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

5. 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.

7. 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.’

8. Chronic Pancreatitis is characterized by
@AbCDEF-Pain
• Pancreatic atrophy
•Fibrosis
• Ductal strictures and distortion [बिग्रेको duct]
•Calcification
•Dysplasia
•Exocrine and endocrine insufficiency
•Chronic pain

10. Risk factors

14. Risk factors
3 factors are identified as potential risk factors.
a. Environmental factors
b. Genetic variants
c. Autoimmune

15. a. Environmental factors
• Alcohol

16. • 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

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

18. Environmental factors
• Smoking

19. 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.

20. 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.

21. Relationship between Sphincter of Oddi
dysfunction and chronic pancreatitis

22. 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.

23. 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

24. Pathophysiology of chronic pancreatitis
Cellular injury
Inflammation
Fibrosis

25. 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.

26. • 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

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

28. 3.Fibrosis

30. 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

31. 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.

32. Clinical presentation

33. 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

34. Assessment and diagnosis

36. 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]

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

40. 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.

41. 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.

42. Diagnosis and management
algorithm

44. Proper management of CP depends on following
1. 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
3. Multi-disciplinary team
4. Well-structured therapeutic plan
5. Adequate patient counselling

48. 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

49. 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

50. 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

51. 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.

52. Endoscopy vs Surgical
management

54. 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

58. Surgical Treatment of CP

59. Timing of surgery

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

64. Parenchymal resection Pancreatic duct drainage
Both

65. • 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:
1. Resectional procedure:
small duct disease( pancreatic duct <=6mm)
or non dilated pancreatic duct
2. Decompression/Drainage procedure:
dilated pancreatic duct(diameter>7mm)
or large duct disease

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

67. Indications for surgery
• Intractable pain
• Biliary or Pancreatic duct obstruction
• Duodenal obstruction
• Pseudocyst
• Pseudoaneurysm formation
• Inability to rule out malignant disease

70. 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

71. 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.

73. • 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

74. 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

75. 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

77. 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

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

80. 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.

81. 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.

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

83. 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.

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

85. Outcomes of surgical strategies in chronic
pancreatitis

86. • 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.

87. 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)

88. 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.

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

91. 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

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

93. 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