Diagnosis and management of Chronic Pancreatitis.pptx

Presentation detailing the management and features of Chronic Pancreatitis

1. Chronic Pancreatitis Nabin Paudyal

2. Topic outline Introduction Risk factors Pathophysiology if Chronic Pancreatitis Hypothesis for development of Chronic Pancreatitis Assessment and diagnosis Medical Management Endoscopic and surgical management Pain in chronic pancreatitis Prognosis What’s new?

3. Introduction

4. Introduction ‘A continuing inflammatory disease of the pancreas, characterized by irreversible morphological change, and typically causing pain and/or permanent loss of function’ - (Proceedings of the Japan Pancreas society 2009) Insights to the definition: Focuses only on abnormal morphology. Makes early diagnosis challenging. Excludes inflammation without fibrosis, atrophy, endocrine/exocrine dysfunction, pains syndromes and metaplasia.

5. Mechanistic definition of Chronic Pancreatitis ‘ Chronic pancreatitis (CP) is a pathologic fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress .’

6. Chronic Pancreatitis is characterized by @AbCDEF-Pain Pancreatic a trophy F ibrosis Ductal strictures and distortion [ बि ग्रेको duct] C alcification D ysplasia E xocrine and endocrine insufficiency C hronic pain

7. Risk factors

8. Risk factors 3 factors are identified as potential risk factors. Environmental factors Genetic variants Autoimmune

9. a. Environmental factors Alcohol

10. Alcohol Prolonged alcohol is the most important risk factor for developing chronic pancreatitis Pathophysiology Alcohol exerts multiple noxious effects in pancreas It increases the total protein concentration in the pancreatic juice Promotes synthesis and secretion of lithostatine by acinar cells It increases glycoprotein secretion in pancreatic juice Subsequent formation of protein-plugs and stones within MPD Chronic alcohol intake is associated with increased NF-XB activation  decreased perfusion to pancreas increased intracellular Ca levels Other factors responsible involve ROS production, increase fragility of intraacinar cell organelles and direct injury

11. It has been reported that antioxidants, ACEI, PPAR-γ ligands and Vitamin-A inhibit the activity of PSCs

12. Environmental factors Smoking

13. b. Genetic factors Trypsin dependent PRSS1 (cationic trypsinogen) SPINK1 (serine protease inhibitor) CTRC (Human Chymotrypsin C gene) Trypsin independent CFTR CPA1 CLDN2 PRSS1 gene is located in Chromosome 7 and regulates trypsinogen production. PRSS1 gene mutation are associated with hereditary pancreatitis with an autosomal dominant inheritance. SPINK1 regulates premature activation of trypsinogen. SPINK1 mutation is more common in alcoholic, hereditary and idiopathic pancreatitis.

14. c. Other risk factors Hypercalcemia (Parathyroid adenoma) Hypertriglyceridemia Autoimmune disease (Celiac disease) Inflammatory bowel disease Anatomic anomalies  Annular pancreas Roles of pancreas divisum and sphincter of Oddi dysfunction as cause of CP are controversial.

15. Relationship between Sphincter of Oddi dysfunction and chronic pancreatitis

16. Age and chronic pancreatitis Usually affects patients of all age groups, however affected age group depends on the etiology. Alcohol induced CP  Age 40- 60 years Gene induced CP Age 10-40 years Idiopathic CP Bimodal age group Early 19 years and late 56 years.

17. Types of Chronic Pancreatitis Autoimmune pancreatitis 2 different histologic variants are defined Type 1  Immunoglobulin G-4 related disease; Characterized by dense periductal lymphoplasmacytic infiltrates, storiform fibrosis and obliterative venulitis Type 2--> neutrophils, lymphocytes and plasma cells destroy and obliterate the epithelium in MPD M>>F Mimics pancreatic adenocarcinoma as it causes jaundice Is associated with abnormal elevation of amylase and lipase. Tropical pancreatitis Common in tropical areas within 30 degrees of the equator A/w cassava ingestion and SPINK1 mutation Idiopathic pancreatitis

18. Pathophysiology of chronic pancreatitis

19. 1. Cellular injury Acinar cell injury is considered the inciting event in pancreatic inflammation. Alcoholic metabolites like acetaldehyde, fatty acid ethyl esters produce oxidative stress. Smoking causes release of nitrosamine ketones which is a toxic metabolite.

20. Genetic mutations can be gain of function or loss of function mutations Genetic mutations associated with CP can be trypsin dependent or independent. Trypsin dependent  Trypsin activation involved Trypsin independent Trypsin activation not involved

21. 2. Inflammation Acinar injury  Release of damage associated molecular patterns (DAMP) activation of NF-kB Triggers release of mediators of inflammation

22. 3.Fibrosis

23. Hypothesis for development of Chronic Pancreatitis a. SAPE hypothesis Fibrosis Focal duct strictures with proximal duct dilation Stasis of secretions causes formation of calculi and calcification of protein plugs Repeated injury causes parenchymal loss and pancreatic atrophy

24. Hypothesis for development of Chronic Pancreatitis b. Obstructive hypothesis Hypersecretion of proteins due to inflammation Protein plug formation Calcification and obstruction of pancreatic duct Acinar cells dysfunction and atrophy CFTR dysfunction  formation of intraductal proteins.

25. Clinical presentation

26. Clinical features Pain  increased with food intake initially, increases as the disease gradually worsens Nausea/ vomiting Nutritional deficiency deficiency of fat soluble vitamins (Bleeding, osteopenia, osteoporosis) In long standing cases Exocrine insufficiency [AT LEAST 90% OF GLAND NEEDS TO BE DYSFUNCTIONAL BEFORE STEATORRHOEA, DIARRHOEA AND OTHER MALABSORPTION SYMPTOMS DEVELOP] 40-80% patients will have endocrine insufficiency  DM Jaundice/ cholangitis (5-10%) of patients

27. Assessment and diagnosis

28. Imaging studies CT scan  Establish diagnosis, assess complications (pancreatic duct disruption, pseudocysts, portal and splenic vein thrombosis, splenic and pancreaticoduodenal artery aneurysms) MRI scan Changes on pancreatic parenchyma [changes in intensity, pancreatic atrophy, irregularities in contour] MRI with secretin evaluate strictures and pancreatic duct disruption EUS most accurate technique to diagnose chronic pancreatitis in patients with minimal change disease or EARLY STAGES. [Histologic evidence of inflammation, atrophy and fibrosis is the gold standard for diagnosis of chronic pancreatitis]

29. If clinical suspicion of CP is high, regular follow-up and repeat imaging is required as morphological and functional changes will evolve with time.

30. Limitations of the diagnostic tests. Investigative tests perform well in advanced disease and are more limited for diagnosing earlier stages of the disease. Conceptual understanding of the natural history of the disease is important. Evolution of the morphological and functional changes of CP may require years to manifest.

31. Functional test Fecal elastase 1 level  Using monoclonal antibodies or polyclonal anti-human elastase 1 antibodies Fecal elastase1 concentration above 200 mcg/g of feces is normal Level between 100-200 mcg/g defines mild to moderate pancreatic insufficiency Level below 100 mcg/g establishes diagnosis of severe pancreatic exocrine insufficiency Fecal fat and weight estimation test measures stool concentration of fat > 7g/d  steatorrhea diagnosis is established.

32. Diagnosis and management algorithm

33. Proper management of CP depends on following Correct diagnosis of the condition 2. Determination of the etiology History (Chronic alcohol, smoking, family history, personal history) Physical examination Laboratory tests (Hypertriglyceridemia, genetic variants) Imaging Multi-disciplinary team Well-structured therapeutic plan Adequate patient counselling

34. Medical management Management of pain No guidelines regarding the choice, use and dosage of analgesics available WHO analgesic ladder for cancer pain is used to treat CP pain. Role of Pregabalin in CP

35. Medical management Management of pain Alternative agents  TCA, SSRI, SNRI, Gabapentin. Neurolysis Not much successful Medicine for pain Line of therapy NSAIDS First line therapy for pain management Tramadol For moderate to severe pain, NSAIDS refractory cases If Tramadol doesn’t work Long-acting narcotics

36. Role of anti-oxidants in management of pain Antioxidant supplementation in doses of - 0.54 g of ascorbic acid - 9000 IU of B-carotene - 270 IU of alpha-tocopherol - 600 micro-gram of organic selenium - 2 g of methionine

37. Pancreatic insufficiency Exocrine insufficiency Pancreatic enzyme supplementation Thorough nutritional evaluation before initiation of therapy Generally, 90,000 USP of lipase is required to avoid malabsorption Given for at least 6 weeks along with a PPI Endocrine insufficiency Diabetes due to deficiency of insulin and other regulatory substance like glucagon Endocrinologist consultation is required for optimal management.

38. Endoscopy vs Surgical management

39. Interventional therapy: Endoscopic treatment Endoscopy may be preferred when Number of stones <3 Size of stone <1 cm Located in the head and body of the pancreas Goal: to improve drainage of pancreatic duct and biliary duct by relieving ductal obstruction, relieve pain as well Malignant disease should be ruled out ERCP + polyethylene stent placement ESWL followed by therapeutic ERCP may be required for treatment of large impacted stones

40. Surgical Treatment of CP

41. Timing of surgery

42. Timing of surgery in Chronic Pancreatitis Studies show that early surgery is superior in providing pain relief and improvement of life.

43. Parenchymal resection Pancreatic duct drainage Both

44. Surgery in CP can be technically demanding. Carries a significant risk of morbidity but a low risk of mortality. Surgical treatment of chronic pancreatitis has shown excellent long-term results. Timing of surgery is a matter of debate and no guidelines regarding the proper timing has been published . Choice of surgery depends mainly on the morphological changes of the pancreas. Based on two main concepts: Resectional procedure: small duct disease( pancreatic duct <=6mm) or non dilated pancreatic duct Decompression/Drainage procedure: dilated pancreatic duct(diameter>7mm) or large duct disease

45. Named Surgery in Chronic Pancreatitis Resection Berne Beger Frey Hamburg modification of Frey Izbicki Drainage Puestow Partington Rochelle Duval

46. Indications for surgery Intractable p ain B iliary or Pancreatic duct obstruction D uodenal obstruction P seudocyst Pseudo a neurysm formation Inability to rule out malignant disease

47. Pancreatic duct dilation secondary to duct stones or strictures [Chronic pancreatitis without involvement of pancreatic head] Head of the pancreas are considered to be the “pacemaker” of chronic pancreatitis. Dilated main pancreatic duct (MPD) is defined by size of >7mm. Dilation may be diffuse along the pancreas or more located upstream from a single stricture. Duct dilation observed on pancreatography for chronic pancreatitis is classically described as “chain of lakes” appearance reflecting multiple dilations and stenosis Lateral Pancreaticojejunostomy or Partington-Rochelle or (Modified) Puestow Procedure is the operation of choice

48. Partington-Rochelle or (Modified) Puestow Procedure Procedure of choice for MPD dilation in absence of inflammatory mass and no biliary obstruction in pancreatic head. Steps: Full mobilization of the pancreatic head and duodenum (Kocher’s maneuver) for full exposure of the anterior surface of pancreas . Identification and suture ligation of the gastroduodenal artery at the superior and inferior border of pancreas. Identification of the dilated MPD (by palpation, aspiration or intraoperative USG). Longitudinal incision of the pancreatic duct (full length) followed by removal of stones and strictures. Roux-en-Y lateral Pancreaticojejunostomy.

49. Proximal extent of tissue resection is within 1 cm of the duodenum Distal extent is within 1-2 cm of the end of pancreas Outcomes of the [Partington-Rochelle] Modified Puestow procedure are generally favorable. 70-80% durable pain relief is achieved during 5-10 years follow up. Exocrine and endocrine function of the gland is preserved. Limitation of the operation  Ongoing inflammation in the head of pancreas may be missed and this may lead to failure of the anastomosis causing operation failure. Cause of recurrence of pain  Smoking and alcohol, failure to decompress head and uncinate process, small length of PJ

50. Pancreatic duct dilation secondary to duct stones or strictures [Chronic pancreatitis with enlarged pancreatic head] Pancreatic head with size >4 cm are enlarged. Four types of procedures are described. a. Pancreaticoduodenectomy (with/ without pyloric preservation) b. The Frey procedure c. The Berne procedure d. The Beger procedure

51. a. Pancreaticoduodenectomy (Whipple Procedure) Advantages of the procedure Possibility of removal of suspected tumor in pancreatic head Concomitant CBD obstruction can be removed Disadvantages of the procedure Resection of duodenum affects the hormonal axis of the GI tract It is not to be done if there is more than one obstruction present in the duct

52. b. The Frey Procedure Combines duodenum-preserving head resection with drainage of the MPD. Steps: Coring out of the pancreatic head until a rim of pancreatic tissue is left on the duodenum and portal vein. Usually 1 cm rim of tissue is left along the duodenal margin Longitudinal drainage of the MPD into the pancreatic tail. Roux-en Y lateral Pancreaticojejunostomy

53. Rim of pancreatic tissue Longitudinal drainage of MPD into pancreatic tail Lateral Pancreaticojejunostomy

54. Advantages of Frey procedure Safer than Whipple procedure [where pancreatic head resection was done]. Can be done even during portal hypertension MPD dilation due to pancreatic head stricture a/w severe inflammation can be done. Disadvantage of Frey procedure Active disease may be left at the rim of the pancreatic tissue in the pancreatic head. Removal of pancreatic parenchyma  Increased risk of exocrine and endocrine insufficiency.

55. c. The Berne Procedure Performed when there is inflammatory mass of the pancreatic head in absence of the enlarged pancreatic duct. Duodenum preserving pancreatic head resection without MPD drainage. Features: Head is cored out similar to Frey procedure. Pancreaticojejunostomy is made on the head pancreatic head.

56. Anastomosis of the pancreatic head to jejunum Roux en-Y jejunal loop as side to side duodenojejunostomy

57. d. The Beger Procedure First procedure described as duodenum-preserving head resection. Developed to avoid adverse affect of Pancreaticoduodenectomy. Technically demanding operation with difficult anastomosis. Rule out malignancy first. Beger procedure is done for focal inflammatory mass without significant dilation of pancreatic duct Features: Pancreatic head resection done with small pancreatic tissue rim on the duodenum. Two sided Pancreaticojejunostomy is done, one on small part of pancreatic tissue on the duodenum and other on pancreatic remnant.

58. Pancreatic tissue rim on the duodenum Two sided Pancreaticojejunostomy Roux-en Y loop

59. Outcomes of surgical strategies in chronic pancreatitis

60. 6 RCT have focused on comparison of pancreaticoduodenectomy and duodenum-preserving operations In 4 studies, no differences were observed in terms of outcome in patients. All studies showed 80 % pain relief after 10-15 years of follow-up, equal exocrine and endocrine functional status. No studies have recommended a procedure of choice. Every procedure has some disease specific advantages.

61. 3. Chronic Pancreatitis with Small Duct Disease or Diffuse Sclerosis [Diffuse glandular involvement without dilation of the pancreatic duct Total pancreatectomy/ near-total pancreatectomy with islet auto-transplant (TP-IAT). Most effective for patients with small duct disease, hereditary pancreatitis and pediatric pancreatitis. Indications for TPIAT (must have all in most centers) Chronic narcotic dependence (for pain) Impaired quality of life No reversible cause of chronic pancreatitis identified Unresponsive to maximal medical, endoscopic and sometimes surgical therapy Adequate islet cell function (non-diabetic)

62. Pain in Chronic Pancreatitis Pain in chronic pancreatitis is caused by complex interaction between structural and morphological changes of the pancreas, neurobiological mechanisms and structural abnormalities in the peripheral and central nervous system. Peripheral and central sensitization of the nervous system together with alternative nociceptive pathways may explain why pain processing can change during disease progression. 3 mechanisms have been described for pain Inflammation of the pancreas Increased intrapancreatic pressure within the parenchyma and/or PD causing tissue ischemia Pain due to pancreatic and extra-pancreatic complications.

63. Management of neuropathic pain in Chronic Pancreatitis 1. Pharmacological therapy: Pregabalin and S ketamine 2. Neuroablation procedures: Endoscopic celiac plexus blockade Bilateral thoracoscopic splanchnicectomy

64. Pancreatic pseudocyst 30-40% of patients with CP develop pseudocyst at some part of the disease course Spontaneous regression is less likely Indications for treatment Gastric, duodenal / Biliary compression Bleeding Pancreaticopleural fistula Rupture of pseudocyst Spontaneous bleeding

65. Management Surgery Cystogastrostomy Roux-en-Y Cystojejunostomy ERCP based drainage Drainage with EUS

66. Prognosis Median survival in patients with CP is 15-20 years after the diagnosis Cumulative risk of pancreatic carcinoma is 1.8% at 10 yeas and 4% at 20 years . Risks are higher in those with genetically determined CP. Routine screening for pancreatic cancer in patients with CP is not recommended. Survival is affected by Complications of the disease Adverse effects of alcoholism Smoking Diabetes