Acute and Chronic Pancreatitis

Pancreas

 secretes 1500–3000 mL of isosmotic alkaline (pH >8)/day

 pancreatic secretions: provide the enzymes and bicarbonate needed to affect the major digestive activity of the
gastrointestinal tract

REGULATION OF PANCREATIC SECRETION

Exocrine pancreas

 influenced by hormonal and neural systems

Secretin

 stimulated by gastric acid

 secreted by S cells in the duodenal mucosa
 stimulates the secretion of water and electrolytes from pancreatic ductal cells
 depends on vagal afferent and efferent pathways


Cholecystokinin (CCK)

 secreted by Ito cells in the duodenal and proximal jejunal mucosa

 triggered by:
o long-chain fatty acids
o essential amino acids - tryptophan, phenylalanine, valine, methionine
o gastric acid
o evokes an enzyme-rich secretion from acinar cells in the pancreas
 depends on vagal afferent and efferent pathways

Enzyme secretion depends on vagal afferent and efferent pathways

Water and Bicarbonate Secretions

 dependent on secretin and CCK

Parasympathetic Nervous System

 exerts significant control over pancreatic secretion via the vagus nerve

Vasoactive Intestinal Peptide

 secretin agonist
 secretion is affected by vagal stimulation

Pancreatic Exocrine Secretion

 influenced by:
o inhibitory neuropeptides – somatostatin – acts on multiple sites
o pancreatic polypeptide – act outside of the pancreas
o peptide YY - act outside of the pancreas
o neuropeptide Y
o encephalin
o pancreastatin
o calcitonin gene–related peptides
o glucagon
o galanin

Nitric Oxide (NO) is also an important neurotransmitter.

WATER AND ELECTROLYTE SECRETION

Bicarbonate

 ion of primary physiologic importance within pancreatic secretion

 secreted by ductal cells
 Derive from plasma (93%) and intracellular metabolism (7%)
 enters the duct lumen through the sodium bicarbonate cotransporter
 depolarization caused by chloride efflux through the cystic fibrosis transmembrane conductance regulator (CFTR)\

Secretin and VIP

 bind at the basolateral surface

 cause an increase in secondary messenger intracellular cyclic AMP
 act on the apical surface of the ductal cells opening the CFTR in promoting secretion

CCK

 acting as a neuromodulator
 markedly potentiates the stimulatory effects of secretin
 physiologic concentrations stimulates pancreatic secretion by stimulating afferent vagal and intrapancreatic nerves
 no CCK receptors on acinar cells of humans

Acetylcholine

 role in ductal cell secretion

Intraluminal bicarbonate

 secreted from the ductal cells

 helps neutralize gastric acid
 creates the appropriate pH for the activity of pancreatic enzymes and bile salts on ingested food

ENZYME SECRETION

Acinar cell

 highly compartmentalized
 concerned with the secretion of pancreatic enzymes

Endoplasmic Reticulum ---protein sysntheis---  Golgi apparatus  appropriate site --- zymogen granules, lysosomes, or
other cell compartments---

Zymogen granules

 migrate to the apical region of the acinar cell awaiting the appropriate neural or hormonal stimulatory response

Pancreas

 nervous system initiates its enzyme secretion

 cholinergic
o extrinsic innervation by the vagus nerve and subsequent innervation by intrapancreatic cholinergic nerves
 acetylcholine and gastrin-releasing peptides
o stimulatory neurotransmitters
o they activate calcium-dependent secondary messenger systems  release of zymogens into the pancreatic
duct
o VIP - present in intrapancreatic nerves and potentiates the effect of acetylcholine
 secretes amylolytic, lipolytic, and proteolytic enzymes into the duct lumen
 Amylolytic enzymes
o amylase
 o hydrolyze starch to oligosaccharides and to the disaccharide maltose
 Lipolytic enzymes
o include lipase, phospholipase A2, and cholesterol esterase
o Bile salts
 inhibit lipase
 Colipase - binds to lipase and prevents inhibition by bile salts
 activate phospholipase A and cholesterol esterase

 Proteolytic enzymes
o Include:
 endopeptidases - trypsin, chymotrypsin
 act on internal peptide bonds of proteins and polypeptides
 exopeptidases - carboxypeptidases, aminopeptidases
 act on the free carboxyl- and amino-terminal ends of peptides respectively
 elastase
o secreted as inactive zymogen precursors
 Ribonucleases - deoxyribonucleases, ribonuclease

Enterokinase

 enzyme found in the duodenal mucosa

 cleaves the lysine-isoleucine bond of trypsinogen to form trypsin

Trypsin

 activates the other proteolytic zymogens and phospholipase A2

All pancreatic enzymes have pH optima in the alkaline range

AUTOPROTECTION OF THE PANCREAS

Autodigestion of the pancreas is prevented by:
 the packaging of pancreatic proteases in precursor (proenzyme) form
 intracellular calcium homeostasis
o low intracellular calcium in the cytosol of the acinar cell  destruction of spontaneously activated trypsin
 acid-base balance
 the synthesis of protective protease inhibitors
o pancreatic secretory trypsin inhibitor [PSTI] or SPINK1
o bind and inactivate about 20% of intracellular trypsin activity
o Chymotrypsin C - lyse and inactivate trypsin
o Found in:
1. acinar cell
2. pancreatic secretions
3. α1- and α2-globulin fractions of plasma

Loss of any of these four protective mechanisms  premature enzyme activation, autodigestion, and acute pancreatitis

ENTEROPANCREATIC AXIS AND FEEDBACK INHIBITION

Active serine proteases

 a negative feedback mechanism that controls pancreatic enzyme secretion in the duodenum
 phenylalanine (stimulates early digestion)
o causes a prompt increase in plasma CCK levels
o increased secretion of chymotrypsin and other pancreatic enzymes
o trypsin (stimulates late digestion)
 blunts both responses
 perfusion of the duodenal lumen with protease inhibitors  leads to enzyme hypersecretion
 CCK-releasing factor (CCK-RF)
o a peptide contained in duodenum
o involved in stimulating CCK release
 serine proteases
 o inhibit pancreatic secretion by inactivating a CCK-releasing peptide in the lumen of the small intestine
 integrative result of both bicarbonate and enzyme secretion
o depends on a feedback process for both bicarbonate and pancreatic enzymes

Acidification of the duodenum  releases secretin (stimulates vagal and other neural pathways  activate pancreatic duct cells)
 secrete bicarbonate (neutralizes duodenal acid)

Dietary proteins (bind proteases)  increase in free CCK-RF CCK release into blood (acting primarily through the neural
pathways, vagal – vagal)  acetylcholine mediated pancreatic enzyme secretion

Proteases
 continue to be secreted from the pancreas until the protein within the duodenum is digested

ACUTE PANCREATITIS

GENERAL CONSIDERATIONS

Acute pancreatitis
 most common inpatient principal gastrointestinal dx
 caused by: alcohol, gallstones, metabolic factorsdrugs
 average hospital stay = 4 days
 hospitalization rates increase with age
 higher among blacks and males
 Common Causes
1. Gallstones (including microlithiasis)
2. Alcohol (acute and chronic alcoholism)
3. Hypertriglyceridemia
4. Endoscopic retrograde cholangiopancreatography (ERCP), especially after biliary manometry
5. Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline,valproic acid, anti-HIV
medications, 5-aminosalicylic acid [5-ASA])
6. Trauma (especially blunt abdominal trauma)
7. Postoperative (abdominal and nonabdominal operations)
 Uncommon Causes
1. Vascular causes and vasculitis (ischemic-hypoperfusion states after cardiac surgery)
2. Connective tissue disorders and thrombotic thrombocytopenic purpura (TTP)
3. Cancer of the pancreas
4. Hypercalcemia
5. Periampullary diverticulum
6. Pancreas divisum
7. Hereditary pancreatitis
8. Cystic fibrosis
9. Renal failure
10. Infections (mumps, coxsackievirus, cytomegalovirus, echovirus, parasites)
11. Autoimmune (e.g., type 1 and type 2)
 Causes to Consider in Patients with Recurrent Bouts of Acute Pancreatitis Without an Obvious Etiology
1. Occult disease of the biliary tree or pancreatic ducts, especially microlithiasis, biliary sludge
2. Drugs
3. Alcohol abuse
4. Metabolic: Hypertriglyceridemia, hypercalcemia
5. Anatomic: Pancreas divisum
6. Pancreatic cancer
7. Intraductal papillary mucinous neoplasm (IPMN)
8. Hereditary pancreatitis
9. Cystic fibrosis
10. Autoimmune
11. Idiopathic
Study Table 371-1

ETIOLOGY AND PATHOGENESIS

1. Gallstones
  leading cause of acute pancreatitis in most series (30–60%)
 risk of acute pancreatitis in patients with at least one gallstone <5 mm in diameter is fourfold greater than that
in patients with larger stones

2. Alcohol
 second most common cause (15–30%)

3. Cigarette smoking
 causes pancreatic injury

4. Post-ERCP
 5–10% of patients
 prophylactic pancreatic duct stent and rectal nonsteroidal anti-inflammatory drugs (NSAIDs)
o reduce pancreatitis after ERCP

 Risk factors for post-ERCP pancreatitis:

o minor papilla sphincterotomy
o sphincter of Oddi dysfunction
o prior history of post-ERCP pancreatitis
o age <60 years
o >2 contrast injections into the pancreatic duct
o endoscopic trainee

5. Hypertriglyceridemia
 acute pancreatitis in 1.3–3.8%
 serum triglyceride levels are usually >11.3 mmol/L (>1000 mg/dL)
 deficiency of apolipoprotein CII have an increased incidence of pancreatitis
o Apolipoprotein CII - activates lipoprotein lipase, clears chylomicrons from the bloodstream
 diabetes mellitus who developed ketoacidosis and oral contraceptives
6. Drug related
 0.1–2% of cases
 Caused by hypersensitivity reaction or generation of a toxic metabolite

Acute pancreatitis varies from:

1. interstitial pancreatitis
 pancreas blood supply maintained
 self-limited
2. necrotizing pancreatitis
 pancreas blood supply interrupted
 necrosis may correlate with the severity of the attack and its systemic complications

Autodigestion
 currently accepted pathogenic theory
 proteolytic enzymes (trypsinogen, chymotrypsinogen, proelastase and lipolytic enzymes such as
phospholipase A2) – activated in the pancreas acinar cell rather than in the intestinal lumen -- 
pancreatitis results

Factors of premature activation of trypsin:

1. endotoxins
2. exotoxins
3. viral infections
4. ischemia
5. oxidative stress
6. lysosomal calcium
7. direct trauma

Activated proteolytic enzymes (especially trypsin)

 digest pancreatic and peripancreatic tissues
 activate other enzymes
o such as: elastase and phospholipase A2
 spontaneous activation of trypsin also can occur
ACTIVATION OF PANCREATIC ENZYMES IN THE PATHOGENESIS OF ACUTE PANCREATITIS

Pancreatitis is a disease that evolves in three phases:

1. initial phase
 intrapancreatic digestive enzyme activation and acinar cell injury
 Trypsin activation
o mediated by cathepsin B
o results to acinar cell injury

2. second phase
 involves the activation, chemoattraction, and sequestration of leukocytes and macrophages in the pancreas enhanced
intrapancreatic inflammatory reaction
 neutrophil
o depletion can reduce severity of experimentally induced pancreatitis
o can activate trypsinogen
o intrapancreatic acinar cell activation of trypsinogen is a two-step process:
 early neutrophil-independent
 later neutrophil-dependent phase

3. third phase
 effects of activated proteolytic enzymes and cytokines, released by the inflamed pancreas, on distant organs

activated trypsin  digest pancreatic and peripancreatic tissues and activate elastase phospholipase A2 active enzymes
and cytokines then digest cellular membranes  cause proteolysis, edema, interstitial hemorrhage, vascular damage,
coagulation necrosis, fat necrosis, and parenchymal cell necrosis  cellular injury and death release of bradykinin
peptides, vasoactive substances, and histamine  vasodilation  increased vascular permeability  edema  SIRS,
ARDS and multi organ failure

Genetic factors
 increase the susceptibility and modify the severity of pancreatic injury in acute pancreatitis, recurrent pancreatitis, and
chronic pancreatitis

Five genetic variants have been identified as being associated with susceptibility to pancreatitis:
1. cationic trypsinogen gene (PRSS1)
2. pancreatic secretory trypsin inhibitor (SPINK1)
3. cystic fibrosis transmembrane conductance regulator gene (CFTR)
4. chymotrypsin C gene (CTRC)
5. calcium-sensing receptor (CASR)

Abdominal Pain
 major symptom of acute pancreatitis
 vary from a mild discomfort to severe, constant, and incapacitating distress
 characterized by:
o pain
 steady and boring in character
 located in the epigastrium and periumbilical region
 may radiate to the back chest, flanks, and lower abdomen
o nausea
o vomiting
o abdominal distension
 due to gastric and intestinal hypomotility and chemical peritonitis

 distressed and anxious patient

 Low-grade fever, tachycardia, and hypotension
 Shock result from:
o hypovolemia secondary to exudation of blood and plasma proteins into the retroperitoneal space
o increased formation and release of kinin peptideds  vasodilation and increased vascular permeability
o systemic effects of proteolytic and lipolytic enzymes released into the circulation
 jaundice
 o edema of the head of the pancreas  compression of the intrapancreatic portion of the common bile duct or
passage of a biliary stone or sludge
 Erythematous skin nodules
o due to subcutaneous fat necrosis
 pulmonary findings: basilar rales, atelectasis, and pleural effusion (left sided)
 Abdominal tenderness and muscle rigidity
 Bowel sounds are usually diminished or absent
 enlarged pancreas (4–6 weeks)
o due to acute fluid collection, walled off necrosis, or a pseudocyst may be palpable in the upper abdomen
 Cullen’s sign
o faint blue discoloration around the umbilicus
o result of hemoperitoneum
 Turner’s sign
o blue-red-purple or green-brown discoloration of the flanks
o reflects tissue catabolism of hemoglobin from severe necrotizing pancreatitis with hemorrhage

LABORATORY DATA

 Serum amylase and lipase values 3x or more

o diagnostic to acute pancreatitis if gut perforation, ischemia, and infarction are excluded

 Serum lipase
o preferred test

 No correlation between the severity of pancreatitis and the degree of serum lipase and amylase elevations

 Serum amylase
o return toward normal after 3–7 days even if pancreatitis is still present
o amylase elevations in serum and urine occur in many conditions
o increase may indicate acute cholecystitis and acute pancreatitis

 Isoamylase and lipase levels

o remain elevated for 7–14 days
o Serum lipase activity increases in parallel with amylase activity and is more specific than amylase
o can differentiate pancreatic or nonpancreatic cause for hyperamylasemia

 Acidemia
o arterial pH ≤7.32
o spurious elevations in serum amylase
o Patients with diabetic ketoacidosis
o have marked elevations in serum amylase without any other evidence of acute pancreatitis

 Leukocytosis (15,000–20,000 leukocytes/μL) occurs frequently

 Hemoconcentration w/ hematocrit values >44%
o harbinger of more severe disease (pancreatic necrosis)
 Prerenal azotemia with a blood urea nitrogen (BUN) level >22 mg/dL
o due to loss of plasma into the retroperitoneal space and peritoneal cavity
o significant risk factor for mortality
 Hyperglycemia
o common and is due to multiple factors including:
 decreased insulin release
 increased glucagon release
 increased output of adrenal glucocorticoids and catecholamines
 Hypocalcemia
o Intraperitoneal saponification of calcium by fatty acids in areas of fat necrosis occurs
o soap formation is significant in patients with:
 pancreatitis
 mild hypocalcemia
 little or no obvious ascites

 Hyperbilirubinemia (serum bilirubin >68 mmoL or >4.0 mg/dL)

 o Jaundice is transient
o return to normal in 4–7 days

 Serum alkaline phosphatase and aspartate aminotransferase

o transiently elevated
o parallel with serum bilirubin values
o may point to gallbladder-related disease or inflammation in the pancreatic head

 Hypertriglyceridemia
o serum amylase levels are normal

 Hypoxemia (arterial PO2 ≤60 mmHg)

o herald the onset of ARDS

 Electrocardiogram
o occasionally abnormal in acute pancreatitis
o ST-segment and T-wave abnormalities simulating myocardial ischemia

 Abdominal ultrasound
o recommended in the emergency ward
o initial diagnostic imaging modality
o most useful to evaluate for gallstone disease and the pancreatic head

 Revised Atlanta criteria have clearly outlined the morphologic features of acute pancreatitis on computed tomography
(CT) scan as follows:

1. Interstitial pancreatitis
o Acute inflammation of the pancreatic parenchyma and peripancreatic tissues, but without
recognizable tissue necrosis

2. Necrotizing pancreatitis
o Inflammation associated with pancreatic parenchymal necrosis and/or peripancreatic necrosis

3. Acute pancreatic fluid collection

o Peripancreatic fluid associated with interstitial edematous pancreatitis with no associated
peripancreatic necrosis.
o This term applies only to areas of peripancreatic fluid seen within the first 4 weeks after onset of
interstitial edematous pancreatitis and without the features of a pseudocyst

4. Pancreatic pseudocyst
o An encapsulated collection of fluid with a well-defined inflammatory wall usually outside the
pancreas with minimal or no necrosis. This entity usually occurs >4 weeks after onset of interstitial
edematous pancreatitis

5. Acute necrotic collection (ANC)

o A collection containing variable amounts of both fluid and necrosis associated with necrotizing
pancreatitis
o the necrosis can involve the pancreatic parenchyma and/or the peripancreatic tissues

6. Walled-off pancreatic necrosis (WON)

o A mature, encapsulated collection of pancreatic and/or peripancreatic necrosis that has developed a
well-defined inflammatory wall
o usually occurs >4 weeks after onset of necrotizing pancreatitis

DIAGNOSIS
Acute Pancreatitis
 severe acute pain in the abdomen or back
 The diagnosis is established by two of the following three criteria:
1. typical abdominal pain in the epigastrium that may radiate to the back
2. threefold or greater elevation in serum lipase and/or amylase
3. confirmatory findings of acute pancreatitis on cross-sectional abdominal imaging
 associated:
o nausea
o emesis
o fever
o tachycardia
o abnormal findings on abdominal examination
 leukocytosis
 hypocalcemia
 hyperglycemia
 Markers of severity:
o Hemoconcentration (hematocrit >44%)
o Admission azotemia (BUN >22 mg/dL)
o SIRS
o Signs of organ failure
 Differential diagnosis:
1. perforated viscus – especially peptic 6. inferior myocardial infarction
ulcer 7. dissecting aortic aneurysm
2. acute cholecystitis biliary colic 8. connective tissue disorders w/
3. acute intestinal obstruction vasculitis
4. mesenteric vascular occlusion 9. pneumonia
5. renal colic 10. diabetic ketoacidosis

Pain of biliary tract origin is more right sided or epigastric than periumbilical or left upper quadrant and can be more severe.
Ileus is usually absent

Ultrasound
 helpful in establishing the diagnosis of cholelithiasis and cholecystitis

Intestinal obstruction due to mechanical factors

 differentiated from pancreatitis by the history of crescendo-decrescendo pain, findings on abdominal examination, and
CT of the abdomen

Acute mesenteric vascular occlusion

 elderly debilitated patients with brisk leukocytosis, abdominal distention, and bloody diarrhea
 confirmed by: CT or magnetic resonance angiography

Vasculitides secondary to systemic lupus erythematosus and polyarteritis nodosa

 confused with pancreatitis
 pancreatitis may develop as a complication of these diseases

Diabetic ketoacidosis
 abdominal pain
 elevated total serum amylase levels
 serum lipase level is not elevated

CLINICAL COURSE, DEFINITIONS, AND CLASSIFICATIONS

The Revised Atlanta Classification

1. defines phases of acute pancreatitis
2. defines severity of acute pancreatitis
3. clarifies imaging

 Phases of Acute Pancreatitis

o Two phases of acute pancreatitis (primarily describes the hospital course of the disease)
 early
  <2 weeks
 Severity: clinical parameters
 Most exhibit SIRS –if persist--  organ failure
 CT imaging is usually not needed or recommended during the first 48 h of admission
 Three organ systems should be assessed to define organ failure:
o Respiratory
o Cardiovascular
o Renal
* Organ failure
 defined as a score of 2 or more for one of these three organ systems using the modified Marshall scoring
system.
 Persistent organ failure (>48 h)
o Most important clinical finding in regard to severity of the acute pancreatitis
episode

 late
 >2 weeks
 protracted course of illness
 require imaging to evaluate for local complications
 severity: persistent organ failure (clinical parameter)
 require supportive measures
o renal dialysis
o ventilator support
o need for supplemental nutrition via nasojejunal or parenteral route
 necrotizing pancreatitis
o radiographic feature of greatest importance
o prolongs hospital stay
o if infected - require operative, endoscopic, or percutaneous intervention

 Severity of Acute Pancreatitis

o Three severity classifications have also been defined: mild, moderately severe, and severe
 Mild acute pancreatitis
 without local complications or organ failure
 most interstitial acute pancreatitis
 disease is self-limited and subsides spontaneously within 3–7 days after treatment
 Oral intake can be resumed if:
1. patient is hungry
2. normal bowel function
3. without nausea and vomiting
o clear or full liquid diet has been recommended for the initial meal
o low-fat solid diet following recovery from mild acute pancreatitis

 Moderately severe acute pancreatitis

o transient organ failure or local or systemic complications the absence of persistent organ
failure
o resolves in <48 h)
o may or may not have necrosis
o develop a local complication

 Severe acute pancreatitis

o persistent organ failure (single or multiple)
o >48 h
o CT scan or magnetic resonance imaging (MRI)
 obtained to assess for necrosis and/or complications
 Local complication management is dictated by:
 clinical symptoms
 evidence of infection
 maturity of fluid collection
 clinical stability of the patient
o Prophylactic antibiotics are not recommended
 Imaging in Acute Pancreatitis
o Two types of pancreatitis recognized on imaging:
 Interstitial
 90–95% of admissions for acute pancreatitis
 characterized:
o diffuse gland enlargement
o homogenous contrast enhancement
o mild inflammatory changes or peripancreatic stranding
 resolve with a week of hospitalization

 Necrotizing
 5–10% of acute pancreatitis
 evolve until several days of hospitalization
 characterized:
o lack of pancreatic parenchymal enhancement
o presence of findings of peripancreatic necrosis
 CT identification of local complications is critical in patients
 infected and sterile necrosis = greatest risk of mortality (increases with multisystem organ
failure
 organ failure
o median prevalence is >50%
o infected > sterile necrosis

o CT imaging
 3–5 days into hospitalization

ACUTE PANCREATITIS MANAGEMENT

Emergency ward
 First step of acute pancreatitis management begins here

Dx – confirmed-- aggressive fluid resuscitation (initiated)  administration of IV analgesics  assessment of severity 

search for etiologies -- if does not respond to aggressive fluid resuscitation -- intensive care unit (aggressive fluid resuscitation,
hemodynamic monitoring, and management of necrosis or organ failure)

Fluid Resuscitation and Monitoring Response to Therapy

 Safe, aggressive intravenous fluid resuscitation

o most important treatment intervention for acute pancreatitis

 NPO patient
o to rest the pancreas

 Narcotic analgesics IV
o control abdominal pain

 Supplemental oxygen (2 L)
o via nasal cannula

 Intravenous fluids of lactated Ringer’s or normal saline

o Lactated Ringer’s solution
 decrease systemic inflammation
 better crystalloid than normal saline

1. initially bolused at 15–20 cc/kg (1050–1400 mL)

2. followed by 3 mg/kg per hour (200–250 mL/h)
 o to maintain urine output >0.5 cc/kg per hour

 Serial bedside evaluations

o required every 6–8 h to assess vital signs, oxygen saturation, and change in physical
examination

 Targeted resuscitation Strategy

o measurement of hematocrit and BUN every 8–12 h
o recommended to ensure adequacy of fluid resuscitation and monitor response to therapy
o Less aggressive resuscitation strategy
 needed in milder forms of pancreatitis
o Rising BUN during hospitalization
 due to inadequate resuscitation
 higher hospital mortality rate

 Decrease in hematocrit and BUN during the first 12–24 h

o sufficient fluid is administered
o serial measurements and bedside assessment for fluid overload are continued
o fluid rates are maintained at the current rate

 Adjustments in fluid resuscitation:

1. Cardiac disease
2. Pulmonary disease
3. Renal disease

 Increased hematocrit or BUN during serial measurement  treated with a repeat volume challenge (2-L crystalloid
bolus) increasing the fluid rate by 1.5 mg/kg per hour -- if fails to respond --  transfer ICU

Assessment of Severity and Hospital Triage

The Bedside Index of Severity in Acute Pancreatitis (BISAP)

 incorporates 5 clinical and laboratory parameters obtained within the first 24 h of hospitalization
1. BUN >25 mg/dL
2. Impaired mental status (Glasgow coma score <15)
3. SIRS
4. Age >60 years
5. Pleural effusion on radiography – useful to assess severity
 Presence of 3 or more of these factors = increased hospital mortality
 Lower BISAP scores, hematocrits and BUNs = respond to initial management
o SIRS is not present at 24 h = unlikely to develop organ failure or necrosis
o Persistent SIRS at 24 h or underlying comorbid illnesses = step down unit setting
 Higher BISAP scores and elevations in hematocrit and BUN + do not respond to initial fluid resuscitation + exhibit
evidence of respiratory failure, hypotension, or organ failure  direct admission to ICU

Elevated hematocrit >44% and admission BUN >22 mg/dL

 associated with more severe acute pancreatitis

Special Considerations Based on Etiology

Recommended in the emergency ward to assess for etiologies that may impact acute management:
1. careful history
2. review of medications
3. selected laboratory studies (liver profile, serum triglycerides, serum calcium)
4. abdominal ultrasound
o initial imaging modality of choice
o evaluate the gallbladder and common duct and assess pancreatic head

Gallstone pancreatitis
 evidence of ascending cholangitis (rising white blood cell count, increasing liver enzymes)
o undergo ERCP within 24–48 h of admission
o increased risk of recurrence
 o Surgical candidate
 cholecystectomy during the same admission or within 4–6 weeks of discharge
o Nonsurgical candidate
 endoscopic biliary sphincterotomy before discharge

Hypertriglyceridemia
 Serum triglycerides >1000 mg/dL associated w/ acute pancreatitis
 Initial therapy
o Insulin
o Heparin
o Plasmapheresis
 OPD therapies
o control of diabetes
o lipid-lowering agents
o weight loss
o avoidance of drugs that elevate lipid levels

Potential etiologies that may impact acute hospital care include:

o hypercalcemia
 Treatment of hyperparathyroidism reduce serum calcium
o autoimmune pancreatitis
 responsive to glucocorticoid administration
o post-ERCP pancreatitis
 Pancreatic duct stenting and rectal indomethacin administration effective at decreasing
pancreatitis after ERCP
o drug-induced pancreatitis

Nutritional Therapy
 mild acute pancreatitis + abdominal pain resolve = low-fat solid diet
 sever pancreatitis = Enteral nutrition should be considered 2–3 days
o Enteral feeding maintains gut barrier integrity, limits bacterial translocation, is less expensive, and has fewer
complications than TPN (total parenteral nutrition)

Management of Local Complications

Assessed for local complications

 If exhibits signs of clinical deterioration despite aggressive fluid resuscitation and hemodynamic monitoring
 Includes:
o Necrosis
o Pseudocyst formation
o Pancreatic duct disruption
o Peripancreatic vascular complications
o Extrapancreatic infections
 multidisciplinary team approach is recommended
o gastroenterology, surgery, interventional radiology and intensive care specialists

Complications of Acute Pancreatitis

Local

 Necrosis
Sterile
Infected
 Walled-off necrosis
 Pancreatic fluid collections
 Pancreatic pseudocyst
 Disruption of main pancreatic duct or secondary branches
 Pancreatic ascites
 Involvement of contiguous organs by necrotizing pancreatitis
 Thrombosis of blood vessels (splenic vein, portal vein)
  Pancreatic enteric fistula
 Bowel infarction
 Obstructive jaundice

Systemic

 Pulmonary
o Pleural effusion
o Atelectasis
o Mediastinal fluid
o Pneumonitis
o Acute respiratory distress syndrome
o Hypoxemia (unrecognized)

 Cardiovascular
o Hypotension
o Hypovolemia
o Nonspecific ST-T changes in electrocardiogram simulating myocardial
o infarction
o Pericardial effusion

 Hematologic
o Disseminated intravascular coagulation
o Gastrointestinal hemorrhage
o Peptic ulcer disease
o Erosive gastritis
o Hemorrhagic pancreatic necrosis with erosion into major blood vessels
o Portal vein thrombosis, splenic vein thrombosis, variceal hemorrhage
 Renal
o Oliguria (<300 mL/d)
o Azotemia
o Renal artery and/or renal vein thrombosis
o Acute tubular necrosis

 Metabolic
o Hyperglycemia
o Hypertriglyceridemia
o Hypocalcemia
o Encephalopathy
o Sudden blindness (Purtscher’s retinopathy)

 Central nervous system

o Psychosis
o Fat emboli

 Fat necrosis
o Subcutaneous tissues (erythematous nodules)
o Bone
o Miscellaneous (mediastinum, pleura, nervous system)

Necrosis
 management requires a multidisciplinary team approach
 Percutaneous aspiration of necrosis with Gram stain and culture should be performed if there are ongoing signs of
possible pancreatic infection such as:
o Leukocytosis
o Fever
o Organ failure
 patient who appears septic
o reasonable to start broad-spectrum antibiotics
 Repeated fine-needle aspiration and Gram stain with culture of pancreatic necrosis + persistent fever
o done every 5–7 days
  Sterile necrosis
o managed conservatively unless complications arise
 Infected necrosis
o Targeted antibiotics is instituted
o Pancreatic debridement (necrosectomy)
 definitive management

Pseudocyst
 persistent fluid collections after 6 weeks
 incidence is low
 mostly resolve over time
 Symptomatic px:
o collections should be drained with surgery or endoscopy or by percutaneous route

Pancreatic duct disruption

 increasing abdominal pain or shortness of breath
o due to enlarging fluid collection
 Magnetic resonance cholangiopancreatography (MRCP) or ERCP
o Can confirmed the diagnosis
 Placement of a bridging pancreatic stent for at least 6 weeks
o >90% effective at resolving the leak

Perivascular complications
 splenic vein thrombosis with gastric varices and pseudoaneurysms
o Gastric varices
 bleed less than 5% of the time
o Ruptured pseudoaneurysm
 Life-threatening bleeding
 diagnosed and treated with mesenteric angiography and embolization

Extrapancreatic infections
 Hospital-acquired infections occur in up to 20% of patients with acute pancreatitis
 Continually monitored for the development of:
o Pneumonia
o urinary tract infection
o line infection

Follow-Up Care

Weeks to months
 hospitalizations for moderately severe and severe acute pancreatitis
 involve a period of ICU admission and outpatient rehabilitation or subacute nursing care
 assessment of:
o evelopment of diabetes
o exocrine insufficiency
o recurrent cholangitis
o development of infected fluid collections
 cholecystectomy
o should be performed at the same admission or 4-6 weeks after discharge

RECURRENT PANCREATITIS

Alcohol and cholelithiasis

 two most common etiologic factors

Recurrent pancreatitis w/o an obvious cause

 Differential Dx
o occult biliary tract disease
o microlithiasis
  cuases 2/3 of px w/ recurrent acute pancreatitis to have occult gallstone disease
o hypertriglyceridemia
o drugs
o pancreatic cancer
o pancreas divisum
o cystic fibrosis
Genetic defects
 hereditary pancreatitis and cystic fibrosis mutations

Other diseases of the biliary tree and pancreatic ducts that cause AP include:
 choledochocele
 ampullary tumors
 pancreas divisum
 pancreatic duct stones
 stricture
 tumor

PANCREATITIS IN PATIENTS WITH AIDS

2 reasons
1. high incidence of infections of the pancreas such as CMV, Cryptosporidium, and Mycobacterium avium complex
2. frequent use of AIDS of medications such as didanosine, pentamidine, trimethoprim-sulfamethoxazole, and protease
inhibitors

CHRONIC PANCREATITIS AND PANCREATIC EXOCRINE INSUFFICIENCY

Chronic pancreatitis
 disease process characterized by irreversible damage to the pancreas
 cytokine expression and production of extracellular matrix proteins  stellate cell activation  cause acute
and chronic inflammation and collagen deposition in the pancreas
 defined by the presence of histologic abnormalities:
o chronic inflammation
o fibrosis
o progressive destruction of both exocrine and eventually endocrine tissue
 cardinal manifestations of the disease:
o abdominal pain
o Steatorrhea
o weight loss
o diabetes mellitus
 associated w/ alcohol and smoking
 Cigarette smoke  increased susceptibility to pancreatic autodigestion and predisposes to dysregulation of
duct cell CFTR function
o independent, dose-dependent risk factor for chronic pancreatitis and recurrent acute pancreatitis
 continued alcohol and smoking exposure associated w/:
o pancreatic fibrosis
o calcifications
o progression of disease
 Pancreatic stellate cells (PSCs)
o play a role in maintaining normal pancreatic architecture that can shift toward fibrogenesis in the
case of chronic pancreatitis
o possess transforming growth factor β (TGF-β)
 mediated self-activating autocrine pathways that may explain disease progression in
chronic pancreatitis even after removal of noxious stimuli
o induce PSCs:
 proinflammatory cytokines
 tumor necrosis factor α (TNF-α)
 interleukin 1 (IL-1)
 interleukin 6 (IL-6)
 oxidant complexes
 The Sentinel acute pancreatitis event (SAPE) hypothesis
o describes the pathogenesis of chronic pancreatitis
  Tx of STEATORRHEA
o treatment with pancreatic enzymes is straightforward
o Enzyme therapy
 brings diarrhea under control and restores absorption of fat to an acceptable level and
affects weight gain
 replacement has been the cornerstone of therapy

Chronic Pancreatitis and Pancreatic Exocrine Insufficiency: TIGAR-O Classification System

 Toxic-metabolic
o Alcoholic
o Tobacco smoking
o Hypercalcemia
o Hyperlipidemia
o Chronic renal failure
o Medications—phenacetin abuse
o Toxins—organotin compounds (e.g., dibutylin dichloride, DBTC)

 Idiopathic
o Early onset
o Late onset
o Tropical

 Genetic
o Cationic trypsinogen (PRSS1)
o Cystic fibrosis transmembrane conductance regulator gene (CFTR)
o Calcium-sensing receptor (CASR)
o Chymotrypsin C gene (CTRC)
o Pancreatic secretory trypsin inhibitor gene (SPINK1)

 Autoimmune
o Type 1 autoimmune chronic pancreatitis
o IgG4 systemic
o Type 2 autoimmune chronic pancreatitis

 Recurrent and severe acute pancreatitis

o Postnecrotic (severe acute pancreatitis)
o Recurrent acute pancreatitis
o Vascular diseases/ischemia
o Radiation induced

 Obstructive
o Pancreas divisum
o Duct obstruction (e.g., tumor)
o Preampullary duodenal wall cysts
o Posttraumatic pancreatic duct scars

ETIOLOGIC CONSIDERATIONS

Alcoholism
 most common chronic pancreatitis in adults

Cystic fibrosis
 most frequent cause in children w/ AP

Idiopathic pancreatitis
 due to genetic defects

Whitcomb and associates

 identify a genetic defect that affects the gene encoding for trypsinogen
 defect prevents the destruction of prematurely activated trypsin and allows it to be resistant to the intracellular
protective effect of trypsin inhibitor
  Mutations of CFTR
o gene functions as a cyclic AMP–regulated chloride channel
o cystic fibrosis - high concentration of macromolecules can block the pancreatic ducts
o sweat test
 diagnostic of cystic fibrosis

Frequency of Mutation
 Single CFTR mutation = 11x
 Two mutant alleles = 80x
 Two CFTR mutations (compound heterozygotes) = 40-fold increased risk of pancreatitis
 N34S SPINK1 mutation = 20-fold
 Combination of two CFTR mutations and an N34S SPINK1 mutation = 900-fold

AUTOIMMUNE PANCREATITIS

Autoimmune pancreatitis (AIP)

 uncommon disorder of presumed autoimmune causation with characteristic laboratory, histologic and morphologic
findings
 associated with other disorders of presumed autoimmune etiology
 also known as IgG4 systemic disease
 Type 1 AIP
o Pancreas involve as part of an IgG4 systemic disease meets HISORt criteria
o Histologic finding characteristics:
 lymphoplasmacytic infiltrate
 storiform fibrosis
 abundant IgG4 cells
 Type 2 AIP
o Histologically characterized:
 confirmed idiopathic duct centric pancreatitis with granulocytic infiltration of the duct wall
(termed GEL)
 without IgG4 positive cells and systemic involvement
 clinical features includes:
o IgG4-associated cholangitis o tubulointerstitial nephritis
o rheumatoid arthritis o retroperitoneal fibrosis
o Sjogren’s syndrome o chronic periaortitis
o ulcerative colitis o chronic sclerosing sialadenitis
o mediastinal fibrosis and Adenopathy o Mikulicz’s disease
o autoimmune thyroiditis
 Symptoms:
o abdominal pain
o recurrent acute pancreatitis
o Weight loss
o new onset of diabetes
o elevated serum alkaline phosphatase and elevated serum aminotransferases
 due to obstruction
o Elevated serum levels of IgG4 provide
 marker for the disease
 elevated values >280 mg/dL in AIP
 CT scans abnormalities:
o diffuse enlargement
o focal enlargement
o distinct enlargement at the head of the pancreas
 ERCP or MRCP
o reveals strictures in the bile duct in more than one-third of AIP
 common bile duct strictures
 intrahepatic bile duct strictures
 proximal bile duct strictures
o termed autoimmune IgG4 cholangitis
 charteristic histologic finding:
o extensive lymphoplasmacytic infiltrates with dense fibrosis around pancreatic ducts
o lymphoplasmacytic infiltration
 o obliterative phlebitis
 The Mayo Clinic HISORt criteria indicate that AIP can be diagnosed by the presence of at least two of the following:
1. Histology
2. Imaging
3. Serology (elevated serum IgG4 levels)
4. Organ involvement
5. response to glucocorticoid therapy

o Glucocorticoids
 decreasing the size of the pancreas, and reversing histopathologic features in patients with AIP
 respond w/in within a 2- to 4-week period
 poor response = pancreatic cancer
o Prednisone
 administered at an initial dose of 40 mg/d for 4 weeks
 taper of the daily dosage by 5 mg/wk
 Patients w/ steroids are associated w/ remission
o Type 1 – 99%
o Type 2 – 92%
 Treatment of disease relapse:
o Glucocorticoids
 most relapses occur after glucocorticoids are discontinued
o Azathioprine
o 6-mercaptapurine
o Rituximab
o Cyclosporine
o Cyclophosphamide
 Types 1 and 2 AIP are highly responsive to initial glucocorticoid treatment
 Patients with refractory symptoms and strictures
o require immunomodulator therapy

Clinical Features of Chronic Pancreatitis

 Patients with chronic pancreatitis seek medical attention predominantly because of two symptoms:
o abdominal pain or maldigestion
 variable in location, severity, and frequency
 constant or intermittent with frequent pain-free intervals
 Tx: narcotics
 Maldigestion is manifested as chronic diarrhea, steatorrhea, weigh loss, and fatigue
o weight loss
 eating may exacerbate the pain

 Dx of early or mild chronic pancreatitis can be challenging

o no biomarker for the disease
o serum amylase and lipase levels are ar not elevated in CP
o Elevation of serum bilirubin and ALP  cholestasis secondary to common bile duct stricture caused by
chronic inflammation
 Impaired glucose tolerance with elevated fasting blood glucose levels
 Suspected pancreatic Steatorrhea
o Fecal elastase-1 and small-bowel biopsy
o fecal elastase = abnormal
o small-bowel histology = normal
 decrease of fecal elastase level to <100 μg per gram of stool
o strongly suggests severe pancreatic exocrine insufficiency
 Abdominal CT imaging (modality of choice)  MRI  EUS  pancreas function testing
 Secretin test
o test with the best sensitivity and specificity
o ≥60% of the pancreatic exocrine function has been lost = abnormal secretin
 A total of nine endosonographic features have been described in chronic pancreatitis
o presence of five or more features is considered diagnostic of chronic pancreatitis
o not a sensitive test for detecting early chronic pancreatitis alone
 Diffuse calcifications noted on plain film of the abdomen  significant damage to the pancreas (pathognomonic to CP)
 o Alcohol
 the most common cause of pancreatic calcification
o Calcification can also be noted in:
 hereditary pancreatitis
 posttraumatic pancreatitis
 hypercalcemic pancreatitis
 idiopathic chronic
 pancreatitis
 tropical pancreatitis

Complications of Chronic Pancreatitis

 Chronic abdominal pain  Retinopathy

 Jaundice  Biliary stricture and/or biliary cirrhosis
 Narcotic addiction  Pseudocyst
 Diabetes mellitus/impaired glucose  Metabolic bone disease
 tolerance  Pancreatic cancer
 Gastroparesis
 Malabsorption/maldigestion
Hereditary pancreatitis = 10-fold risk for pancreatic cancer

Read Table 371 – 8

Abdominal Pain
 Gastroparesis quite common in patients with chronic pancreatitis
 Endoscopic treatment of chronic pancreatitis
o Sphincterotomy
o Stenting
 Complications:
 Bleeding
 Cholangitis
 stent migration
 pancreatitis
 stent clogging
o stone extraction
o drainage of a pancreatic pseudocyst
 Large-duct disease
o Usually from alcohol-induced chronic pancreatitis
o ductal decompression with surgical therapy
 therapy of choice
 Decreasisng abdominal pain and improving quality oflife
o Surgery > Endoscopy
 used in selected patients with chronic pancreatitis and abdominal pain refractory to conventional therapy:
o Whipple procedure
o total pancreatectomy
o autologous islet cell transplantation