Acute Pancreatitis

Thiruvengadam Muniraj, MD, PhD, MRCP (UK), Mahesh Gajendran, MD, Sudha Thiruvengadam, MD, Karthik Raghuram, MD, Seema Rao, MD, and Prathab Devaraj, MD
The pancreas, a retroperitoneal gland that is often quoted as an organ of mystery, has both endocrine and exocrine functions (Fig 1). Approximately 80% of the gross weight of the pancreas supports exocrine function, while the remaining 20% is involved with endocrine function.1 Enzymes are produced within the pancreatic acinar cells, packaged into storage vesicles called zymogens, and then released via the pancreatic ductal cells into the pancreatic duct, from where they are secreted into the small intestine to begin the metabolic process needed to affect the major digestive activity of the gastrointestinal tract. The pancreas secretes 1500-3000 mL of iso-osmotic alkaline (pH 8.0) uid per day containing many enzymes and zymogens.

Literature Search
We searched MEDLINE using the keywords acute pancreatitis (AP) AND etiology, diagnosis, laboratories, imaging, clinical features, treatment, management, complications, and differential diagnosis. The information is synthesized from the review articles, guidelines from gastroenterology societies, and original articles (1974-2011).

Pathophysiology
Following ingestion of food, the vagal nerves, vasoactive intestinal peptide, gastrin releasing peptide, secretin, cholecystokinin (CCK), and encephalins stimulate enzymatic release into the pancreatic duct. The pancreas secretes amylolytic, lipolytic, and proteolytic enzymes. Amylase, the major amylolytic enzyme, hydrolyzes starch to oligosaccharides. The lipolytic enzymes include lipase, phospholipase A, and cholesterol esterase. Proteolytic enzymes which include trypsin, chymotrypsin, carboxypeptidases, aminopeptidases, and elastases act on peptide bonds of proteins and polypeptides. The proteolytic enzymes are secreted as
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FIG 1. Anatomy of the pancreas.

inactive precursors (zymogens). These precursor enzymes reach the duodenum where trypsinogen, the proenzyme for trypsin, is activated by the brush border enzyme enterokinase. Trypsin then facilitates the conversion of the other pro-enzymes to their active form. Autodigestion of the pancreas is prevented by the packaging of proteases in precursor form and by the synthesis of protease inhibitors, such as pancreatic secretory trypsin inhibitor and serine protease inhibitor (SPINK1).2 In addition, the acidic pH and a low calcium concentration in the zymogen granules guard against premature activation of the proenzymes. Whenever there is a loss of any of these protective mechanisms, zymogen activation and autodigestion occur, leading to AP. Pancreatic enzyme secretion is controlled by a negative feedback mechanism induced by the presence of active unbound proteases in the duodenum.
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TABLE 1. Etiology of pancreatitis Acute biliary pancreatitis (ABP) Alcoholic pancreatitis Smoking Post-ERCP pancreatitis (PEP) Hypertriglyceridemia (HTG) Hypercalcemia Autoimmune pancreatitis Hereditary pancreatitis Sphincter of Oddi dysfunction (SOD) Pancreatic divisum Drug-induced pancreatitis Traumatic pancreatitis Infectious causes Hypoperfusion-induced pancreatitis Idiopathic pancreatitis

Pancreatic inammatory disease may be classied as AP and chronic pancreatitis. The pathologic spectrum of AP varies from a mild selflimited form of interstitial pancreatitis to a severe systemic form of necrotizing pancreatitis.3

Denition of AP
AP is dened by the presence of 2 of the 3 criteria4: 1. Abdominal pain characteristic of AP; 2. Serum amylase and/or lipase 3 times the upper limit of normal; and 3. Characteristic ndings of AP on computed tomography (CT) scan. In 1992, the Atlanta International Symposium classied AP into mild AP (edematous/interstitial pancreatitis), which has a mortality of 1%, and severe AP (necrotizing pancreatitis), which constitutes about 20% to 30% of the AP with a mortality rate around 20% to 30%.5

Etiology
Determining the etiology of AP is crucial in the management of an acute episode and in the prevention of recurrent pancreatitis. Biliary and alcoholic pancreatitis constitute the majority of cases. In up to 30% of cases, etiology cannot be determined and they are labeled as Idiopathic pancreatitis. The potential causes are outlined in Table 1.

Acute Biliary Pancreatitis

Biliary pancreatitis is the most common cause of AP in the western world, accounting for 35% to 60% of patients with AP. The incidence of
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biliary pancreatitis has been increasing over the past decade.6 A higher incidence of gallstone pancreatitis is noted in Hispanics, whites, women, and persons over the age of 75 years.7 The signicance of determining a biliary etiology is important as it needs invasive treatment, and failure to identify it can lead to recurrent pancreatitis. The pathogenesis is multifaceted, including duct, stone, and genetic related.8 The passage of a gallstone or sludge causes local edema or transient spasm of the ampulla of Vater (Fig 1), causing transient obstruction of the pancreatic duct, resulting in increased pancreatic secretion, pancreatic edema, and/or necrosis.9 The risk is increased with small gallstones 5 mm, cystic duct diameter 5 mm, multiple gallstones (20), excess cholesterol crystals, and good gallbladder emptying.10 Common bile duct diameter 13 mm and a wide angle between bile duct and pancreatic duct are known ductal risk factors for AP.11 Duodenal exclusion of pancreatic juices has been postulated in the pathogenesis.12 The lack of trypsin results in an increase in CCKreleasing peptide because it is inactivated by trypsin. As a result, there is an increased level of CCK, resulting in increased pancreatic secretion.13 During ampullary obstruction, the pressure gradient between pancreatic duct and biliary duct disappears, resulting in a reux of infected bile juice into the pancreatic duct, which triggers pancreatitis. Genetic defects have also been postulated in the etiology of AP, the most important being the SPINK1 mutation, which results in decreased production of trypsin inhibitor.14 Other genetic causes for acute recurrent biliary pancreatitis include mutations in the ABCB4 and CFTR genes.

Alcoholic Pancreatitis
Alcohol is considered the leading cause of AP in patients with a history of alcohol consumption. Heavy alcohol use is the second most common cause of AP in developed countries. Moderate drinkers are dened as having 4-14 drinks/week in men and 4-7 drinks/week in women. Heavy drinkers are dened as having more than 14 drinks/week in men and more than 7 drinks/week in women. Alcohol does not cause AP directly. There has to be a cofactor involved with alcohol in the causation of pancreatitis. The cofactors identied are smoking, African American race, and a high-fat, high-protein diet.15 Likewise, only a small proportion of alcohol abusers develop pancreatitis. Alcohol decreases the threshold for trypsin activation, which leads to pancreatic injury and also alters the severity of pancreatic inammation. There is no established threshold for the amount of alcohol that causes pancreatitis. Several studies have postulated that the consumption of more than 80-100 g/d of alcohol for 5 years is a threshold
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for causing pancreatitis. Papachristou et al. identied chronic alcohol consumption (2 drinks/day) as a major risk factor for the development of pancreatic necrosis in AP.16 The theory is that the alcohol exposure shifts the mechanism of cell death from apoptosis to necrosis.17

Smoking
Recent studies have demonstrated smoking as an important cause of both chronic and idiopathic pancreatitis.18-20 It is an independent risk factor and the risk is dose dependent.20 It also has an additive/synergistic effect, with alcohol in the progression of pancreatitis.21 The role of oxidative stress in the induction of pancreatitis has been postulated in active smokers.22 Genetic inuence has also been shown to affect the complex alcoholsmoking interaction.23 The gastroenterology community continues to raise awareness of smoking as a risk factor for pancreatitis.19

Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) Pancreatitis

The 1991 consensus denition for Post-ERCP Pancreatitis (PEP) is new onset of pancreatic type abdominal pain associated with a rise in serum amylase 3-fold above the upper limit of normal within 24 hours of ERCP and also requiring more than one additional night of hospital stay. The severity of PEP is based on the length of stay after the procedure. A length of stay of 2-3 days is graded as mild, 4-10 days as moderate and 10 days or requiring intensive care and/or intervention for complications as severe PEP.24 The consensus denition of PEP is distinct from the clinical denition of AP per 2006 American College of Gastroenterology (ACG) practice guidelines.4 The combined use of CT scan with lipase level increases the diagnostic yield for PEP.25 There are various mechanisms proposed for the etiology of PEP. The most common theory is mechanical trauma to the papilla, causing obstruction to the outow of pancreatic juice. This is supported by prophylactic placement of a pancreatic duct stent, which decreased the incidence of PEP. Another theory is increased pancreatic duct pressure from the injection of contrast or saline, causing acinarization of the pancreas. Pancreatic infection from instrumentation is another hypothesis supported by prophylactic antibiotic usage decreasing the rate of postprocedure pancreatitis.26
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High-risk indications: Suspected sphincter of Oddi dysfunction High-risk patients: Female sex Young patient (50 years) Prior history of PEP History of recurrent AP Absence of chronic pancreatitis Normal bilirubin Procedure-related risk factors: Difcult or failed cannulation 1 contrast injection into the pancreatic duct Pancreatic sphincterotomy Failed attempt in placing pancreatic duct stent Precut sphincterotomy Pancreatic or biliary sphincterotomy for sphincter of Oddi dysfunction Less experienced endoscopist Prevention of PEP: Placement of pancreatic duct stent in high-risk patient Use of a soft guidewire to assess the bile duct before contrast injection Use of pure-cut current during endoscopic sphincterotomy No pharmacologic agent has been shown to denitively reduce the risk. Gabexate was promising in some studies but other studies failed to conrm the results.27

Hypertriglyceridemia (HTG)
HTG is a rare cause of AP contributing 1% to 4% of all cases. Interestingly, a signicant proportion of gestational pancreatitis (nearly 50%) are HTG associated.28 Triglycerides higher than 1000 mg/dL is an identiable risk factor. HTG can be either primary (genetic defect in lipid metabolism) or secondary (diabetes, obesity, hypothyroidism, alcohol abuse, or medicationrelated).29 The main pathogenesis includes hydrolysis of triglyceride by lipase into free fatty acid, which causes free radical damage.28 The majority of them have primary defect in lipoprotein metabolism. Most common abnormality is deciency of apolipoprotein C2 have an increased incidence of pancreatitis; apolipoprotein C2 activates lipoprotein lipase, which is important in clearing chylomicrons from the bloodstream. Any factor (eg,
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drugs or alcohol) that causes an abrupt increase in serum triglycerides to levels 1000 mg/dL can precipitate a bout of pancreatitis that can be associated with signicant complications and even become fulminant. To avert the risk of triggering pancreatitis, a fasting serum triglyceride measurement should be obtained before estrogen replacement therapy is begun in postmenopausal women. Fasting levels 300 mg/dL pose no risk, whereas levels 750 mg/dL are associated with a high probability of developing pancreatitis. Dietary modication and antilipidemic therapy with brates are the main lines of therapy to keep triglyceride levels below 1000 mg/dL. Case reports have shown apheresis and intravenous insulin to be effective in treating HTG-induced AP.30 Insulin and Heparin infusion has shown to increase lipoprotein lipase (LPL) activity and reduce triglyceride levels. Puried apoC-II infusion has yielded transient normalization of triglyceride levels and clinical improvement in pancreatitis patients with apoC-II deciency.31

Hypercalcemia
Hypercalcemia is a rare cause of pancreatitis and therefore even in the presence of elevated calcium levels other common causes of pancreatitis should rst be excluded.32 Hypercalcemia induced by hyperparathyroidism,33 milk alkali syndrome, and sarcoidosis has been reported to cause pancreatitis. Secretory block, accumulation of secretory proteins, and activation of intracellular trypsinogen are the proposed mechanisms for causation of pancreatitis in hypercalcemia.

Autoimmune Pancreatitis
Autoimmune pancreatitis is a subset of chronic pancreatitis. It is the pancreatic manifestation of a systemic disorder characterized by dense lymphoplasmocytic inltration with immunoglobulin G4 (IgG4)-positive plasma cells and brosis.34 It affects elderly males and closely mimics pancreatic cancer. One of the diagnostic and therapeutic features is its response to steroids.35

Hereditary Pancreatitis
Hereditary pancreatitis is characterized by recurrent episodes of pancreatitis, which can progress to chronic pancreatitis. This is also associated with a 40% increased lifetime risk of developing pancreatic cancer. Hereditary pancreatitis was rst described in 1952 and the research work on it has paved the way for the understanding of pathogenesis of pancreatitis. Mutation in the cationic trypsinogen gene (PRSS1) leads to the premature activation of trypsinogen.36 Furthermore, there is a failure of a secondary brake mechanism, which is responsible for inactivation of
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prematurely activated cationic trypsin in acinar cells.37 The inheritance pattern is autosomal dominant with 80% penetrance.36 The symptoms begin in early childhood with recurrent AP, resulting in chronic pancreatitis and having a 40% risk of pancreatic cancer.38

Sphincter of Oddi Dysfunction (SOD)

SOD is a poorly dened functional disorder typically presenting as a post cholecystectomy, biliary-type pain. Rome III denes it as an episodic (not daily) pain lasting more than 30 minutes, which disrupts normal activities but is not associated with bowel disturbances.39 It comprises sphincter of Oddi stenosis and sphincter of Oddi dyskinesia.40 Endoscopic sphincterotomy is effective in patients with elevated sphincter of Oddi basal pressure.41

Pancreatic Divisum
Pancreatic divisum occurs when the dorsal and ventral pancreatic duct fail to fuse during embryogenesis, occurring in 10% of individuals.42 With a greater number of ERCP being performed, we are nding more incidental pancreatic divisum. Usually pancreas divisum does not have any clinical signicance. However, a small percentage of these individuals may present symptomatic with recurrent AP. The most widely accepted hypothesis is that pancreatitis is due to stenosis of minor papillae causing increased intraductal pressure in the dorsal pancreatic duct. A small subset of them may also develop chronic pancreatitis.43,44

Drug-Induced Pancreatitis
Drug-induced pancreatitis is a rare cause of pancreatitis. It is difcult to diagnose as in most cases only stopping and rechallenging the drug can conrm the diagnosis. Badalov et al.45 reviewed the drug-induced AP using a MEDLINE search and classied the drugs into Class Ia, Ib, II, III, and IV based on the evidence of rechallenging, exclusion of other causes, latency of presentation and number of published case reports. The pathogenesis is by either intrinsic toxicity or idiosyncratic reaction. An idiosyncratic reaction can be due to an accumulation of toxic metabolite or by hypersensitivity reaction. Class I drugs include medications which had positive rechallenge and recurrence of acute pancreatitis (Table 2). Class II drugs include those in which there is a consistent latency of 75% or more of the reported cases. Class III drugs include drugs that had 2 or more case reports published but neither had a rechallenge nor a consistent latency period. Class IV drugs are dened similarly to Class III but have only one published case report.
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TABLE 2. Drugs causing pancreatitis Class Ia (positive rechallenge and excluded other causes): Mesalamine Benzabrate Cannabis Carbamizole Codeine Enalapril Isoniazid Metronidazole Stibogluconate Statins Procainamide Pyritinol Sulfa drugs Sulindac Tetracycline Class Ib (positive rechallenge but other causes not ruled out): alpha-Methyldopa Al-trans-retinoic acid Amiodarone Azathioprine and 6-mercaptopurine Cytosine arabinoside Dapsone Dexamethasone and other steroids Estrogen Furosemide Ifosfamide Lamivudine Losartan Meglumine Methimazole Nelnavir Omeprazole Pentamidine

Traumatic Pancreatitis
Trauma is an infrequent cause of pancreatitis but is associated with a high mortality.46 Both blunt and penetrating trauma can cause pancreatitis. The retroperitoneal location makes the injuries uncommon. The injury can vary in severity from mild contusion to rupture of pancreas. The scarring and stricture of the main pancreatic duct (MPD) can result in obstructive pancreatitis.47 Both the trauma and the surgical procedure to repair the injury cause pancreatitis. Therefore, all patients should be managed as cases of potential pancreatitis.48 The amylase elevation following blunt trauma has no correlation to pancreatic injury and severity.49

Infectious Causes
Infection is a rare cause of pancreatitis. Immunocompromised patients are more susceptible to have infection-related pancreatitis.50 Viruses: Mumps, Rubella, Coxsackie, EpsteinBarr virus,51 Cytomegalovirus,52 Hepatitis A, Hepatitis B, Hepatitis E,53 Human immunodeciency virus54 (mainly opportunistic infections55) Parasites: Ascariasis,56 Clonorchis (physical blockage) Bacteria: Mycoplasma, Campylobacter jejuni, Mycobacterium tuberculosis, Mycobacterium avium complex, Legionella57 Fungi: Cryptococcus, Toxoplasma, Cryptosporidium
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Hypoperfusion-Induced Pancreatitis
Shock is now considered a cause of pancreatitis, mainly in intensive care units.58 Shock can cause pancreatitis, pancreatic necrosis, or abscess. Pancreatitis has a positive correlation with acute tubular necrosis.59 The splanchnic hypoperfusion causes pancreatic injury, resulting in enzyme elevation, but clinically the majority of these patients are asymptomatic and can tolerate the enteral feeding.60 In intensive care units, around 40% of the patients were found to have elevated lipase and amylase without any clinical signs or symptoms of pancreatitis. Radiographic evidence of pancreatitis was present only in a minority of these patients and when present, these patients had greater elevations of lipase when compared to those without radiographic evidence.60 There are several nonpancreatic causes of enzyme elevation, like head injury, emergent surgery, and cardiac surgery. Lipase elevation is better correlated with pancreatic inammation than amylase.60 The other causes of decreased pancreatic perfusion include vasculitis61 (systemic lupus erythematosus and polyarteritis nodosa) and atheroembolism.62

Idiopathic Pancreatitis
Idiopathic pancreatitis is the term used to dene when there is no cause found for pancreatitis despite thorough history, examination, laboratory testing, and noninvasive testing.63 With recent advances in testing, Kaw et al. was able to nd the cause of pancreatitis in about 79% of the patients who were labeled as having idiopathic pancreatitis.64 Some of the disorders that were diagnosed earlier as idiopathic pancreatitis include autoimmune pancreatitis, microlithiasis, biliary sludge, sphincter of Oddi dysfunction, and pancreatobiliary ductal anomalies.63

Clinical Features
Symptoms
In the standard denition of AP, abdominal pain characteristic of AP is a key feature in the diagnosis of AP. Pain is usually acute, constant, and localized to the epigastric area or the right upper quadrant, often radiating to the back.5,65,66 Gallstone pancreatitis is characterized by sudden, sharp pain, whereas the pain in pancreatitis due to alcoholic, metabolic, and hereditary pancreatitis is poorly localized and less abrupt in onset.2 Pain is usually associated with nausea and vomiting.

Signs
Physical examination ndings may be variable and include severe abdominal tenderness, fever, hypotension, guarding, and respiratory distress. In the
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Assessing Severity Diagnosing AP

Finding Eology

FIG 2. Simplied approach to laboratory tests in AP.

Synthesis of Enzymes in Pancreas

Leakage via basolateral membrane of acinar cell

Secreon into Pancreac Duct

Intersal Space & Destrucon of pancreas

Intesnal Lumen

Enzymes leak to systemic Circulaon

FIG 3. Basic principles of pancreatic enzyme elevation in AP. The left side of the gure represents the normal physiology of the pancreatic enzyme ow. However, If the ampulla is blocked due to a gallstone ( symbol), the enzymes leak into pancreatic parenchyma resulting in AP (as shown in the right).

mild form, abdominal palpation may elicit tenderness in the epigastric region. Patients are usually restless and may go into a knee chest position in an effort to reduce the pain because lying supine exacerbates the intensity of symptoms. In the case of necrotizing pancreatitis, the exudates from a
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TABLE 3. Laboratory tests for pancreatitis Tests for diagnosis of pancreatitis: Serum amylase Serum lipase Tests for determining etiology: Triglyceride Immunoglobulin G, isotype 4 (IgG4) Alanine aminotransferase Alkaline phosphatase Urinary amylase Serum calcium Tests for severity of pancreatitis: Hematocrit C-reactive peptide (CRP) Creatinine Urinary TAP Interleukins Polymorphonuclear elastase Tumor necrosis factor

necrotic pancreas can track down along the falciform ligament into the retroperitoneum, which can be seen as bruising in the periumbilical region (Cullens sign) or in the ank (GreyTurners sign).67 Although these signs are seen in only around 3% of cases with AP, they predict a severe attack of pancreatitis with high mortality rate rising to 37%. However, these signs may be seen in any condition resulting in retroperitoneal hemorrhage. Extension of exudates to the diaphragm can cause shallow respiration.67

Laboratory Investigations
In the standard denition of AP, elevation of amylase and lipase is a key feature in the diagnosis. The laboratory tests also guide in determining the etiology of the pancreatitis and henceforth treating the cause along with pancreatitis (Fig 2). Unfortunately, amylase and lipase levels do not predict the severity of pancreatitis. There is an ongoing search for an ideal laboratory test to predict the severity of AP at the time of admission. Fig 3 depicts the basic physiology behind the pancreatic enzyme elevation. Table 3 lists the investigations used in pancreatitis.

Tests for Diagnosis of Pancreatitis

Amylase. Amylase is the most commonly performed laboratory test to diagnose AP.68 It is expressed in either Somogyi Units (60-160 SU/100 mL in serum) or International Units (110-300 IU/L in serum). It can be measured in both serum and urine. The recommended cutoff for diagnosis of AP is 3 times above the normal.4 If the amylase and/or lipase levels are
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TABLE 4. Causes of elevated amylase176 Pancreatic: Acute pancreatitis Chronic pancreatitis Pseudocyst Pancreatic ascites Gallstone Post endoscopic retrograde cholangio pancreatography (post ERCP)177 Pancreatic trauma Decreased clearance: Renal failure179 Liver failure180 Macroamylasemia70 Female reproductive system: Salphingitis182 Ruptured ectopic pregnancy183 Intestinal: Mesenteric infarction178 Inammatory conditions of small intestine Peritonitis Perforation

Salivary: Parotitis Calculi of salivary duct Chronic alcoholism Malignancy181 Miscellaneous: Acidosis184 Eating disorders185

normal or less than 3 times normal in a patient with acute abdominal pain typical of AP, then a CT scan can be performed to conrm the diagnosis of AP.4 The sensitivity of amylase at a cutoff of 300 IU/L is 91% to 100% and the specicity is around 71% to 98%.68 The urine amylase is primarily used to rule out macroamylasemia, where the serum amylase is elevated and urine amylase levels are low.69-71 A normal amylase level does not rule out pancreatitis. It can be normal in AP secondary to hypertriglyceridemia, acute on chronic pancreatitis and sometimes in recurrent alcoholic pancreatitis if the testing is done 24 hours after the onset of symptoms. Spechler et al. showed an inverse relationship between amylase levels and the number of alcoholic pancreatitis attacks.72 According to Keim et al., simultaneous determination of amylase and lipase marginally improved the diagnosis of AP in patients with acute abdominal pain.73 Checking daily enzymes has no value in the management of pancreatitis.74 The enzymes can be rechecked if there is worsening of symptoms or persistence of pain despite management. This may represent a recurrent attack of pancreatitis or a complication like pancreatic pseudocyst. There are many conditions that cause elevated amylase levels other than AP. Table 4 lists several other causes of elevated amylase. Lipase. Lipase, along with amylase, is considered the rst-line laboratory test for diagnosing AP.75 Lipase rises within 4-8 hours of onset of pancreatitis, peaks at 24 hours, and normalizes in 8-14 days.76 The advantage of lipase over amylase is that it is more sensitive in alcoholic pancreatitis and in patients who present 24 hours after onset of pancreatitis.72 Within 24 hours of onset of symptoms, both amylase and lipase have similar sensitivity and
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specicity.77 Therefore, performing both tests does not offer any advantage in that scenario. It does not have any role in assessing the severity of AP.

Tests for Determining Etiology

Urinary Amylase. The only use of urinary amylase is in the diagnosis of macroamylasemia. Amylase-to-creatinine clearance ratio is normally around 3% and is increased to 10% in AP.71 In macroamylasemia the amylase is bound to large molecules like immunoglobulin, which prevents it from being secreted into the tubules and urine.70 Therefore, the amylase-to-creatinine clearance ratio is not elevated. Macroamylasemia usually is not of any clinical signicance.69 Liver Function Tests. Alanine aminotransferase of more than 3 times the normal (150 IU/L) has a positive predictive value of 95% in diagnosing gallstone pancreatitis.69 In the meta-analysis done by Smotkin et al., bilirubin and alkaline phosphatase levels were not useful in diagnosing gallstone pancreatitis.75 A biliary cause of AP should not be excluded solely based on the normal liver function tests.78 Triglyceride. Serum triglyceride levels above 1000 mg/dL are usually considered necessary to ascribe causation for AP. Interestingly, an elevated cholesterol level by itself is not associated with pancreatitis.79 HTG is the third most common cause of AP after gallstones and alcohol. The incidence is particularly high in AP during pregnancy.80 HTG does not cause chronic pancreatitis.29 The retrospective study done by Forston et al. in 1995 on patients discharged with AP showed hypertriglyceridemia as the etiology in 1.3% to 3.8% of the cases.81 In this study, the average triglyceride level was 4587 mg/dL and the clinical presentation was similar to AP caused by other etiologies. The triglyceride levels should be measured within 24 hours of presentation, after which the levels start to trend down.29 This is secondary to decreased oral intake, which decreases the supply of chylomicrons from the intestines. Intravenous uids decrease the production of very low density lipoprotein from the liver, which in turn decreases the production of triglyceride.29 Even though there is an association between a triglyceride level of 1000 mg/dL and a causation of AP, the levels do not correlate with the severity.82 The falsely low amylase levels in HTG-induced pancreatitis is due to the presence of an inhibitor to amylase and HTG interference with calorimetric reading of the assay. Serial dilutions of serum sample may reduce the interference and increase the amylase levels facilitating the diagnosis of AP.83 Immunoglobulin G4. Autoimmune pancreatitis is new in the world of pancreatitis.84 There has been much interest in diagnosing this condition. IgG4 plays a key role in the diagnosis of autoimmune pancreatitis. The cutoff
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used for the diagnosis is 135 mg/dL.85 In 2001, Hamano et al. reported a sensitivity of 95%, specicity of 95%, and an accuracy of 97%.85 Later reported studies showed wide variations in the sensitivity ranging from 40% to 95%. Therefore, a normal level of IgG4 does not exclude a diagnosis of autoimmune pancreatitis.86 The IgG4 levels are elevated in 10% of pancreatic cancer patients and this is important because pancreatic cancer is a close differential for autoimmune pancreatitis.87 The IgG4 levels correlate with the disease activity and it has been demonstrated by decreasing levels after 12 weeks of steroid treatment along with the clinical improvement.85 If the level of IgG4 remains elevated after the 4 weeks of steroid treatment, an alternative diagnosis should be considered.88

Tests for Severity of Pancreatitis

Creatinine. Muddana et al. in 2009 rst described that an increase in creatinine greater than 1.8 mg/dL within 48 hours of admission despite adequate hydration is a marker for the development of pancreatic necrosis. This study had a positive predictive value of 93%.89 Later in 2010, Lankisch et al. published a prospective study with 462 patients in which a rise in serum creatinine did not correlate with the development of pancreatic necrosis.90 Hematocrit (Hct). In the cohort study published in 2000, Brown et al. showed hemoconcentration as an early marker for necrotizing pancreatitis and organ failure.91 The cutoff used was a hematocrit of 44% at admission and a failure of the admission hematocrit to decrease at 24 hours. The negative predictive value at 24 hours was 96% for necrotizing pancreatitis and 97% for organ failure. The admission hematocrit was comparable to Acute Physiology and the Chronic Health Evaluation II (APACHE II) in predicting necrotizing pancreatitis. It is recommended that these patients need a higher level of care and more intensive uid management. Urinary Trypsinogen Activation Peptide (TAP). Unlike other markers of severity, urinary TAP and Hct are not surrogate markers of inammation. Intrapancreatic activation of trypsin releases many protein products, including TAP, trypsinogen II, and carboxypeptidase B. Of these, TAP is used in successfully predicting the severity. Its level is most stable in the urine. Khan et al. used a cutoff 35 nmol/L within 12 hours of onset of symptoms with a sensitivity of 100%, specicity of 77%, and negative predictive value of 100%.92 Serum C-Reactive Protein (CRP). CRP has been well established as a marker for pancreatic necrosis since the 1990s. According to the Santorini consensus conference in 1999, a cutoff of 150 mg/L done at 48 hours after the onset of symptoms has been accepted as the predictor for pancreatic necrosis.93 It is considered the gold standard
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TABLE 5. Imaging in acute pancreatitis The key imaging modalities used are Abdominal ultrasound (USG)/Endoscopic ultrasound (EUS) Computed tomography (CT) scan abdomen with intravenous contrast Magnetic resonance imaging/magnetic resonance cholangiopancreatography The uses of imaging are in: Diagnosis of pancreatitis Determining etiology Detecting complications (pseudoaneurysm, abscess, pseudocyst) Assessing severity (necrosis)

test because it has an overall accuracy of 93% and is widely available, easy to measure, and cheap to perform. The only drawback is that there is a lag period of 48-72 hours from the onset of pancreatitis to the peak rise of CRP.68 This is a signicant amount of time because considerable damage can be done by this time. That is the reason there is still an ongoing search for a better test. Polymorphonuclear (PMN) Elastase. PMN elastase is a lysosomal protease released from the neutrophils in the inamed pancreas. It is responsible for the activation of the complement and brinolytic pathway. In 1991, Uhl et al. from Germany showed that the accuracy of PMN elastase was 84% with a cutoff of 120 g/L when compared to CRP at 86%.94 The key advantage over CRP was that it reached its peak on Day 1. Tumor Necrosis Factor (TNF)-alpha. TNF-alpha is a pleiotrophic cytokine expressed in acinar cells, which plays a pivotal role in AP. The ability to be a clinically useful test is limited because it is rapidly cleared from blood. Soluble TNF receptor binds to TNF-alpha and acts as an antiinammatory molecule.95 de Beaux et al. explained that the soluble TNF receptor levels were better than TNF-alpha levels in predicting severe AP from Day 1.96 Interleukins (IL). IL-1 is a biomarker for sterile necrosis and severity of AP at admission.97 IL-6 is a cytokine released by macrophages mediating the synthesis of acute phase proteins. According to Chen et al., IL-6 is the most useful parameter for early prediction of the prognosis of AP.98 It is superior to CRP and APACHE II at 24 hours. Chen et al. showed that at a cutoff of 400 pg/mL on Day 1, it has a sensitivity of 89%, a specicity of 87%, and accuracy of 88%.98 Also, it remains elevated until Day 7.

Imaging in AP
Imaging has played a key role in the management of AP for many years. The development in radiology has not only improved the diagnostic capabilities but also paved the way for interventions (Table 5).
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Abdominal Ultrasound
Abdominal ultrasound is the most commonly used imaging test in the evaluation of pancreatitis.99 The advantages of ultrasound are that it is cheap, readily available, and easily portable for bedside application. The inamed pancreas is seen as enlarged and hypo-echoic. The sensitivity in detecting a gallstone is 95%, whereas it is only 50% for the common bile duct stone.100 Sonic penetration is limited by bowel gas and adipose tissue. CT is more accurate than ultrasound in the detection of pancreatic inammation and necrosis.100

Endoscopic Ultrasound (EUS)

EUS has gained importance in recent years in the evaluation of suspected choledocholithiasis instead of ERCP.101 It has a sensitivity of 91% and a specicity of 100% in diagnosing choledocholithiasis.102 It is also the test of choice to distinguish between pseudocyst and other cystic lesions of pancreas. The features suggestive of cystic neoplasm include wall thickness greater than 3 mm, macroseptations, presence of mass and/or nodules in the cyst, and cystic dilatation of the MPD.103 EUS also enables ne-needle aspiration of the cystic uid for further evaluation. Further endoscopic drainage of the pancreatic pseudocyst can be performed with EUS.103

CT Scan
Abdominal CT with intravenous contrast is the imaging test of choice to diagnose and assess the severity of pancreatitis.104 The presence of inammatory changes in the pancreas is 1 of the 3 criteria to diagnose AP.4 CT allows detection of complications such as pseudoaneurysm.99 Pancreatic necrosis is seen as hypo-attenuated areas in the parenchymal phase. The venous phase can diagnose splenic vein thrombosis.105 Other complications, such as pancreatic abscess, can also be diagnosed by the presence of air within a uid collection. Initial mortality in pancreatitis is related to organ failure or pancreatic necrosis; hence, early diagnosis and grading are important. The major contraindication for contrast is renal failure, which is a common problem in severe AP. Also, 15% to 30% of the CT scans can be normal in AP.106 Doing a CT scan at the time of presentation is not always necessary and clinicians should be aware that an early CT scan (within 72 hours) might underestimate the amount of pancreatic necrosis. The position statement from American Gastroenterology Association (AGA) 2007 mentions that there is potential for intravenous contrast to impair pancreatic microcirculation and potentially
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aggravate the degree of pancreatic necrosis and worsen the course of AP.107 Nevertheless, in the case of diagnostic dilemma, CT scan plays a key role in diagnosing other causes of acute abdominal pain, such as perforated peptic ulcer disease, mesenteric ischemia, acute cholecystitis, and bowel obstruction. CT may detect atypical features that may suggest unusual causes of pancreatitis, such as groove pancreatitis, tropical pancreatitis, and autoimmune causes among others.108 The key pathologic ndings in AP are acute uid collections, pancreatic necrosis, and abscess.105 They are described in the following paragraphs. i. Acute inammatory changes/acute uid collections: there is a spectrum of acute inammatory changes, which includes the following: 1. Edematous pancreatic enlargement109 (Fig 4) 2. Soft tissue changes extending into anterior and lateral peripancreatic fat 3. Peripancreatic uid collections110: Acute uid collections have poorly dened inammatory walls and irregular shapes, which resolve within 4 weeks without any interventions. Pancreatic pseudocysts (Fig 5) persist beyond 4 weeks and have a welldened inammatory wall.111 These may or may not need intervention depending on the size and growth.103 ii. Pancreatic necrosis (Figs 6, 7, and 8): About 5% to 20% of the patients with AP develop pancreatic necrosis.2 The process starts within 48 hours after the onset of inammation and the optimal timing for the CT scan is Day 4.112 As the microcirculation is disrupted in necrosis, the contrast does not penetrate into the necrotic tissue and therefore the necrotic gland does not enhance. The normal pancreas has more than 40 HU enhancement, whereas the necrotic tissue has less than 30 HU.105 All heterogeneous peripancreatic collections should be considered as areas of fat necrosis until proven otherwise.93 Tables 6-8 describe the formula for calculating the CT severity Index (CTSI) score, which has been shown to be better than RANSON and APACHE II for predicting severity and mortality. iii. Infected pancreatic necrosis vs sterile pancreatic necrosis Infection develops in 30% to 70% cases of pancreatic necrosis, which accounts for 80% of the deaths from AP. The mortality rate in infected necrosis is 17.5% to 40% when compared to 10% mortality rate in sterile necrosis.113-115 It is difcult to distinguish between them because the clinical presentation is similar with fever and leukocytosis. A CT scan can detect infected necrosis only by the presence of gas in the necrotic tissue.106 Otherwise, CT-guided
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FIG 4. Edematous pancreatitis (arrow points at the inamed pancreas).

FIG 5. Pancreatic pseudocyst. 116 DM, March 2012

FIG 6. Pancreatic necrosis (arrow points at the area of necrosis).

FIG 7. Partial necrosis of the pancreas. (A) Necrosis. (B) Normal (arrow points at the demarcation between A and B). DM, March 2012 117

FIG 8. Complete necrosis of the pancreas (arrow points at the area of necrosis).

ne-needle aspiration with Gram stain and culture is the recommended method to diagnose necrotic infection.4

Magnetic Resonance Imaging (MRI)/Magnetic Resonance Cholangiopancreatography

Magnetic resonance cholangiopancreatography is evolving as an important imaging modality, replacing ERCP in the diagnosis of choledocholithiasis and pancreatic duct abnormalities.116 MRI has several advantages over CT scan, including evaluation of biliary tract and the pancreatic duct, and is free of radiation risk.117 However, its advantage over CT scan in renal failure patients has been obviated because of the risk of nephrogenic systemic brosis in patients with an estimated glomerular ltration rate less than 30. The disadvantages are its limited availability, longer time for testing, and greater expense. It is contraindicated in patients with pacemakers or ferromagnetic intracranial aneurysm clips. Contrast MRI can assess the severity of AP by detecting the extent of necrosis and uid collections similar to contrast CT, but allows better denition of solid debris within collections. The presence of necrosis is identied by well-marginated areas of decreased signal intensity compared with the signal intensity of the normal pancreas. Balthazars grading system, previously used for CT, is also adapted for MRI and is called magnetic resonance severity index.116 It is comparable to CTSI and corresponds well
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TABLE 6. Severity grading based on CT Grade of acute pancreatitis based on noncontrast CT ndings A. Normal pancreas B. Pancreatic enlargement C. Pancreatic or peripancreatic fat inammation D. Single peripancreatic uid collection E. 2 or more uid collections and/or retroperitoneal air TABLE 7. Severity grading based on CT112 Degree of pancreatic necrosis based on contrast CT ndings A. No pancreatic necrosis B. Up to 30% of the gland C. 30%-50% of the gland D. 50% of the gland TABLE 8. Severity grading based on CT112 CT severity index (CTSI) Mild pancreatitis Moderate pancreatitis Severe pancreatitis AB 0-2 3-6 7-10 Points (B) 0 2 4 6 Points (A) 0 1 2 3 4

with RANSONs score and CRP. MRI is also more effective than CT in detecting gallstones, common bile duct stones, and pancreatic duct disruptions. Secretin-enhanced magnetic resonance cholangiopancreatography allows the evaluation of the MPD. Abnormal response is dened by the lack of MPD distention less than 4 mm in the head and less than 3 mm in the tail at 10 minutes from the injection of secretin or by delayed duodenal lling (5 minutes).116 It correlates with a RANSONs score greater than 3 and magnetic resonance severity index greater than 3 in predicting the outcome of AP.116

Prediction of Severity and Scoring Systems

The 1992 Atlanta symposium classied AP into mild AP and severe AP.5 The patients with AP were classied as severe AP if they met 1 of the 4 criteria: (1) organ failure with 1 or more of the following: shock (systolic blood pressure 90 mm Hg), pulmonary insufciency (PaO2 60 mm Hg), renal failure (serum creatinine level 2 mg/dL after rehydration), and gastrointestinal tract bleeding (500 mL in 24 hours); (2) local complications, such as pseudocyst, necrosis, or abscess; (3) systemic complications, such as disseminated intravascular coagulation (platelets 100,000/mm3, brinogen 1 g L1, brin split product 80 g/mL) or severe metabolic disturbances (calcium 7.5 mg/dL); (4) at least 3 of the RANSONs criteria and/or at least 8 of the APACHE II criteria.5 Mortality ranges from less than
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1% in mild disease to 10% in sterile necrosis and 30% in the presence of infected necrosis.93 This underscores the need for early evaluation and risk stratication to differentiate patients between mild and severe disease who will need intensive care treatment and close monitoring.

Scoring Systems for AP

Despite the advances in technology, it is still a challenge to predict who is at increased risk for severe disease at the time of admission. The clinical examination in the rst 24-hour period of hospitalization has poor sensitivity and reliability, which implicates the need for scoring systems to stratify patients. The most popular scoring systems to determine the severity of AP include RANSONs criteria, APACHE II, CTSI, and Bedside Index for Severity in AP (BISAP) criteria. BISAP is the newest of the scoring systems and it has been recently validated.118 APACHE II has the advantage of being used at the time of admission and thus has been preferred so far.119 RANSONs criteria were the rst clinically relevant criteria proposed in 1974. It has 11 variables: 5 of these are measured during admission and the remaining at 48 hours postadmission. The variables used at admission include age 55 years, white blood cell count 16,000 cells/mm3, blood glucose 200 mg/dl, serum aspartate aminotransferase 250 IU/L, and serum lactate dehydrogenase 350 IU/L. The variables measured at 48 hours include serum calcium 8 mg/dL, 10% fall in hematocrit, hypoxemia with PO2 60 mm Hg, blood urea nitrogen increased by 1.8 mmol/L or more after rehydration, base decit 4 mEq/L, and the sequestration of uids 6 L. One point is given for each criterion and the presence of more than 3 criteria at 48 hours is associated with increased mortality.120 A score of less than 3 points has a predicted mortality of less than 1%, 3-4 points a 16% predicted mortality, 5-6 points a 40% mortality, and more than 6 points a 100% predicted mortality.120 The greatest disadvantage is that it can assess the severity of the disease only after 48 hours after admission. APACHE II scoring was developed in 1985 to predict the severity.121 It measures 12 physiological parameters and additional points for age and underlying medical conditions. The parameters used include rectal temperature, mean arterial pressure, heart rate, respiration rate, FiO2, arterial pH, serum sodium, serum potassium, serum creatinine, hematocrit, and white cell blood count. It can be applied at the time of admission and measuring the score daily is useful to assess the progression of the disease.122 A score of more than or equal to 8 points predicts 11% to 18% mortality. Because obesity is a risk factor for severe disease and increased mortality, it was included in APACHE II and called APACHE-O.123,124
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TABLE 9. Comparison between the scoring systems Criteria Ranson 3 at 48 h186 APACHE 8 at admission186 CTSI 3 at admission187 BISAP187 Sensitivity 75% 65% 87% 38% Specicity 77% 76% 83% 92% Positive predictive value 49% 43% 53% 58% Negative predictive value 91% 89% 97% 84%

CTSI, computed tomography severity index; BISAP, bedside index for severity in AP.

Systemic inammatory response syndrome (SIRS) is associated with a signicant increase in mortality among AP patients. Patients with persistent SIRS 48 hours into admission had a mortality rate of 25.4% compared to 8% in those with transient SIRS and 0.7% in the absence of SIRS.125 The presence of one or more organ failure has increasingly been recognized as one of the predictors of mortality of AP. The most widely used scores to assess organ dysfunction in critically ill patients are multiple organ dysfunction score (MODS) and sequential organ failure assessment (SOFA). As most of the above scoring systems are complicated or cannot be used at the time of admission, a new mortality-based scoring system called the BISAP scoring system was derived and validated.118 This BISAP scoring was compared with APACHE II and found to be equally effective in predicting mortality rates in patients with AP. There was no signicant difference in the predictive accuracy of the BISAP score and the APACHE II score (Table 9). The BISAP score consists of the following variables: Blood urea nitrogen level greater than 25 mg/dL; Impaired mental status; Systemic inammatory response syndrome; Age older than 60 years; Pleural effusion.

Each point on the BISAP score is worth 1 point. There is a steady increase in the risk for mortality with an increasing number of points: 0 1 2 3 4 5 points: observed mortality rate of 0.1% point: observed mortality rate of 0.4% points: observed mortality rate of 1.6% points: observed mortality rate of 3.6% points: observed mortality rate of 7.4% points: observed mortality rate of 9.5%
121

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In addition, there are several individual parameters that predict increased risk for severe AP. They include body mass index 30, age 70 years, and CRP 150 mg/L at 48 hours.

Differential Diagnosis
The differential diagnosis for AP should include the following disorders: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Peptic ulcer disease, especially perforated viscus Acute cholecystitis and biliary colic Acute intestinal obstruction Mesenteric vascular occlusion Ureteric or renal colic Acute myocardial infarction Dissecting aortic aneurysm Connective tissue disorders with vasculitis Pneumonia Diabetic ketoacidosis

Peptic Ulcer Disease, Especially Perforated Viscus

The pain of peptic ulcer disease may be exactly the same in distribution, mimicking pancreatitis; however, a perforated duodenal ulcer is readily diagnosed by the presence of free intraperitoneal air. The patients suspected to have gut perforation should have emergent plain and upright lms, water-soluble contrast studies of the gut, and/or CT scanning.

Acute Cholecystitis and Biliary Colic

The pain of biliary tract origin is more right-sided than periumbilical and is gradual in onset; ileus is usually absent. Serum amylase may be elevated in either condition. Sonography and radionuclide scanning are helpful in establishing the diagnosis of cholelithiasis and cholecystitis.

Acute Intestinal Obstruction

Intestinal obstruction because of mechanical factors can be differentiated from pancreatitis by the history of colicky pain, ndings on abdominal examination, and x-rays of the abdomen showing changes characteristic of mechanical obstruction.

Mesenteric Vascular Occlusion

Acute mesenteric vascular occlusion is suspected in the elderly patient with brisk leukocytosis, abdominal distention, and bloody diarrhea.
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Angiography would show vascular occlusion if present. However, serum amylase levels would be increased in both these conditions.

Ureteric or Renal Colic

Renal colic pain usually starts as a colicky pain radiating from the loin to the groin along with urinary symptoms. The presence of hematuria favors the diagnosis of ureteric colic rather than pancreatitis.

Connective Tissue Disorders with Vasculitis

Systemic lupus erythematosus and polyarteritis nodosa may be confused with pancreatitis, especially because pancreatitis may develop as a complication of these diseases. Other systemic signs, such as skin and joint features, help distinguish these conditions.

Acute Myocardial Infarction

Acute myocardial infarction, especially inferior wall infarction, might present as epigastric or periumbilical pain. Electrocardiographic changes and elevated cardiac enzymes clearly differentiate the conditions.

Dissecting Aortic Aneurysm

An elderly patient might have similar abdominal pain in a dissecting abdominal aortic aneurysm. However, elevation of enzymes amylase and lipase is unlikely.

Pneumonia
Lower lobe pneumonia might present with abdominal pain, which is often in the right or left hypochondriac region. Patients with pneumonia have respiratory symptoms, leukocytosis, and chest radiological features.

Diabetic Ketoacidosis
Diabetic ketoacidosis is often accompanied by abdominal pain and elevated total serum amylase levels, thus closely mimicking AP. However, the serum lipase level is not elevated in diabetic ketoacidosis.

Principles in Management of AP
The main goals in the management of AP are adequate uid resuscitation and the prevention of organ failure. Failure to do so increases the risk of pancreatic necrosis and multiple organ failure. Hypovolemia can impair the pancreatic microcirculation, resulting in further pancreatic damage. Another implication of hypovolemia is intestinal ischemia, causing bacterial translocation and release of cytokines, which can result in pancreatic infection and inammation, respectively. Monitoring vital signs with pulse oximetry at
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least every 4 hours is crucial in the rst 24 hours, especially when the patient is receiving parenteral narcotics. Supplemental oxygen in the rst 24 to 48 hours is also necessary.

Level of Care
Once the diagnosis of AP is made, triaging the patient to the proper unit is very important. Evidence of organ failure, such as sustained hypoxemia, hypotension refractory to intravenous uid boluses, renal insufciency (creatinine 2 mg/dL), persistent tachycardia (120/min), urine output 50 mL/h, encephalopathy, and increasing need for intravenous narcotics warrant an intensive care unit transfer.

Fluid Therapy
Fluid therapy is the cornerstone in the management of AP. Hemoconcentration (Hct 44) is a marker of poor prognosis and indicates the need for uid resuscitation. Crystalloids (Ringer lactate or normal saline) are the most commonly used uid for resuscitation. The rst 48 to 72 hours after onset after admission is the crucial period. The amount and rate of uids should be determined by the factors like urine output, vital signs, and serial hematocrit.126

Nutrition
AP is a hyperdynamic, hypermetabolic state that results in increased protein catabolism, increased ureagenesis, glucose intolerance, and increased lipolysis. This results in negative nitrogen balance, resulting in increased mortality.127 In mild pancreatitis the inammation resolves within 5-7 days and the patient can resume oral intake. However, in severe pancreatitis and pancreatic necrosis, this process of healing takes a longer time, which limits oral intake.128In the past, parenteral nutrition was used increasingly in severe pancreatitis, which prevented pancreatic stimulation but was associated with higher incidence of metabolic and electrolyte disturbances.129 Total parenteral nutrition (TPN) is also associated with hyperglycemia and catheter-related sepsis.107 In critically ill patients the gastrointestinal tract serves as a potential source of immunoinammatory process as the gut absorbs the endotoxins and bacterial products, resulting in the stimulation of endogenous cytokines.130 This forms the basis for initiating early enteral nutrition in severe AP to preserve the gut barrier.131 The 2010 Cochrane review by Al-Omran et al. showed that enteral nutrition when compared with parenteral nutrition was associated with signicant reduction in mortality, multiorgan failure, operative interventions, and systemic infections.132
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The risk of pancreatic stimulation is overcome by feeding via nasojejunal tube and thus delivering the tube feeds beyond the ligament of Treitz into the jejunum. Trouble might arise with enteral nutrition when there is a proximal tube migration, resulting in pancreatic stimulation and ileus. The 3 major categories of tube feeds include elemental/semielemental, polymeric, and immunoenhanced.133 Elemental feeds have a theoretical advantage of superior intestinal absorption, lesser pancreatic stimulation, and better tolerance.134 The recent Cochrane review by Petrov et al. in 2009 showed no signicant feeding intolerance between elemental and polymeric tube feeds.133 Polymeric feeds are cheaper than elemental feeds. Also, the polymeric feeds signicantly decreased the infectious complication and mortality rates, similar to elemental tube feeds. The immunoenhanced feeds specically contain glutamine, arginine, and omega-3 fatty acids. So far, there is no evidence to use immunoenhanced feeds or probiotics. The ber-enhanced formulas have a lower incidence of diarrhea when compared with the elemental feeds.135

Analgesia
According to the 2006 ACG practice guidelines, the pain in AP should be managed with parenteral narcotics. The most commonly used medications are hydromorphone, morphine, meperidine, and fentanyl. There is no proven superiority of one medication over the other. The dose and frequency of administration should be adjusted according to the pain. Patient-controlled analgesia can be used if needed. The vital signs and pulse-oximetry should be monitored at least every 4 hours when using narcotics.4

Pharmacologic Agents in AP
Somatostatin/Octreotide. Somatostatin is a peptide that is produced in the gastrointestinal tract and has an inhibitory action on gastrointestinal motility and pancreatic secretion. Octreotide is the pharmacologic analogue of somatostatin. Studies have shown no signicant difference in the treatment outcomes with octreotide.136 A meta-analysis done in 2007 by Andriulli et al.137 did not show any benet of octreotide in preventing PEP but it did not include a study published in 2007 by Li et al., which showed a reduced incidence of PEP with octreotide.138 Gabexate. Gabexate is a protease inhibitor that could decrease physiologically the production of pancreatic enzymes. There is a difference of opinion in the use of gabexate between different societies. The ACG guidelines do not recommend it in the treatment of AP, whereas the Japanese
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guidelines recommend its use for both mild and severe pancreatitis.139 It is also widely used in certain countries for prophylaxis of PEP.140 N-Acetylcysteine (NAC). NAC is an antioxidant that theoretically can reduce the oxidative stress in the early phases of AP and thus reduce pancreatic injury. So far, studies show no benet of NAC in either treatment or prophylaxis.141 Corticosteroids/Nonsteroidal Anti-Inammatory Drugs (NSAID). Steroid is a nonspecic anti-inammatory agent, whereas NSAIDs have analgesic as well as anti-inammatory properties. There is no evidence for the use of steroids in the treatment or prophylaxis of AP. However, steroids are the mainstay in the treatment of autoimmune pancreatitis, which is a form of chronic pancreatitis. Interestingly NSAIDs (indomethacin, diclofenac) have been shown to decrease the incidence of PEP when compared with placebo in a select group of patients undergoing pancreatic duct injection. When used in the treatment of AP, the NSAID group demanded less opiates as analgesics during hospitalization.142 Interleukin-10. IL-10 is an anti-inammatory cytokine produced by the T-helper cells. There is no evidence for its use in either treatment or prophylaxis of AP. Tumor Necrosis Factor (TNF)- Inhibitors. TNF- is produced in the macrophages of secretory acinar cells and is involved in mediating the inammatory process. There are no human studies done so far using TNF inhibitors. One of main reasons for this is the higher risk of bacterial infection in patients with AP. A study done in acute alcoholic hepatitis using iniximab showed increased rates of bacterial infection and mortality, so the study had to be prematurely terminated.143 Probiotics. Intestinal permeability is increased in AP and the probiotics are believed to exert benecial effects by replenishing the gut ora, thereby preventing bacterial infection. So far there is no strong evidence in the use of probiotics in AP.144

Role of ERCP and Biliary Sphincterotomy in AP

ERCP is a useful tool in the diagnosis and management of AP. The main role of ERCP is in gallstone disease and other etiologies that cause pancreatic duct obstruction like pancreatic divisum, sphincter of Oddi dysfunction, and occult tumors. Gallstones are the most common cause of AP in the western world, accounting for one-half of the cases. Most of the stones cause transient obstruction and pass into duodenum spontaneously. Pancreatic edema and necrosis occur when there is a persistent ampullary obstruction because of impacted stone or peri-ampullary edema. Urgent ERCP is in indicated in patients who fail to demonstrate improvement in
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bilirubin by 24 to 48 hours after admission, show persistent choledocholithiasis on imaging, or have cholangitis.145 Recurrence of pancreatitis after ERCP with sphincterotomy for gallstone pancreatitis is rare. Cholecystectomy vs ERCP with sphincterotomy is a controversial topic. In general, cholecystectomy is performed if the patient is a surgical candidate. Selective postcholecystectomy ERCP is performed if choledocholithiasis is found intraoperatively.146 Microlithiasis or biliary sludge as a cause of pancreatitis is still controversial. Microlithiasis is a viscous precipitate of mucin, cholesterol, and calcium bilirubinate found in biliary sludge. Ultrasound is only 55% sensitive in detecting biliary sludge.147 Bile analysis with microscopic examination is the gold standard in diagnosing microlithiasis. It can be done by ERCP with bile aspirate, which is 83% sensitive. ERCP is usually performed 4 to 6 weeks after the episode of AP when microlithiasis is suspected as the culprit.148 Pancreatic divisum is found in 7% to 10% of the population. It is associated with increased prevalence of pancreatitis. The role of ERCP is mainly therapeutic using sphincterotomy with or without pancreatic duct stent placement, which reduced the recurrence rate of pancreatitis.149 SOD is the abnormality in sphincter of Oddi contractility, resulting in intermittent biliary and pancreatic duct obstruction. It is the cause of pancreatitis in nearly one-third of recurrent unexplained pancreatitis. If SOD is suspected, sphincter of Oddi manometry is done. A resting pressure more than 40 mm Hg is the best predictor of response to endoscopic sphincterotomy.146 ERCP is also useful in the diagnosis of ampullary and intraductal papillary mucinous tumors. Pancreatic duct stent placement helps in relieving the obstruction.

Complications
Local Complications
Pancreatic uid collections Pancreatic abscess Pancreatic pseudocyst Pancreatic ascites Pancreatic necrosis Intraperitoneal hemorrhage Thrombosis of blood vessels (splenic vein, portal vein) Bowel infarction Obstructive jaundice
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Systemic Complications
Cardiovascular Hypotension/hypovolemia Sudden cardiac death Nonspecic ST-T changes Pericardial effusion Pulmonary Pleural effusion Pneumonitis Atelectasis Adult respiratory distress syndrome (ARDS) Gastrointestinal Peptic ulcer disease/hemorrhage Hemorrhagic pancreatic necrosis with erosion into major blood vessels Portal vein thrombosis, variceal hemorrhage Renal Oliguria/azotemia Renal artery and/or renal vein thrombosis Acute tubular necrosis Hematologic Disseminated intravascular coagulation Thrombosis Metabolic Hyperglycemia Hypocalcemia Hypertriglyceridemia Fat emboli Sudden blindness (Purtschers retinopathy) Central nervous system Encephalopathy Psychosis In the rst 2-3 weeks after AP, patients can develop an inammatory mass, which may be due to organized pancreatic necrosis (with or without infection) or a pseudocyst. Pancreatic abscess develops later, usually after 6 weeks.
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Pancreatic Fluid Collections. Approximately up to 57% of patients who are hospitalized with AP develop uid collections, with 39% having 2 areas involved and 33% having 3 or more areas involved. Fluid collections that are initially ill-dened evolve over time and are usually managed conservatively. If the uid collections continue to enlarge, cause pain, become infected (as suggested by the presence of unexplained fever, leukocytosis, or gas in the uid collection), or compress adjacent organs, then medical, endoscopic, or surgical intervention may be needed. Fluid collections with very high levels of pancreatic enzymes are usually associated with pancreatic-duct disruptions and may eventually form pseudocysts (usually over a period of several weeks), ascites, or pleural effusions. Pancreatic Pseudocysts. Pseudocysts of the pancreas are collections of tissue, uid, debris, pancreatic enzymes, and blood that develop over a period of 4 to 6 weeks after the onset of AP; they form in 15% of patients with AP. In contrast to true cysts, pseudocysts do not have an epithelial lining, their walls consist of necrotic tissue, granulation tissue, and brous tissue. Pseudocysts are usually preceded by pancreatitis in 90% of cases and by trauma in 10%. Almost 85% are located in the body or tail of the pancreas and 15% are located in the head. The usual presenting symptom is abdominal pain. A palpable, tender mass may be found in the middle or left upper abdomen. The serum amylase level is elevated in 75% of patients at some point during their illness and may uctuate markedly. Ultrasound is reliable in diagnosing pseudocysts. Ultrasound also permits differentiation between an edematous, inamed pancreas, which can give rise to a palpable mass, and an actual pseudocyst. Furthermore, serial ultrasound studies will indicate whether a pseudocyst has resolved. CT complements ultrasonography in the diagnosis of pancreatic pseudocyst, especially when the pseudocyst is infected.150 Asymptomatic pseudocysts can be managed conservatively, whereas symptomatic pseudocysts can often be drained endoscopically.151 In earlier studies with ultrasound, pseudocysts were seen to resolve in 25% to 40% of patients. Pseudocysts that are more than 5 cm in diameter may persist for more than 6 weeks. Recent studies suggest that a noninterventional, expectant management is the best course in selected patients who are minimally symptomatic, do not have evidence of active alcohol usage, and have a mature-looking pseudocyst, not resembling a cystic neoplasm radiographically. The old teaching that cysts of more than 6 cm in diameter that have been present for 6 weeks should be drained is no longer true. Indications for drainage are the presence of symptoms, enlargement of cyst, complications (infection, hemorrhage, rupture, and obstruction), and suspicion of malignancy. The available forms of therapy include percutaneous drainDM, March 2012 129

age, transendoscopic approach, and surgery, which may be open or laparoscopic. The choice of procedure depends on several factors including the general condition of the patient; size, number, and location of cysts; presence or absence of communication of the cyst with the pancreatic duct; presence or absence of infection; and suspicion of malignancy. Expertise of the radiologist and the endoscopist is also a major deciding factor in the choice of therapy.152 A signicant number of these pseudocysts resolve spontaneously more than 6 weeks after their formation. Also, these studies demonstrate that initial large pseudocyst size is not an absolute indication for interventional therapy and that many peripancreatic uid collections detected on CT in cases of AP resolve spontaneously. A pseudocyst that does not resolve spontaneously may lead to serious complications such as (1) pain caused by expansion of the lesion and pressure on other viscera, (2) rupture, (3) hemorrhage, and (4) abscess. Rupture of a pancreatic pseudocyst is a serious complication following which shock almost always supervenes, and mortality rates range from 14% if the rupture is not associated with hemorrhage to more than 60% if hemorrhage has occurred. Rupture and hemorrhage are the prime causes of death from pancreatic pseudocyst. The possibility of hemorrhage from a pseudocyst exists in the presence of the triad of ndings: an increase in the size of the mass, a localized bruit over the mass, and a sudden decrease in hemoglobin level and hematocrit without obvious external blood loss. Thus, in patients who are stable and free of complications and in whom serial sonographic studies show that the pseudocyst is shrinking, conservative therapy is indicated. Conversely, if the pseudocyst is expanding and is complicated by rupture, hemorrhage, or abscess, operation should be performed on the patient. Furthermore, it is clear that, in the acute stage of pancreatitis, the size of the pseudocyst is not in itself a predictor of invasive treatment and the growth of the pancreatic pseudocysts during follow-up is the strongest predictor of the need for invasive treatment in both acute and chronic cases.126 With ultrasound or CT guidance, sterile chronic pseudocysts can be treated safely with single or repeated needle aspiration or more prolonged catheter drainage with a success rate of 45% to 75%. The success rate of these techniques for infected pseudocysts is considerably less (40% to 50%). Patients who do not respond to drainage require surgical therapy for internal or external drainage of the cyst.

Pancreatic Necrosis
In the international symposium on AP in 1992, pancreatic necrosis was dened as the presence of one or more focal or diffuse areas of nonviable
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pancreatic parenchyma.5 Contrast-enhanced CT scan is the gold standard for diagnosing pancreatic necrosis with 90% accuracy.116 The extent of necrosis is predictive of the risk of infection.153 Approximately one-third of patients with AP develop necrotizing pancreatitis, of which 30% develop infected necrosis. Infected necrosis has a high mortality rate of 30% vs a 12% mortality rate for sterile necrosis. Therefore, differentiating between sterile necrosis and infected necrosis is crucial. Fine-needle aspiration with Gram stain and culture is the recommended method to diagnose infection.4 In a small percentage of patients CT scan can diagnose infection by identifying gas within the necrotic pancreas.154 Uncommonly a large area of necrotic pancreas may be mistaken as a pseudocyst on CT. Placement of a percutaneous or endoscopic tube in such collections will not achieve drainage and will instead just convert an uninfected necroma into an infected necrosis. It is recommended that patients with infected necrosis be managed in centers with specialist units with appropriate endoscopic, radiologic, and surgical expertise.107

Antibiotic Prophylaxis for Pancreatic Necrosis

In the 2010 Cochrane review on antibiotic prophylaxis against infection of pancreatic necrosis there was no statistically signicant effect on the reduction of mortality, infection of pancreatic necrosis, nonpancreatic infection rate, incidence of overall infection, operative treatment, and fungal infection with the antibiotic prophylaxis.155 In a subgroup analysis, the -lactam group had less mortality (9.4% treatment, 15% controls), and less infected pancreatic necrosis (16.8% treatment group, 24.2% controls) but both were not statistically signicant. Imepenem on its own showed no difference in the mortality rates, but there was a signicant reduction in the rate of pancreatic infection (P 0.02, relative risk 0.34, 95% condence interval 0.13 to 0.84).155 However none of these studies were adequately powered. The 2007 American Gastroenterology Association guidelines stated that antibiotic prophylaxis should be restricted to patients with substantial pancreatic necrosis (30% of the gland necrotic by CT criteria) and should not be continued for more than 14 days. Antibiotic therapy should be based on the microbiology obtained from ne-needle aspiration because overuse of broad spectrum antibiotics is associated with an increased risk of resistant organism and fungal superinfection.

Diagnosis of Pancreatic Necrosis

The key aspect of the management of pancreatitis is the recognition of the severity of pancreatitis early enough to allow proper triage of the patient to the intensive care unit. This is determined using severity scores
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involving clinical, laboratory, and radiological parameters. APACHE II score 8, C-reactive protein 150 mg/dL, and hematocrit 44 have been identied as predictors of severe pancreatitis requiring intensive resuscitation and management. Contrast-enhanced CT is the imaging test of choice to diagnose and assess the severity of pancreatitis.112

Management of Pancreatic Necrosis

The surgical indications of pancreatic necrosis include infection, persistent symptomatic uid collections, and worsening clinical status with ongoing organ failure in the absence of documented infection.156 Infected pancreatic necrosis without intervention is associated with 100% mortality, whereas with surgery there is 25% mortality. Delayed surgical interventions (2 weeks) have reduced mortality when compared with early surgery.157 Open necrosectomy is the gold standard procedure but is associated with increased mortality, complications, and pancreatic insufciency.157 In recent years, minimally invasive techniques have evolved, especially in tertiary care centers. Techniques include percutaneous interventional drainage, endoscopic approach, laparoscopic approach, and the retroperitoneal approach.158 The percutaneous approach can avoid surgery in critically ill patients and the drainage of the infected uid promotes healing. The disadvantages are the need for repeated drainage and risk of stula formation. The failure rate is around 31% to 87%.159 The endoscopic approach is again used in poor surgical candidates and has a lesser risk of stula formation. The disadvantages are bleeding risk, need for repeated procedures, waiting for walled off pancreatic necrosis, and limited accessibility only to areas near the gastric and medial duodenal wall.160 The laparoscopic approach is more invasive with the risk of pneumoperitoneum and infection but has the advantage of the complete removal of the sequestrum.161 The retroperitoneal approach has an advantage of direct access with complete removal of the sequestrum and less infection and bleeding risk with the opportunity for subsequent liqueed necrosis drainage by gravity.162 The pancreatitis, necrosectomy versus step up approach (PANTER) trial published by the Dutch Pancreatitis Group in 2010 compared the step-up approach with open necrosectomy. The step-up approach is dened as the use of percutaneous drainage followed, if necessary, by the video-assisted retroperitoneal drainage. The result was that the arm with the step-up approach had lower major complications and death when compared with open necrosectomy.163
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Pseudoaneurysms
Pseudoaneurysms develop in almost 10% of patients with AP at locations in accordance to the distribution of pseudocysts and uid collections. The splenic artery is most frequently involved, followed by the inferior and superior pancreatic duodenal arteries. When patients with pancreatitis develop upper gastrointestinal bleeding without an obvious cause or in whom thin-cut CT scanning reveals a contrast-enhanced lesion within or adjacent to a suspected pseudocyst, pseudoaneurysms are suspected. Arteriography is necessary to conrm the diagnosis and allow treatment.164-167 ERCP may help to dene the anatomy of the pancreatic duct and identify any duct disruptions to guide further intervention.2

Systemic Complications
Systemic complications include cardiovascular, pulmonary, gastrointestinal, renal, hematologic, metabolic, and central nervous system abnormalities (as listed above). Numerous theories were described explaining the pathogenesis of complications. The severe inammatory state of pancreatitis induces a surge of vasoactive peptides such as bradykinin. Vasoactive peptides have been postulated to cause myocardial depression, vasodilatation, shock and even sudden cardiac death. Pulmonary complications include atelectasis, pleural effusion and ARDS. The majority of patients develop atelectasis during an early stage when the abdominal symptoms are acute, causing diaphragmatic impairment. Presence of pleural effusion is one of the prognostic markers (eg, BISAP scoring) indicating the severity of pancreatitis. The main causes of pleural effusion include transdiaphragmatic lymphatic blockage and pancreaticopleural stulae secondary to disruption of the pancreatic duct. The most serious pulmonary complication is ARDS which results from an increase in proinammatory cytokines and/or microvascular thrombosis. A significant proportion of patients develop adynamic ileus presenting with constipation or obstipation. Other notable gastrointestinal complications include pancreatic ascites and gastrointestinal hemorrhage. The volume depleted state in AP predispose to acute kidney injury. In the background of severe intravascular dehydration, patients are prone to develop venous thrombosis and sometimes even arterial thrombosis. The breakdown of free fatty acids and the resulting lipotoxicity causes multiorgan dysfunction syndrome and worsens acute pancreatitis in obese individuals. Gut mucosa also play an important role in the development of multiorgan dysfunction syndrome. Multiorgan dysDM, March 2012 133

function syndrome and severe inammatory state could trigger disseminated intravascular coagulation as well. Complex interactions in pancreatic enzymes, free fatty acids and calcium results in calciumsoap formation leading to hypocalcemia. Insulin requiring hyperglycemia and hypertriglyceridemia are well known metabolic complications. In rare occasions, patients develop fat emboli with or without retinal complications (Purtschers retionopathy) which may present as sudden blindness. Pancreatic encephalopathy is a serious neurological complication and considered to be a poor prognostic sign.

AP in Children
AP is not very common in children as compared to the adult population; however, it accounts for signicant morbidity and mortality. Recent studies indicate that the incidence of AP is increasing in number in children and adolescents.168 This has been attributed to increasing physician awareness and advances in imaging modalities but the actual reason for the increase in incidence still remains unclear.2 AP occurs in all age groups, including infants.169 The pathophysiology and clinical features are similar to that of adult disease. In children, blunt abdominal injuries, biliary stones, systemic illnesses, drugs, and toxins are the most common etiologies regardless of age. However, in children less than 3 years of age trauma is a less frequent cause. Many patients are classied as idiopathic.169 Gallstone pancreatitis is probably much more common in adolescents than previously thought. Juvenile tropical pancreatitis is a form of chronic pancreatitis usually seen in young children of both sexes residing in tropical climates of developing countries, such as Asia and sub-Saharan Africa. It is usually associated with malnutrition and leads to pancreatic calcication, steatorrhea, and diabetes mellitus.170 Hereditary pancreatitis is an autosomal-dominant disorder and is linked to the chromosome 7q35. It manifests initially in either infancy or adolescence and progresses to chronic pancreatitis.171 The measurements of serum lipase and amylase levels are not well studied in children, unlike in adults. However, serum lipase levels tend to be more specic than serum amylase levels and remain elevated for as long as 1 to 2 weeks. In 10% to 15% of children the serum amylase levels can be normal. In infants and toddlers sometimes the serum lipase levels are elevated and the serum amylase levels are normal. This can be explained by the late expression of pancreatic isoamylase.172 Therefore, both tests need to be performed to diagnose AP. Imaging and management of AP are similar to that of the adult population. Feeding is commenced once vomiting and pain are under
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control. Complete recovery typically takes between 4 and 5 days. About 13% to 20% of children have a prolonged hospital stay because of the disease process and associated complications.173 In children with gallstone pancreatitis the mainstay of treatment is removal of the offending stones. ERCP is the preferred method. Post procedure pancreatitis is the most common complication of ERCP. About 13% to 16% of patients develop pseudocyst and uid collections in the peripancreatic space, making them the most common complication encountered in children.174 In general prognosis is excellent. Depending on the age, etiology and associated complications prognosis differ. Severe pancreatitis is rare in children less than 3 years of age.169 The mortality rate with AP is about 20%. About 10% of children suffer another attack of pancreatitis after the initial episode. Multiple episodes occur in very few patients. Structural abnormalities, genetic causes, and idiopathic pancreatitis are the most common etiologies in this category. Appropriate investigations are necessary to diagnose and prevent repeated attacks and complications.168 Genetic testing to detect cystic brosis transmembrane conductance regulator mutations is useful especially if there is a strong family history of cystic brosis.175

Acknowledgments
The authors thank Anil Dasyam, MD, Department of Radiology, University of Pittsburgh; Dorothea M.G. Wild, MD, MPH, Yale University School of Medicine and Public Health; and Nisha Chawla, medical student, Richard Ivey School of Business, University of Western Ontario.

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