1. BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
GASTRIC ACID
SECRETIN
WATER AND ELECTROLYTES

2. BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
LONG CHAIN FATTY ACIDS, AMINO ACIDS, GASTRIC ACID
(DUODENUM –JEJUNUM)
CHOLECYSTOKININ
ENZYME RICH PANCREATIC SECRETIONS

3. BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
PARASYMPATHETIC STIMULATION
(VAGUS NERVE)
CHOLECYSTOKININ-SECRETIN
VASOACTIVE PEPTIDE
WATER AND ELECTROLYTE
ENZYMES
Secretion evoked by secretin and
CCK depends on permissive roles of vagal afferent and efferent pathways.
This is particularly true for enzyme secretion, whereas water
and bicarbonate secretion is heavily dependent on the hormonal effects
of secretin and CCK.

4. BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
BILE SALTS
PANCREATIC SECRETION

5. INHIBITORY NEUROPEPTIDES
SOMASTOTIN
PANCREATIC POLYPEPTIDE
PEPTIDE YY
NEUROPEPTIDE Y
ENKEPHALIN
PANCREASTATIN
CALCITONIN GENE RELATED PEPTIDE
GLUCAGON
GALANIN
NITROUS OXIDE

7. Normal Enzyme Activation
enterokinase
duodenal lumen
trypsinogen
trypsin
chymotrypsinogen
proelastase
prophospholipase
procarboxypeptidase
chymotrypsin
elastase
phospholipase
carboxypeptidase
This slide shows the mechanism of proenzyme activation in the intestinal lumen.
The duodenum is the most important sensory organ involved in pancreatic secretion, and is the site where the meal and pancreatic exocrine secretions meet. The duodenal mucosa contains endocrine cells, which release secretin in response to luminal acid, and cholecystokinin (CCK) in response to proteins or fats. The duodenum is also rich in sensory (afferent) vagal nerve fibers that respond to changes in pH, amino acids, lipids, and express receptors for CCK and secretin.
Trypsin can catalyze the activation of other zymogens Once trypsin is present in
an amount that exceeds the ability of trypsin inhibitor to inactivate it,
trypsin can catalyze the activation of other zymogens (eg, chymotrypsinogen,
proelastase, procarboxypeptidase A and B, prophospholipase A), as well as of
trypsinogen itself, initiating the ;autodigestion; of the pancreas.

8. Acute Pancreatitis Epidemiology
Second most common principal inpatient GI diagnosis after cholelithiasis and acute cholecystitis
Unreliable data due to misdiagnosis
Estimated yearly incidence of 5-40/100,000
1998 data from the U.S. about “pancreatic diseases”
327,000 inpatient stays
78,000 outpatient hospital visits
195,000 ER visits
531,000 office visits
>2800 deaths due to acute pancreatitis in 2000
Estimated annual cost in 2000 was $2,500,000,000

9. Natural History 80% of cases are mild
20% are severe with organ failure and local complications
Estimated 25-33% mortality
Overall mortality estimates range from 2% to 10%
Half of death occur within the first week, perhaps 25% to 33% of deaths occur within the first 48 hours
Obese patients have higher rates of local complications, respiratory failure, severe acute pancreatitis and death from sterile necrosis than non-obese patients
Older and multi-morbid patients have higher mortality rates

10. Acute Pancreatitis Definition
Acute inflammatory process involving the pancreas
Usually painful and self-limited
Isolated event or a recurring illness
Pancreatic function and morphology return to normal after (or between) attacks
Here are the details…

11. Acute Pancreatitis Etiology

12. Acute Pancreatitis Associated Conditions
Cholelithiasis
Ethanol abuse
Idiopathic
Medications
Hyperlipidemia
ERCP
Trauma
Pancreas divisum
Hereditary
Hypercalcemia
Viral infections
Mumps
Coxsackievirus
End-stage renal failure
Penetrating peptic ulcer

13. Acute Pancreatitis Causative Drugs
AIDS therapy: didanosine, pentamidine
Anti-inflammatory: sulindac, salicylates
Antimicrobials: metronidazole, sulfonamides, tetracycline, nitrofurantoin
Diuretics: furosemide, thiazides
IBD: sulfasalazine, mesalamine
Immunosuppressives: azathioprine, 6-mercaptopurine
Neuropsychiatric: valproic acid
Other: calcium, estrogen, tamoxifen, ACE-I

14. Pancreas divisum

15. Adjusted ORs for Pancreatitis
ORs adjusted for their independent effect relative to a reference rate of pancreatitis of 1.1% for a typical low-risk patient (male, elevated bilirubin but no chronic pancreatitis and w/o any risk factors)
Freeman et al. Gastrointest Endosc. ‘97.

16. Pancreas divisum

17. Hereditary Pancreatitis
Autosomal dominant with 80% phenotypic penetrance
Recurrent acute pancreatitis, chronic pancreatitis, and 50-fold increased risk of pancreatic cancer
Mutation in cationic trypsinogen gene (R122H)
Other genetic defects
CFTR
SPINK1

18. Acute Pancreatitis Pathogenesis
acinar cell
injury
premature enzyme activation
talk about failure of compartmentalization, premature activation, and overwhelming or absence of inhibitors
failed protective mechanisms

19. Acute Pancreatitis Pathogenesis
premature enzyme activation
autodigestion of pancreatic tissue
local
vascular
insufficiency
activation
of white
blood cells
release of enzymes into
the circulation
local complications
distant organ failure

20. Acute Pancreatitis Pathogenesis
SEVERITY
Mild
Severe
STAGE 1: Pancreatic Injury
Edema
Inflammation
STAGE 2: Local Effects
Retroperitoneal edema
Ileus
STAGE 3: Systemic Complications
Hypotension/shock
Metabolic disturbances
Sepsis/organ failure
Three stages of pathophysiology of acute pancreatitis
The pathophysiology of
acute pancreatitis can be considered as involving three stages. The first stage
is pancreatic injury with edema, inflammation, necrosis of pancreatic fat, and
variable degrees of necrosis of pancreatic secretory cells. The second stage is
spread of the inflammatory process to surrounding tissues, with development of
retroperitoneal edema, peripancreatic fat necrosis, and an ileus, with ;third
spacing; of fluid and electrolytes in the gastrointestinal tract resulting in
hemoconcentration (increased hematocrit). The third stage involves systemic
complications, such as hypotension/shock, multiorgan system failure (eg,
respiratory, renal), metabolic disturbances, such as hypoalbuminemia and
hypocalcemia, and sepsis.

21. Acute Pancreatitis Clinical Presentation
Abdominal pain
Epigastric
Radiates to the back
Worse in supine position
Nausea and vomiting
Fever

22. Acute Pancreatitis Differential Diagnosis
Choledocholithiasis
Perforated ulcer
Mesenteric ischemia
Intestinal obstruction
Ectopic pregnancy

23. Acute Pancreatitis Diagnosis
Symptoms
Abdominal pain
Laboratory
Elevated amylase or lipase
> 3x upper limits of normal
Radiology
Abnormal sonogram or CT

24. Clinical Findings Usually acute onset of severe pain
Epigastric, upper quadrants
Radiation to back and chest (DDx myocardial ischemia)
Nausea, vomiting, hematemesis
Bowel obstruction
Fever, tachypnea, shock
Ecchymoses on the flanks (Turner’s sign)
Periumbilical ecchymosis (Cullen’s sign)

25. Clinical Manifestations
Abdominal distention
Abdominal guarding
Abdominal tympany
Hypoactive bowel sounds
Severe disease: peritoneal signs, ascites, jaundice, palpable abdominal mass, Grey Turner’s sign, Cullen’s sign, and signs of hypovolemic shock

26. Causes of Increased Pancreatic Enzymes
Amylase
Lipase
Pancreatitis ↑
Parotitis
Normal
Biliary stone
Intestinal injury
Tubo-ovarian disease
Renal failure
Macroamylasemia

27. Acute Pancreatitis Diagnosis
EtOH: history
Gallstones: abnormal LFTs & sonographic evidence of cholelithiasis
Hyperlipidemia: lipemic serum, Tri>1,000
Hypercalcemia: elevated Ca
Trauma: history
Medications: history, temporal association

28. Acute Pancreatitis Clinical Manifestations
PANCREATIC
PERIPANCREATIC
SYSTEMIC
Mild: edema, inflammation, fat necrosis
Severe: phlegmon, necrosis, hemorrhage, infection, abscess, fluid collections
Retroperitoneum, perirenal spaces, mesocolon, omentum, and mediastinum
Adjacent viscera: ileus, obstruction, perforation
Cardiovascular: hypotension
Pulmonary: pleural effusions, ARDS
Renal: acute tubular necrosis
Hematologic: disseminated intravascular coag.
Metabolic: hypocalcemia, hyperglycemia

29. Acute Pancreatitis Time Course
ER presentation
cytokine release
organ failure
In the early stages of
pancreatic injury and inflammation, proinflammatory cytokines, such as
interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-A, appear to be
released from tissue macrophages within the pancreas. Neutrophil activation
likely results from release of IL-8 from macrophages and endothelial cells and
release of platelet-activating factor (PAF) from endothelial cells. Later in the
process, release of cytokines from T-helper lymphocytes (eg, IL-2, interferon-
C) may also participate in the inflammatory response [3]

30. Predictors of Severity
Why are they needed?
appropriate patient triage & therapy
compare results of studies of the impact of therapy
When are they needed?
optimally, within first 24 hours (damage control must begin early)
Which is best?

31. Severity Scoring Systems
Ranson and Glasgow Criteria (1974)
based on clinical & laboratory parameters
scored in first hours of admission
poor positive predictors (better negative predictors)
APACHE Scoring System
can yield a score in first 24 hours
APACHE II suffers from poor positive predictive value
APACHE III is better at mortality prediction at > 24 hours
Computed Tomography Severity Index
much better diagnostic and predictive tool
optimally useful at hours after symptom onset
Resent data has curbed some of the excitement re: use of APACHE in early pancreatitis. In short, prediction of severity is sub optimal at the present time.

32. Ranson Criteria Alcoholic Pancreatitis
AT ADMISSION
Age > 55 years
WBC > 16,000
Glucose > 200
LDH > 350 IU/L
AST > 250 IU/L
WITHIN 48 HOURS
HCT drop > 10
BUN > 5
Arterial PO2 < 60 mm Hg
Base deficit > 4 mEq/L
Serum Ca < 8
Fluid sequestration > 6L
Number
<2 1%
3-4
16%
5-6
40%
7-8
100%
Mortality

33. Glasgow Criteria Non-alcoholic Pancreatitis
WBC > 15,000
Glucose > 180
BUN > 16
Arterial PO2 < 60 mm Hg
Ca < 8
Albumin < 3.2
LDH > 600 U/L
AST or ALT > 200 U/L

34. CT Severity Index appearance necrosis normal enlarged inflamed
1 fluid collection
2 or more collections
grade A B C D E
score 1 2 3 4
necrosis
none
< 33%
33-50%
> 50%
score 2 4 6
So, even if we can’t identify severe cases sooner, the CT index appears to be the best way to judge severity.
score
morbidity
mortality
1-2 4% 0%
7-10
92%
17%
Balthazar et al. Radiology 1990.

35. Edematous (Interstitial) Pancreatitis
Usually mild
Resolves in about 7 days
Results in fluid accumulation and swelling

36. Severe or Necrotizing Pancreatitis
Associated with a high degree of complications and mortality
Caused by the release of cytokines and other proinflammatory mediators that produce a hyperinflammatory reaction, resulting in cell death and tissue damage

37. Severe Acute Pancreatitis
Scoring systems
 3 Ranson criteria
 8 APACHE II points
 5 CT points
Organ failure
shock (SBP < 90 mmHg)
pulmonary edema / ARDS (PaO2 < 60 mmHg)
renal failure (Cr > 2.0 mg/dl)
Local complications
fluid collections  pseudocysts
necrosis (mortality 15% if sterile, 30-35% if infected)
abscess

38. Goals of Treatment Limit systemic injury
support and resuscitation – effective
decrease pancreatic secretion – ineffective / harmful?
inhibit inflammatory mediators – ineffective
inhibit circulating trypsin – ineffective (too late)
removing gallstones – mostly ineffective
Prevent necrosis – how?
Prevent infection
antibiotics (imipenem and ciprofloxacin) – probably effective in necrotic pancreatitis
prevent colonic bacterial translocation
removing gallstones – variably effective
intestinal decontamination study – no improvement

39. Treatment of Mild Pancreatitis
Pancreatic rest
Supportive care
fluid resuscitation – watch BP and urine output
pain control
NG tubes and H2 blockers or PPIs are usually not helpful
Refeeding (usually 3 to 7 days)
bowel sounds present
patient is hungry
nearly pain-free (off IV narcotics)
amylase & lipase not very useful here
mild panc – support is all that’s needed
hypotension probably predisposes to necrosis (poor microcirculation)

40. Treatment of Severe Pancreatitis
Pancreatic rest & supportive care
fluid resuscitation* – may require 5-10 liters/day
careful pulmonary & renal monitoring – ICU
maintain hematocrit of 26-30%
pain control – PCA pump
correct electrolyte derangements (K+, Ca++, Mg++)
Rule-out necrosis
contrasted CT scan at hours
prophylactic antibiotics if present
surgical debridement if infected
Nutritional support
may be NPO for weeks
TPN vs. enteral support (TEN)
*common serious error to underestimate volume needs
may need SG catheter – lookout for ARF or ARDS
we have impacted the early mortality by better support…late mortality still problem

41. Treatment IV replacement of fluids, proteins, and electrolytes
Fluid volume replacement and blood transfusions
Withholding food and fluids to rest the pancreas
NG tube suctioning
Drugs
Peritoneal lavage
Surgical drainage
Laparotomy to remove obstruction

42. Fluid Resuscitation
Patients with acute pancreatitis may have fluid shifts of 4 to 12 L into retroperitoneal space and peritoneal cavity due to inflammation
In severe acute pancreatitis, blood vessels in and around the pancreas may also become disrupted, resulting in hemorrhage.
Replace fluids with colloids, crystalloids, or blood products
Monitor for S/S of hemorrhage

43. Rest the Pancreas NPO status
Avoiding use of GI tract is recommended until the patient no longer reports abdominal pain and the serum amylase has returned to normal
Provide nutrition enterally using a jejunal tube to prevent pancreatic enzyme secretion.
If parenteral therapy is used, the solution is usually a mixture of hypertonic glucose and amino acids.
The use of lipid emulsion is contraindicated during acute phase because it increases pancreatic exocrine secretion.

44. Pharmacologic Agents Somatostatin Anticholinergic agents Glucagon
Used to decrease pancreatic secretion in acute pancreatitis
Decreases intestinal motility and reduces endocrine/exocrine pancreatic secretion
Anticholinergic agents
Glucagon
Cimetidine
calcitonin

45. Pharmaceutical Treatment
Demerol for pain
Morphine causes spasm of Sphincter of Oddi
However, use of demerol leads to metabolite accumulation
Pneumatic compressions
TPN/early enteral feedings

46. Role of ERCP Gallstone pancreatitis Recurrent acute pancreatitis
Cholangitis
Obstructive jaundice
Recurrent acute pancreatitis
Structural abnormalities
Neoplasm
Bile sampling for microlithiasis
Sphincterotomy in patients not suitable for cholecystectomy

48. Nutrition in Acute Pancreatitis
Metabolic stress
catabolism & hypermetabolism seen in 2/3 of patients
similar to septic state (volume depletion may be a major early factor in the above derangements)
Altered substrate metabolism
increased cortisol & catecholamines
increased glucagon to insulin ratio
insulin resistance
Micronutrient alterations
calcium, magnesium, potassium, etc

49. Systemic Changes in Acute Pancreatitis
Hyperdynamic
Increased cardiac output
Decreased systemic vascular resistance
Increased oxygen consumption
Hypermetabolism
Increased resting energy expenditure
Catabolism
Increased proteolysis of skeletal muscle

50. Reduced Oral Intake in Acute Pancreatitis
Abdominal pain with food aversion
Nausea and vomiting
Gastric atony
Ileus
Partial duodenal obstruction

51. Factors Differentiating Mild from Severe Pancreatitis
Parameter
Mild
Pancreatitis
Severe
Admissions
80%
20%
Pancreatic necrosis No
Yes
Oral diet within 5 days 0%
Morbidity 8%
38%
Mortality 3%
27%

52. TPN in Acute Pancreatitis
delay until volume repleted & electrolytes corrected
check triglycerides first – goal <400
lipids are OK to use (possible exception of sepsis)
monitor glucose levels carefully
can see insulin insufficiency and resistance
may need to limit calories at first
separate insulin drip may be needed
elevated TG cause acute panc and are present in EtOH panc.

53. TPN in Acute Pancreatitis
Benefit or harm?
early uncontrolled studies suggested benefit
two retrospective studies (70’s & 80’s) showed no benefit with TPN in pancreatitis
1987 – randomized study of early TPN vs. IVF alone showed more sepsis, longer stays, & no fewer complications with TPN
When to use TPN?
jejunal access is unavailable
ileus prevents enteral feeding
patients in whom TEN clearly exacerbates pancreatitis
No evidence that early TPN does anything but increase infectious events.

54. Enteral Nutrition in Acute Pancreatitis
studies
late 80’s – patients who received jejunal feeding tubes at the time of surgery, did well with early post-op enteral support
1991 – randomized study of early TPN vs. early TEN post-op showed no short-term difference
1997 – early TPN vs. early TEN (Peptamen) via nasojejunal tube in 32 patients showed no difference except 4x less cost & less hyperglycemia
1997 – similar study showed fewer complications and lower cost without change in length of stay
1998 – similar study showed more sepsis and organ failure in the TPN group

55. Summary of Prospective RCTs Enteral vs Parenteral Nutrition for Acute Pancreatitis
McClave et al.
1997
Kalfarenztos et al.
Windsor et al.
1998
No of patients 32 38 34
Etiology
EtOH 19/32
- -
Biliary 23/34
Severe pancreatitis
19%
100%
38%
Enteral formula
Semi-elemental
Polymeric
Cost
5x less
3x less
Outcome
No difference
Fewer comp
Less SIRS

56. Total Enteral Nutrition in Severe Pancreatitis
may start as early as possible
when emesis has resolved
ileus is not present
nasojejunal route preferred over nasoduodenal
likely decreases risk of infectious complications by reducing transmigration of colonic bacteria