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Acute Pancreatitis
Updated: Jul 25, 2019
Author: Jeffrey C F Tang, MD; Chief Editor: BS Anand, MD

Overview

Practice Essentials
Recognizing patients with severe acute pancreatitis as soon as possible is critical for achieving optimal outcomes. Management
depends largely on severity. Medical treatment of mild acute pancreatitis is relatively straightforward. Treatment of severe acute
pancreatitis involves intensive care. Surgical intervention (open or minimally invasive) is indicated in selected cases.

Signs and symptoms

Symptoms of acute pancreatitis include the following:

Abdominal pain (cardinal symptom): Characteristically dull, boring, and steady; usually sudden in onset and gradually
becoming more severe until reaching a constant ache; most often located in the upper abdomen and may radiate directly
through to the back

Nausea and vomiting, sometimes with anorexia

Diarrhea

Patients may have a history of the following:

Recent operative or other invasive procedures

Family history of hypertriglyceridemia

Previous biliary colic and binge alcohol consumption (major causes of acute pancreatitis)

The following physical findings may be noted, varying with the severity of the disease:

Fever (76%) and tachycardia (65%); hypotension

Abdominal tenderness, muscular guarding (68%), and distention (65%); diminished or absent bowel sounds

Jaundice (28%)

Dyspnea (10%); tachypnea; basilar rales, especially in the left lung

In severe cases, hemodynamic instability (10%) and hematemesis or melena (5%); pale, diaphoretic, and listless
appearance

Occasionally, extremity muscular spasms secondary to hypocalcemia

The following uncommon physical findings are associated with severe necrotizing pancreatitis:

Cullen sign (bluish discoloration around the umbilicus resulting from hemoperitoneum)

Grey-Turner sign (reddish-brown discoloration along the flanks resulting from retroperitoneal blood dissecting along
tissue planes); more commonly, patients may have a ruddy erythema in the flanks secondary to extravasated pancreatic
exudate
 Erythematous skin nodules, usually no larger than 1 cm and typically located on extensor skin surfaces; polyarthritis

See Presentation for more detail.

Diagnosis

Once a working diagnosis of acute pancreatitis is reached, laboratory tests are obtained to support the clinical impression, such
as the following:

Serum amylase and lipase

Liver-associated enzymes

Blood urea nitrogen (BUN), creatinine, and electrolytes

Blood glucose

Serum cholesterol and triglyceride

Complete blood count (CBC) and hematocrit; NLR

C-reactive protein (CRP)

Arterial blood gas values

Serum lactic dehydrogenase (LDH) and bicarbonate

Immunoglobulin G4 (IgG4)

Diagnostic imaging is unnecessary in most cases but may be obtained when the diagnosis is in doubt, when pancreatitis is
severe, or when a given study might provide specific information required. Modalities employed include the following:

Abdominal radiography (limited role): Kidneys-ureters-bladder (KUB) radiography with the patient upright is primarily
performed to detect free air in the abdomen

Abdominal ultrasonography (most useful initial test in determining the etiology, and is the technique of choice for
detecting gallstones)

Endoscopic ultrasonography (EUS) (used mainly for detection of microlithiasis and periampullary lesions not easily
revealed by other methods)

Abdominal computed tomography (CT) scanning (generally not indicated for patients with mild pancreatitis but always
indicated for those with severe acute pancreatitis)

Endoscopic retrograde cholangiopancreatography (ERCP); to be used with extreme caution in this disease and never as
a first-line diagnostic tool[1]

Magnetic resonance cholangiopancreatography (MRCP) (not as sensitive as ERCP but safer and noninvasive)

Other diagnostic modalities include the following:

CT-guided or EUS-guided aspiration and drainage

Genetic testing

Acute pancreatitis is broadly classified as either mild or severe. According to the Atlanta classification, severe acute pancreatitis
is signaled by the following[2] :

Evidence of organ failure (eg, systolic blood pressure below 90 mm Hg, arterial partial pressure of oxygen [Pa O2] 60
mm Hg or lower, serum creatinine level 2 mg/dL or higher, GI bleeding amounting to 500 mL or more in 24 hours)

Local complications (eg, necrosis, abscess, pseudocyst)

Ranson score of 3 or higher or APACHE score of 8 or higher

See Workup for more detail.

Management
Medical management of mild acute pancreatitis is relatively straightforward; however, patients with severe acute pancreatitis
require intensive care.

Initial supportive care includes the following:

Fluid resuscitation[3]

Nutritional support

Antibiotic therapy is employed as follows:

Antibiotics (usually of the imipenem class) should be used in any case of pancreatitis complicated by infected pancreatic
necrosis but should not be given routinely for fever, especially early in the presentation

Antibiotic prophylaxis in severe pancreatitis is controversial; routine use of antibiotics as prophylaxis against infection in
severe acute pancreatitis is not currently recommended

Surgical intervention (open or minimally invasive) is indicated when an anatomic complication amenable to a mechanical
solution is present. Procedures appropriate for specific conditions involving pancreatitis include the following:

Gallstone pancreatitis: Cholecystectomy

Pancreatic duct disruption: Image-guided percutaneous placement of a drainage tube into the fluid collection[4] ; stent or
tube placement via ERCP; in refractory cases, distal pancreatectomy or a Whipple procedure

Pseudocysts: None necessary in most cases; for large or symptomatic pseudocysts, percutaneous aspiration,
endoscopic transpapillary or transmural techniques, or surgical management

Infected pancreatic necrosis: Image-guided aspiration; necrosectomy

Pancreatic abscess: Percutaneous catheter drainage and antibiotics; if no response, surgical debridement and drainage

See Treatment and Medication for more detail.

Background
This article focuses on the recognition and management of acute pancreatitis. Pancreatitis is an inflammatory process in which
pancreatic enzymes autodigest the gland. The gland sometimes heals without any impairment of function or any morphologic
changes; this process is known as acute pancreatitis. Pancreatitis can also recur intermittently, contributing to the functional and
morphologic loss of the gland; recurrent attacks are referred to as chronic pancreatitis.

Both forms of pancreatitis may present in the emergency department (ED) with acute clinical findings. Recognizing patients with
severe acute pancreatitis as soon as possible is critical for achieving optimal outcomes (see Presentation).

Once a working diagnosis of acute pancreatitis is reached, laboratory tests are obtained to support the clinical impression, to
help define the etiology, and to look for complications. Diagnostic imaging is unnecessary in most cases but may be obtained
when the diagnosis is in doubt, when severe pancreatitis is present, or when an imaging study might provide specific information
needed to answer a clinical question. Image-guided aspiration may be useful. Genetic testing may be considered (see Workup).

Management depends largely on severity. Medical treatment of mild acute pancreatitis is relatively straightforward. Treatment of
severe acute pancreatitis involves intensive care; the goals of medical management are to provide aggressive supportive care,
to decrease inflammation, to limit infection or superinfection, and to identify and treat complications as appropriate. Surgical
intervention (open or minimally invasive) is indicated in selected cases (see Treatment).

Pathophysiology
Normal pancreatic function
The pancreas is a gland located in the upper posterior abdomen. It is responsible for insulin production (endocrine pancreas)
and the manufacture and secretion of digestive enzymes (exocrine pancreas) leading to carbohydrate, fat, and protein
metabolism. Approximately 80% of the gross weight of the pancreas supports exocrine function, and the remaining 20% is
involved with endocrine function. The focus of this article is on the exocrine function of the pancreas.

The pancreas accounts for only 0.1% of total body weight but has 13 times the protein-producing capacity of the liver and the
reticuloendothelial system combined, which together make up 4% of total body weight. Digestive 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, where they are secreted into the small intestine to begin the metabolic process.

In normal pancreatic function, up to 15 different types of digestive enzymes are manufactured in the rough endoplasmic
reticulum, targeted in the Golgi apparatus and packaged into zymogens as proenzymes. When a meal is ingested, the vagal
nerves, vasoactive intestinal polypeptide (VIP), gastrin-releasing peptide (GRP), secretin, cholecystokinin (CCK), and
encephalins stimulate release of these proenzymes into the pancreatic duct.

The proenzymes travel to the brush border of the duodenum, where trypsinogen, the proenzyme for trypsin, is activated via
hydrolysis of an N-terminal hexapeptide fragment by the brush border enzyme enterokinase. Trypsin then facilitates the
conversion of the other proenzymes into their active forms.

A feedback mechanism exists to limit pancreatic enzyme activation after appropriate metabolism has occurred. It is
hypothesized that elevated levels of trypsin, having become unbound from digesting food, lead to decreased CCK and secretin
levels, thus limiting further pancreatic secretion.

Because premature activation of pancreatic enzymes within the pancreas leads to organ injury and pancreatitis, several
mechanisms exist to limit this occurrence. First, proteins are translated into the inactive proenzymes. Later, posttranslational
modification of the Golgi cells allows their segregation into the unique subcellular zymogen compartments. The proenzymes are
packaged in a paracrystalline arrangement with protease inhibitors.

Zymogen granules have an acidic pH and a low calcium concentration, which are factors that guard against premature
activation until after secretion has occurred and extracellular factors have triggered the activation cascade. Under various
conditions, disruption of these protective mechanisms may occur, resulting in intracellular enzyme activation and pancreatic
autodigestion leading to acute pancreatitis.

Pathogenesis of acute pancreatitis

Acute pancreatitis may occur when factors involved in maintaining cellular homeostasis are out of balance. The initiating event
may be anything that injures the acinar cell and impairs the secretion of zymogen granules; examples include alcohol use,
gallstones, and certain drugs.

At present, it is unclear exactly what pathophysiologic event triggers the onset of acute pancreatitis. It is believed, however, that
both extracellular factors (eg, neural and vascular response) and intracellular factors (eg, intracellular digestive enzyme
activation, increased calcium signaling, and heat shock protein activation) play a role. In addition, acute pancreatitis can develop
when ductal cell injury leads to delayed or absent enzymatic secretion, as seen in patients with the CFTR gene mutation.

Once a cellular injury pattern has been initiated, cellular membrane trafficking becomes chaotic, with the following deleterious
effects:

Lysosomal and zymogen granule compartments fuse, enabling activation of trypsinogen to trypsin

Intracellular trypsin triggers the entire zymogen activation cascade

Secretory vesicles are extruded across the basolateral membrane into the interstitium, where molecular fragments act as
chemoattractants for inflammatory cells

Activated neutrophils then exacerbate the problem by releasing superoxide (the respiratory burst) or proteolytic enzymes
(cathepsins B, D, and G; collagenase; and elastase). Finally, macrophages release cytokines that further mediate local (and, in
severe cases, systemic) inflammatory responses. The early mediators defined to date are tumor necrosis factor-alpha (TNF-α),
interleukin (IL)-6, and IL-8.

These mediators of inflammation cause an increased pancreatic vascular permeability, leading to hemorrhage, edema, and
eventually pancreatic necrosis. As the mediators are excreted into the circulation, systemic complications can arise, such as
bacteremia due to gut flora translocation, acute respiratory distress syndrome (ARDS), pleural effusions, gastrointestinal (GI)
hemorrhage, and renal failure.

The systemic inflammatory response syndrome (SIRS) can also develop, leading to the development of systemic shock.
Eventually, the mediators of inflammation can become so overwhelming that hemodynamic instability and death ensue.
In acute pancreatitis, parenchymal edema and peripancreatic fat necrosis occur first; this is known as acute edematous
pancreatitis. When necrosis involves the parenchyma, accompanied by hemorrhage and dysfunction of the gland, the
inflammation evolves into hemorrhagic or necrotizing pancreatitis. Pseudocysts and pancreatic abscesses can result from
necrotizing pancreatitis because enzymes can be walled off by granulation tissue (pseudocyst formation) or via bacterial
seeding of pancreatic or peripancreatic tissue (pancreatic abscess formation).

Li et al compared two sets of patients with severe acute pancreatitis—one with acute renal failure and the other without it—and
determined that a history of renal disease, hypoxemia, and abdominal compartment syndrome were significant risk factors for
acute renal failure in patients with severe acute pancreatitis.[5] In addition, patients with acute renal failure were found to have a
significantly greater average length of stay in the hospital and in the intensive care unit (ICU), as well as higher rates of
pancreatic infection and mortality.

Etiology
Long-standing alcohol consumption and biliary stone disease cause most cases of acute pancreatitis, but numerous other
etiologies are known. In 10%-30% of cases, the cause is unknown, though studies have suggested that as many as 70% of
cases of idiopathic pancreatitis are secondary to biliary microlithiasis.

Biliary tract disease

One of the most common causes of acute pancreatitis in most developed countries (accounting for approximately 40% of cases)
is gallstones passing into the bile duct and temporarily lodging at the sphincter of Oddi. The risk of a stone causing pancreatitis
is inversely proportional to its size.

It is thought that acinar cell injury occurs secondary to increasing pancreatic duct pressures caused by obstructive biliary stones
at the ampulla of Vater, although this has not been definitively proven in humans. Occult microlithiasis is probably responsible for
most cases of idiopathic acute pancreatitis.

Alcohol

Alcohol use is a major cause of acute pancreatitis (accounting for at least 35% of cases[6] ). At the cellular level, ethanol leads
to intracellular accumulation of digestive enzymes and their premature activation and release. At the ductal level, it increases
the permeability of ductules, allowing enzymes to reach the parenchyma and cause pancreatic damage. Ethanol increases the
protein content of pancreatic juice and decreases bicarbonate levels and trypsin inhibitor concentrations. This leads to the
formation of protein plugs that block pancreatic outflow.

Most commonly, the disease develops in patients whose alcohol ingestion is habitual over 5-15 years. Alcoholics are usually
admitted with an acute exacerbation of chronic pancreatitis. Occasionally, however, pancreatitis can develop in a patient with a
weekend binging habit, and several case reports have described a sole large alcohol load precipitating a first attack.
Nevertheless, the alcoholic who imbibes routinely remains the rule rather than the exception for the development of pancreatitis.

Currently, there is no universally accepted explanation for why certain alcoholics are more predisposed to developing acute
pancreatitis than other alcoholics who ingest similar quantities.

Endoscopic retrograde cholangiopancreatography

Pancreatitis occurring after endoscopic retrograde cholangiopancreatography (ERCP) is probably the third most common type
(accounting for approximately 4% of cases). Whereas retrospective surveys indicate that the risk is only 1%, prospective studies
have shown the risk to be at least 5%.

The risk of post-ERCP acute pancreatitis is increased if the endoscopist is inexperienced, if the patient is thought to have
sphincter of Oddi dysfunction, or if manometry is performed on the sphincter of Oddi. Aggressive preintervention intravenous
(IV) hydration has been durably shown to prevent post-ERCP pancreatitis in randomized studies. More recently, rectal
indomethacin has been employed; it has been shown to reduce the incidence of post-ERCP pancreatitis and is now widely
accepted at most institutions. The literature continues to debate the role of rectal indomethacin.[7]

Trauma

Abdominal trauma (approximately 1.5%) causes an elevation of amylase and lipase levels in 17% of cases and clinical
pancreatitis in 5% of cases. Pancreatic injury occurs more often in penetrating injuries (eg, from knives, bullets) than in blunt
abdominal trauma (eg, from steering wheels, horses, bicycles). Blunt injury to the abdomen or back may crush the gland across
the spine, leading to a ductal injury.

Drugs

Considering the small number of patients who develop pancreatitis compared to the relatively large number who receive
potentially toxic drugs, drug-induced pancreatitis is a relatively rare occurrence (accounting for approximately 2% of cases) that
is probably related to an unknown predisposition. Fortunately, drug-induced pancreatitis is usually mild.

Drugs definitely associated with acute pancreatitis include the following:

Azathioprine

Sulfonamides

Sulindac

Tetracycline

Valproic acid,

Didanosine

Methyldopa

Estrogens

Furosemide

6-Mercaptopurine

Pentamidine

5-aminosalicylic acid compounds

Corticosteroids

Octreotide

Drugs probably associated with acute pancreatitis include the following:

Chlorothiazide and hydrochlorothiazide

Methandrostenolone (methandienone)

Metronidazole

Nitrofurantoin

Phenformin

Piroxicam

Procainamide

Colaspase

Chlorthalidone

Combination cancer chemotherapy drugs (especially asparaginase)

Cimetidine

Cisplatin

Cytosine arabinoside

Diphenoxylate
 Ethacrynic acid

In addition, there are many drugs that have been reported to cause acute pancreatitis in isolated or sporadic cases.

Less common causes

The following causes each account for less than 1% of cases of pancreatitis.

Infection

Several infectious diseases may cause pancreatitis, especially in children. These cases of acute pancreatitis tend to be milder
than cases of acute biliary or alcohol-induced pancreatitis.

Viral causes include mumps virus, coxsackievirus, cytomegalovirus (CMV), hepatitis virus, Epstein-Barr virus (EBV), echovirus,
varicella-zoster virus (VZV), measles virus, and rubella virus. Bacterial causes include Mycoplasma pneumoniae, Salmonella,
Campylobacter, and Mycobacterium tuberculosis. Worldwide, Ascaris is a recognized cause of pancreatitis resulting from the
migration of worms in and out of the duodenal papillae.

Pancreatitis has been associated with AIDS; however, this may be the result of opportunistic infections, neoplasms,
lipodystrophy, or drug therapies.

Hereditary pancreatitis

Hereditary pancreatitis is an autosomal dominant gain-of-function disorder related to mutations of the cationic trypsinogen gene
(PRSS1), which has an 80% penetrance. Mutations in this gene cause premature activation of trypsinogen to trypsin.

In addition, the CFTR mutation plays a role in predisposing patients to acute pancreatitis by causing abnormalities of ductal
secretion. At present, however, the phenotypic variability of patients with the CFTR mutation is not well understood. Certainly,
patients homozygous for the CFTR mutation are at risk for pancreatic disease, but it is not yet clear which of the more than 800
mutations carries the most significant risk. In addition, the role of CFTR heterozygotes in pancreatic disease is unknown.

Mutations in the SPINK1 protein, which blocks the active binding site of trypsin, rendering it inactive, also probably play a role in
causing a predisposition to acute pancreatitis.

This probably explains the predisposition, rather than the cause, of acute pancreatitis in these patients. If enough mutant
enzymes become activated intracellularly, they can overwhelm the first line of defense (ie, pancreatic secretory trypsin inhibitor)
and resist backup defenses (ie, proteolytic degradation by mesotrypsin, enzyme Y, and trypsin itself). Activated mutant cationic
trypsin can then trigger the entire zymogen activation cascade.

Hypercalcemia

Hypercalcemia from any cause can lead to acute pancreatitis. Causes include hyperparathyroidism, excessive doses of vitamin
D, familial hypocalciuric hypercalcemia, and total parenteral nutrition (TPN). Routine use of automated serum chemistries has
allowed earlier detection and reduced the frequency of hypercalcemia manifesting as pancreatitis.

Developmental abnormalities of pancreas

The pancreas develops from two buds stemming from the alimentary tract of the developing embryo. There are two
developmental abnormalities commonly associated with pancreatitis: pancreas divisum and annular pancreas.

Pancreas divisum is a failure of the dorsal and ventral pancreatic ducts to fuse during embryogenesis. Probably a variant of
normal anatomy, it occurs in approximately 5% of the population (see the images below); in most cases, it may actually protect
against gallstone pancreatitis. It appears that the presence of stenotic minor papillae and an atretic duct of Santorini are
additional risk factors that together contribute to the development of acute pancreatitis through an obstructive mechanism
(although this is controversial).
Acute pancreatitis. This image was obtained from a patient with pancreas divisum associated with minor papilla stenosis
causing recurrent pancreatitis. Because pancreas divisum is relatively common in the general population, it is best regarded
as variant of normal anatomy and not necessarily as cause of pancreatitis. In this case, note the bulbous contour of the duct
adjacent to the cannula. This appearance has been termed Santorinicele. Dorsal duct outflow obstruction is a probable cause
of pancreatitis when Santorinicele is present, and it is associated with a minor papilla that accommodates only a guide wire.

Acute pancreatitis. Recurrent pancreatitis was associated with pancreas divisum in an elderly man. The pancreatogram of the
dorsal duct shows distal stenosis with upstream chronic pancreatitis. After the stenosis was dilated and stented, his pain
resolved and the patient improved clinically during 1 year of quarterly stent exchanges. Follow-up computed tomography (CT)
scans showed resolution of the inflammatory mass. Although ductal biopsies and cytology were repeatedly negative, the
patient's pain and pancreatitis returned when the stents were removed. He developed duodenal outflow obstruction and was
sent to surgery; during the Whipple procedure, periampullary adenocarcinoma (of minor papilla) was revealed.

Annular pancreas is an uncommon congenital anomaly in which a band of pancreatic tissue surrounds the second part of the
duodenum. Usually, it does not cause symptoms until later in life. This condition is a rare cause of acute pancreatitis, probably
through an obstructive mechanism.

Sphincter of Oddi dysfunction can lead to acute pancreatitis by causing increased pancreatic ductal pressures. However, the
mechanism of pancreatitis induced by such dysfunction in patients without elevated sphincter pressures on manometry remains
controversial.

Hypertriglyceridemia

Clinically significant pancreatitis usually does not occur until a person’s serum triglyceride level reaches 1000 mg/dL. It is
associated with type I and type V hyperlipidemia. Although this view is somewhat controversial, most authorities believe that the
association is caused by the underlying derangement in lipid metabolism rather than by pancreatitis causing hyperlipidemia.
This type of pancreatitis tends to be more severe than alcohol- or gallstone-induced disease.

Tumors

Obstruction of the pancreatic ductal system by a pancreatic ductal carcinoma, ampullary carcinoma, islet cell tumor, solid
pseudotumor of the pancreas, sarcoma, lymphoma, cholangiocarcinoma, or metastatic tumor can cause acute pancreatitis. The
chances of pancreatitis occurring when a tumor is present are approximately 14%. Pancreatic cystic neoplasms, such as
intraductal papillary-mucinous neoplasm (IPMN), mucinous cystadenoma, or serous cystadenoma, can also cause pancreatitis.

Toxins

Exposure to organophosphate insecticide can cause acute pancreatitis. Scorpion and snake bites may also be causative; in
Trinidad, the sting of the scorpion Tityus trinitatis is the most common cause of acute pancreatitis. Hyperstimulation of pancreas
exocrine secretion appears to be the mechanism of action in both instances.

Surgical procedures

Acute pancreatitis may occur in the postoperative period of various surgical procedures (eg, abdominal or cardiopulmonary
bypass surgery, which may damage the gland by causing ischemia). Postoperative acute pancreatitis is often a difficult
diagnosis to confirm, and it has a higher complication rate than pancreatitis associated with other etiologies. The mechanism is
unclear.

Vascular abnormalities

Vascular factors, such as ischemia or vasculitis, can play a role in causing acute pancreatitis. Vasculitis can predispose patients
to pancreatic ischemia, especially in those with polyarteritis nodosa and systemic lupus erythematosus.

Autoimmune pancreatitis

Autoimmune pancreatitis, a relatively newly described entity, is an extremely rare cause of acute pancreatitis (prevalence, 0.82
per 100,000 individuals). When it does cause acute pancreatitis, it is usually in young people (approximately age 40 years) who
also suffer from inflammatory bowel disease. The pathogenesis is unclear, but it is potentially related to immunoglobulin (Ig) G4
autoimmune disease.[8]

Epidemiology
United States statistics

Acute pancreatitis has an approximate incidence of 40-50 cases per year per 100,000 adults.[9] In 2009, approximately 275,000
hospitalizations were attributed to acute pancreatitis.[10] In 2007, approximately 220,000 patients with acute pancreatitis were
admitted to non–federally funded hospitals. In 1998, 183,000 patients with acute pancreatitis were admitted. This trend in rising
incidence has been recognized over the past several decades.[11, 9, 12]

International statistics

Worldwide, the incidence of acute pancreatitis ranges between 5 and 80 per 100,000 population, with the highest incidence
recorded in the United States and Finland.[13] In Luneburg, Germany, the incidence is 17.5 cases per 100,000 people. In
Finland, the incidence is 73.4 cases per 100,000 people. Similar incidence rates have been reported in Australia. The incidence
of disease outside North America, Europe, and Australia is less well known.

In Europe and other developed nations, such as Hong Kong, more patients tend to have gallstone pancreatitis, whereas in the
United States, alcoholic pancreatitis is most common.

Age-related demographics

The median age at onset depends on the etiology.[14] The following are median ages of onset for various etiologies:

Alcohol-related - 39 years

Biliary tract–related - 69 years

 Trauma-related - 66 years

Drug-induced etiology - 42 years

ERCP-related - 58 years

AIDS-related - 31 years

Vasculitis-related - 36 years

Hospitalization rates increase with age. For people aged 35-75 years, the rate doubles for males and quadruples for females.

Sex-related demographics

Generally, acute pancreatitis affects males more often than females. In males, the etiology is more often related to alcohol; in
females, it is more often related to biliary tract disease. Idiopathic pancreatitis has no clear predilection for either sex.

Race-related demographics

The hospitalization rates of patients with acute pancreatitis per 100,000 population are 3 times higher for blacks than whites.
These racial differences are more pronounced for males than females. The risk for African Americans aged 35-64 years is 10
times higher than for any other group. African Americans are at a higher risk than whites in that same age group.

The annual incidence of acute pancreatitis in Native Americans is 4 per 100,000 population; in whites, 5.7 per 100,000
population; and in blacks, 20.7 per 100,000 population.[15]

Prognosis
The overall mortality in patients with acute pancreatitis is 10%-15%. Patients with biliary pancreatitis tend to have a higher
mortality than patients with alcoholic pancreatitis. This rate has been falling over the last 2 decades as improvements in
supportive care have been initiated. Type 2 diabetes mellitus has also been associated with higher severity and mortality in the
setting of acute pancreatitis.[16] In patients with severe disease (organ failure), who account for about 20% of presentations,
mortality is approximately 30%.[17] This figure has not decreased in the past 10 years. In patients with pancreatic necrosis
without organ failure, the mortality approaches zero.

In the first week of illness, most deaths result from multiorgan system failure. In subsequent weeks, infection plays a more
significant role, but organ failure still constitutes a major cause of mortality. Acute respiratory distress syndrome (ARDS), acute
renal failure, cardiac depression, hemorrhage, and hypotensive shock all may be systemic manifestations of acute pancreatitis
in its most severe form.

Identifying patients in the greatest need of aggressive medical treatment by differentiating their disease severity as mild or
severe is recommended. In mild disease, the pancreas exhibits interstitial edema, an inflammatory infiltrate without hemorrhage
or necrosis, and, usually, minimal or no organ dysfunction. In severe disease, the inflammatory infiltrate is severe, associated
with necrosis of the parenchyma, often accompanied by evidence of severe gland dysfunction, and it may be associated with
multiorgan system failure.

Different strategies have been used to assess the severity of acute pancreatitis and predict outcome (see Workup and Staging).
Several clinical scoring systems (eg, Ranson criteria, Glasgow, Imrie) are available. The APACHE II scoring system, though
cumbersome, appears to be the best validated (see the APACHE II Scoring System calculator). Biological markers have also
been used for this purpose. Genetic markers are being studied and have not yet come into clinical use.

Peritoneal lavage has a high specificity (93%); however, it has a low sensitivity (54%). Dynamic CT scanning of the abdomen is
widely available and useful in predicting the outcome of acute pancreatitis. When the Balthazar criteria (see Workup and
Computed Tomography Scanning) are used, sensitivity is 87% and specificity is 88%.

Suppiah et al examined the prognostic value of the neutrophil-lymphocyte ratio (NLR) in 146 consecutive patients with acute
pancreatitis.[18] They found that elevation of the NLR during the first 48 hours of hospital admission was significantly associated
with severe acute pancreatitis and was an independent negative prognostic indicator. The NLR is calculated from the white cell
differential and provides an indication of inflammation.

In a retrospective study of data from 822 patients hospitalized with acute pancreatitis, Mikolasevic et al found that patients who
had nonalcoholic fatty liver at admission (n = 198; 24.1%) had a statisically higer incidence of moderately severe (35.4% vs
14.6%) and severe acute pancreatitis (20.7% vs 9.6%) than those without nonalcoholic fatty liver.[19] Moreover, these patients
had higher (1) C-reactive protein levels not only on the day of admission but also at day 3, (2) APACHE II scores at admission,
(3) CT scan severity index, and (4) occurrence of organ failure and local complications. Although mortality was also higher in the
nonalcoholic fatty liver group compared to the group without this disease, the difference was not statistically significant.[19]

Complications

Acute fluid collections may occur, typically early in the course of acute pancreatitis. These are primarily detected by imaging
studies rather than by physical examination. Because they lack a defined wall and usually regress spontaneously, most acute
fluid collections require no specific therapy.

An acute pseudocyst is a collection of pancreatic fluid that is walled off by granulation tissue after an episode of acute
pancreatitis; it requires 4 or more weeks to develop. Although pseudocysts are sometimes palpable on physical examination,
they are usually detected with abdominal ultrasonography or computed tomography (CT).

Intra-abdominal infection is common. Within the first 1-3 weeks, fluid collections or pancreatic necrosis can become infected and
jeopardize clinical outcome. From 3 to 6 weeks, pseudocysts may become infected or a pancreatic abscess may develop. A
pancreatic abscess is a circumscribed intra-abdominal collection of pus, within or in proximity to the pancreas. It is believed to
arise from localized necrosis, with subsequent liquefaction that becomes infected.

The intestinal flora is the predominant source of bacteria causing the infection. The usual suspects are Escherichia
coli (26%), Pseudomonas species (16%), Staphylococcus species (15%), Klebsiella species (10%), Proteus species
(10%), Streptococcus species (4%), Enterobacter species (3%), and anaerobic organisms (16%). Fungal superinfections may
occur weeks or months into the course of severe necrotizing pancreatitis.

Pancreatic necrosis is a nonviable area of pancreatic parenchyma that is often associated with peripancreatic fat necrosis and is
principally diagnosed with the aid of dynamic spiral CT scans. Distinguishing between infected and sterile pancreatic necrosis is
an ongoing clinical challenge. Sterile pancreatic necrosis is usually treated with aggressive medical management, whereas
almost all patients with infected pancreatic necrosis require surgical debridement or percutaneous drainage if they are to
survive.

Hemorrhage into the gastrointestinal (GI) tract, retroperitoneum, or the peritoneal cavity is possible because of erosion of large
vessels. Intestinal obstruction or necrosis may occur. Common bile duct obstruction may be caused by a pancreatic abscess,
pseudocyst, or biliary stone that caused the pancreatitis. An internal pancreatic fistula from pancreatic duct disruption or a
leaking pancreatic pseudocyst may occur.

In the weeks (to months) following presentation, the physician’s attention shifts to developing signs of intra-abdominal infection,
pancreatic pseudocyst, intra-abdominal hemorrhage, colon perforation, obstruction or fistulization, and multiorgan system
failure.

Patient Education
Educate patients about the disease, and advise them to avoid alcohol in binge amounts and to discontinue any risk factor, such
as fatty meals and abdominal trauma.

For patient education resources, see the Cholesterol Center, as well as Pancreatitis and Gallstones.

Presentation

History
The cardinal symptom of acute pancreatitis is abdominal pain, which is characteristically dull, boring, and steady. Usually, the
pain is sudden in onset and gradually intensifies in severity until reaching a constant ache. Most often, it is located in the upper
abdomen, usually in the epigastric region, but it may be perceived more on the left or right side, depending on which portion of
the pancreas is involved. The pain radiates directly through the abdomen to the back in approximately one half of cases.
Nausea and vomiting are often present, along with accompanying anorexia. Diarrhea can also occur. Positioning can be
important, because the discomfort frequently improves with the patient sitting up and bending forward. However, this
improvement is usually temporary. The duration of pain varies but typically lasts more than a day. It is the intensity and
persistence of the pain that usually causes patients to seek medical attention.

Ask the patient about recent operative or other invasive procedures (eg, endoscopic retrograde cholangiopancreatography
[ERCP]) or family history of hypertriglyceridemia. Patients frequently have a history of previous biliary colic and binge alcohol
consumption, the major causes of acute pancreatitis.

Physical Examination
The following physical examination findings may be noted, varying with the severity of the disease:

Fever (76%) and tachycardia (65%) are common abnormal vital signs; hypotension may be noted

Abdominal tenderness, muscular guarding (68%), and distention (65%) are observed in most patients; bowel sounds are
often diminished or absent because of gastric and transverse colonic ileus; guarding tends to be more pronounced in the
upper abdomen

A minority of patients exhibit jaundice (28%)

Some patients experience dyspnea (10%), which may be caused by irritation of the diaphragm (resulting from
inflammation), pleural effusion, or a more serious condition, such as acute respiratory distress syndrome (ARDS);
tachypnea may occur; lung auscultation may reveal basilar rales, especially in the left lung

In severe cases, hemodynamic instability is evident (10%) and hematemesis or melena sometimes develops (5%); in
addition, patients with severe acute pancreatitis are often pale, diaphoretic, and listless

Occasionally, in the extremities, muscular spasm may be noted secondary to hypocalcemia

A few uncommon physical findings are associated with severe necrotizing pancreatitis:

The Cullen sign is a bluish discoloration around the umbilicus resulting from hemoperitoneum

The Grey-Turner sign is a reddish-brown discoloration along the flanks resulting from retroperitoneal blood dissecting
along tissue planes; more commonly, patients may have a ruddy erythema in the flanks secondary to extravasated
pancreatic exudate

Erythematous skin nodules may result from focal subcutaneous fat necrosis; these are usually not more than 1 cm in size
and are typically located on extensor skin surfaces; in addition, polyarthritis is occasionally seen

Rarely, abnormalities on funduscopic examination may be seen in severe pancreatitis. Termed Purtscher retinopathy, this
ischemic injury to the retina appears to be caused by activation of complement and agglutination of blood cells within the retinal
vessels. It may cause temporary or permanent blindness.

DDx

Diagnostic Considerations
Recognizing patients with severe acute pancreatitis as soon as possible is critical for achieving optimal outcomes.

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

Acute peritonitis

Macroamylasemia

Macrolipasemia
 Malabsorption syndromes/processes

Perforated viscus

Differential Diagnoses
Acute Mesenteric Ischemia

Acute Respiratory Distress Syndrome

Bacterial Pneumonia

Cholangitis

Cholecystitis

Chronic Pancreatitis

Colon Cancer

Community-Acquired Pneumonia (CAP)

Emergent Treatment of Gastroenteritis

Gallstones (Cholelithiasis)

Gastric Cancer

Irritable Bowel Syndrome (IBS)

Large-Bowel Obstruction

Myocardial Infarction

Pancreatic Cancer

Pancreatic Pseudocysts

Peptic Ulcer Disease

Viral Hepatitis

Workup

Workup

Approach Considerations
See the Guidelines section for guidelines recommendations from the American College of Gastroenterology, American
Gastroenterology Association, and the World Society of Emergency Surgery.

Once a working diagnosis of acute pancreatitis is reached, laboratory tests are obtained to support the clinical impression. In
addition to confirming the diagnosis, laboratory tests are helpful in determining the etiology and looking for complications.

Although diagnostic imaging is unnecessary in most cases of pancreatitis,[20] visualization of inflammatory changes within the
pancreas provides morphologic confirmation of the diagnosis. Obtain imaging tests when the diagnosis is in doubt, when severe
pancreatitis is present, or when a given imaging study might provide specific information needed to answer a clinical question.

Image-guided aspiration may be useful for differentiating infected from sterile necrosis and for draining fluid collections. Genetic
testing for mutations associated with acute pancreatitis may be considered, even if effective treatments for these genetic
conditions are lacking.
Laboratory Studies
Amylase and lipase

Serum amylase and lipase levels are typically elevated in persons with acute pancreatitis. However, these elevations may only
indicate pancreastasis. In research studies, amylase or lipase levels at least 3 times above the reference range are generally
considered diagnostic of acute pancreatitis.

Serum amylase determinations are routinely available, but they are not specific for pancreatitis. Preferably, the amylase P level
should be measured, which is somewhat more specific to pancreatic pathology. Elevations can occur in patients with small
intestinal obstruction, mesenteric ischemia, tubo-ovarian disease, renal insufficiency, or macroamylasemia. Rarely, elevations
may reflect parotitis. The serum half-life of amylase is short, and elevations generally return to the reference ranges within a few
days.

Lipase has a slightly longer half-life and its abnormalities may support the diagnosis if a delay occurs between the pain episode
and the time the patient seeks medical attention. Elevated lipase levels are more specific to the pancreas than elevated amylase
levels. Lipase levels remain high for 12 days. In patients with chronic pancreatitis (usually caused by alcohol abuse), lipase
levels may be elevated in the presence of a normal serum amylase level.

The level of serum amylase or lipase does not indicate whether the disease is mild, moderate, or severe, and monitoring levels
serially during the course of hospitalization does not offer insight into the prognosis.

Liver-associated enzymes

Determine alkaline phosphatase, total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels to
search for evidence of gallstone pancreatitis. An ALT level higher than 150 U/L suggests gallstone pancreatitis and a more
fulminant disease course.

Serum electrolytes, BUN, creatinine, glucose, cholesterol, and triglycerides

Obtain measurements for blood urea nitrogen (BUN), creatinine, and electrolytes; a great disturbance in the electrolyte balance
is usually found, secondary to third spacing of fluids. Measure blood glucose level because it may be elevated from B-cell injury
in the pancreas.

Measure calcium, cholesterol, and triglyceride levels to search for an etiology of pancreatitis (eg, hypercalcemia or
hyperlipidemia) or complications of pancreatitis (eg, hypocalcemia resulting from saponification of fats in the retroperitoneum).
However, be aware that baseline serum triglyceride levels can be falsely lowered during an episode of acute pancreatitis.

Complete blood count and hematocrit

A complete blood count (CBC) demonstrates leukocytosis (white blood cell [WBC] count higher than 12,000/µL) with the
differential being shifted toward the segmented polymorphonuclear (PMN) cells. Leukocytosis may represent inflammation or
infection.

Hemoconcentration at admission (an admission hematocrit value greater than 47%) has been proposed as a sensitive measure
of more severe disease. However, this has subsequently been shown to have value only as a negative predictor—that is, a lack
of hemoconcentration effectively rules out severe disease.

If blood transfusion is necessary, as in cases of hemorrhagic pancreatitis, obtain type and cross-match.

C-reactive protein

A C-reactive protein (CRP) value can be obtained 24-48 hours after presentation to provide some indication of prognosis.
Higher levels have been shown to correlate with a propensity toward organ failure. A CRP value in double figures (ie, ≥ 10
mg/dL) strongly indicates severe pancreatitis. CRP is an acute-phase reactant that is not specific for pancreatitis.

Other tests

Evaluate arterial blood gases if a patient is dyspneic. Whether tachypnea is due to acute respiratory distress syndrome (ARDS)
or diaphragmatic irritation must be determined.

Lactic dehydrogenase (LDH), BUN, and bicarbonate levels should be measured both at admission and at 48 hours in order to
help determine the Ranson criteria for survival.
Immunoglobulin G4 (IgG4) levels can be checked to evaluate for autoimmune pancreatitis, especially in recurrent acute
pancreatitis that is not explained by an obvious etiology. However, this test is not specific, because IgG4 levels can be elevated
in as many as 10% of patients with acute pancreatitis who do not have autoimmune pancreatitis.

Trypsin and its precursor trypsinogen-2 in both the urine and the peritoneal fluid have been evaluated as possible markers for
acute pancreatitis (especially post-ERCP pancreatitis) but are not widely used. Trypsinogen activation peptide (TAP) is formed
when trypsinogen is cleaved to form trypsin and can be measured commercially in the urine to diagnose acute pancreatitis and
to help determine severity.

Although not currently in use clinically, polymorphisms in the chemokine monocyte chemotactic protein 1 (MCP-1) gene may
also predict severity. This is the first gene identified that plays a role strictly in predicting the severity of disease.

Abdominal Radiography
Abdominal radiographs have a limited role in acute pancreatitis. Kidneys-ureters-bladder (KUB) radiography with the patient in
the upright position is primarily performed to detect free air in the abdomen, indicating a perforated viscus, as would be the case
in a penetrating, perforated duodenal ulcer. In some cases, the inflammatory process may damage peripancreatic structures,
resulting in a colon cut-off sign, a sentinel loop, or an ileus. The presence of calcifications within or around the pancreas may
indicate chronic pancreatitis.

Ultrasonography
Abdominal ultrasonography

Ultrasonography of the abdomen is the most useful initial test in determining the etiology of pancreatitis and is the technique of
choice for detecting gallstones. In the setting of acute pancreatitis, sensitivity is reduced to 70%-80%. In addition, the ability to
identify choledocholithiasis is limited. Although ultrasonography can be used as a screening test, it may not be specific if
overlying gas shadows secondary to bowel distention are present. Ultrasonography cannot measure the severity of disease.

Endoscopic ultrasonography

Endoscopic ultrasonography (EUS) is an endoscopic procedure that allows a high-frequency ultrasound transducer to be
inserted into the gastrointestinal (GI) tract to visualize the pancreas and the biliary tract. This study allows a more detailed image
to be obtained than with transcutaneous ultrasonography because the high-frequency transducer can be introduced directly
adjacent to the pancreas.

Its principal role in the evaluation of acute pancreatitis is the detection of microlithiasis and periampullary lesions not easily
revealed by other methods. This modality should not be used to help identify chronic pancreatitis until several months after the
episode of acute pancreatitis.

In specialized centers with highly trained medical staff, a secretin-stimulated EUS study may reveal resistance to ductal outflow
at the level of the papilla, as evidenced by dilatation of the pancreatic duct to a greater extent and longer duration than in a
healthy population. This can be helpful in evaluating patients with recurrent idiopathic pancreatitis.

Computed Tomography Scanning

Abdominal computed tomography (CT) scanning is generally not indicated for patients with mild pancreatitis unless a pancreatic
tumor is suspected (usually in elderly patients). It is always indicated in patients with severe acute pancreatitis and is the
imaging study of choice for assessing complications. Scans are seldom needed within the first 72 hours after symptom onset
unless the diagnosis is uncertain, because inflammatory changes are often not radiographically present until this time.[23]
Abdominal CT scans also provide prognostic information based on the following grading scale developed by Balthazar and
colleagues[24, 25, 26] :

Grade A - Normal pancreas

Grade B - Focal or diffuse gland enlargement

Grade C - Intrinsic gland abnormality recognized by haziness on the scan

Grade D - Single ill-defined collection or phlegmon

Grade E - Two or more ill-defined collections or the presence of gas in or near the pancreas

The chances of infection and death are virtually nil in grades A and B but steadily increase in grades C through E. Patients with
grade E pancreatitis have a 50% chance of developing an infection and a 15% chance of dying.

Dynamic spiral CT scanning is used to determine the presence and extent of pancreatic necrosis. After the administration of an
oral agent to define bowel structures, a study of the upper abdomen is performed twice, before and after administration of an
intravenous (IV) bolus of iodine contrast agent.

For a healthy pancreas, density numbers are in the range of 30-40 Hounsfield units on an unenhanced study, increasing to 100-
150 Hounsfield units on an enhanced study. When pancreatic necrosis is present, focal or diffuse areas of unenhanced
parenchyma on the second study suggest pancreatic necrosis. Pancreatic necrosis for research purposes is defined as loss of
enhancement in at least 30% of the pancreatic parenchyma.

Magnetic Resonance Cholangiopancreatography

Magnetic resonance cholangiopancreatography (MRCP) has an emerging role in the diagnosis of suspected biliary and
pancreatic duct obstruction in the setting of pancreatitis. Heavily T2–weighted images provide a noninvasive image of the biliary
and pancreatic ducts.[1]

Although MRCP is not as sensitive as endoscopic retrograde cholangiopancreatography (ERCP), it is safer, noninvasive, and
fast, as well as provides images useful in guiding clinical care decisions. MRCP should be used if choledocholithiasis is
suspected but there is concern that pancreatitis might worsen if ERCP is performed.

Endoscopic Retrograde Cholangiopancreatography

Endoscopic retrograde cholangiopancreatography (ERCP) is an endoscopic procedure used to evaluate the biliary and
pancreatic ductal systems and is indicated in a subset of patients with acute pancreatitis (see the image below). However,
ERCP should be used with extreme caution in patients with acute pancreatitis and should never be used as a first-line
diagnostic tool in this disease.[1] This procedure should be performed only in the following situations:

The patient has severe acute pancreatitis that is believed, and is seen on other radiographic studies, to be secondary to
choledocholithiasis

The patient has biliary pancreatitis and is experiencing worsening jaundice and clinical deterioration despite maximal
supportive therapy
 Acute pancreatitis. A patient with acute gallstone pancreatitis underwent endoscopic retrograde
cholangiopancreatography. The cholangiogram showed no stones in common bile duct and multiple small stones in
gallbladder. The pancreatogram shows narrowing of the pancreatic duct in area of genu, resulting from extrinsic
compression of ductal system by inflammatory changes in the pancreas.

When combined with sphincterotomy and stone extraction, ERCP may reduce the length of hospital stay, the complication rate,
and, possibly, mortality.

In the case of biliary pancreatitis where a dilated obstructed common bile duct is diagnosed on the basis of the findings of
computed tomography (CT) scanning or any other imaging modality and an elevated plasma bilirubin level (>5 mg/dL), ERCP
with sphincterotomy is warranted within the first 72 hours. Biliary pancreatitis should always be treated eventually with a
cholecystectomy after the process has subsided.

Occasionally, ERCP with sphincter of Oddi manometry reveals sphincter of Oddi dysfunction (SOD) as the cause of recurrent
idiopathic pancreatitis. Known risk factors for post-ERCP pancreatitis are summarized in table 1, below.[27, 28]

Table 1. Risk Factors for Post-ERCP Pancreatitis. (Open Table in a new window)

Acute pancreatitis (any) or a history of post-ERCP pancreatitis

Younger age

Female sex

Absence of bile duct stones

More than 10 attempts to cannulate the papilla of Vater

Pancreatic duct cannulation

Contrast medium injection of the the pancreatic system

Pancreatic sphincterotomy

Sphincter of Oddi dysfunction

In suspected SOD, especially SOD type 3, the risk of procedure-induced pancreatitis can exceed 30%. It is generally thought
that the experience of the operator is a risk factor for post-ERCP pancreatitis. Although no difference was found between case
volume of the endoscopist or center, high-volume centers treated a larger number of patients at high risk of pancreatitis and
performed a significantly greater number of procedures.[28]

Image-Guided Aspiration and Drainage

Computed tomography (CT)-guided needle aspiration is used to differentiate infected necrosis from sterile necrosis in patients
with severe necrotizing pancreatitis. The needle is placed into an area of low attenuation in or around the pancreas of a patient
with fever and tachycardia or other signs of a systemic inflammatory response syndrome, generally following the first week of
severe pancreatitis. The procedure may be repeated weekly if clinically indicated.

The specimen should be delivered to the laboratory within an hour and interpreted promptly. The specimen should always be
evaluated for Gram stain, culture, and sensitivity. If the Gram stain shows bacteria or fungi, surgical debridement of the infected
necrosis is generally indicated. An exception would be if the patient cannot tolerate surgery; in that case, CT-guided catheter
drainage may be more effective.

Endoscopic ultrasonography (EUS)-guided needle aspiration can often be used to differentiate infected necrosis from sterile
necrosis in the same manner as CT-guided needle aspiration. EUS can also be used to guide drainage of pancreatic and
peripancreatic fluid collections that have complicated an episode of acute pancreatitis.[29] These procedures should only be
carried out once the pseudocyst has had the opportunity to mature.

A complete description of these procedures is beyond the scope of this article.

Genetic Testing
With the advent of molecular medicine, various genetic abnormalities have been identified with pancreatitis. Although effective
treatments for these conditions have yet to be discovered, it is sometimes reasonable to begin testing for these mutations in
patients with otherwise idiopathic pancreatitis, rather than subjecting the entire group to the risks of endoscopic sphincterotomy
or stent placement for presumptive diagnosis of sphincter of Oddi dysfunction.

As more is learned about molecular mechanisms and therapy, logical novel treatments may eventually be offered to these
patients as part of clinical trials. Of course, as with any type of genetic testing, expert genetic counseling that addresses social,
familial, insurance, and financial issues is essential for all persons before testing. In fact, it is the author’s policy not to perform
any genetic testing unless patients are first counseled by a qualified genetic counselor.

Hereditary pancreatitis has been associated with a mutation of cationic trypsinogen (PRSS1). At least 4 mutations have thus far
been identified. These mutations appear to render the protein resistant to second-line proteolytic defense mechanisms. Patients
with PRSS1 mutations typically develop their first episode of pancreatitis by the time they are in their mid teens. Most often,
there is a strong family history of pancreatic disease (eg, acute or chronic pancreatitis, pancreatic malignancy). It should be
noted that PRSS1 -related pancreatitis is very rare.

Some patients with idiopathic pancreatitis have atypical mutations in the CFTR gene, which follows an autosomal recessive
pattern of inheritance. This is a fascinating advance in understanding the spectrum of cystic fibrosis, in which phenotypic
expression depends on the degree to which the mutation affects the activity of the CFTR enzyme’s function. Relatively minor
mutations that do not affect pulmonary function may influence chloride transport in the pancreas enough to predispose
individuals to recurrent idiopathic pancreatitis.

Mutations in the SPINK1 gene can predispose patients to acute pancreatitis. The SPINK1 protein blocks the active binding site
of trypsin, rendering it inactive. However, approximately 1 in 100 persons in the United States are at least heterozygotes for
SPINK1. It is an autosomal recessive gene pattern of inheritance. Therefore, although mutations of the SPINK1 gene are not
usually enough to cause pancreatitis, they are likely to be a cofactor responsible for pancreatitis in some individuals.

Histologic Findings
For practical purposes, the infinite spectrum of pancreatitis severity is usually subdivided into mild and severe categories as
follows:

Mild pancreatitis - The gland exhibits interstitial edema and an inflammatory infiltrate without hemorrhage or necrosis,
usually with minimal or no organ dysfunction

Severe pancreatitis - Extensive inflammation and necrosis of the pancreatic parenchyma are present, often associated
with severe gland dysfunction and multiorgan system failure

At surgery, peripancreatic fatty tissue is predominantly involved by necrosis, whereas the gland is usually less affected; hence,
the extent of pancreatic necrosis is commonly overestimated. In very severe cases, arterial thrombosis may lead to panlobular
infarction, in which the gland becomes a hemorrhagic, necrotic, gangrenous mass. The natural history of fat necrosis depends
on its location and extent; small areas (< 1 cm) may resolve entirely, whereas large areas (>5 cm) may liquefy within a fibrotic
capsule.

Staging
Various strategies have been used to predict the severity and outcome of acute pancreatitis, including the Ranson, Acute
Physiology and Chronic Health Evaluation (APACHE) II, Glasgow, and Imrie scoring systems. Each has advantages and
disadvantages, and none is currently recognized as a criterion standard.

For research purposes, the Atlanta classification of acute pancreatitis has been used to differentiate between severe and mild
cases of acute pancreatitis.[2] According to this classification, patients are diagnosed with severe acute pancreatitis if they show
the following:

Evidence of organ failure (eg, systolic blood pressure below 90 mm Hg, arterial partial pressure of oxygen [Pa O2] 60
mm Hg or lower, serum creatinine level 2 mg/dL or higher, GI bleeding amounting to 500 mL or more in 24 hours)

Local complications (eg, necrosis, abscess, pseudocyst)

Ranson score of 3 or higher or APACHE score of 8 or higher

Ranson criteria

Ranson used a series of different criteria for the severity of acute pancreatitis to formulate a scoring system that is still widely
used.[30]

Criteria present on admission include the following:

Patient older than 55 years

WBC count higher than 16,000/µL

Blood glucose level higher than 200 mg/dL

Serum LDH level higher than 350 IU/L

AST level higher than 250 IU/L

Criteria developing during the first 48 hours include the following:

Hematocrit fall of more than 10%

BUN level increase by more than 8 mg/dL

Serum calcium level lower than 8 mg/dL

Pa O2 less than 60 mm Hg

Base deficit higher than 4 mEq/L

Estimated fluid sequestration higher than 6 L

Each of the above criteria counts for 1 point toward the score. A Ranson score of 0-2 has a minimal mortality, and the patient is
admitted to the regular ward for medical therapy and support. A Ranson score of 3-5 has a 10%-%20% mortality rate, and the
patient should be admitted to the intensive care unit (ICU). A Ranson score higher than 5 after 48 hours has a mortality of more
than 50% and is associated with more systemic complications.

Although the Ranson criteria are perhaps the best known scoring system, they have several drawbacks. First, 11 criteria are
used, some of which are evaluated on day 1 and others on day 2. The Ranson score is valid only at 48 hours after onset and
not at any other time during the disease. Second, the threshold for an abnormal value depends on whether the pancreatitis is
caused by alcohol or gallstones. Finally, the sensitivity is only 73% and the specificity is 77% for predicting mortality.

BUN

An elevated BUN level at admission has been associated with an increase in severe acute pancreatitis and/or death. This
corresponds well with the APACHE II score. The rise in BUN is thought to be due to hemoconcentration, which is a surrogate
marker for intravascular depletion. Intravascular depletion is thought to be a key mediator of the inflammatory response in acute
pancreatitis.

APACHE II

The APACHE score has the advantage of being able to assess the patient at any point during the illness; however, it is very
cumbersome for routine clinical use. Attempts have been made to make this evaluation user friendly (eg, with APACHE II, the
Simplified Acute Physiology Score [SAPS], and the Imrie score), but it remains cumbersome. The sensitivity is 77%, and the
specificity is 84%. See the APACHE II Scoring System calculator.

Biological markers

The most widely available biological marker for staging acute pancreatitis is the hematocrit value. Admission hemoconcentration
to a hematocrit value greater than 47% had been reported as a sensitive predictor of pancreatic necrosis at admission.
However, a subsequent study has revealed admission hematocrit to be useful only as a negative predictor for necrosis in
patients without hemoconcentration.

CRP, a nonspecific acute-phase reactant produced by the liver in response to interleukin (IL)–6, is a useful marker at 36-48
hours. A CRP level greater than 6 at 24 hours or greater than 7 at 48 hours is consistent with severe acute pancreatitis. The
sensitivity of this test is 73%, and the specificity is 71%.

IL-6 levels begin to rise in the first several hours of pancreatitis, stimulating the release of CRP. Early studies of IL-6 as a
biological marker appear promising, indicating that this may be a reliable indicator of pancreatitis severity. However, this
conclusion is not yet validated, and IL-6 is not yet commercially available for clinical use in this setting.

Several other blood tests show promise in predicting the severity of acute pancreatitis. These include trypsinogen activation
peptide (TAP), polymorphonuclear elastase, and phospholipase A2. Like IL-6, they are generally not used in clinical practice and
are more expensive than typically used tests. Some are only slightly better than using CRP.

Genetic markers

Polymorphisms in the chemokine monocyte chemotactic protein 1 (MCP-1) gene may play a role in predisposing patients to
severe acute pancreatitis, although this marker is still under investigation and is not used clinically.

Treatment

Approach Considerations
See the Guidelines section for guidelines recommendations from the American College of Gastroenterology, American
Gastroenterology Association, and the World Society of Emergency Surgery.

Medical management of mild acute pancreatitis is relatively straightforward. The patient is kept NPO (nil per os—that is, nothing
by mouth), and intravenous (IV) fluid hydration is provided. Analgesics are administered for pain relief. Antibiotics are generally
not indicated.
If ultrasonograms show evidence of gallstones and if the cause of pancreatitis is believed to be biliary, a cholecystectomy should
be performed during the same hospital admission. Feeding should be introduced enterally as the patient’s anorexia and pain
resolves. Patients can be initiated on a low-fat diet initially and need not invariably start their dietary advancement using a clear
liquid diet. Systematic reviews and meta-analyses have shown that administration of enteral nutrition may reduce mortality and
infectious complications compared with parenteral nutrition.[31] Although the ideal timing to initiate enteral feeding remains
undetermined, administration within 48 hours appears to be safe and tolerated.[31]

Serum amylase and lipase levels can be elevated in patients with brain injury (eg, cerebrovascular accident or brain trauma).
These patients are generally cared for in an intensive care unit (ICU) and require mechanical ventilation. Pancreatic enzyme
elevations may rise and fall considerably over many days to weeks. The elevation is believed to result from hyperstimulation of
the pancreas via a central mechanism, but no evidence of acute pancreatitis is present on imaging studies.

Patients with severe acute pancreatitis require intensive care. Within hours to days, a number of complications (eg, shock,
pulmonary failure, renal failure, gastrointestinal [GI] bleeding, or multiorgan system failure) may develop. The goals of medical
management are to provide aggressive supportive care, to decrease inflammation, to limit infection or superinfection, and to
identify and treat complications as appropriate.

Autoimmune pancreatitis is a rare condition. Corticosteroids should not be used to treat this condition in the short term in
patients who are suspected of having autoimmune pancreatitis and who present with acute pancreatitis.

No evidence-based guidelines specify when a patient should be transferred to a more experienced or skilled medical center.
However, if severe acute pancreatitis is suggested either by the Atlanta criteria[2] or by a C-reactive protein (CRP) level above
10 mg/dL, Ranson score of 4 or higher, or Acute Physiology and Chronic Health Evaluation (APACHE) II score of 9 or higher,
consider transfer to an institution where an intensivist staffs the critical care unit and an interested subspecialist experienced in
the diagnosis and treatment of pancreatitis is available.

Further inpatient care depends on whether any of the complications of severe pancreatitis develop and how well patients
respond to treatment. This ranges from a few days to several months of intensive care.

Patients can be discharged when their pain is well controlled with oral analgesia, they are able to tolerate an oral diet that
maintains their caloric needs, and all complications have been addressed adequately.

Initial Supportive Care

Fluid resuscitation

Patients with acute pancreatitis lose a large amount of fluids to third spacing into the retroperitoneum and intra-abdominal areas.
Accordingly, they require prompt intravenous (IV) hydration within the first 24 hours. Especially in the early phase of the illness,
aggressive fluid resuscitation is critically important. This cannot be overemphasized.

There is no universal consensus definitively favoring one type of fluid over another type; both crystalloids and colloids are used.
Resuscitation should be sufficient to maintain hemodynamic stability. This usually involves administration of several liters of fluid
as a bolus, followed by continuous infusion at a rate of 250-500 mL/h.

Central venous pressure, pulmonary artery wedge pressure, and urine output (>0.5 mL/kg/h) can be followed up as markers of
adequate hydration. Careful attention should be paid to signs of overhydration, such as pulmonary edema causing hypoxia.

Nutritional support

General guidelines for nutritional support of patients with acute pancreatitis include the following:

In patients with mild uncomplicated pancreatitis, no benefit is observed from nutritional support, and the energy (caloric)
intake received with IV dextrose 5% in water (D5W) suffices; oral feedings should be initiated once the patient’s pain and
anorexia resolve

In patients with moderate-to-severe pancreatitis, begin nutritional support early in the course of management, as soon as
stabilization of fluid and hemodynamic parameters permits; optimally, nasojejunal feedings with a low-fat formulation
should be initiated at admission

Total parenteral nutrition (TPN) may be required when patients cannot meet their caloric needs with enteral nutrition or
when adequate jejunal access cannot be maintained; the TPN solution should include fat emulsions in amounts sufficient
to prevent essential fatty acid deficiency
 If surgery is required for diagnosis or complications of the disease, place a feeding jejunostomy at the time of the
operation; use a low-fat formula

Begin oral feedings once abdominal pain has resolved and the patient regains appetite; the diet should be low in fat and
protein

Theoretical considerations regarding the ability of the enterocyte to maintain a barrier against bacterial translocation favor
nasojejunal feedings—hence the recommendation to attempt initiating nasojejunal feedings at admission in all patients admitted
to the intensive care unit (ICU). For patients with mild acute pancreatitis, nasojejunal feedings can be avoided unless patients
are unable to tolerate oral intake for over 1 week.

Research has not established whether nasojejunal tubes have an advantage over nasogastric tubes for enteral feeding.

Although TPN, which has been shown to reduce mortality, may be necessary in certain situations, it should generally be
reserved for use as a second-line therapy, behind enteral feeding.

A prospective, randomized study showed that initiating oral feeding with a low-fat solid diet was as well tolerated as initiating
feeding with a clear liquid diet, but it did not result in a shorter length of hospital stay.[32]

In a 2014 randomized, multicenter study of 208 patients with acute pancreatitis, early nasoenteric tube feeding was not superior
to an oral diet initiated 72 hours after presentation.[33] Tube feeding was provided if the oral diet was not tolerated.

During 6 months of follow-up, major infection or death occurred in 30 of 101 patients (30%) in the early nasoenteric tube feeding
group and in 28 of 104 patients (27%) in the oral diet group (risk ratio, 1.07; 95% confidence interval, 0.79 to 1.44; P = 0.76).[33]
Of the 104 patients in the oral diet group, 72 (69%) did not require tube feeding.

Antibiotic Therapy
Antibiotics, usually drugs of the imipenem class, should be used in any case of pancreatitis complicated by infected pancreatic
necrosis. However, they should not be given routinely for fever, especially early in the disease course, because this symptom is
almost universally secondary to the inflammatory response and typically does not reflect an infectious process.

Several controlled trials have evaluated the role of empiric antibiotics in patients with severe acute necrotizing pancreatitis for
infectious prophylaxis.

One such trial evaluated the role of imipenem-cilastatin initiated at admission to prevent infected pancreatic necrosis. This drug
combination penetrates the pancreatic parenchyma and reduces the risk of intra-abdominal infection. It appeared to offer some
benefit in preventing infectious complications. Unfortunately, fungal superinfection tends to develop later in the clinical course,
although this risk is probably overemphasized.[34]

A randomized trial failed to show any benefit from giving ciprofloxacin and metronidazole to prevent infectious complications.
Accordingly, this drug combination is not routinely used for prophylaxis in the setting of acute pancreatitis.[35]

The bottom line is that antibiotic prophylaxis in severe pancreatitis is controversial. At this time, the routine use of antibiotics as
prophylaxis against infection in severe acute pancreatitis is not recommended.

Emerging Pharmacologic Treatments

Although the role that cytokines play in the systemic inflammatory response syndrome (SIRS) appears to be important, a large
clinical trial of lexipafant, a platelet-activating factor antagonist, has shown no benefit in patients with severe acute pancreatitis.
Because multiple pathways are involved in the inflammatory response, further research is needed in order to define which
cytokine or combination of cytokines should be targeted to ameliorate the complications of acute pancreatitis.[36]

Therapy directed against tumor necrosis factor-alpha (TNF-α) has been targeted as a potential treatment of acute pancreatitis;
however, clinical trials have not yet determined its value in this setting.
Surgical Interventions
Surgical intervention, whether by minimally invasive or conventional open techniques, is indicated when an anatomic
complication amenable to a mechanical solution is present (eg, acute necrotizing pancreatitis in which the necrotic phlegmon is
excised to limit a potential site of sepsis, or hemorrhagic pancreatitis in which surgical control of bleeding is warranted).
Depending on the situation and local expertise, this may require the talents of an interventional radiologist, an interventional
endoscopist, or surgeon (individually or in combination).

The images below provide examples of the treatment of severe acute pancreatitis by means of minimally invasive techniques.

Acute pancreatitis. Endoscopic retrograde cholangiopancreatography excluded suppurative cholangitis and established the
presence of anular pancreas divisum in a patient. The dorsal pancreatogram showed extravasation into the retroperitoneum,
and sphincterotomy was performed on the minor papilla. A pigtail nasopancreatic tube was then inserted into dorsal duct and
out into retroperitoneal fluid collection. The other end of the tube was attached to bulb suction and monitored every shift.

Acute pancreatitis. Although percutaneous drains remove loculated fluid collections elsewhere in the abdomen, a
nasopancreatic tube drains the retroperitoneal fluid collection. One week later, the retroperitoneal fluid collection was much
smaller (the image is reversed in a horizontal direction). By this time, patient was off pressors and was ready to be extubated.

Gallstone pancreatitis
It is optimal for patients admitted with gallstone pancreatitis to undergo cholecystectomy before discharge, rather than being
scheduled for a later date as an outpatient. Patients discharged with gallstone pancreatitis without a cholecystectomy are at high
risk for recurrent bouts of pancreatitis.

Aboulian et al found that in patients with mild gallstone pancreatitis, performing laparoscopic cholecystectomy within 48 hours of
admission—regardless of whether abdominal pain or laboratory abnormalities had resolved—resulted in a shorter hospital stay
and had no apparent impact on the technical difficulty of the procedure or the perioperative complication rate.[37]

In a retrospective study of data from 316 Italian patients admitted for nonsevere acute gallstone pancreatitis over 14 years,
investigators found that less than one third (31%) underwent early laparoscopic cholecystectomy (≤72 hours).[38] The most
common factors related to surgical delay were the need to (1) stablilize comorbid conditions and (2) preoperatively investigate
the common bile duct; other factors were significantly advanced age and an increased incidence of clinical signs indicating the
presence of common bile duct stones. Although early laparoscopic cholecystectomy appeared to shorten overall hospitalization,
the clinical outcomes were similar between those who underwent early surgery and those who underwent delayed laparoscopic
cholecystectomy.[38]

If the imaging and laboratory study findings are consistent with severe acute gallstone pancreatitis that is not responding to
supportive therapy or with ascending cholangitis with worsening signs and symptoms of obstruction, early endoscopic
retrograde cholangiopancreatography (ERCP) with sphincterotomy and stone extraction is indicated.

Pancreatic duct disruption

Damage to the pancreatic ductal system may allow the pancreatic juice to leak from the gland. The sudden development of
hypocalcemia or a rapid increase in retroperitoneal fluid on computed tomography (CT) is suggestive of this condition.

When imaging studies provide corroborating evidence, the condition is initially managed by percutaneous placement of a
drainage tube into the fluid collection under the guidance of ultrasonography or CT scanning.[4] Fluid amylase or lipase levels in
the 10,000s strongly suggest the presence of a ductal disruption.

In the appropriate clinical setting, ERCP confirms the diagnosis and provides a treatment option. Transpapillary stent placement
or, preferably, placement of a 6 French nasopancreatic tube attached to an external bulb suction device can successfully treat
leaks by removing the sphincter tone and changing the dynamics of fluid flow in favor of ductal healing. Occasionally, leaks are
associated with downstream stenoses that are also amenable to endoscopic treatment.

Refractory cases may warrant surgery. If a persistent leak is present in the tail of the gland, a distal pancreatectomy is preferred.
If the leak is in the head of the gland, a Whipple procedure is the operation of choice.

Pseudocysts

Peripancreatic fluid collections persisting for more than 4 weeks are referred to as acute pseudocysts. Pseudocysts lack an
epithelial layer and thus are not considered true cysts. They also differ from true cysts in that they are usually filled with necrotic
debris rather than fluid. Accordingly, pseudocysts may be better described by the term organized necrosis.

Most pseudocysts can be followed clinically. However, when they are symptomatic (ie, associated with pain, bleeding, or
infection) or are larger than 7 cm and are rapidly expanding in an acutely ill patient, intervention is indicated. Several different
therapeutic approaches may be implemented, depending on the anatomic relations and on the duration of the natural history of
the complication.

In selected patients with very large fluid collections, percutaneous aspiration of pancreatic pseudocysts is a reasonable
approach. Even though treatment failures are common when the pseudocyst communicates with the pancreatic ductal system,
percutaneous drainage serves as a temporizing measure that may later lead to successful endoscopic or surgical intervention.
Often, an infected pseudocyst (which by definition is regarded as a pancreatic abscess) can be successfully managed by means
of percutaneous drainage.

Pseudocysts may also be managed endoscopically with transpapillary or transmural techniques. Transpapillary drainage
requires the main pancreatic duct to communicate with the pseudocyst cavity, ideally in the head or body of the gland. The
proximal end of the stent (which should be smaller than the diameter of the pancreatic duct) is placed into the cavity. The
technical success rate is 83%, the complication rate 12%. Generally, however, pancreatic stents are difficult to monitor, are
prone to obstruction, and carry an increased risk of infection and ductal injury.

Some noncommunicating pseudocysts may be amenable to transmural enterocystostomy. Technical success requires a mature
cyst that bulges into the foregut, and the distance from the lumen to the cyst cavity should be less than 1 cm. The success rate
is 85%, the complication rate 17%. The transduodenal approach is associated with fewer complications and recurrences than
the transgastric approach.
On the basis of prospective studies in the 1970s, surgery was recommended for persistent large (> 7 cm) pancreatic
pseudocysts because complications developed in 41% of patients, 13% of whom died. Internal pseudocyst-enteric anastomosis
became the standard of care, with an operative mortality of 3-5%. This dogma was subsequently challenged by 2 retrospective
studies in which patients with smaller (ie, < 5 cm) asymptomatic pseudocysts rarely (< 10%) developed complications.

Infected pancreatic necrosis

The clinician cannot rely on clinical findings alone to differentiate infected and sterile pancreatic necrosis. When clinical signs of
infection or SIRS are present in the setting of necrotizing pancreatitis, CT-guided needle aspiration is indicated.

Surgery is recommended when large areas of the pancreas are necrotic and percutaneous CT-guided aspiration demonstrates
infection on the basis of a positive Gram stain. Antibiotic therapy alone is not sufficient to achieve a cure. Aggressive surgical
debridement and drainage are necessary to remove dead tissue and to clear the infection.

A study of patients with necrotizing pancreatitis and infected necrotic tissue determined that a step-up approach to treatment
(consisting of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy) yielded better
results than standard care with open necrosectomy.[39] Patients who received step-up treatment had a lower rate of major
complications (new-onset multiorgan failure, multiple systemic complications, perforation of a visceral organ, enterocutaneous
fistula, or bleeding) and death.

Pancreatic abscess

Pancreatic abscesses generally occur late in the course of pancreatitis. Many of these respond to percutaneous catheter
drainage and antibiotics. Those that do not respond require surgical debridement and drainage.

Prevention
When the cause of pancreatitis can be determined, prevention depends on stopping the etiologic agent from causing
subsequent episodes.

In patients with documented gallstone pancreatitis—and probably in those with idiopathic recurrent pancreatitis as well—
cholecystectomy is required. In patients who abuse alcohol, a dedicated person (eg, physician, psychologist, addiction
counselor) who can help the patient overcome the addiction to alcohol is required. When an uncommon cause of pancreatitis is
identified, the path of prevention is specific to the etiology.

Consultations
The most effective and soundly based treatment plan for any disorder is one aimed at the mechanism responsible for the
development of the disorder. With that axiom in mind, consultations must be obtained with an eye to addressing the underlying
cause of pancreatitis.

Treatment of patients with alcohol-induced pancreatitis should go beyond the physical manifestations of this disease and
address the underlying psychological addiction to alcohol. Simply telling patients they must stop drinking alcohol is not
satisfactory. Successful treatment often requires the involvement and expertise of a chemical dependency counselor. The author
favors in-hospital consultation for all patients admitted with alcoholic pancreatitis.

Patients with hypertriglyceridemia- or hypercalcemia-induced pancreatitis require consultation with an endocrinologist. Rarely,
such patients require surgical intervention for treatment of hyperparathyroidism or control of hyperlipidemia refractory to medical
therapy.

Patients with gallstones or microlithiasis revealed on imaging studies should have a surgical consultation for gallbladder
removal. Because microlithiasis is the most common cause of idiopathic pancreatitis, a patient with recurrent idiopathic
pancreatitis should undergo cholecystectomy before procedures associated with a higher risk of complications (eg, ERCP) are
performed.

Patients with medication-induced acute pancreatitis may benefit from clinical pharmacology consultation during their
hospitalization to optimize their therapeutic regimen.
Long-Term Monitoring
Once the patient is stable enough to be discharged from the hospital, routine clinical follow-up care (typically including physical
examination and amylase and lipase assays) is needed to monitor for potential complications of pancreatitis, especially
pseudocysts.

No evidence-based guidelines have been established for outpatient follow-up care. Generally, a reasonable time to see the
patient is within 7-10 days from the date of hospital discharge to evaluate how he or she is doing and to check for signs or
symptoms of complications. If the pancreatitis was moderate to severe and was associated with peripancreatic fluid collections,
subsequent imaging studies are indicated to determine if a pseudocyst has developed.

Recurrent acute pancreatitis

Recurrent acute pancreatitis (see the image below) can be a challenging clinical problem. First, seek to determine the etiology
using modalities that subject the patient to the least risk while simultaneously assessing for treatable causes.

Acute pancreatitis. A normal-appearing ventral pancreas is seen in a patient with recurrent acute pancreatitis. Dorsal
pancreas (not pictured) showed evidence of chronic pancreatitis.

Abdominal computed tomography (CT) scanning is a reasonable first approach. If neoplasia or chronic pancreatitis is found, it
must be addressed and treated accordingly.

If the CT scan is not diagnostic, order a magnetic resonance cholangiopancreatography (MRCP). If MRCP shows
developmental abnormalities, strictures, or evidence of chronic pancreatitis, remember that endoscopic or surgical treatment
may be of benefit in a subset of patients.

If the MRCP findings are normal, further evaluation with endoscopic ultrasonography (EUS) is indicated. EUS has better
sensitivity for detecting biliary sludge and microlithiasis, which are probably the most common causes of recurrent idiopathic
pancreatitis. It may also help detect periampullary lesions missed by abdominal CT scanning or MRCP.

If previous studies showed evidence of microlithiasis or biliary sludge, cholecystectomy is indicated. If the patient has already
undergone cholecystectomy or if pancreatitis recurs, further evaluation by ERCP is indicated. This may reveal papillary stenosis,
in which case a pancreatic and, possibly, biliary sphincterotomy is indicated.
The role of genetic testing is emerging, and whether testing for cationic trypsinogen mutations, SPINK1 mutations, or CFTR
mutations should be performed remains unclear, because no effective treatment currently exists for these diseases.

If recurrent pancreatitis continues, ERCP with sphincter of Oddi manometry is indicated. This procedure is placed last in the
evaluation because patients with suspected sphincter of Oddi dysfunction (especially that resulting from dyskinesia of the
sphincter) have a very high rate of post-ERCP pancreatitis, and the possibility that ERCP may create iatrogenic complications
rather than cure the recurrent pancreatitis is a concern.

Guidelines

ACG Guidelines
In 2013, the Amercan College of Gastroenterology (ACG) issued guidelines for the management of acute pancreatitis (AP),
including the following[21] :

Because AP can usually be diagnosed based on clinical symptoms and laboratory testing, contrast-enhanced computed
tomography (CT) scanning and/or magnetic resonance imaging (MRI) of the pancreas should be performed only in the
absence of clinical improvement or if the diagnosis is unclear

Assessment of the patient’s hemodynamic status should occur immediately upon presentation, with resuscitative
measures initiated as necessary

Patients with systemic inflammatory response syndrome (SIRS) and/or organ failure should, if possible, be admitted to
an intensive care unit (ICU) or an intermediary care setting

All patients should receive aggressive hydration, unless this is precluded by cardiovascular and/or renal comorbidities;
aggressive intravenous (IV) hydration is most effective within the first 12-24 hours, with possibly little benefit derived from
its administration after this point

Within 24 hours of admission, patients with concurrent acute cholangitis should undergo endoscopic retrograde
cholangiopancreatography (ERCP); in high-risk patients, the risk of severe post-ERCP pancreatitis should be reduced
through the use of postprocedure rectal nonsteroidal anti-inflammatory drug (NSAID) suppositories and/or pancreatic
duct stents

The guidelines recommend against routinely using prophylactic antibiotics in cases of severe acute pancreatitis and/or
sterile necrosis; however, intervention in patients with infected necrosis may be delayed through the use of antibiotics
that do not penetrate the necrotic tissue

In mild cases of acute pancreatitis with no nausea and vomiting, oral feeding can be initiated immediately; enteral
nutrition should be used in severe cases to prevent infectious complications, and parenteral nutrition should be avoided

Regardless of the lesion's size, location, and/or extension, intervention is not necessary for asymptomatic pancreatic
and/or extrapancreatic necrosis and/or pseudocysts

Surgical, radiologic, and/or endoscopic drainage in stable patients with infected necrosis should be postponed (for 4
weeks if possible) to permit a wall to develop around the necrosis

AGA Guidelines
2018 AGA guidelines (initial AP management)

In March 2018, the American Gastroenterological Association (AGA) released guidelines on the initial management of acute
pancreatitis (AP).[45] These are outlined below.

The diagnosis of AP requires at least two of the following features: characteristic abdominal pain; biochemical evidence of
pancreatitis (ie, amylase or lipase elevated >3 times the upper limit of normal); and/or radiographic evidence of pancreatitis on
cross-sectional imaging.

Presentations of AP occur along a clinical spectrum and can be categorized as mild, moderately severe, or severe, based on
the recent revised Atlanta classification.

Most cases of AP (around 80%) are mild, with only interstitial changes of the pancreas without local or systemic complications.

Moderately severe pancreatitis is characterized by transient local or systemic complications or transient organ failure (< 48
hours), and severe AP is associated with persistent organ failure.

Necrotizing pancreatitis is characterized by the presence of pancreatic and/or peripancreatic necrosis, and is typically seen in
patients with moderately severe or severe AP.

There are two overlapping phases of AP, early and late. The early phase of AP takes place in the first 2 weeks after disease
onset, and the late phase can last weeks to months thereafter.

In patients with AP, the AGA suggests against the use of hydroxymethyl starch (HES) fluids.

In patients with predicted severe AP and necrotizing AP, the AGA suggests against the use of prophylactic antibiotics.

In patients with acute biliary pancreatitis and no cholangitis, the AGA suggests against the routine use of urgent endoscopic
retrograde cholangiopancreatography (ERCP).

In patients with AP, the AGA recommends early (within 24 hours) oral feeding as tolerated, rather than keeping the patient nil
per os (NPO).

In patients with AP and inability to feed orally, the AGA recommends enteral rather than parenteral nutrition.

In patients with predicted severe or necrotizing pancreatitis requiring enteral tube feeding, the AGA suggests either nasogastric
or nasojejunal route.

In patients with acute biliary pancreatitis, the AGA recommends cholecystectomy during the initial admission rather than after
discharge.

In patients with acute alcoholic pancreatitis, the AGA recommends brief alcohol intervention during admission.

2015 AGA guidelins (pancreatic cysts)

As of 2015, the AGA recommends the following in the diagnosis and management of asymptomatic neoplastic pancreatic
cysts[22] :

For asymptomatic mucinous cysts, a 2-year interval is recommended for a cyst of any size undergoing surveillance, with
surveillance being stopped after 5 years if there is no change.

Perform surgery only if there is more than one concerning feature on MRI confirmed on endoscopic ultrasonography
(EUS) and only in centers with high volumes of pancreatic surgery, and there should be no surveillance after surgery if
there is no invasive cancer or dysplasia.

The risk of malignant transformation of pancreatic cysts is approximately 0.24% per year, and the risk of cancer in cysts
without a significant change over a 5-year period is likely to be lower.

The small risk of malignant progression in stable cysts is likely outweighed by the costs of surveillance and the risks of
surgery.

Positive cytology on EUS-guided fine-needle aspiration (FNA) has the highest specificity for diagnosing malignancy; if
there is a combination of high-risk features on imaging, that is likely to increase the risk of malignancy even further.
Similarly, if a cyst has both a solid component and a dilated pancreatic duct (confirmed on both EUS and MRI), the
specificity for malignancy is likely to be high even in the absence of positive cytology.

There is lower immediate postoperative mortality, as well as long-term mortality, for patients who undergo surgery in high-
volume pancreatic centers.

It seems sensible to offer screening even after the cyst has been resected, provided the patients have not undergone
total pancreatectomy. Surveillance should continue as long as the patient remains a good candidate for surgery. MRI
every 2 years may be a reasonable approach for these patients. The clinician may elect to offer more frequent
surveillance in the case of invasive cancer resection, particularly if there is concern that the lesion has not been fully
resected.
WSES Guidelines
In June 2019, the World Society of Emergency Surgery (WSES) released updated guidelines for the management of severe
acute pancreatitis.[48] Their strong recommendations are summarized below.

Severity grading

Grade 1C recommendations

Severe acute pancreatitis is associated with persistent organ failure (cardiovascular, respiratory, and/or renal), and high
mortality. Both new classification systems, Revised Atlanta Classification and Determinant-based Classification of Acute
Pancreatitis Severity, are similar in establishing the diagnosis and severity of acute pancreatitis.

Patients who have persistent organ failure with infected necrosis have the highest risk of death.

Patients with organ failures should be admitted to an intensive care unit (ICU) whenever possible.

Diagnostic laboratory parameters

The cut-off value of serum amylase and lipase is normally defined to be three times the upper limit.

A hematocrit level above  44% represents an independent risk factor of pancreatic necrosis (grade 1B recommendation).

Imaging
Grade 1C recommendations

On admission, perform ultrasonography (US) to determine the etiology of acute pancreatitis (biliary).

When doubt exists, computed tomography (CT) scanning provides good evidence of the presence or absence of pancreatitis.

Assess all patients with severe acute pancreatitis with contrast-enhanced CT (CE-CT) scanning or magnetic resonance imaging
(MRI). Optimal timing for first the CE-CT assessment is 72-96 hours after symptomatic onset.

Consider MR cholangiopancreatography (MRCP) or endoscopic ultrasonography to screen for occult common bile duct stones
in patients with unknown etiology.

Follow-up imaging (all grade 1C recommendations)

In severe acute pancreatitis (CT scan severity index ≥ 3), a follow-up CE-CT scan is indicated 7-10 days from the initial CT scan.

Additional CE-CT scans are recommended only if the patient's clinical status deteriorates or fails to show continued
improvement, or when invasive intervention is considered.

Surgical intervention

The following are indications for surgical intervention (all grade IC recommendations):

As a continuum in a step-up approach after percutaneous/endoscopic procedure with the same indications

Abdominal compartment syndrome

Acute ongoing bleeding when an endovascular approach is unsuccessful

Bowel ischemia or acute necrotizing cholecystitis during acute pancreatitis

Bowel fistula extending into a peripancreatic collection

The following are indications for emergent endoscopic retrograde cholangiopancreatography (ERCP):

Routine ERCP with acute gallstone pancreatitis is not indicated (grade 1A recommendation).

ERCP in patients with acute gallstone pancreatitis and cholangitis is indicated (grade 1B recommendation).
Surgical strategies include the following:

Infected pancreatic necrosis: Percutaneous drainage as the first-line treatment (step-up approach) delays the surgical
treatment to a more favorable time or results in complete resolution of the infection in 25-60% of patients; it is
recommended as the first line of treatment (grade 1A recommendation).

Minimally invasive surgical strategies (transgastric endoscopic necrosectomy, video-assisted retroperitoneal debridement
[VARD]): These result in less postoperative new-onset organ failure but require more interventions (grade 1B
recommendation).

Mortality: There is insufficient evidence to support an open surgical, mini-invasive, or endoscopic approach (grade 1B
recommendation).

Consideration of the timing of cholecystectomy includes the following:

Laparoscopic cholecystectomy during the index admission is recommended in mild acute gallstone pancreatitis (grade
1A recommendation).

When ERCP and sphincterotomy are performed during the index admission, the risk for recurrent pancreatitis is reduced;
same admission cholecystectomy is still advised owing to an increased risk for other biliary complications (grade 1B
recommendation).

Open abdomen
Considerations regarding open abdominal surgery include the following:

Clinicians should be cautious not to over-resuscitate patients with early severe acute pancreatitis and to measure intra-
abdominal pressure regularly (grade 1C recommendation).

Avoid the open abdomen if other strategies can be used to mitigate or treat severe intra-abdominal hypertension (IAH) in
severe acute pancreatitis (grade 1C recommendation).

It is recommended not to use the open abdomen after necrosectomy for severe acute pancreatitis (unless severe IAH
mandates open abdomen as a mandatory procedure) (grade 1C recommendation).

It is recommend not to debride or undertake early necrosectomy if forced to undertake an early open abdomen due
abdominal compartment syndrome or visceral ischemia (grade 1A recommendation).

The use of negative pressure peritoneal therapy is recommended for open abdomen management (grade 1B
recommendation).

Timing for abdominal closure (grade 1B recommendation)

Early fascial and/or abdominal definitive closure should be the strategy for management of the open abdomen once any
requirements for ongoing resuscitation have ceased, the source control has been definitively reached, no concern regarding
intestinal viability persist, no further surgical reexploration is needed, and there are no concerns for abdominal compartment
syndrome.

Medication

Medication Summary
The goal of pharmacotherapy is to relieve pain and minimize complications. Currently, no medications are used to treat acute
pancreatitis specifically. Therapy is primarily supportive and involves intravenous (IV) fluid hydration, analgesics, antibiotics (in
severe pancreatitis), and treatment of metabolic complications (eg, hyperglycemia and hypocalcemia).

Analgesics, Other
Class Summary
Pain control is essential for quality patient care. It ensures patient comfort, promotes pulmonary toilet, and has sedating
properties, which are beneficial for patients who have sustained trauma or have painful lesions. Propoxyphene products were
withdrawn from the US market on November 19, 2010. The withdrawal was based on new data showing QT prolongation at
therapeutic doses. For more information, see the FDA MedWatch safety information.

Acetaminophen (Tylenol, Feverall, Aspirin Free Anacin)

Acetaminophen is a peripherally acting drug of choice for mild to moderate pain and elevation of body temperature.

Tramadol (Ultram, Ryzolt, Rybix)

Tramadol is a centrally acting analgesic for moderately severe pain. It inhibits the ascending pain pathways, altering perception
of and response to pain. It also inhibits reuptake of norepinephrine and serotonin.

Meperidine (Demerol)
Meperidine is a synthetic opioid narcotic analgesic for the relief of severe pain. It has multiple actions similar to those of
morphine. It may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses
of morphine.

Antibiotics, Other

Class Summary
Antibiotics are used to cover the microorganisms that may grow in biliary pancreatitis and acute necrotizing pancreatitis. The
empiric antibiotic regimen is usually based on the premise that enteric anaerobic and aerobic gram-bacilli microorganisms are
often the cause of pancreatic infections. Once culture sensitivities are obtained, the antibiotic regimen can be adjusted
accordingly.

Imipenem and cilastatin (Primaxin)

Imipenem is a thienamycin derivative with greater potency and broader antimicrobial spectrum than other beta-lactam
antibiotics. Cilastatin inhibits dehydropeptidase activity and reduces cilastatin metabolism. Imipenem-cilastatin is used for the
treatment of multiple-organism infections in which other agents either do not provide wide-spectrum coverage or are
contraindicated because of potential toxicity. The 2 agents are generally administered in a 1:1 ratio.

Ampicillin
Ampicillin has bactericidal activity against susceptible organisms. It is an alternative to amoxicillin when the patient is unable to
take medication orally.

Ceftriaxone (Rocephin)
Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity; it has lower efficacy against gram-
positive organisms and higher efficacy against resistant organisms. Ceftriaxone arrests bacterial growth by binding to 1 or more
penicillin-binding proteins.

Questions & Answers

Overview

How is acute pancreatitis treated?

What are the signs and symptoms of acute pancreatitis?

Which findings in a patient history may suggest acute pancreatitis?

Which physical findings suggest acute pancreatitis?

Which physical findings suggest severe necrotizing pancreatitis?

What is the role of lab testing in the diagnosis of acute pancreatitis?

What is the role of imaging studies in the diagnosis of acute pancreatitis?

Is genetic testing useful in the diagnosis of acute pancreatitis?

How is acute pancreatitis classified?

How is acute pancreatitis managed initially?

What is the role of antibiotic therapy in the management of acute pancreatitis?

When is surgical intervention indicated for acute pancreatitis?

What is pancreatitis?

How does the presentation of chronic pancreatitis differ from that of acute pancreatitis?

How is the diagnosis of acute pancreatitis confirmed?

How is acute pancreatitis managed?

What is the pancreas and what does it do?

How does the exocrine pancreas function?

How does a normal pancreas function?

Which factors may trigger acute pancreatitis?

What is the pathogenesis of acute pancreatitis following a cellular injury?

What is acute edematous pancreatitis?

What are the risk factors for acute renal failure in acute pancreatitis?

What is the etiology of acute pancreatitis?

Can gallstones cause acute pancreatitis?

Does alcohol cause acute pancreatitis?

How much alcohol is required to cause acute pancreatitis?

What are the risk factors for developing post-ERCP acute pancreatitis?

What is the role of abdominal trauma or injury in the development of acute pancreatitis?

Which drugs can cause acute pancreatitis?

Which infections can cause acute pancreatitis?

Which genes may cause hereditary pancreatitis?

What causes of hypercalcemia may lead to acute pancreatitis?

Which development abnormalities cause pancreatitis?

What is pancreas divisum?

What is annular pancreas?

How does sphincter of Oddi dysfunction cause acute pancreatitis?

Does hyperlipidemia cause acute pancreatitis?

Which tumors cause acute pancreatitis?

Which toxins cause acute pancreatitis?

Can acute pancreatitis be a complication of surgery?

Do vascular factors cause acute pancreatitis?

What is autoimmune pancreatitis?

What is the incidence of acute pancreatitis in the US?

What is the global incidence of acute pancreatitis?

What age groups are most affected by acute pancreatitis?

Is acute pancreatitis more prevalent in males or females?

Does acute pancreatitis have a racial predilection?

What is the mortality rate associated with acute pancreatitis?

What are the most common causes of death in patients with acute pancreatitis?

What is the difference between mild and severe acute pancreatitis?

Which methods are used to predict the outcome of acute pancreatitis?

Does the neutrophil-lymphocyte ratio (NLR) have prognostic value in severe acute pancreatitis?

How does nonalcoholic fatty liver affect the prognosis of acute pancreatitis?

How are pseudocysts detected in acute pancreatitis?

Which organisms may cause intra-abdominal infection in acute pancreatitis?

What is pancreatic necrosis and how is it diagnosed and treated?

Can acute pancreatitis cause intra-abdominal hemorrhage?

What education information should be provided to patients with acute pancreatitis?

Presentation

Which characteristics of abdominal pain suggest acute pancreatitis?

What are the symptoms of acute pancreatitis?

What is the focus of the medical history in a patient who presents with symptoms of acute pancreatitis?

Which physical findings suggest acute pancreatitis?

Which physical findings suggest severe necrotizing pancreatitis?

DDX

Which disorders should be included in the differential diagnoses of acute pancreatitis?

Workup

How is a diagnosis of acute pancreatitis confirmed?

What are the ACG guidelines for the management of acute pancreatitis?

What are the AGA guidelines for the initial management of acute pancreatitis and for the diagnosis/management of
asymptomatic neoplastic pancreatic cysts?

What are the ACG recommendations for the diagnosis and management of asymptomatic neoplastic pancreatic cysts?

What is the role of serum amylase and lipase testing in the diagnosis of acute pancreatitis?

What is the role of liver enzyme testing in the diagnosis of acute pancreatitis?

What is the role blood tests in the diagnosis of acute pancreatitis?

What is the role of a CBC count in the diagnosis of acute pancreatitis?

Does hemoconcentration suggest acute pancreatitis?

What is the role of C-reactive protein (CRP) testing in the diagnosis of acute pancreatitis?

When are arterial blood gases evaluated in acute pancreatitis?

Why are lactic dehydrogenase (LDH), BUN, and bicarbonate levels measured in acute pancreatitis?

What is the role of IgG4 testing in the diagnosis of acute pancreatitis?

What is the role of trypsin and trypsinogen-2 in the diagnosis of acute pancreatitis?

Is genetic testing useful in predicting the severity of acute pancreatitis?

What is the role of abdominal X-ray in the diagnosis of acute pancreatitis?

What is the role of abdominal ultrasonography in the diagnosis of acute pancreatitis?

What are the benefits of endoscopic ultrasonography (EUS) in the diagnosis of acute pancreatitis?

What is the role of endoscopic ultrasonography (EUS) in the diagnosis of acute pancreatitis?

What is the role of abdominal CT scanning in the diagnosis of acute pancreatitis?

What prognostic information is provided by abdominal CT scans of the pancreas?

What is the role of dynamic spiral CT scanning in the diagnosis of acute pancreatitis?

What is the normal density range finding for a healthy pancreas on CT scanning?

How is MRCP used in the diagnosis of acute pancreatitis?

What is the role of ERCP in the diagnosis of acute pancreatitis?

What are the risk factors for post-ERCP pancreatitis?

Can infected necrotizing pancreatitis be differentiated from sterile necrotizing pancreatitis using CT-guided needle aspiration?

Can infected necrotizing pancreatitis be differentiated from sterile necrotizing pancreatitis using EUS-guided needle aspiration?

How can genetic testing be used in the diagnosis of acute pancreatitis?

Which genetic mutations are associated with hereditary pancreatitis?

Which genetic mutations are associated with idiopathic pancreatitis?

Which genetic mutations may predispose an individual to develop acute pancreatitis?

How are mild and severe pancreatitis differentiated histologically?

What are the Ranson criteria for staging acute pancreatitis?

What are the limitations of the Random criteria for staging acute pancreatitis?

Does an elevated BUN level at admission indicate increased severity of acute pancreatitis?
What are the advantages and limitations of APACHE II scoring for acute pancreatitis?

Which biological markers can be used to stage acute pancreatitis?

Are there genetic markers for acute pancreatitis?

Treatment

How is mild acute pancreatitis managed?

How is biliary-caused pancreatitis managed?

How is brain injury-caused pancreatitis managed?

How is severe acute pancreatitis managed?

How is autoimmune pancreatitis managed?

When should patients be transferred to a skilled medical center for acute pancreatitis?

How long should patients with acute pancreatitis remain hospitalized?

How is hydration provided to patients with acute pancreatitis?

What are the guidelines for nutritional support in acute pancreatitis?

Should nasojejunal feedings be initiated in the treatment of acute pancreatitis?

Do nasojejunal tubes have an advantage over nasogastric tubes for enteral feeding in patients with acute pancreatitis?

When is TPN indicated in acute pancreatitis?

Which nutritional support method is the most effective in acute pancreatitis?

How are antibiotics used in the management of acute pancreatitis?

Is imipenem-cilastatin effective as a treatment of acute pancreatitis?

Are ciprofloxacin and metronidazole effective as a treatment of acute pancreatitis?

Is antibiotic prophylaxis recommended in severe pancreatitis?

Is lexipafant effective as a treatment for acute pancreatitis?

When is surgical intervention indicated in the treatment of acute pancreatitis?

When is cholecystectomy indicated in the treatment of gallstone pancreatitis?

How common is early cholecystectomy in nonsevere acute gallstone pancreatitis?

When is cholecystectomy indicated for severe acute gallstone pancreatitis?

How is pancreatic duct disruption in acute pancreatitis diagnosed and managed?

How are pancreatic pseudocysts differentiated from true cysts?

When is intervention indicated for pancreatic pseudocysts in patients with acute pancreatitis?

When is percutaneous aspiration of pancreatic pseudocysts indicated in patients with acute pancreatitis?

Can pancreatic pseudocysts be managed endoscopically?

How effective is transmural enterocystostomy for pancreatic pseudocysts?

When is surgery indicated for pancreatic pseudocysts in patients with acute pancreatitis?

How is infected pancreatic necrosis managed in patients with acute pancreatitis?

How are pancreatic abscesses treated in patients with acute pancreatitis?

How is acute pancreatitis prevented?

When is consultation required in the treatment of acute pancreatitis?

Which consultations are necessary in the treatment of alcohol-induced pancreatitis?

Which consultations are necessary for patients with hypertriglyceridemia- or hypercalcemia-induced pancreatitis?

Which consultations are indicated in the treatment of gallstones or microlithiasis in acute pancreatitis?

Which consultations are indicated in the treatment of medication-induced acute pancreatitis?

What routine follow-up is indicated after hospital discharge of patients with acute pancreatitis?

Are there guidelines for outpatient follow-up care for acute pancreatitis?

How is recurrent acute pancreatitis evaluated and managed?

Medications

What is the goal of pharmacotherapy for acute pancreatitis?

Contributor Information and Disclosures

Author

Jeffrey C F Tang, MD Senior Staff Gastroenterologist, Henry Ford Health System

Jeffrey C F Tang, MD is a member of the following medical societies: American College of Gastroenterology, American College
of Physicians, American Medical Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Coauthor(s)

Johnathon T Markus, MD Fellow, Department of Gastroenterology, Henry Ford Hospital

Johnathon T Markus, MD is a member of the following medical societies: American Association for the Study of Liver Diseases,
American Gastroenterological Association, American Medical Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American
College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

Tushar Patel, MB, ChB Professor of Medicine, Ohio State University Medical Center

Tushar Patel, MB, ChB is a member of the following medical societies: American Association for the Study of Liver Diseases
and American Gastroenterological Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Noel Williams, MD Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor,
Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada

Noel Williams, MD is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Paul Yakshe, MD Assistant Professor of Medicine, University of Minnesota, Medical Director of Pancreas and Biliary Clinic,
Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Fairview University Medical Center

Paul Yakshe, MD is a member of the following medical societies: American College of Gastroenterology, American Pancreatic
Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

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