PANCRETITIS Etiology , Clinical features , diagnosis and management

Etiology , Clinical features , diagnosis and management of pancreatitis

1. Acute Pancreatitis -DR BAHAR KULKARNI

2. Embryology of the Pancreas Origin-Derived from the endoderm of the foregut. Two pancreatic buds: Dorsal bud: arises from the dorsal aspect of the duodenum. Ventral bud: arises near the hepatic diverticulum. Development Week 5–7 of gestation: Dorsal bud forms superior part (head, body, tail). Ventral bud forms inferior head and uncinate process. Around week 7:Ventral bud rotates posteriorly to the right around the duodenum and fuses with the dorsal bud .

3. Pancreatic Duct Formation Duct of Wirsung (main pancreatic duct): from ventral duct, continues into dorsal duct. Duct of Santorini (accessory duct): from dorsal duct, if persists. Main duct opens into major duodenal papilla (with common bile duct). Accessory duct (if present) drains via minor papilla.

4. Anatomy of the Pancreas Location-Retroperitoneal. Transversely lies across L1–L2 vertebrae. Divided into: Head (in the C-loop of duodenum) Uncinate process Neck (over SMV & portal vein) Body (over aorta, L2 vertebra) Tail (in splenorenal ligament; touches spleen)

5. Relations Anterior: Stomach, transverse mesocolon Posterior: IVC, aorta, SMA, SMV, splenic vein, left kidney Superior: Celiac trunk Inferior: 3rd part of duodenum Vascular Supply Arterial: Head:Anterior & posterior superior pancreaticoduodenal arteries Inferior pancreaticoduodenal artery Body and Tail:Pancreatic branches of splenic artery (great, dorsal pancreatic arteries)

6. Venous Drainage- Drain into splenic vein and Superior mesenteric vein, forming portal vein. Lymphatic Drainage- Pancreaticosplenic nodes, celiac nodes, SMA nodes. Nerve Supply Sympathetic:celiac plexus Parasympathetic: vagus

7. Epidemiology Acute pancreatitis is a common disease and is the leading cause of hospitalization among gastrointestinal disorders in the United States. It involves the acute inflammation of the pancreas. The mortality of acute pancreas ranges from 3% in patients with mild edematous pancreatitis to as high as 20% in patients with pancreatic necrosis.

8. The Atlanta classification broadly classifies acute pancreatitis into 2 categories: Interstitial edematous acute pancreatitis is characterized by the acute nflammation of the pancreatic parenchyma and surrounding peri -pancreatic tissue. Necrotizing acute pancreatitis is characterized by necrosis of pancreatic parenchyma and peri -pancreatic tissue.

9. Acute pancreatitis may occur when factors involved in maintaining cellular homeostasis are out of balance. However, the predominant theories are the bile pancreatic common pathway theory and gallstone migration theory which shows that acute biliary pancreatitis occurs due to bile- pancreatic duct obstruction that raises the pancreatic duct pressure causing bile reflux. This prematurely activates the trypsin and causes pancreatic autodigestion. Intra acinar pancreatic enzyme activation causes autodigestion of normal pancreatic parenchyma. This causes release of proinflammatory cytokines such as TNF- a, and IL- 1,2,6 and inflammatory mediators such as IL10 and IL1 receptor antagonist. PATHOPHYSIOLOGY

10. In severe cases, it may cause local haemorrhage and sometimes pancreatic necrosis. This inflammatory response is self- limiting in 80% of the cases, however in some, a vicious cycle is formed leading to local and systemic complication Lysosomal and zymogen granule compartments fuse, enabling activation of trypsinogen to trypsin. Intracellular trypsin triggers the entire zymogen activation cascade. Secretory vesicles are extruded across the basolateral membrane into the interstitium, where molecular fragments act as chemoattractants for inflammatory cells

11. Biliary or Gallstone Pancreatitis Gallstone pancreatitis is the most common cause of Acute Pancreatitis In the obstructive theory, pancreatic injury is the result of excessive pressure inside the pancreatic duct. This increased intraductal pressure is the result of continuous secretion of pancreatic juice in the presence of pancreatic duct obstruction. The reflux theory proposes that stones become impacted in the ampulla of Vater and form a common channel that allows bile salt reflux into the pancreas.

12. When gallstones or sludge are visualized in USG, a diagnosis of biliary pancreatitis can be presumed. In the absence of gallstones or sludge- A dilated common bile duct >8 mm if the patient is 75 years or younger A dilated common bile duct >10 mm if the patient is older than 75 years Elevation of serum alanine aminotransferase (ALT) greater than 100 U/L with ALT >AST level strongly suggests the disease is of biliary origin. If gallstones are the cause of pancreatitis, cholecystectomy with bile duct clearance is required to prevent recurrent biliary pancreatitis.

13. Alcohol- Induced Injury Excessive ethanol consumption is the second most common cause of Acute Pancreatitis worldwide. Factors that contribute to ethanol- induced pancreatitis include Heavy ethanol abuse (>100 g/day for at least 5 years) Smoking Genetic predisposition. Alcohol has a number of deleterious effects in the pancreas such as It triggers proinflammatory pathways which increase the production of TNF- α and IL- 1. It also increases the expression and activity of caspases that mediate apoptosis. In addition, alcohol decreases pancreatic perfusion, induces sphincter of Oddi spasm, and obstructs pancreatic ducts through the precipitation of proteins inside the ducts.

14. Developmental abnormalities of pancreas There are two developmental abnormalities commonly associated with pancreatitis: Pancreas divisum Annular pancreas Pancreas divisum is a failure of the dorsal and ventral pancreatic ducts to fuse during embryogenesis contribute to the development of acute pancreatitis through an obstructive mechanism. Annular pancreas is congenital anomaly in which a band of pancreatic tissue surrounds the second part of the duodenum.

15. “Santorinicele ” Distal stenosis of dorsal duct in a patient with chronic pancreatitis

16. ERCP – Induced Pancreatitis Acute Pancreatitis is the most common complication after ERCP, occurring in up to 5% of patients. Acute Pnacreatitis occurs more frequently in patients who have undergone therapeutic procedures compared with diagnostic procedures. It is also more common in patients who have had multiple attempts of cannulation, sphincter of Oddi dysfunction, and abnormal visualization of the secondary pancreatic ducts after injection of contrast material.

17. Drug- Induced Pancreatitis Up to 2% of Acute Pancreatitis cases are caused by medications , usually mild in nature. The most common agents include Sulfonamides Metronidazole Erythromycin Tetracyclines Didanosine Thiazides HMG- CoA reductase inhibitors (statins), azathioprine 6-mercaptopurine

18. Anatomic Obstruction Abnormal flow of pancreatic juice into the duodenum can result in pancreatic injury. Acute pancreatitis has been described in patients with pancreatic tumors, parasites, and congenital defects. Ascaris lumbricoides infection and annular pancreas.

19. Metabolic Factors Hypertriglyceridemia and hypercalcemia can also lead to pancreatic damage. It is more common in patients with type I, II, or V hyperlipidemia. It should be suspected in patients with a triglyceride level higher than 1000 mg/dL. A triglyceride level higher than 2000 mg/dL confirms the diagnosis. Hypercalcemia is postulated to induce pancreatic injury through the activation of trypsinogen to trypsin and intraductal precipitation of calcium, leading to ductal obstruction and subsequent attacks of pancreatitis. Approximately 1.5% to 13% of patients with primary hyperparathyroidism develop Acute Pancreatitis

20. Miscellaneous Conditions Blunt and penetrating abdominal trauma can be associated with Acute Pancreatitis in 0.2% and 1% of cases, respectively. Prolonged intraoperative hypotension and excessive pancreatic manipulation during abdominal surgery can also result in Acute Pancreatitis. Pancreatic ischemia in association with acute pancreatic inflammation can develop after splenic artery embolization. Other rare causes include scorpion venom stings and perforated duodenal ulcers.

21. Autoimmune Pancreatitis It can be associated with primary sclerosing cholangitis, Sjogren's syndrome, biliary cirrhosis. Lymphoplasmacytic autoimmune pancreatitis is a condition which causes high levels of circulating lgG4, pancreatitis, bile and pancreatic ductal strictures (double duct sign like mimicking the pancreatic cancer), pancreatic head mass.

22. Hereditary Pancreatitis In normal individuals small amount of spontaneous trypsinogen activation into trypsin occurs in pancreas which is further prevented and protected by trypsin inhibitors. In hereditary pancreatitis genetic mutation causes defective trypsin inhibitors and trypsin becomes resistant to trypsin inhibitors leading into high concentration of intra pancreatic active trypsin which activates all other enzymes leading into pancreatitis. Here even though acute pancreatitis can occur; this is commonly subclinical leading into chronic pancreatitis.

23. Idiopathic Pancreatitis It is probably due to gallbladder sludge or microcrystals which often can be very well controlled or further prevented by cholecystectomy and sphincterotomy. It also can be due to malfunction of sphincter of Oddi which is treated by sphincterotomy and pancreatic septotomy.

24. CLINICAL FEATURES

25. In severe cases, extensive necrosis with haemorrhage occurs causing acute haemorrhagic necrotising pancreatitis (Fulminant pancreatitis) , which has got a high mortality. Here enzymes seep across the retroperitoneum causing haemorrhagic spots and ecchymosis in the flanks ( Grey- Turner's sign ), or through falciform ligament causing discolouration around the umbilicus ( Cullen’s sign ), umbilical black eye or below the inguinal ligament ( Fox sign ).

26. Toxins released may lead to acute tubular necrosis and acute renal failure. Left sided diaphragm gets elevated and left sided pleural effusion occurs. Lecithinase reduces the surfactant in the alveoli of lung,and infection leads to pulmonary insufficiency, ARDS and respiratory failure. Because calcium is utilised for saponification, hypocalcaemia sets in. Diffuse oozing in pancreatic bed occurs which utilizes platelets and causes disseminated intravascular coagulation (DIC) . CLINICAL FEATURES

27. EARLY AND LATE ORGAN FAILURE Acute pancreatitis typically runs a biphasic course. Bacteremia and V entilator A ssociated P neumonia are the most prominent types of infections seen in S ystemic I nflammatory R esponse phase. Organ failure in C ompensatory A nti inflammatory response is related to the secondary infections like infected necrosis.

28. INVESTIGATI ONS IN ACUTE PANCREATITIS

29. DIAGNOSTIC CRITERIA Most often established by the presence of two of the three following criteria: abdominal pain consistent with the disease, serum amylase and/or lipase greater than three times the upper limit of normal, and/or characteristic findings from abdominal imaging. CT and/or MRI of the pancreas should be reserved for patients in whom the diagnosis is unclear(typical pain with normal enzymes) who fail to improve clinically within the first 48–72 h after hospital admission (e.g., persistent pain, fever, nausea, unable to begin oral feeding) to evaluate complications

30. HAEMATOLOGIAL CBC: Low Hb: prolonged hemetemesis/melena, internal hemorrhage Leucocytosis (10,000-30,000/mcL)- infection, non infectious inflammation Low platelets- DIC ◦ LFT’s: raised bilirubin, AST/ALT/LDH, ALP, GGTP- gall stone pancreatitis ◦ RFT’s: raised BUN/cretainine- ATN- >ARF Coagulation profile: increased INR- DIC BSR: > 180 mg/dl- diabetes as a sequelae or cause Serum electrolytes: Low sodium/potassium: persistent vomiting Hypocalcemia/Hypomagnesemia- saponification/fat necrosis Serum Protein: low protein/ albumin

31. Pancreatic Enzymes’ Assays Serum Amylase: ONSET: almost immediately PEAK: within several hours 3- 4 times upper limit of normal within 24 hrs (90%) RETURN to normal in (3- 5 days) normal at time of admission in 20% cases Compared with lipase, returns more quickly to normal values. Serum Lipase: more sensitive/specific than amylase Remains elevated longer than amylase(12 days) Useful in late presentation and if the cause is High TG.

32. Urine Amylase More sensitive than serum levels Remain elevated for several days after serum levels returned to normal Pancreatic- specific amylase (p- amylase) Measuring p- amylase instead to total amylase(also includes salivary amylase) makes diagnosis more specific(88- 93%).

33. ROLE OF INFLAMATORY MARKERS C- reactive protein Values greater than 120 mg/L can detect between 67 and 100% of pancreatic necrosis Moreover, the increased detection of both CRP and neutrophil elastase in plasma accurately predicts the outcome of the disease Interleukin 6 (IL- 6) is produced by a wide range of cells including monocytes/macrophages, endothelial cells, fibroblasts, and smooth muscle cells in response to stimulation by endotoxin, IL- 1b, and TNF- a Administration of IL- 6 induces pyrexia. IL- 6 is an excellent predictor of disease severity and mediates the acute phase response, since circulating levels peak 24±48 h before those of CRP

34. Procalcitonin procalcitonin has been proposed as a valuable tool for the noninvasive diagnosis of infection in pancreatic necrosis. In this study, the sensitivity of serum amyloid A was higher than that of procalcitonin in assessing the severity of the disease whereas procalcitonin and CRP had a higher specificity than serum amyloid A. Serum amyloid A was significantly higher in patients who had complications, such as necrosis, infection, or multiple organ dysfunction syndrome and better discriminated necrotizing from interstitial edematous pancreatitis

35. Several other inflamatory markers includes- Cytokines- IL- 8 has 12–24 hrs latency. Correlated to neutrophil activation. One of the most useful factors for early detection of severity. IL- 10 has 24 hrs latency. (anti-inflamatory) The lower the concentration at the time of admission, the more severe the pancreatitis. TNF- alpha has 6–18 hrs latency. Not correlated to the severity of the disease. TNF- alpha receptor has 6–18 hrs latency. Predicts the severity of the disease.

36. RADIOLOGY Plain CXR- PA view Left sided Pleural effusion: blunting of costophrenic and cardiophrenic angles + haziness in lower zones Elevated diaphragm on left side Linear focal atelactasis of lower lobe of lungs ARDS : diffuse alveolar interstitial shadowing

37. Plain X- ray abdomen erect AP view Sentinel* loop sign Localized isolated Distended gut loop (Ileus) seen near the site of injured viscus or inflamed organ RATIONALE: body's effort to localize the traumatic or inflamed lesions ETIOLOGY: Localized paralysis followed by accumulation of gas SITE: Acute Pancreatitis- Left hypochondrium (PROXIMAL JEJUNUM) Acute Appendicitis - Right iliac fossa Acute Cholecystitis- Right Hypochondrium Diverticuliti- Left iliac fossa

38. SENTINAL LOOP SIGN

39. Colon cut- off sign Gas filled (Distended) segment of proximal(mainly transverse) colon associated with narrowing of the splenic flexure with collapse of descending colon Due to extension of inflammatory process from the pancreas into the phrenicocolic ligament via the transverse mesocolon resulting in functional spasm and/or mechanical narrowing of the splenic flexure at the level where the colon returns to the retroperitoneum . Differential DIAGNOSIS: IBD Carcinoma of colon Mesenteric Ischemia

40. COLON CUT- OFF SGN

41. Transcutaneous Abdominal Ultrasonography Should be performed within 24 hours in all patients to detect gall stones* as a potential cause Rule out acute cholecystits as differential diagnosis to Detect dilated CBD. Gallstone pancreatitis is usually an acute event and resolves when the stone is removed or passes spontaneously. IV Contrast enhanced Computed Tomography Scan Provides over 90 % sensitivity and specificity for the diagnosis of acute pancrea titis

42. IV Contrast enhanced Computed Tomography Scan* INDICATIONS- DIAGNOSTIC Diagnostic uncertainty (differentiating pancreatitis from other possible intra- abdominal catastrophes) Severe acute pancreatitis- distinguish interstitial from necrotizing pancreatitis - Necrosis( non enhancement area > 30 % or 3 cm) done at 72 hrs Systemic complications: -Progressive deterioration, MOF, sepsis Localized complications: - Altered fat and fascial planes, Fluid collection, pseudo cyst, pseduoaneurysm,Bowel distension, mesenteric edema, hemorrhage.

43. Initial assessment of prognosis (CT severity index). Perfusion CT at 3rd day - > area of ischemia predict pancreatic necrosis.

44. Morphologic Types of Acute Pancreatitis THE REVISED ATLANTA CLASSIFICATION Interstitial Edematous Pancreatitis Necrotizing Pancreatitis Parenchymal necrosis Peripancreatic necrosis Combined Type

45. Interstitial Edematous Pancreatitis

46. Pancreatic Fluid Collection : Revised Atlanta 2012

47. Pancreatic Fluid Collection : REVISED ATLANTA 2012 Acute Peripancreatic Fluid Collection (APFC) Pancreatic Pseudocyst (PP) Acute Necrotic Collection (ANC) Walled- off Necrosis (WOPN)

48. Local Complications should be suspected if : Persistence or recurrence of abd. pain Secondary increases in Serum Pancreas activity Increasing organ dysfunction Development of clinical signs of Sepsis i.e. fever, leucocytosis Prompt CECT to be done in these cases.

49. 1) Acute Peripancreatic Fluid Collection (APFC) Peripancreatic Fluid associated with IEP with no necrosis Usually seen within first 4 weeks Homogenous collection of fluid Usually resolve spontaneously When a localised APFC persists > 4 weeks - > develop into a Pseudocyst

50. 2) Pancreatic Pseudo cyst Encapsulated collection of fluid with a well defined inflammatory wall usually outside the pancreas. With minimal or no necrosis. Usually round or oval. Appears after 4 weeks of onset IEP.

51. 3) Acute Necrotic Collection (ANC) A collection containing of both fluid & necrosis < 4 weeks Occurs only in setting of NP Single or multiple heterogeneous collection No defined wall

52. 4) Walled- off Necrosis (WON) A mature, encapsulated collection of pancreatic /peripancreatic necrosis that has developed a well- defined inflammatory wall Appears >4 weeks after onset of NP Heterogeneous with liquid & non- liquid density

53. Balthazar Score Points .1 N a rmal pancreas B Pancreatic en large ment 1 Pancreatic inflammation and/o r peripancrcatic fat 2 D Single pcripancrcatic fluid co Election 3 E Two a r mo re fluid co llcctions and/a r rctro pcritonoal air Percentage necrosis 10 2 10— S0 4 *0 6 CT Severity index Low’ Alex ee 0— . Llirlrlle rle‹u ee (0°» iiioitalin ) J— 6 Him rleei ee (1?° a mci talin ) "- 10

54. Magnetic Resonant Cholangiopancreatography - INDICATION: diagnosis of suspected biliary and pancreatic duct obstruction in the setting of pancreatitis. Repeated attacks of idiopathic acute pancreatitis (Microlithiasis).

55. CT angiography is done to rule out the complications of acute pancreatitis like pseudoaneurysm or active bleed due to ruptured pseudoaneurysm of spleenic artery.

56. MANAGEMENT OF ACUTE PANCREATITIS AND MANAGEMENT OF ACUTE NECROTIZING PANCREATITIS

57. Initial assessment first 4 hours Analgesia,H2 blocker Fluid resuscitation Predict the severity of pancreatitis [ ransons score,HAPS score Assessment of systemic response[SOFA Score,SIRS score] Antisecretary agents

58. REASSESSMENT /MANAGEMENT Assess fluid resuscitation- Mean arterial pressure heart rate Urine output, hematocrit

59. MRCP/URGENT ERCP if concomitant cholangitis Intensive support for persistant organ failure Enteral nutrition via nasogastric tube Prophylactic antibiotics given only for proven infection. Conservative management and monitoring Supplemental parenteral nutrition by day 4

60. Invasive intervention For deteriorating patients with suspected infected local complications STEP UP APPROACH with initial drain guided by CT scan [percutaneous or endoscopic drainage ] If failure to respond or secondary deterioration repet ct scan and by minimally invasive technique – Video assisted retroperitoneal debridement or percutaneous nephroscopic debridement Large bore drainage Endoscopic transluminal debridement

61. Indication for laparotomy- Acute abdomen Severe abdominal compartment syndrome Failed step up approach

62. PANCREATIC ASCITES: P aracentesis will reveal turbid fluid with a high amylase level. Adequate drainage with wide- bore drains placed under imaging guidance is essential. Measures that can be taken to suppress pancreatic secretion include parenteral or nasojejunal feeding and administration of octreotide. An ERCP may allow demonstration of the duct disruption and placement of a pancreatic stent .

63. HAEMORRHAGE: Bleeding may occur into the gut, into the retroperitoneum or into the peritoneal cavity. CT, angiography or MR angiography helps to make the diagnosis. Treatment involves embolization or surgery.

64. PSEUDOCYST : A pseudocyst is a collection of amylase- rich fluid enclosed in a well- defined wall of fibrous or granulation tissue. Formation of a pseudocyst requires 4 weeks or more from the onset of acute pancreatitis. Pseudocysts will resolve spontaneously in most instances. There are three possible approaches to draining a pseudocyst: percutaneous, endoscopic and surgical.

65. ACUTE PERIPANCREATIC FLUID COLLECTION (APFC) : No intervention is necessary unless a large collection causes symptoms or pressure effects, in which case it can be percutaneously aspirated under ultrasound or CT guidance. Transgastric drainage under EUS guidance is another option.

66. ACUTE NECROTIZING PANCREATITIS: The term ‘pancreatic necrosis’ refers to a diffuse or focal area of non- viable parenchyma. Pancreatic necrosis is typically associated with lysis of peripancreatic fat. This may lead to what is described as an acute necrotic collection (ANC). This is typically an intra or extra- pancreatic collection containing fluid and necrotic material, with no definable wall. Gradually, over a period of over 4 weeks, this may develop a well- defined inflammatory capsule, and evolve into what is termed as walled- off necrosis (WON).

67. ENDOSCOPIC DRAINAGE AND NECROSECTOMY: An increasingly popular alternative to the surgical step- up approach is endoscopic internal transluminal catheter drainage of the necrotic collection, followed by endoscopic transluminal necrosectomy if drainage is not completely successful. This can be performed through the stomach or through the duodenal wall . . .

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