exopeptidases (carboxypeptidases, aminopeptidases), which act on the free carboxyl- and amino-terminal ends of peptides, respectively; • elastase. • The proteolytic enzymes are secreted as inactive precursors and packaged as zymogens. • Enterokinase, an enzyme found in the duodenal mucosa, cleaves the lysine-isoleucine bond of trypsinogen to form trypsin. • Trypsin then activates the other proteolytic zymogens in a cascade phenomenon.

11. The neurologic stimulation is cholinergic by the vagus nerve. • The stimulatory neurotransmitters are acetylcholine and gastrin-releasing peptides. • These neurotransmitters activate calcium-dependent second messenger systems, resulting in the release of zymogen granules. • VIP is present in intrapancreatic nerves and potentiates the effect of acetylcholine.

12. Autodigestion of the pancreas • Prevented by the packaging of pancreatic proteases in precursor form and by the synthesis of protease inhibitor[i.e., pancreatic secretory trypsin inhibitor (PSTI) or SPINK1], which can bind and inactivate about 20% of trypsin activity. • These protease inhibitors are found in: • the acinar cell, • the pancreatic secretions, • the α1 and α2 globulin fractions of plasma. • Loss of any of these protective mechanisms leads to zymogen activation, autodigestion, and acute pancreatitis.

13. Enteropancreatic Axis and Feedback Inhibition • Pancreatic enzyme secretion is controlled, by a negative feedback mechanism induced by active serine proteases in the duodenum. • To illustrate, perfusion of the duodenal lumen with phenylalanine causes a prompt result in increased plasma CCK levels as well as increased secretion of pancreatic enzymes.

14. Acute pancreatitis • varies from interstitial pancreatitis, which is usually a mild and self-limited disorder, to necrotizing pancreatitis, in which the extent of pancreatic necrosis may correlate with the severity of the attack and its systemic manifestations.

15. Interstitial pancreatitis

16. Necrotizing pancreatitis

17. Etiology • Common Causes • Gallstones (including microlithiasis) • Alcohol (acute and chronic alcoholism) • Hypertriglyceridemia • Endoscopic retrograde cholangiopancreatography (ERCP), especially after biliary manometry • Trauma (especially blunt abdominal trauma) • Postoperative (abdominal and nonabdominal operations) • Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline, valproic acid, anti-HIV medications) • Sphincter of Oddi dysfunction

18. Etiology • Uncommon Causes • Vascular causes and vasculitis (ischemic-hypoperfusion states after cardiac surgery) • Connective tissue disorders • Thrombotic thrombocytopenic purpura (TTP) • Cancer of the pancreas • Hypercalcemia • Periampullary diverticulum • Pancreas divisum • Hereditary pancreatitis • Cystic fibrosis • Renal failure

19. Etiology • Rare Causes • Infections (mumps, coxsackievirus, cytomegalovirus, echovirus, parasites) • Autoimmune (e.g., Sjögren's syndrome) • Causes to Consider in Patients with Recurrent Bouts of Acute Pancreatitis without an Obvious Etiology • Occult disease of the biliary tree or pancreatic ducts, especially microlithiasis, sludge • Drugs • Hypertriglyceridemia • Pancreas divisum • Pancreatic cancer • Sphincter of Oddi dysfunction • Cystic fibrosis • Idiopathic

20. Pathogenesis • Autodigestion is a currently accepted pathogenic theory; • Pancreatitis results when proteolytic enzymes are activated in the pancreas rather than in the intestinal lumen. • A number of factors (e.g., endotoxins, exotoxins, viral infections, ischemia, anoxia, lysosomal calcium, and direct trauma) are believed to facilitate activation of trypsin. • Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but also can activate other enzymes,(such as elastase and phospholipase A2).

22. Activation of Pancreatic Enzymes • The initial phase is characterized by intrapancreatic digestive enzyme activation and acinar cell injury. • Trypsin activation appears to be mediated by lysosomal hydrolases such as cathepsin B that become colocalized with digestive enzymes in intracellular organelles; • it is currently believed that acinar cell injury is the consequence of trypsin activation.

23. The second phase of pancreatitis involves the activation, chemoattraction, and sequestration of leukocytes and macrophages in the pancreas, resulting in an enhanced intrapancreatic inflammatory reaction. • The third phase of pancreatitis is due to the effects of cytokines, released by the inflamed pancreas, on distant organs.

24. Trypsinogen Trypsin Alfa2-M Alfa2 + Trypsin Alfa1-AT PSTI Alfa1-AT + Trypsin PSTI + Trypsin Trypsin Procolipase Proelastase Chymotrypsinogen Prophospholipase A2 Xanthynedehydrogenase Prokallycrein C3 C5 Plasminogen XII Factor Systemic circulation RES Liver Spleen Bone marrow Nodes Mesotrypsin Kininogens Enzyme Y Clearance Kinins Colipase Elastase Chymotrypsin Phospholipase A2 Xanthynedehydrogenase Kallycrein C3a C5a Plasminogen XIIa Factor

25. Activated proteolytic enzymes, especially trypsin, activate other enzymes such as elastase and phospholipase A2. • The active enzymes and cytokines then digest cellular membranes and cause: • proteolysis, • edema, • interstitial hemorrhage, • vascular damage, • coagulation necrosis, • fat necrosis, • and parenchymal cell necrosis.

26. Cellular injury and death result in the liberation of bradykinin, vasoactive substances, and histamine that can produce vasodilation, increased vascular permeability, and edema with profound effects on many organs. • The systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS) as well as multiorgan failure may occur as a result of this cascade of local as well as distant effects.

27. Acute Pancreatitis TNF Other leucocyte products Oxygen radicals Elastase IFN-α,γ IL-10 IL-2 IL-1 IL-6 IL-8 PAF N.O. • Complications: • Vascular leakage • Hypovolemia • Shock • ARDS • Acute renal tubular necrosis

28. There appear to be a number of genetic factors that can increase the susceptibility and/or modify the severity of pancreatic injury in acute pancreatitis. • Four susceptibility genes have been identified: • (1) cationic trypsinogen mutations (PRSS1m, R122Hm, and N291), • (2) pancreatic secretory trypsin inhibitor (SPINK1), • (3) CFTR, • (4) monocyte chemotactic protein (MCP-1). • Experimental and clinical data indicate that MCP-1 may be an important inflammatory mediator in the early pathologic process of acute pancreatitis, a determinant of the severity of the inflammatory response, and a promoter of organ failure.

29. Approach to the Patient • Abdominal pain, vary from a mild and tolerable discomfort and more commonly to severe, constant, and incapacitating distress. is steady and boring. • Is located in the epigastrium and periumbilical region and often radiates to the back as well as to the chest, flanks, and lower abdomen. • More intense when the patient is supine, and patients may obtain some relief by sitting with the trunk flexed and knees drawn up.

30. Nausea, vomiting, and abdominal distention due to gastric and intestinal hypomotility and chemical peritonitis are also frequent complaints.

31. Physical examination • A distressed and anxious patient. • Low-grade fever, • Tachycardia, • Hypotension. • Shock • (1) hypovolemia secondary to exudation of blood and plasma proteins into the retroperitoneal space and a "retroperitoneal burn" due to activated proteolytic enzymes; • (2) increased formation and release of kinin peptides, which cause vasodilation and increased vascular permeability; and • (3) systemic effects of proteolytic and lipolytic enzymes released into the circulation.

32. Jaundice occurs infrequently; when present, it usually is due to edema of the head of the pancreas with compression of the intrapancreatic portion of the common bile duct. • Erythematous skin nodules due to subcutaneous fat necrosis may occur. • There are pulmonary findings(In 10–20% of patients), including: • Basilar rales, • Atelectasis, • Pleural effusion, (frequently left sided)

33. Abdominal tenderness and muscle rigidity • Diminished bowel sounds • An enlarged pancreas with walled off necrosis or a pseudocyst may be palpable in the upper abdomen later in the disease course • A faint blue discoloration around the umbilicus (Cullen's sign) may occur as the result of hemoperitoneum, • Blue-red-purple or green-brown discoloration of the flanks (Turner's sign) reflects tissue catabolism of hemoglobin.

34. Grey Turner sign Cullen’s sign

35. Laboratory Data • Increased level of serum amylase and lipase. Values threefold or more above normal virtually clinch the diagnosis if gut perforation, ischemia, and infarction are excluded. • No correlation between the severity of pancreatitis and the degree of lipase and amylase elevations. • After three to seven days, total serum amylase values tend to return toward normal. • Pancreatic isoamylase and lipase levels may remain elevated for 7 to 14 days

36. Markers of Severity within 24 Hours • SIRS [temperature >38° or < 36°C, Pulse > 90, Tachypnea > 24, WBC > 12,000] • Hemoconcentration (Hct >44%) • BISAP (bedside index of severity in acute pancreatitis) • (B) Blood urea nitrogen (BUN) >22 mg% • (I) Impaired mental status • (S) SIRS: 2/4 present • (A) Age >60 years • (P) Pleural effusion • Organ Failure • Cardiovascular: systolic BP <90 mmHg, heartrate >130 • Pulmonary: Pao2 <60 mmHg • Renal: serum creatinine >2.0 mg% • Gastrointestinal: bleeding >500 mL/24 hours

37. Severity • Risk Factors • Age > 60 years • Obesity, BMI > 30 • Comorbid disease • Markers during Hospitalization • Persistent organ failure • Pancreatic necrosis • Hospital-acquired infection

38. LaboratoryData • Leukocytosis (15,000–20,000 leukocytes per L) • Hemoconcentration • with hematocrit values >44% • and/or blood urea nitrogen (BUN) level >22 mg/Dl • Hyperglycemia • decreased insulin release, • increased glucagon release, • increased output of adrenal glucocorticoids and catecholamines. • Hypocalcemia

39. Laboratory Data • Hyperbilirubinemia (>4.0 mg/dL) in 10% • is transient • return to normal in four to seven days. • Serum alkaline phosphatase • and aspartate aminotransferase levels are also transiently elevated • Elevated serum lactic dehydrogenase levels (>500 U/dL) • Hypertriglyceridemia occurs in 5–10%

40. Hypoxemia (arterial Po2 60 mmHg), which may herald the onset of ARDS. • Electrocardiogram is occasionally abnormal in acute pancreatitis with ST-segment and T-wave abnormalities simulating myocardial ischemia.

43. CT shows significant swelling and inflammation of the pancreas CT Scan of acute pancreatitis

47. Gall stone pancreatitis by ERCP

49. Diagnosis • Requires two of the following: • typical abdominal pain, • threefold or greater elevation in serum amylase and/or lipase level, • and/or confirmatory findings on cross-sectional abdominal imaging.

50. Differential diagnosis • (1) perforated viscus, especially peptic ulcer • (2) acute cholecystitis and biliary colic • (3) acute intestinal obstruction • (4) mesenteric vascular occlusion • (5) renal colic • (6) myocardial infarction • (7) dissecting aortic aneurysm • (8) connective tissue disorders with vasculitis • (9) pneumonia • (10) diabetic ketoacidosis.