Chronic pancreatitis

a summary of chronic pancreatitis

1. CHRONIC PANCREATITIS

2. INTRODUCTION The pancreas secretes 1500–3000 mL of isosmotic alkaline (pH >8) fluid per day containing about 20 enzymes. The pancreatic secretions provide the enzymes needed to effect the major digestive activity of the gastrointestinal tract and provide an optimal pH for the function of these enzymes.

3. DEFINITION The traditional definition of chronic pancreatitis has been permanent and irreversible damage to the pancreas, with histologic evidence of chronic inflammation, fibrosis, and destruction of exocrine ( acinar cell) and endocrine (islets of Langerhans) tissue.

4. ANATOMY The pancreas is a soft, elongated, flattened gland 12 to 20 cm in length. The adult gland weighs between 70 and 110 g. The head lies behind the peritoneum of the posterior abdominal wall and has a lobular structure. The pancreas is covered with a fine connective tissue but does not have a true capsule. The head of the pancreas is on the right side and lies within the curvature of the duodenum. The neck, body, and tail of the pancreas lie obliquely in the posterior abdomen, with the tail extending as far as the gastric surface of the spleen .

5. ANATOMY

6. HISTOLOGY The pancreas is a compound, finely nodular gland that is grossly similar to but less compact than the salivary glands. It is surrounded by fine connective tissue but does not have a fibrous tissue capsule. The lobules are visible on gross examination and are connected by connective tissue septa that contain the blood vessels, nerves, lymphatics , and excretory ducts (constituting about 18% of this organ). The gland is a mixed exocrine (about 80%) and endocrine (about 2%) organ . The endocrine portion consists of the islets of Langerhans, which are spherical clusters of light-staining cells scattered throughout the pancreas . The exocrine portion consists of numerous dark-staining acini composed of tubular and spherical masses of cells, which are the subunits of the lobule.Silicone casts of the duct lumen formed by retrograde injection indicate that the tubular portions of the acini are extensive and that the exocrine cells are arranged primarily as curved, branching tubules that anastomose and end blindly

7. HISTOLOGY

8. EPIDEMIOLOGY Estimates of annual incidence of chronic pancreatitis in several retrospective studies range from 3 to 9 cases per 100,000 population.The only prospective study, which was largely limited to alcoholic chronic pancreatitis, noted an annual incidence of 8.2 cases per 100,000 population and an overall prevalence of 27.4 cases per 100,000. A nationwide cross-sectional survey in Japan revealed an overall prevalence rate of 35.5 cases per 100,000 population with an estimated incidence of 14.4 per 100,000 and a male-to-female ratio of 3.5 : 1 Overall, 10-year survival in patients with chronic pancreatitis is about 70%, and 20-year survival about 45%

9. PATHOLOGY The pathophysiology of chronic pancreatitis remains incompletely understood. The pathophysiologic processes must ultimately account for the features of chronic pancreatitis, including loss of parenchymal cells, self-sustaining chronic inflammation, and fibrosis. Any proposed mechanism must therefore include explanations for cellular necrosis or apoptosis, initiation and maintenance of inflammatory cell activation, and fibrogenesis by pancreatic stellate cells Alcohol and its metabolites like fatty acid ethanol esters, have direct injurious effects on pancreatic acinar cells Alcohol may also lead to pathologic increases in acinar cell sensitivity to physiologic stimuli such as cholecystokinin (CCK) [ and redirect CCK-mediated zymogen exocytosis to the basolateral rather than apical membrane Pancreatic stellate cells are found in association with the acinar units

10. TIGAR-O CLASSIFICATION Toxic-metabolic Alcoholic Tobacco Smoking Hypercalcemia Hyperlipidemia Chronic renal failure Medications— phenacetin abuse Toxins— organotin compounds (e.g., DBTC)

11. TIGAR-O CLASSIFICATION Idiopathic Early Onset Late onset Tropical Genetic Hereditary pancreatitis Cationic trypsinogen PRSS 1 PRSS 2 CFTR mutations SPINK1 mutations

12. TIGAR-O CLASSIFICATION Autoimmune Isolated autoimmune chronic pancreatitis Autoimmune chronic pancreatitis associated with Sjögren's syndrome Inflammatory bowel disease Primary biliary cirrhosis

13. TIGAR-O CLASSIFICATION Recurrent and Severe Acute Pancreatitis Postnecrotic (severe acute pancreatitis) Recurrent acute pancreatitis Vascular diseases/ischemia Postirradiation

14. TIGAR-O CLASSIFICATION Obstructive Pancreas divisum Sphincter of Oddi disorders (controversial) Duct obstruction (e.g., tumor) Preampullary duodenal wall cysts Posttraumatic pancreatic duct scars

15. Autoimmune Pancreatitis – Clinical features Mild symptoms usually abdominal pain, but without frequent attacks of pancreatitis, which are unusual Presentation with obstructive jaundice Diffuse swelling and enlargement of the pancreas, especially the head, the latter mimicking carcinoma of the pancreas Diffuse irregular narrowing of the pancreatic duct in ERCP Increased levels of serum gamma globulins especially IgG4 Presence of other autoantibodies (ANA), rheumatoid factor (RF) Can occur with other autoimmune diseases: Sjögren's syndrome, primary sclerosing cholangitis, ulcerative colitis, rheumatoid arthritis Extra pancreatic bile duct changes such as stricture of the common bile duct and intrahepatic ducts Absence of pancreatic calcifications or cysts Pancreatic biopsies reveal extensive fibrosis and lymphoplasmacytic infiltration Glucocorticoids are effective in alleviating symptoms, decreasing size of the pancreas, and reversing histopathologic changes Two-thirds of patients present with either obstructive jaundice or a "mass" in the head of the pancreas mimicking carcinoma

16. Autoimmune Pancreatitis – PATHOPHYSIOLOGY Infiltration of inflammatory cells and fibrosis around medium-sized interlobular ducts. Obliterative phlebitis of medium and small veins and a whirling or storiform fibrosis of the pancreas T lymphocytes and plasma cells. Interstitial fibrosis with acinar cell atrophy Two histologic variants have been described LPSP Idiopathic duct centric chronic pancreatitis (IDCP) Neutrophilic infiltrate with microabscesses Obliterative phlebitis is rare End-stage disease may demonstrate atrophy and calcification in the gland, and at that point it may be indistinguishable from other forms of chronic pancreatitis.

17. An IgG 4 level greater than 135 mg/ dL has a sensitivity of 90% and a specificity of greater than 95% for autoimmune pancreatitis Patients with histologically proven autoimmune pancreatitis may have a normal serum level of IgG4 Up to 10% of patients with pancreatic ductal adenocarcinoma may have elevations in IgG 4 levels. Antinuclear antibodies (ANAs), antilactoferrin antibodies , anticarbonic anhydrase II antibodies , antismooth muscle antibodies (ASMs), rheumatoid factor (RF), and antimitochondrial antibody (AMA).

18. Mayo Clinic Criteria - HISORt Histology Imaging Serology Other organ involvement Response to glucocorticoid therapy

19. The disease may progress rapidly within months. Glucocorticoid therapy Rapid resolution of both symptoms and radiographic abnormalities. No clear recommendations for glucocorticoid dose 30 to 40 mg of prednisone orally per day for four to eight weeks Once a response is clear-cut, tapering of the prednisone dose at a rate of 5 mg per week Between 30% and 40% of patients experience a relapse after glucocorticoid therapy Repeat course of glucocorticoids followed by maintenance at a low dose of prednisone (e.g., 5 to 10 mg/day). Immunodulators - azathioprine

20. Alcoholic chronic pancreatitis Why only 10% of chronic alcoholics develop pancreatitis Alcohol metabolism – liver + pancreas Liver – acetaldehyde Pancreas – FAEEs

21. Alcohol and Chronic pancreatitis

22. Stellate cells Typically found in the periacinar space Long cytoplasmic processes extending to the acini themselves Quiescent pancreatic stellate cells - vitamin A lipid droplets in the cytoplasm. When activated, they assume a stellate or myofibroblastic appearance, and lose the lipid droplets. Activation of pancreatic stellate cells can occur by alcohol or one of its metabolites, Growth factors (platelet-derived growth factor, transforming growth factor-β1), hormones, intracellular signaling molecules, transcription factors, and angiotensin II can activate pancreatic stellate cells. Pancreatic stellate cells can proliferate in response to stimulation, migrate to areas of inflammation, and participate in phagocytosis.

23. Hypotheses Ductal obstruction hypothesis Toxic metabolic hypothesis Necrosis – fibrosis hypothesis

24. SAPE Sentinel acute pancreatitis event A genetic background that predisposes the patient to pancreatitis Include mutations in genes that code for digestive enzymes protease-enzyme inhibitors ion channels genes that affect the metabolism of environmental toxins (e.g., tobacco or alcohol) genes that have a role in inflammation or fibrosis others yet to be discovered

25. Clinical features Abdominal pain Weight loss Malabsorption Diabetes mellitus

26. Abdominal Pain There is no single characteristic pain pattern Most commonly described as being felt in the epigastrium Radiation to the back Boring, deep, and penetrating type Associated nausea and vomiting Relieved by sitting forward or leaning forward by assuming the knee-chest position on one side by squatting and clasping the knees to the chest. Pain may worsen after a meal Nocturnal.

27. Steatorrhea Does not occur until pancreatic lipase secretion is reduced to less than 10% of the maximum output A feature of far-advanced chronic pancreatitis Maldigestion of fat, protein, and carbohydrates Azotorrhea (protein maldigestion ) Diarrhea and weight loss Bulky foul-smelling stools Passage of frank oil droplets Watery diarrhea , excess gas, and abdominal cramps are uncommon  these help to differentiate from malabsorption syndromes of the small intestine Even when there is significant loss of fat in stool, most patients pass only three or four stools daily and some may pass only one.

28. Diabetes Mellitus Common after pancreatic resection and in tropical ( fibrocalcific ) pancreatitis Amylin may be elevated in patients with diabetes due to chronic pancreatitis A loss of hepatic insulin receptor expression and an impairment in hepatic insulin receptor function a relative decrease in stimulated glucagon secretion from these damaged islets, although basal levels may remain normal half of patients with chronic pancreatitis who develop diabetes will require insulin Microangiopathic complications are as common in patients with diabetes associated with chronic pancreatitis as in patients with type 1 diabetes with similar duration of disease

29. Complications of Chronic Pancreatitis Narcotic addiction Impaired glucose tolerance Gastroparesis Cobalamin malabsorption Nondiabetic retinopathy Effusions with high amylase content Gastrointestinal bleeding Jaundice Cholangitis and/or biliary cirrhosis Subcutaneous fat necrosis Bone pain Pancreatic cancer

30. DIAGNOSIS Tests Of Function Tests of Structure

31. Tests of Function Direct hormone stimulation Via oroduodenal tube Via Endoscopy MRCP with secretin stimulation Fecal Elastase Fecal Chymotrypsin Serum trypsinogen /trypsin Fecal fat Blood Glucose

32. Tests of structure Endoscopic ultrasonography MRI with MRCP CT Abdominal USG Plain abdominal film

33. LARGE DUCT Vs SMALL DUCT

34. Laboratory studies Imaging studies Pancreatic function tests Genetic testing

35. Laboratory studies Serum amylase and lipase Maybe elevated BUT FREQUENTLY NORMAL Chronic pancreatitis is a patchy, focal disease When fibrosis occurs, there is decrease in enzymes, not increase. CBC, electrolytes and LFTs – usually normal TB, ALP may be ELEVATED – indicate compression of the intrapancreatic portion of the bile duct by edema , fibrosis or cancer Autoimmune Pancreatitis – Elevated ESR, IgG4, RF, ANA, Anti-smooth muscle antibody Steatorrhea – A 72 hour fecal fat determination – excretion of >7g fat per day Fecal Elastase more sensitive and specific

36. Imaging – Plain Film of abdomen Plain film of abdomen – diffuse speckled calcification of pancreas on a plain film of abdomen 30-40% sensitive Alcoholic pancreatitis Tropical pancreatitis Hereditary pancreatitis

37. Imaging Studies CT, MRI & USG Calcifications Ductal Dilatation Size of the pancreas Fluid collections MRCP is becoming the diagnostic test of choice Secretin enhanced MRCP – evaluates the exocrine function of the pancreas

38. ERCP Bead pattern of the main pancreatic duct Ectatic side branches Cambridge classification: Cambridge I – Equivocal changes Cambridge II – Mild to moderate changes Cambridge III – Considerable changes A normal study should not rule out the diagnosis of chronic pancreatitis

39. Cambridge Grading of Chronic Pancreatitis on Endoscopic Retrograde Pancreatography

40. Diagnosis of Chronic Pancreatitis on Endoscopic Ultrasonography Parenchymal abnormalities Ductal abnormalities Hyperechoic foci Main duct dilatation Hyperechoeic strands Main duct irregularity Lobularity Hyperechoeic ductal walls Cysts Visible side branches Calcifications

41. Pancreatic Function Tests DIRECT or INDIRECT Direct – stimulate the pancreas by administering a meal or hormonal secretagogues Indirect – Measure the consequences of pancreatic insufficiency Direct – mainly used for early diagnosis of chronic pancreatitis where the clinical features are compatible bur radiographic findings are not consistent with chronic pancreatitis Indirect – more readily available – more widely used

42. Genetic testing CFTR – cystic fibrosis SPINK1 – Trypsin inhibitor PRSS1 gene – linked to hereditary pancreatitis

43. TREATMENT PAIN MANAGEMENT Pain is d/t hyperstimulation , ischemia, and acidosis, and neuropathic mechanisms Stepwise approach to pain GENERAL RECOMMENDATIONS PANCREATIC ENZYME SUPPLEMENTATION JUDICIOUS ANALGESIC USE INVASIVE/SURGICAL THERAPY

44. General recommendations Cessation of alcohol Small meals, low in fat Hydration Cessation of smoking

45. Pancreatic enzyme supplements Suppression of feedback loops in the duodenum that regulate the release of CCK CCK – releasing factors – these are increased in pancreatitis A reduced intraduodenal free enzyme activity stimulates/prolongs the life of these CCK releasing factors  increasing the intraduodenal enzyme activity may decrease this feedback Who benefits the most? Without large duct involvement Without steatorrhea Idiopathic chronic pancreatitis

46. Analgesics Amitryptilline , Nortryptylline Short course of opioids – 10 mg nightly for 3 weeks Chronic opioid analgesia – morphne and fentanyl patches

47. Antioxidant therapy Insufficient evidence to support

48. Specialised Approaches Celiac nerve block – limited success Endoscopic therapy – when the pain is d/t Ductal hypertension d/t sphincter of Oddi dysfunction Strictures of the main pancreatic duct Extracorporeal shock wave lithotripsy Pancreatic duct stones – 22 – 60% Radiation Guarner et al – Am J Gastroenterol . 2009 – 15 patients. 12 patients had no further flare ups

49. Surgery Patients who fail medical therapy What surgery is to be done?? Area of pancreas that is involved Dilatation of the duct Surgical options available: Decompression/drainage operations Pancreatic resections Denervation procedures

50. Decompression Refractory pain with a dilated pancreatic duct Normal PD = 2 – 4 mm diameter Pancreatico-duodenostomy or pancreatico-jejunostomy Short term pain relief in 80% patients Relief of pain > 2 years – 60% Surgery > Endoscopy in patients with obstructive chronic pancreatitis and dilated pancreatic duct

51. Resection Resection of a part of the pancreas In patients who have failed other forms of therapy and those NOT candidates for a drainage procedure – SMALL DUCT DISEASE Whipples Pylorus preserving pancreaticoduodenostomy Total pancreatectomy Duodenal preserving resection of the pancreatic head Pancreatic head resection – good pain relief even if pancreatitis extends to the tail

52. In a normal pt , only 20% of HEALTHY pancreatic parenchyma is required to maintain clinically adequate function Supplementation Autologous islet cell preparation

53. Management of Steatorrhea Reduced fat intake Lipase supplementation 30000IU or 90000 USP per meal First bite of meal Vitamin supplementation Medium chain triglycerides

54. Pseudocyst pancreas – walled off collection 10 - 25% of patients with chronic pancreatitis Alcoholic chronic pancreatitis 70% - Ductal communication Abdominal pain Palpable mass Nausea and vomiting ; Intestinal obstruction (due to compression of the stomach or duodenum) Jaundice (due to compression of the bile duct) Bleeding Asymptomatic

55. Elevations in serum lipase and amylase values – 50% patients Persistent elevation in serum lipase or amylase can be a clue to the presence of a pseudocyst . Imaging studies, including US, CT, MRI, and EUS CT and MRI visualization of the capsule of the pseudocyst Determination of the relation of the pseudocyst to the stomach and duodenum. MRI can also give some additional information on the character of the contents of the pseudocyst ERCP 70% of pseudocysts communicate with the pancreatic duct ERCP is associated with an approximately 15% chance of infection of a previously uninfected pseudocyst Should be undertaken only after antibiotics have been administered and therapy is imminent.

56. Treatment of pseudocysts Asymptomatic  irrespective of size  FOLLOW UP for 6 weeks  reassess  if still asymptomatic, size not increasing  Reassess after 6 weeks  FOLLOW UP TILL A YEAR/ upto 12 cm size Indications for intervention Rapid enlargement Pain Compression of surrounding structures Infected cyst

57. Treatment options Percutaneous Endoscopic Surgical

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