A. Introduction

1. Over 220,000 hospitalizations per year in USA
2. Increasing incidence: ~44 per 100,000 annually
3. ~20% with severe course; ~20% of these severe patients die of pancreatitis
4. Mainly due to gallstones and excessive alcohol consumption
5. Increased risk in persons with increased gallstone risk and alcohol abuse

B. Causes [5]

1. Gallstone (~35%)
   1. Most common cause of acute pancreatitis
   2. Small stones (<4mm) and mulberry shape are major risk factors
2. Alcoholic (~40%; sphincter spasm)
3. Hypertriglyceridemia (15-20% of pancreatitis): triglycerides > 500mg/dL
4. Obstruction
   1. Gallstones (as above)
   2. Biliary Sludge
   3. Post-operative (iatrogenic)
   4. Pancreatic stricture [2]
   5. Pancreatic, peri-ampulary, and other tumor [6]
   6. Endoscopy (ERCP) induced (iatrogenic)
5. Drugs [2]
   1. Sulfur-Containing Agents: furosemide, azathioprine, sulfa antibiotics, thiazides
   2. Tetracycline
   3. Halothane
   4. Estrogens
   5. Didioxyinosine (DDI, didanosine)
   6. Pentamidine (intravenous)
   7. Octreotide (Sandostatin®)
   8. ACE-inhibitors
   9. Possible (mainly in HIV infected persons): isoniazid, rifampin, erythromycin, others
6. Viral: Mumps, Cocksackie
7. HIV Infected Persons
   1. Cytomegalovirus
   2. Toxoplasma gondii
   3. Possible: Mycobacterium avium intracellulare, HIV, cryptosporidium, tuberculosis
   4. Didanosine (antiretroviral; see above)
8. Miscellaneous Uncommon Causes
   1. Scorpion stings
   2. Ascaris infection
   3. Periarteritis nodosa
   4. Pancreas Divisum
9. Hereditary (Familial) [7]
   1. Less than 1% of all pancreatitis cases
   2. Autosomal dominant condition
   3. Most cases due to mutations in cationic trypsinogen gene (PRSS1)
   4. Median onset 10-11 years
   5. Frequent acute attacks leading to chronic pancreatitis
   6. Generally mild disease but 53X increased risk for pancreatic cancer
   7. Some patients with these mutations are asymptomatic
10. Idiopathic - all should be tested for PRSS1 gene mutations

C. Mechanisms

1. Other than gallstone impaction and other obstruction, etiology is not clear
2. Likely due to pancreatic enzyme autodigestion
   1. Inappropriate activation of trypsinogen to trypsin within pancreatic acinar cells
   2. Lack of prompt elimination of active trypsin inside pancreatic cells
   3. Activated trypsin leads to elevated elastase, phospholipase A2
   4. Complement and kinin pathways activated
   5. Inflammation initiated
3. Very high levels of inflammatory proteins observed
   1. Elevated levels of IL-6, IL1 and IL8
   2. IL6 stimulates elevated C-reactive protein (CRP)
   3. Inflammation itself causes substantial tissue damage
   4. IL8 and other cytokines cause leukocyte recruitment and migration into pancrease
   5. Pancreatic inflammation is therefore further augmented
   6. This may progress beyond pancreas to a systemic inflammatory response syndrome (SIRS)
   7. Multiorgan system failure or death may ensue
4. Ischemia-reperfusion may play a central role

D. Symptoms and Signs

1. Knife-like epigastric pain
   1. Usually radiates to the back
   2. Right upper quadrant pain may also occur
2. Nausea, Anorexia, Vomiting
3. Fever
4. Weakness, Lethargy, Light Headed
5. Dehydration
6. Tachycardia
7. Panniculitis (subcutaneous fat necrosis) [8]
8. Constipation due to ileus may occur
9. Symptoms may be somewhat blunted in alcholism and familial pancreatitis
10. Signs of Intra-Abdominal Hemorrhage [25]
    1. Found with severe pancreatitis (and rarely other diseases)
    2. Cullen's Sign - periumbilical blue-red hemorrhage, appears as trauma
    3. Turner's Sign - black/blue/red bruise like discoloration on abdominal skin

E. Laboratory Findings

1. Elevated Amylase (may resolve in 60-72 hours) and Lipase
   1. Hypertriglyceridemia frequently does not cause amylase increase
   2. Lipase will generally be increase in all forms of pancreatitis
   3. Lipase more specific than amylase for pancreatitis
   4. Both will be increased post-ERCP, usually without symptoms
   5. Most impressive increase will occur in "virgin" pancreas (no history of pancreatitis)
2. Differential for Elevated Amylase
   1. Pancreatic Ca, Lung Ca
   2. Intestinal obstruction, infarction, perforation
   3. Renal failure
   4. Macroamylasemia
   5. Parotid Disease
   6. Hepatitis
   7. Ruptured Ectopic Pregnancy
3. Differential for Elevated Lipase
   1. Pancreatic carcinoma
   2. Intestinal obstruction, infarction, perforation
4. BP reduction, reflex tachycardia with hypovolemia - third spacing of fluid
5. Hemoconcentration - Elevated hematocrit (from hypovolemic due to dehydration)
6. Leukocytosis
7. Bilirubinemia 20%
8. Hyperglycemia 25% or hypoglycemia
9. Hyponatremia, Hypocalcemia
10. Urinary Trypsinogen-2 (Trypsinogen Activation Peptide, TAP) [10]
    1. Urinary dipstick developed for detection of trypsinogen-2 (TAP)
    2. Test threshold is 50ng/mL, and is very useful screening for acute pancreatitis
    3. Sensitivity 94%, specificity 95% for acute pancreatitis
    4. In emergency room patients with acute abdominal pain, can rule out acute pancreatitis
    5. In addition, levels of TAP correlate with severity of disease
    6. Test has better parameters of assessment of outcome in acute pancreatitis than CRP

F. Imaging

1. Computerized Tomography (CT)
   1. Unenhanced then contrast enhanced CT is best initial evaluation
   2. Require oral contrast, however, which may be difficult
   3. Dynamic intravenous contrast enhanced CT is also very specific and sensitive
   4. Can identify necrotic tissue
   5. CT severity score used for triage of patients
2. CT Severity Score [1]
   1. Sum of scores (0-10 points) on unenhanced and enhanced CT
   2. Unenhanced CT: normal pancreas (0 points), pancreatic enlargement (1), pancreatic and peripancreatic changes (2), single fluid collection (3), 2 or more fluid collections (4)
   3. Contrast-Enhanced CT (necrosis % of cells): 0% (0 points), <30% (2 points), 30-50% (4), >50% (6)
   4. Score 7 or higher predicts high morbidity and mortality
3. MRI identifies necrosis and fluid collections better than CT
4. Ultrasound
   1. Usually unsatisfactory due to bowel gas
   2. Images gall bladder and liver well, not pancreas
5. Abdominal Radiograph
   1. Poor sensitivity; may show localized ileus in severe pancreatitis
   2. Calcification of pancreas suggests chronic pancreatitis
6. Magnetic Resonance Cholangiopancreatograhy (MRCP) [11,12,13]
   1. Non-invasive method for evaluation of biliary tract
   2. Good visualization of ducts with luminal clarity similar to ERCP (see below)
   3. Less sensitive than ERCP for stones and malignant conditions
   4. Does not evaluate the ampulla as well as ERCP
   5. Sensitivity and visualization may be increased after giving secretin (SecreFlo®)
   6. Does not require administration of any contrast dye
   7. May precede ERCP in patients with low likelihood of intervention
7. Invasive Procedures
   1. Endoscopic Retrograde Cholangiopancreatography (ERCP)
   2. Angiography
   3. Fine Needle Aspiration
8. ERCP
   1. Imaging biliary tree including pancreatic duct(s)
   2. Gallstone removal
   3. Biopsy
   4. Sphincterotomy / Papillotomy - for common bile duct stones

G. Differential Diagnosis

1. Perforated viscus (especially peptic ulcer) or intestinal obstruction / infarction
2. Acute cholecystitis
3. Renal Cholic
4. Myocardial Infarction, Dissecting Aortic Aneurysm
5. Mesenteric vascular occlusion
6. Pneumonia, diabetic ketoacidosis, Vasculitis
7. MicroRNA expression pattern can be used to differentiate normal pancreas, chronic pancreatitis, and pancreatic adenocarcinoma [17]

H. Prognostic Factors (Ranson's Criteria) [3]

1. Criteria on Presentation
   1. Age > 55 years
   2. WBC > 16K/µL
   3. Blood Glucose > 200mg/dL
   4. Serum LDH > 350
   5. AST > 250
2. Criteria Developing within 48 Hours
   1. Fall in HCT > 10%
   2. BUN Increase > 8mg/dL
   3. Serum Ca2+ < 8 mg/dL
   4. Arterial pO2 < 60mm (<90% Sat); especially high association with ARDS
   5. Estimated Fluid Sequestration (Third Spacing) > 600mL
   6. Base Deficit < 4 (severe acidosis)
3. Mortality Correlates
   1. 0-2 Criteria 2%
   2. 3-4 Criteria 15%
   3. 5-6 Criteria 40%
   4. 7-8 Criteria 100%
4. Acute Physiology and Chronic Health Evaluation II (APACHE II) score is also prognostic
5. Prognosis
   1. Ranson's Criteria and APACHE II Score are useful
   2. Severe disease in young patients without history of pancreatitis is poor
   3. High risk of severe pancreatic inflammation in first episode of pancreatitis

I. Sequential Organ Failure Assessment (SOFA) Score [1]

1. Combined respiratory, coagulation, liver, cardiovascular, central nervous (CNS), renal scores
2. Points are assigned in each category; increasing points associated with worse outcomes
3. Respiratory (PaO2/FiO2 mmHg): >400 (0 points), <400 (1 point), <300 (2), <200 with respiratory support (3), <100 with respiratory support (4)
4. Coagulation - Platelet Count K/µL: >150 (0 points), <150 (1), <100 (2), <50 (3), <20 (4)
5. Liver - Bilirubin (µmol/L): <20 (0 points), 20-32 (1), 33-101 (2), 102-204 (3), >204 (4)
6. Cardiovascular - Mean Arterial Pressure (mm): >70 (0 points), <70 (1), dopamine <6 or any dobutamine (2), dopamine >5 or epi/norepi <0.1 (3), dopamine >15 or epi/norepi >0.1 (4)
7. CNS - Gasgow coma score (GCS): 15 (0 points), 13-14 (1), 10-12 (2), 6-9 (3), <6 (4)
8. Kidney - creatinine: 1.5mg/dL (0 points), 1.5-2.25 (1), 2.25-4 (2), <6 or urine output <500mL/day (3), >6 or urine output <200mL/day

J. Treatment

1. Correct hypovolemia, electrolyte abnormalities
2. Nutrition
   1. Enteral feedings superior to parenteral nutrition in all patients tolerant to it [1,4]
   2. Enteral nutrition is highly preferable to parenteral and may confer mortality benefit [14]
   3. Enteral feedings are usually tolerated even in patients with ileus [3]
   4. Parenteral nutrition only in patients who cannot tolerate enteral feedings within ~4 days
3. Nasogastric Tube
   1. Decreases abdominal distension in patients with paralytic ileus
   2. Used only for symptomatic patients
   3. No benefit to nasojejunal versus nasogastric tube in acute pancreatitis [15]
4. Analgesia
   1. Opiates are generally required
   2. Morphine should be avoided because it causes sphincter spasm
   3. Meperidine (Demerol®) is the preferred agent
5. Antibiotics
   1. Generally indicated for treatment of severe acute necrotizing pancreatitis
   2. Ciprofloxacin+metronidazole are probably beneficial for 5-7 days in non-necrotic disease
   3. Imipenam-cilastatin is recommended in acute necrotizing pancreatitis [1]
   4. Cefuroxime reduced sepsis in severe acute alcohol-induced necrotizing pancreatitis
   5. Prophylactic ciprofloxacin-metronidazole did not reduce incidence of infected necrosis in severe pancreatitis in one study [23]
6. Emergent ERCP
   1. If cholangitis and/or jaundice are present, then emergent ERCP is indicated
   2. Removal of stone is main indication for emergent ERCP with therapeutic modality
   3. Sphincterotomy (papillotomy) is usual procedure and is generally well tolerated [16]
   4. Emergent sphincterotomy is indicated only for patients with biliary obstruction [1,16]
   5. Basic idea is to enlarge common bile duct and allow for stone extraction
   6. In standard treatment, enlargement is accomplished by transection of biliary sphincter
   7. Electrocoagulation is usually used, and result is "sphincterotomy"
   8. Sphincterotomy (destroys sphincter) is effective in >85% of cases
   9. Endoscopic balloon dilation (EBD) does not destroy the sphincter, success ~90%
7. Increased Transaminase (ALT) Levels without Cholangitis/Jaundice [1]
   1. Endoscopic ultrasound and MRCP may help identify stones
   2. If stones are visualized on either of these, emergent ERCP is indicated
   3. If normal on ultrasound and MRCP, then repeat laboratory tests in 12 hours
8. Histamine-2 blocking agents may reduce nausea but have no proven role
9. Probiotic supplements in severe acute pancreatitis worsens outcomes []
10. Lack of improvement within 2-3 days should prompt contrast-enhanced CT evaluation [3]
    1. CT guided needle aspiration to detect infected necrosis should be considered
    2. If infected necrosis found, debridement or drainage, and antibiotics should be performed

K. Optional Treatments

1. Somatostatin (Octreotide, Sandostatin®)
   1. For Pancreatitis, give iv or sc 30 min before trying orals and give bid
   2. FDA approved for VIPomas and Carcinoid Tumors
   3. T1/2 ~ 1.5 hours but action occurs up to 12 hours
   4. Side effects include nausea, diarrhea, and abdominal pain
   5. May also be useful for glucagonomas, insulinomas, fistulas, Zollinger-Ellison Syndrome
   6. No overall benefit, but may decrease local problems with mechanical pancreatitis
2. No Proven Benefit in Controlled Trials
   1. Pancreatic Enzyme replacement
   2. H2 blocking agents
   3. Aprotonin (protease inhibitor)
3. Antibiotics [1]
   1. Overall, these are of questionable efficacy
   2. Efficacy reported in reducing sepsis in severe necrotizing pancreatitis
   3. Should be used in all patients with suspected biliary sepsis
4. Endoscopic papillotomy - very effective for treatment of gallstone pancreatitis
5. Gabexate reduces degree, not frequency, of pancreatic damage related to ERCP
6. High doses of vitamin C and/or other antioxidants may have some benefit
7. Platelet activating factor (PAF) antagonist (lexipafant) showing some promise [1]

L. Complications [4]

1. Local Complications
   1. Necrotizing Pancreatitis and Pancreatic Phlegmon
   2. Pseudocyst
   3. Abscess
2. Necrotizing Pancreatitis
   1. Presence of diffuse or focal area of non-viable pancreatic parenchyma
   2. Often associated with peripancreatic necrosis
   3. Initially, this is a sterile necrosis with a mortality of ~10%
   4. However, becomes infected with bacteria in ~55% of cases
   5. This infected necrosis carries mortality of ~25%
3. Pancreatic Pseudocyst
   1. Collection of pancreatic juice enclosed by wall of fibrous or granulation tissue
   2. Develops as a result of persistent leak of pancreatic juice from pancreatic duct
4. Hemorrhagic Pancreatitis
5. Sepsis (may occur in >10% treated conservatively)
6. GI bleed from inflammatory extension
7. Adult respiratory distress syndrome
8. May progress to medical / surgical emergency (requiring critical care monitoring)

1. Alcoholism
   1. Causative in about 70% of patients with chronic pancreatitis
   2. Only 5-10% of heavy drinkers develop pancreatitis
   3. Exacerbated by smoking
   4. Ethanol may increase secretion of insoluble pancreatic proteins which block ducts
   5. Strongly consider surreptitious alcoholism
2. Obstruction of Pancreatic Ducts
   1. Leads to ductal dilitation proximal to ther obstruction
   2. Trauma - usually with formation of post-traumatic strictures
   3. Pancreatic pseudocysts
   4. Periampullary tumors
   5. Pancreatic Divisum - head and body of pancreas are separate glands
   6. Pancreatic stricture [2]
   7. Pain is prominent, likely due to cholecystikinin (CCK) stimuolation of gland
   8. Pancreatic fluids released from gland into duct are obstructed, dilating ducts, cause pain
3. Recurrent Acute Episodes
   1. Most often related to Stones or Alcoholism
   2. Chronic disease from acute pancreatitis only when complications occur
   3. Such complications include pancreatic pseudocysts or ductal strictures
4. Cystic Fibrosis (CF) Gene (CFTR) Mutations [19,20]
   1. CF protein is a chloride channel called CF transmembrane regulator (CFTR)
   2. CFTR mutations associated with chronic pancreatitis
   3. Patients are typically heterozygous for CFTR mutations
   4. Most heterozygotes do not have lung disease, do not meet criteria for CF
   5. May represent the majority of patients with "idiopathic" chronic pancreatitis
5. Unusual
   1. Hyperparathyroidism - 10-15% of patients with this disease develop pancreatitis
   2. Hyperlipidemia - Types I, IV, V (high triglycerides)
   3. Hereditary pancreatitis - autosomal dominant due to cationic trypsinogen mutation (?)
   4. Alpha-1 antitrypsin deficiency may predispose
   5. Autoimmune Pancreatitis - (below)
6. Autoimmune Pancreatitis [2,9]
   1. Usually associated with other autoimmune disorders
   2. Sjogren Syndrome
   3. Primary biliary cirrhosis
   4. Sclerosing cholangitis
   5. Sclerosing pancreatitis - believed to be autoimmune, increased serum IgG4 levels [21]
   6. Inflammatory bowel disease
   7. Diffuse induration, firm pancreas on gross pathology
   8. On histology, collar-like periductal infiltrate with T > B lymphocytes and plasma cells
   9. Diagnosis based primarily on symptoms with specific CT scan appearance
   10. Biopsy specimen may miss more focal lesions
   11. Elevated serum IgG4 or gamma globulin levels, or ALA, ACA II, ASMA, or ANA found
   12. Responds well to glucocorticoid therapy
7. Analgesic Abuse
8. Idiopathic ~15% (may include surreptitious alcoholism)

B. Morphology of Gland

1. In chronic pancreatitis, gland is abnormal before and/or after an attack
2. Edema, acute inflammation and necrosis are nearly always present in chronic pancreatitis
3. This is superimposed on chronic changes of fibrosis, inflammation, loss of exocrine tissue
4. Ductal elements may be dilateed, with protein plugs (may be calcified)

C. Symptoms and Laboratory Evaluation

1. Pain (>85%), deep epigastrium radiating to the back
2. Steatorrhea - elevated fecal fat due to malabsorption
3. Diabetes: 15% of patients become insulin dependent
4. Diffuse abdominal pain syndrome
5. Serum amylase and/or lipase levels may be normal or slightly elevated
6. Liver function test abnormalities may signify common duct disease
7. Blood tests are unreliable for diagnosis
8. Pancreatic function tests can be performed to assess glandular activity
9. Diabetes is generally only present with severe (>90%) pancreatic destruction

D. Imaging Modalities

1. Calcification of pancreatic atructures is pathognomonic (diagnostic)
   1. Plain abdominal radiographs may show pancreatic calcifications in ~30% of cases
   2. Computerized tomography (CT) scan is ~80% sensitive, 85% specific for chronic pancreatitis
2. Ultrasound
   1. Standard ultrasound has lower sensitivity (~65%) with similar specificity
   2. Endoscopic ultrasound is increasing and may be used to guide fine needle biopsy
   3. Appearance under endoscopic ultrasound can also be diagnostic: hyperechoic walls, stones, ductal dilation, or parenchymal hyperechoic foci and strands, calcifications, lobularity [18]
3. Endoscopic Retrograde Cholangiopancreatography (ERCP)
   1. Diagnostic appearance - abnormal pancreatogram, beading of pancreatic duct, stones
   2. Obtaining tissue for histology
   3. Removing ductal stones
4. Tissue histology confirming chronic pancreatitis

E. Pancreatic Function Tests

1. Useful in patients with recurrent abdominal pain and normal imaging
2. Gold Standard is collection of pancreatic secretions [16]
   1. Patient ingests standard meal or is given intravenous secretin ± cholecystokinin
   2. Duodenal juice volume, bicarbonate and protein concentration is measured
   3. Difficult to perform, not readily available (~80% sensitive; ~85% specific)
3. Substrate-Specific Tests
   1. Oral administration of bentiromide or fluorescein dilaurate
   2. Pancreatic enzymes cleave these, and products are released in the urine
   3. Urine is collected for the products
   4. Secretin induced bicarbonate <75mEq/L is diagnostic
   5. Sensitivity is ~85%, specificity is ~85%
4. Quantitative fecal fat can also be measured as a marker for malabsorption
5. Other tests are available, usually in specialty settings [12]

F. Differential Diagnosis [2]

1. For severe disease with laboratory abnormalities, pancreatitis is clear diagnosis
2. For mild and moderate disease, more difficult differential; tissue should be obtained
3. Pancreatic Cancer (usually painless)
4. Peptic Ulcer Disease
5. Irritable Bowel Syndrome
6. Gallstones
7. Endometriosis
8. Tuberculosis infecting peripancreatic lymph nodes [21]

G. Treatment

1. Pain
   1. Major problem in chronic pancreatitis patients (>85%)
   2. Improved pain is likely due to reducing CCK mediated pancreas stimulation
   3. Exogenous pancreatic enzyme (pancrealipase) replacement has some efficacy
   4. Somatostatin analogs (such as octreotide) also have some efficacy
   5. Drainage of pancreatic duct and/or removal of obstruction are generally required for more definitive treatment
   6. Low fat (<20-25gm/day) diets usually recommended to reduce attacks
   7. No randomized trials proving that low fat diets are actually effective
   8. In patients with persistent pain, narcotics and antiemetics may be needed
   9. Celiac neurolysis or thoracoscopic splanchnicectomy in refractory cases
2. Drainage of Pancreatic Duct [24]
   1. For chronic pancreatitic pain with dilated pancreatic duct, decompression recommended
   2. Surgical or endoscopic modalities are available
   3. Surgery is pancreaticojejunostomy
   4. Endoscopy is transampullary drainage of pancreatic duct
   5. Surgery was superior to endoscopy n both pain (75% versus 32%) and overall outcomes
   6. Simiar rates of complications, length of hospital stay, but endoscopy required more procedures (median of 8 versus 3)
3. Malabsorption
   1. Usually occurs with >90% of pancreatic destruction
   2. Low fat diet is usually helpful
   3. For persistant malabsorption, pancreatic enzyme replacement may be used
   4. Typical enzyme replacement is 6 tablets of Viokase® four times daily
   5. Acid neutralization may also be helpful and prevent exogenous enzyme breakdown
4. Surgical Indications
   1. Complications (pseudocysts, ascites) are usually treated with surgery or stents
   2. Disabling chronic pain is most common indiction for surgery after other modalities failed
   3. Surgery usually for clear anaatomic correctable abnormaltiy

H. Complications

1. Bile Duct Stricture [22]
   1. Common complication of chronic pancreatitis
   2. Occurs in ~14% of patients
   3. May cause hepatic fibrosis and secondary biliary cirrhosis
   4. Surgical or endoscopic biliary drainage often effective
   5. Regression of liver fibrosis may occur after biliary drainage
2. Abscess
   1. Often arising in phlegmon or area of pseudocyst
   2. Spontaneous abscess may occur
   3. Surgical drainage, often open, required
3. Pseudocyst
   1. Pancreatic fluid filled cavity without true lining epithelium
   2. Most are asymptomatic and resolve
   3. Rupture, hemorrhage, or infection can occur
   4. Resection, internal or external drainage may be performed
   5. Octreotide (somatostatin analog) has efficacy in reducing cyst fluid production
4. Phlegmon: enlarged, highly inflamed pancreas
5. GI obstruction due to large pseudocyst formation or Ileus or duodenal strictures
6. Pleural Fistula
   1. Pancreatic fluid tracking into pleural space
   2. Creates pancreaticopleural fistula
   3. Diagnosis by amylase concentration in pleural effusion
7. Pancreatic Ascites
   1. Usually from ruptures pseudocyst or pancreatic duct
   2. High concentration of amylase in ascites fluid
8. Splenomegaly due to splenic vein obstruction
9. Functional Insufficiency
   1. Exocrine Pancreas Deficiency - malabsorption discussed above
   2. Diabetes - usually >90% of pancreatic function loss required before diabetes occurs
10. Pancreatic Carcinoma
    1. Increased risk ~2.1X independent of cause or other risk factors
    2. Overall rate ~4% of patients with chronic pancreatitis over 20 years
11. Mortality is ~50% in 20-25 years of the disease

Resources

Bicarbonate Deficit

References

1. Frossard JL, Steer ML, Pastor CM. 2008. Lancet. 371(9607):143
2. Fernandez-del-Castillo CF, Sahani DV, Lauwers GY. 2003. NEJM. 349(9):893 (Case Record)
3. Whitcomb DC. 2006. NEJM. 354(20):2142
4. Swaroop VS, Chari ST, Clain JE. 2004. JAMA. 291(23):2865
5. Besselink MG, Van Stantvoort HC, Buskens E, et al. 2008. Lancet. 371(9613):651
6. Ross AM IV, Anupindi SA, Balis UJ. 2003. NEJM. 348(15):1464 (Case Record)
7. Keim V, Bauer N, Teich N, et al. 2001. Am J Med. 111(8):622
8. Ashley SW and Lauwers GY. 2002. NEJM. 347(22):1783 (Case Record)
9. Finkelberg DL, Sahani D, Deshpande V, Brugge WR. 2006. NEJM. 355(25):2670
10. Neoptolemos JP, Kemppainen EA, Mayer JM, et al. 2000. Lancet. 355(9219):1955
11. Adamek HE, Albert J, Breer H, et al. 2000. Lancet. 356(9225):190
12. Romagnuolo J, Bardou M, Rahme E, et al. 2003. Ann Intern Med. 139(7):547
13. Barish MA, Yucel EK, Ferrucci JT. 1999. NEJM. 341(4):258
14. Marik PE and Zaloga GP. 2004. Brit Med J. 328:1407
15. Eatock FC, Chong P, Menezes N, et al. 2005. J Gastroenterol. 100:432
16. Folsch UR, Nitsche R, Lutke R, et al. 1997. NEJM. 336(4):237
17. Bloomston M, Frankel WL, Petrocca F, et al. 2007. JAMA. 297(17):1901
18. Callery MP and Freedman SD. 2008. JAMA. 299(13):1588
19. Sharer N, Schwarz M, Malone G, et al. 1998. NEJM. 339(10):645
20. Cohn JA, Friedman KJ, Noone PG, et al. 1998. NEJM. 339(10):653
21. Brugge WR, Mueller PR, Misdraji J. 2004. NEJM. 350(11):1131 (Case Record)
22. Hammel P, Couvelard A, O'Toole D, et al. 2001. NEJM. 344(6):418
23. Isenmann R, Runzi M, Kron M, et al. 2004. Gastroenterology. 126:997
24. Cahen DL, Gouma DJ, Nio Y, et al. 2007. NEJM. 356(7)
25. Chauhan s, Gupta M, Sachdev A, et al. 2008. Lancet. 372(9632):54