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BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION
INHIBITORY NEUROPEPTIDESINHIBITORY NEUROPEPTIDES• SOMASTOTIN• PANCREATIC POLYPEPTIDE• PEPTIDE YY• NEUROPEPTIDE Y• ENKEPHALIN• PANCREASTATIN• CALCITONIN GENE RELATED PEPTIDE• GLUCAGON• GALANIN• NITROUS OXIDE
• SOMASTOTIN• PANCREATIC POLYPEPTIDE• PEPTIDE YY• NEUROPEPTIDE Y• ENKEPHALIN• PANCREASTATIN• CALCITONIN GENE RELATED PEPTIDE• GLUCAGON• GALANIN• NITROUS OXIDE
Normal Enzyme Activation
trypsinogen trypsin
chymotrypsinelastasephospholipasecarboxypeptidase
enterokinase
chymotrypsinogenproelastaseprophospholipaseprocarboxypeptidase
duodenal lumen
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
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
Acute PancreatitisDefinition
• 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
EtOH35%
Idiopathic10%
Other10% Gallstones
45%
Acute PancreatitisEtiology
• Cholelithiasis• Ethanol abuse• Idiopathic• Medications• Hyperlipidemia• ERCP• Trauma
• Pancreas divisum• Hereditary• Hypercalcemia• Viral infections
– Mumps– Coxsackievirus
• End-stage renal failure• Penetrating peptic ulcer
Acute PancreatitisAssociated Conditions
Acute PancreatitisCausative 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
Adjusted ORs for Pancreatitis
2.54.8
12.4
42.1
0
5
10
15
20
25
30
35
40
45
Pan
crea
titi
s, O
Rs
Female Nl TBili SOD Difficultcannulation
Freeman et al. Gastrointest Endosc. ‘97.
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
failed protectivemechanisms
acinar cellinjury
prematureenzyme activation
Acute PancreatitisPathogenesis
autodigestion of pancreatic tissue
release ofenzymes intothe circulation
activationof whiteblood cells
localcomplications
localvascularinsufficiency
premature enzyme activation
distantorgan failure
Acute PancreatitisPathogenesis
• STAGE 1: Pancreatic Injury– Edema– Inflammation
• STAGE 2: Local Effects– Retroperitoneal edema– Ileus
• STAGE 3: Systemic Complications– Hypotension/shock– Metabolic disturbances– Sepsis/organ failure
SEVERITYSEVERITYMildMild
SevereSevere
Acute PancreatitisPathogenesis
• Abdominal pain– Epigastric– Radiates to the back– Worse in supine position
• Nausea and vomiting• Fever
Acute PancreatitisAcute PancreatitisClinical PresentationClinical Presentation
Acute PancreatitisDifferential Diagnosis
• Choledocholithiasis• Perforated ulcer• Mesenteric ischemia• Intestinal obstruction• Ectopic pregnancy
• Symptoms– Abdominal pain
• Laboratory– Elevated amylase or lipase • > 3x upper limits of normal
• Radiology– Abnormal sonogram or CT
Acute PancreatitisAcute PancreatitisDiagnosisDiagnosis
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)
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
Causes of IncreasedPancreatic Enzymes
AmylaseAmylase LipaseLipase
PancreatitisPancreatitis ↑↑ ↑↑
ParotitisParotitis ↑↑ NormalNormal
Biliary stoneBiliary stone ↑↑ ↑↑
Intestinal injuryIntestinal injury ↑↑ ↑↑Tubo-ovarian Tubo-ovarian
diseasedisease ↑↑ NormalNormal
Renal failureRenal failure ↑↑ ↑↑
MacroamylasemiaMacroamylasemia ↑↑ NormalNormal
Acute PancreatitisDiagnosis
• EtOH: history• Gallstones: abnormal LFTs & sonographic
evidence of cholelithiasis• Hyperlipidemia: lipemic serum, Tri>1,000• Hypercalcemia: elevated Ca• Trauma: history• Medications: history, temporal association
Acute PancreatitisAcute PancreatitisClinical ManifestationsClinical Manifestations
PANCREATICPANCREATIC
PERIPANCREATICPERIPANCREATIC
SYSTEMICSYSTEMIC
Mild:Mild: edema, inflammation, fat necrosis edema, inflammation, fat necrosisSevere:Severe: phlegmon, necrosis, hemorrhage, infection, phlegmon, necrosis, hemorrhage, infection, abscess, fluid collectionsabscess, fluid collections
Retroperitoneum, perirenal spaces, mesocolon, Retroperitoneum, perirenal spaces, mesocolon, omentum, and mediastinumomentum, and mediastinum
Adjacent viscera:Adjacent viscera: ileus, obstruction, perforation ileus, obstruction, perforation
Cardiovascular:Cardiovascular: hypotension hypotensionPulmonary:Pulmonary: pleural effusions, ARDS pleural effusions, ARDSRenal:Renal: acute tubular necrosis acute tubular necrosisHematologic:Hematologic: disseminated intravascular coag. disseminated intravascular coag.Metabolic:Metabolic: hypocalcemia, hyperglycemia hypocalcemia, hyperglycemia
Acute PancreatitisTime Course
0 12 24 36 48 60 72 84 96
hours from pain onset
ER presentation cytokine release organ failure
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?
Severity Scoring Systems
• Ranson and Glasgow Criteria (1974)– based on clinical & laboratory parameters– scored in first 24-48 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 48-96 hours after symptom onset
Ranson CriteriaAlcoholic Pancreatitis
AT ADMISSION1. Age > 55 years2. WBC > 16,0003. Glucose > 2004. LDH > 350 IU/L5. AST > 250 IU/L
WITHIN 48 HOURS1. HCT drop > 102. BUN > 53. Arterial PO2 < 60 mm Hg4. Base deficit > 4 mEq/L5. Serum Ca < 86. Fluid sequestration > 6L
NumberNumberMortalityMortality
<2<21%1%
3-43-416%16%
5-65-640%40%
7-87-8100%100%
Glasgow CriteriaNon-alcoholic Pancreatitis
1. WBC > 15,0002. Glucose > 1803. BUN > 164. Arterial PO2 < 60 mm Hg5. Ca < 86. Albumin < 3.27. LDH > 600 U/L8. AST or ALT > 200 U/L
CT Severity Indexappearanceappearance normalnormal enlargedenlarged inflamedinflamed 1 fluid 1 fluid
collectioncollection2 or more 2 or more
collectionscollections
gradegrade AA BB CC DD EE
scorescore 00 11 22 33 44
necrosisnecrosis nonenone < 33%< 33% 33-50%33-50% > 50%> 50%
scorescore 00 22 44 66
scorescore morbiditymorbidity mortalitymortality
1-21-2 4%4% 0%0%
7-107-10 92%92% 17%17%
Balthazar et al. Radiology 1990.Balthazar et al. Radiology 1990.
Edematous (Interstitial) Pancreatitis
• Usually mild• Resolves in about 7
days• Results in fluid
accumulation and swelling
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
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
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
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
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 48-72 hours– prophylactic antibiotics if present– surgical debridement if infected
• Nutritional support– may be NPO for weeks– TPN vs. enteral support (TEN)
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
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
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.
Pharmacologic Agents
• Somatostatin– Used to decrease pancreatic secretion in acute
pancreatitis– Decreases intestinal motility and reduces
endocrine/exocrine pancreatic secretion• Anticholinergic agents• Glucagon• Cimetidine• calcitonin
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
Role of ERCP
• Gallstone pancreatitis– Cholangitis– Obstructive jaundice
• Recurrent acute pancreatitis– Structural abnormalities– Neoplasm– Bile sampling for microlithiasis
• Sphincterotomy in patients not suitable for cholecystectomy
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
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
Reduced Oral Intake in Acute Pancreatitis
• Abdominal pain with food aversion• Nausea and vomiting• Gastric atony• Ileus• Partial duodenal obstruction
Factors Differentiating Mild from Severe Pancreatitis
ParameterParameterMildMild
PancreatitisPancreatitis
SevereSevere
PancreatitisPancreatitis
AdmissionsAdmissions 80%80% 20%20%
Pancreatic Pancreatic necrosisnecrosis NoNo YesYes
Oral diet within 5 Oral diet within 5 daysdays 80%80% 0%0%
MorbidityMorbidity 8%8% 38%38%
MortalityMortality 3%3% 27%27%
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
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
Enteral Nutrition in Acute Pancreatitis
• studies– late 80’s – patients who received jejunal feeding tubes at the
time of surgery, did well with earlypost-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
McClave et al. McClave et al.
19971997
Kalfarenztos et al.Kalfarenztos et al.
19971997
Windsor et al.Windsor et al.
19981998
No of patientsNo of patients 3232 3838 3434
EtiologyEtiology EtOH 19/32EtOH 19/32 - -- - Biliary 23/34Biliary 23/34
Severe Severe pancreatitispancreatitis 19%19% 100%100% 38%38%
Enteral Enteral formulaformula Semi-elementalSemi-elemental Semi-elementalSemi-elemental PolymericPolymeric
CostCost 5x less5x less 3x less3x less - -- -
OutcomeOutcome No differenceNo difference Fewer compFewer comp Less SIRSLess SIRS
Summary of Prospective RCTsEnteral vs Parenteral Nutrition for Acute Pancreatitis
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
