Acute Pancreatitis

Xiaojun Teng, M.D.

September 23, 2021
Normal Anatomy & Physiology

• neutralize
chyme
• digestive
enzymes
• hormones
 Exocrine Function

BODY
common bile
duct
TAIL
HEAD
ampulla pancreatic duct

UNCINATE

pancreatic enzymes
 Enzyme Secretion
acinus

pancreatic duct
microscopic view
of pancreatic acini
duodenum
 Enzyme Secretion

Neural
acetylcholine
VIP
GRP Hormonal
CCK
gastrin

Secretin (hormonal)
H2O
bicarbonate
 Digestive Enzymes in the
Pancreatic Acinar Cell

PROTEOLYTIC LIPOLYTIC ENZYMES

ENZYMES Lipase
Trypsinogen Prophospholipase A2
Chymotrypsinogen Carboxylesterase lipase
Proelastase
Procarboxypeptidase A NUCLEASES
Procarboxypeptidase B Deoxyribonuclease (DNAse)
Ribonuclease (RNAse)
AMYOLYTIC ENZYMES
Amylase OTHERS
Procolipase
Trypsin inhibitor
 Normal Enzyme Activation

enterokinase duodenal lumen

trypsinogen trypsin

chymotrypsinogen chymotrypsin
proelastase elastase
prophospholipase phospholipase
procarboxypeptidase carboxypeptidase
 Exocrine Stimulation

• The more proximal the nutrient infusion…the greater the

pancreatic stimulation (dog studies)
- stomach – maximal stimulation
- duodenum – intermediate stimulation
- jejunum – minimal / negligible stimulation
• Elemental formulas tend to cause less stimulation than
standard intact formulas
- intact protein > oligopeptides > free amino acids
• Intravenous nutrients (even lipids) do not appear to
stimulate the pancreas
 Protective Measures

• COMPARTMENTALIZATION - digestive enzymes are

contained within zymogen granules in acinar cells
• REMOTE ACTIVATION - digestive enzymes are secreted as
inactive proenzymes within the pancreas
• PROTEASE INHIBITORS – trypsin inhibitor is secreted
along with the proenzymes to suppress any premature
enzyme activation
• AUTO “SHUT-OFF” – trypsin destroys trypsin in high
concentrations
 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
 Acute Pancreatitis
Etiology

Other
Idiopathic Gallstones
10%
10% 45%

EtOH
35%
 Acute Pancreatitis
Associated Conditions

• Cholelithiasis • Pancreas divisum

• Ethanol abuse • Hereditary
• Idiopathic • Hypercalcemia
• Medications • Viral infections
- Mumps
• Hyperlipidemia
- Coxsackievirus
• ERCP
• End-stage renal failure
• Trauma
• Penetrating peptic ulcer
 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
Pancreas divisum
 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
 Acute Pancreatitis
Pathogenesis

acinar cell
injury

“premature
enzyme activation

failed protective
mechanisms
 Acute Pancreatitis
Pathogenesis
premature enzyme activation

autodigestion of pancreatic tissue

local activation release of

vascular of white enzymes into
insufficiency blood cells the circulation

local distant
complications organ failure
 Acute Pancreatitis
Pathogenesis

SEVERITY
Mild • STAGE 1: Pancreatic Injury
- Edema
- Inflammation
• STAGE 2: Local Effects
- Retroperitoneal edema
- Ileus
• STAGE 3: Systemic Complications
- Hypotension/shock
- Metabolic disturbances
Severe - Sepsis/organ failure
 Acute Pancreatitis
Clinical Presentation

• Abdominal pain
- Epigastric
- Radiates to the back
- Worse in supine position
• Nausea and vomiting
• Fever
Acute Pancreatitis
Differential Diagnosis

• Choledocholithiasis
• Perforated ulcer
• Mesenteric ischemia
• Intestinal obstruction
• Ectopic pregnancy
 Acute Pancreatitis
Diagnosis

• Symptoms
- Abdominal pain
• Laboratory
- Elevated amylase or lipase
• > 3x upper limits of normal
• Radiology
- Abnormal sonogram or CT
 Causes of Increased
Pancreatic Enzymes

Amylase Lipase
Pancreatitis ↑ ↑
Parotitis ↑ Normal
Biliary stone ↑ ↑
Intestinal injury ↑ ↑
Tubo-ovarian
disease ↑ Normal

Renal failure ↑ ↑
Macroamylasemia ↑ Normal
 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
 Acute Pancreatitis
Clinical Manifestations
PANCREATIC Mild: edema, inflammation, fat necrosis
Severe: phlegmon, necrosis, hemorrhage,
infection, abscess, fluid collections

PERIPANCREATIC Retroperitoneum, perirenal spaces, mesocolon,

omentum, and mediastinum

Adjacent viscera: ileus, obstruction, perforation

SYSTEMIC Cardiovascular: hypotension

Pulmonary: pleural effusions, ARDS
Renal: acute tubular necrosis
Hematologic: disseminated intravascular coag.
Metabolic: hypocalcemia, hyperglycemia
 Acute Pancreatitis
Time Course

ER presentation cytokine release organ failure

0 12 24 36 48 60 72 84 96
hours from pain onset
 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 Criteria
Alcoholic Pancreatitis

AT ADMISSION WITHIN 48 HOURS

1. Age > 55 years 1. HCT drop > 10
2. WBC > 16,000 2. BUN > 5
3. Glucose > 200 3. Arterial PO2 < 60 mm Hg
4. LDH > 350 IU/L 4. Base deficit > 4 mEq/L
5. AST > 250 IU/L 5. Serum Ca < 8
6. Fluid sequestration > 6L

Number <2 3-4 5-6 7-8

Mortality 1% 16% 40% 100%
Glasgow Criteria
Non-alcoholic Pancreatitis

1. WBC > 15,000

2. Glucose > 180
3. BUN > 16
4. Arterial PO2 < 60 mm Hg
5. Ca < 8
6. Albumin < 3.2
7. LDH > 600 U/L
8. AST or ALT > 200 U/L
 CT Severity Index
1 fluid 2 or more
appearance normal enlarged inflamed
collection collections

grade A B C D E

score 0 1 2 3 4

necrosis none < 33% 33-50% > 50%

score 0 2 4 6

score morbidity mortality

1-2 4% 0%
7-10 92% 17%

Balthazar et al. Radiology 1990.

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
 Initial Management

• Monitoring – temp., pulse, blood pressure, and

urine output
• Treatment –
- Cardiopulmonary care
- Sufficient fluid resuscitation
- Pain control
 Clinical Features

• Clinical examination
- Age > 70 years
- Abdominal findings
• increased tenderness
• rebound
• distension
• hypoactive bowel sounds
• In first 24 hours of admission - unreliable
• After 48 hours- as accurate as Ranson score
 Tests

• Trypsinogen
Trypsinogen activation peptide (TAP) I

• Trypsin

• Inflammatory cascade (IL6, IL-8, TNF-) II

C - reactive protein III

• Pancreatic injury

• Amylase, Lipase, Trypsinogen IV

 Markers of Inflammation
• TNF-alpha
- Major role in mediating inflammatory response
- Conflicting reports as a predictor of severity

• Interleukin-6 and 8.
- Principal cytokine mediator
- Measured in serum and urine
- Discriminate severe from mild cases on day 1
 C-reactive protein (CRP)
• Acute phase reactant
• Synthesized by the hepatocytes
• Synthesis is induced by the release of interleukin 1
and 6
• Peak in serum is three days after the onset of pain
• Most popular single test severity marker used today

Isenmann et al Pancreas 1993;8:358-

61
C-reactive protein (CRP)

• Gold standard for the prediction of the

necrotizing course of the disease
• Accuracy of 86%
• Readily available
 C-reactive protein (CRP)
Advantage
• Used to monitor the clinical course of the disease
Disadvantage
• Not always present on admission
• Lack specificity
 Recommendations

• CRP is currently the gold standard

• Amylase and lipase of no value
• High likelihood that IL-6/ TAP will replace the
CRP
 CT Scan
• Normal
- Homogeneous enhancement of the whole
pancreas
• Abnormal
- Non-visualization of a part of the pancreas
• Sensitivity of 90-95%
• Specificity – 100%
 Recommendation

• A dynamic CT scan should be performed in all

(predicted) severe cases between 3 and 10 days
after admission
(Evidence grade B)
Is It Possible to Predict Severity Early
in Acute Pancreatitis?

• Good clinical judgment

- Specificity - 80%
- Sensitivity - 40%
• Scoring or biochemical methods
- Specificity – 60%
- Sensitivity – 95%
 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)
 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
 Evolution in Nutrition
• Fasting
• TPN is better
• Early jejunal feeding is safe
• Early jejunal feeding is superior
• Gastric feeding is as good as jejunal feeding
 Current Recommendations

• Mild to moderate Ranson

<3 APACHE II <
8 do not
require nutritional support

• Severe
Ranson >3
APACHE II >10
Organ failure
Pancreatic necrosis nutritional support
 Current Recommendations

• Jejunal feeding should be started within 48 hours

• The optimal feeding formulae is unknown
• Ensure the jejunal placement of the tube
• Monitor for
- Hypertryglyceridemia/ hyperglycemia
• TPN in patients who do not tolerate enteral feeding
 Antibiotics

• Sepsis
- Accounts for > 80% of deaths
• Intestinal flora
- Gram negative bacteria
• Mechanism – translocation of the bacteria across
the gut wall
 Antibiotics - Rationale

• Early (1 week) Sterile necrosis

- Massive inflammatory response – multi-system
organ failure (SIRS)

• Late –
- Infected necrosis
 Why the controversy ?

• Early trials in 1970’s did not show the benefit

of antibiotics
• Antibiotics that did not penetrated the
pancreatic tissue
 Evidence

• 8 clinical trials
• Five of these trials showed a significant reduction
in the incidence of pancreatic infections
• 1 trial showed a significant reduction in mortality
• Limitations
- Small sample size
- None were double blinded randomized placebo
controlled trials
 Recommendations

• Prophylactic antibacterial treatment is strongly

recommended in severe pancreatitis (Evidence B)
• No evidence when to start prophylactic treatment
or how long to continue therapy
• Appropriate antibiotics are those that are active
against in particular gram-negative organisms
• Commence as early as possible after the
identification of a severe attack
 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
Mild Severe
Parameter
Pancreatitis Pancreatitis
Admissions 80% 20%
Pancreatic
No Yes
necrosis
Oral diet within 5
80% 0%
days
Morbidity 8% 38%

Mortality 3% 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 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
 Summary of Prospective RCTs
Enteral vs Parenteral Nutrition for Acute
Pancreatitis

McClave et al. Kalfarenztos et al. Windsor et al.

1997 1997 1998
No of patients 32 38 34

Etiology EtOH 19/32 -- Biliary 23/34

Severe
19% 100% 38%
pancreatitis
Enteral
Semi-elemental Semi-elemental Polymeric
formula
Cost 5x less 3x less --
Outcome No difference Fewer comp Less SIRS
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
 Management of the Biliary
Pancreatitis

• Passage or impaction of a
stone
• Women (age of 50-70)
• Mortality 6%
 Pancreatic necrosis

• Sterile necrosis – Systemic Inflammatory

Response Syndrome (SIRS) (First week)
- Mortality rate of 10-40%
• Infected necrosis – Sepsis (After 3 weeks)
- Mortality – 20-70%
 Sterile necrosis

• Sterile pancreatic necrosis – surgery in

selected cases
Selected cases
• Massive pancreatic necrosis (>50%) with a
deteriorating clinical course (Evidence C)
• Patients with progression of organ dysfunction
• No signs of the improvement (grade B)
 Infected necrosis

• CT guided FNA with gram stain and culture is a

confirmatory test (Evidence A)
Infected Necrosis
 Infected necrosis

Suspect if:
• Exacerbation of clinical signs
- Laboratory blood test changes
• Shift to immature cells
• Elevation of CRP
- Increased APACHE II
- Positive blood culture

Indication for Fine Needle Asperation (FNA)

 ?
• What are the diagnostic criteria of biliary pancreatitis ?
• What is the optimal method for biliary tract imaging ?
• When is early ERCP indicated ?
 What are the diagnostic criteria of
biliary pancreatitis in patients with AP ?

• Abnormal liver function tests

- ALT elevation of > 3 x normal
• Ultrasound
- Gallstone
What is the optimal method for biliary
tract imaging ?

• ERCP
• Ultrasound
• MRCP
• EUS
 Endoscopic Retrograde
Cholangiopancreatography
(ERCP)

• ERCP
- Gold standard
- Potential serious complications
Abdominal Ultrasound

Sensitivity
• GB stone 60-80%
• CBD stone 30-60%
Magnetic Resonance Cholangio-
Pancreatography (MRCP)

• Sensitivity of > 90%

Endoscopy Ultrasound
(EUS)

• EUS
- Sensitivity of > 95%
- Specificity of > 95-
100%
Management of Acute Pancreatitis
Management of Acute Pancreatitis
 Conclusions

• Acute pancreatitis is a self-limited disease in

which most cases are mild.
• Gallstones and alcohol are the leading causes of
acute pancreatitis.
• In mild pancreatitis, nutritional support is usually
not required
• In severe pancreatitis, nutritional support will
likely be required with the enteral route preferred
over TPN because of both safety and cost.