2656 PART 10 Disorders of the Gastrointestinal System

endoscope that can be directed onto the surface of the pancreas through

the stomach or duodenum. EUS is not beneficial for the evaluation of

pancreas during acute pancreatitis. It is preferable to perform EUS after

the resolution of acute pancreatitis (~4 weeks) to detect any predisposing factors, including malignancy, choledocholithiasis, pancreatic

divisum, or ampullary lesions. EUS can be combined with ERCP in a

single session and is increasingly preferred for the diagnosis and management of choledocholithiasis in acute pancreatitis and pancreatic

neoplasm with biliary obstruction. EUS has been studied as a diagnostic modality for chronic pancreatitis. Criteria for abnormalities on

EUS in severe chronic pancreatic disease have been developed. There is

general agreement that the presence of five or more of the nine criteria

listed in Table 347-3 is highly predictive of chronic pancreatitis in the

correct clinical context. The sensitivity of EUS (81%; 95% CI, 70–89%)

to diagnose chronic pancreatitis is comparable to that of MRI/MRCP

(78%; 95% CI, 69–85%) and better than CT (75%; 95% CI, 66–83%);

however, nonspecific changes are commonly seen in the pancreas that

may be attributable to cigarette smoking, diabetes, or normal aging.

EUS also facilitates the delivery of nerve-blocking agents via fineneedle injection in patients suffering from pancreatic pain from

chronic pancreatitis (celiac plexus block) or cancer (celiac plexus

neurolysis). When clinically suspected, EUS imaging is more sensitive

than MDCT for the detection of pancreatic malignancy and permits

fine-needle aspiration/biopsy (FNA/B). Currently, EUS-guided FNA/B

is the diagnostic modality of choice for the acquisition of diagnostic

tissue and cyst fluid in patients with pancreatic masses and cystic

lesions, respectively.

TABLE 347-3 Endoscopic Ultrasonographic Criteria for Chronic

Pancreatitis (Total Criteria = 9)

DUCTAL PARENCHYMAL

Stones Echogenic strands

Hyperechoic main duct margins Echogenic foci

Main duct irregularity Lobular contour

Main duct dilatation Cysts

Visible side branches

TABLE 347-2 Causes of Hyperamylasemia and Hyperamylasuria

Pancreatic Disease

I. Pancreatitis

A. Acute

B. Chronic: ductal obstruction

C. Complications of pancreatitis

1. Pancreatic pseudocyst

2. Ascites caused by pancreatic duct disruption

3. Pancreatic necrosis

II. Pancreatic trauma

III. Pancreatic adenocarcinoma

Nonpancreatic Disorders

I. Renal insufficiency

II. Salivary gland lesions

A. Mumps

B. Calculus

C. Irradiation sialadenitis

D. Maxillofacial surgery

III. “Tumor” hyperamylasemia

A. Carcinoma of the lung, esophagus, breast, or ovary

IV. Macroamylasemia

V. Burns

VI. Diabetes mellitus, particularly when ketoacidosis is present

VII. Pregnancy

VIII. Renal transplantation

IX. Cerebral trauma

X. Drugs: opiates

Other Abdominal Disorders

I. Biliary tract disease: cholecystitis, choledocholithiasis

II. Intraabdominal disease

A. Perforated or penetrating peptic ulcer

B. Intestinal obstruction or inflammation

C. Ruptured ectopic pregnancy

D. Peritonitis

E. Aortic aneurysm

F. Postoperative hyperamylasemia

Although a pancreatogram during ERCP is the most specific and

sensitive test for evaluating the ductal anatomy, EUS and MRI/MRCP

have largely replaced ERCP in the diagnostic evaluation of pancreatic

disease to avoid the risk of complications. Therefore, ERCP is primarily

of therapeutic value after CT, EUS, or MRI and MRCP has detected

abnormalities requiring endoscopic treatment. ERCP is the most

sensitive modality for the detection of bile duct stones. In the management of acute biliary pancreatitis, ERCP should not be unduly delayed

in patients with high clinical suspicion of biliary obstruction. In

chronic pancreatitis, ERCP abnormalities in the main pancreatic duct

and side branches have been outlined by the Cambridge classification

(Fig. 347-2). The presence of ductal stenosis and irregularity can make

it difficult to distinguish chronic pancreatitis from pancreatic adenocarcinoma. It is important to be aware that ERCP changes interpreted

as indicating chronic pancreatitis actually may be due to the effects

of aging on the pancreatic duct, sequelae of a recent attack of acute

pancreatitis, or changes secondary to placement of pancreatic duct

stent. Although aging may cause impressive ductal alterations, it does

not affect the results of pancreatic secretin function tests. Pancreatic

adenocarcinoma is characterized by stenosis or obstruction of either

the pancreatic duct or the common bile duct; both ductal systems are

often abnormal (double-duct sign). When indicated, ERCP permits

acquisition of diagnostic tissue as in biopsy of ampullary lesions or

biliary brushings for distal bile duct strictures. Elevated serum amylase levels after ERCP have been reported in the majority of patients,

and clinical pancreatitis has been reported in 5–10% of patients. Until

recently, pancreatic duct stents were commonly placed to prevent postERCP pancreatitis. However, recent data suggest that periprocedural

administration of rectal indomethacin can decrease the incidence of

post-ERCP pancreatitis. Studies are currently underway comparing

rectal indomethacin alone versus combination with prophylactic pancreatic duct stents to prevent post-ERCP pancreatitis.

■ TESTS OF EXOCRINE PANCREATIC FUNCTION

Pancreatic function tests (Table 347-1) can be divided into the

following:

1. Direct stimulation of the pancreas by IV infusion of secretin followed

by collection and measurement of duodenal contents: The secretin

test, used to detect diffuse pancreatic disease, is based on the physiologic principle that the pancreatic secretory response is directly

related to the functional mass of pancreatic tissue. In the standard

assay, secretin is given IV in a dose of 0.2 μg/kg of synthetic human

secretin as a bolus. Normal values for the standard secretin test are

(1) volume output >2 mL/kg per h, (2) bicarbonate (HCO3

–

) concentration >80 mmol/L, and (3) HCO3

–

 output >10 mmol/L in 1 h. The

most reproducible measurement, giving the highest level of discrimination between normal subjects and patients with chronic pancreas

dysfunction, appears to be the maximal bicarbonate concentration.

A cutoff point <80 mmol/L is considered abnormal and suggestive

of reduced secretory function that is most commonly observed in

early chronic pancreatitis.

2. There may be a dissociation between the results of the secretin test

and other tests of absorptive function. For example, patients with

chronic pancreatitis often have abnormally low outputs of HCO3

–

after secretin but have normal fecal fat excretion. The secretin test

directly measures the secretory capacity of ductular epithelium,

whereas fecal fat excretion indirectly reflects intraluminal lipolytic

2657Acute and Chronic Pancreatitis CHAPTER 348

activity. Steatorrhea does not occur until intraluminal levels of

lipase are markedly reduced, underscoring the fact that only small

amounts of enzymes are necessary for intraluminal digestive activities. It must be emphasized that an abnormal secretin test result

suggests that pancreatic ductal secretory function is abnormal. This

is an early abnormality in chronic pancreatitis but should not be

considered diagnostic and must be interpreted within the proper

clinical context (for example, a patient with recurrent attacks of pancreatitis and persistent abdominal pain and Cambridge 2 changes

on imaging)

3. Measurement of fecal pancreatic enzymes such as elastase: Measurement of intraluminal digestion products (i.e., undigested muscle

fibers, stool fat, and fecal nitrogen) is discussed in Chap. 325. The

amount of human elastase in stool reflects the pancreatic output

of this proteolytic enzyme. Decreased fecal elastase-1 (FE-1) activity in stool is a test to detect severe EPI in patients with chronic

pancreatitis and cystic fibrosis. FE-1 levels >200 μg/g are normal,

levels of 100–200 μg/g are considered mild-moderate EPI, and levels

<100 μg/g are severe EPI. Although the test is simple and noninvasive, it can yield false-positive results if stools are not formed and

should not generally be used for the evaluation of a patient with

diarrhea. False-positive results have also been observed in diabetes

and irritable bowel syndrome.

Tests useful in the diagnosis of EPI and the differential diagnosis

of malabsorption are also discussed in Chaps. 325 and 348.

■ FURTHER READING

Conwell DL et al: American Pancreatic Association practice guidelines in chronic pancreatitis: Evidence-based report on diagnostic

guidelines. Pancreas 43:1143, 2014.

Hart PA et al: Endoscopic pancreas fluid collection: Methods and relevance for clinical care and translational science. Am J Gastroenterol

111:1258, 2016.

Petrov MS, Yadav D: Global epidemiology and holistic prevention of

pancreatitis. Nat Rev Gastroenterol Hepatol 16:175, 2019.

Singh VK et al: Diagnosis and management of chronic pancreatitis: A

review. JAMA 322:2422, 2019.

348 Acute and Chronic

Pancreatitis

Phil A. Hart, Darwin L. Conwell,

Somashekar G. Krishna

BIOCHEMISTRY AND PHYSIOLOGY OF

PANCREATIC EXOCRINE SECRETION

■ GENERAL CONSIDERATIONS

The pancreas secretes 1500–3000 mL of isosmotic alkaline (pH >8)

fluid per day containing ~20 enzymes. Pancreatic secretions provide

the enzymes and bicarbonate needed to perform the major digestive

activity of the gastrointestinal tract and provide an optimal pH for the

function of these enzymes.

■ REGULATION OF PANCREATIC SECRETION

Secretions from the exocrine pancreas are highly regulated by neurohormonal systems in a phasic manner (cephalic, gastric, and intestinal

phases). Gastric acid is the stimulus for the release of secretin from the

duodenal mucosa (S cells), which stimulates the secretion of water and

electrolytes from pancreatic ductal cells. Release of cholecystokinin

(CCK) from the duodenal and proximal jejunal mucosa (Ito cells)

is largely triggered by long-chain fatty acids, essential amino acids

(tryptophan, phenylalanine, valine, methionine), and gastric acid

itself. CCK evokes an enzyme-rich secretion from acinar cells in the

pancreas. The parasympathetic nervous system (via the vagus nerve)

exerts significant control over pancreatic secretion, particularly during

the cephalic phase. Secretion evoked by secretin and CCK depends on

the permissive roles of vagal afferent and efferent pathways. This is

particularly true for enzyme secretion, whereas water and bicarbonate

secretions are heavily dependent on the hormonal effects of secretin

and to a lesser extent CCK. Also, vagal stimulation affects the release

of vasoactive intestinal peptide (VIP), a secretin agonist. Pancreatic

exocrine secretion is also influenced by inhibitory neuropeptides

including somatostatin, pancreatic polypeptide, peptide YY, neuropeptide Y, enkephalin, pancreastatin, calcitonin gene–related peptides,

glucagon, and galanin. Pancreatic polypeptide and peptide YY may act

primarily on nerves outside the pancreas, while somatostatin acts at

multiple sites.

■ WATER AND ELECTROLYTE SECRETION

Bicarbonate is the ion of primary physiologic importance within pancreatic secretion. The ductal cells secrete bicarbonate predominantly

derived from plasma (93%) more than from intracellular metabolism

(7%). Bicarbonate enters the duct lumen through the sodium bicarbonate cotransporter with depolarization caused by chloride efflux

through the cystic fibrosis transmembrane conductance regulator

(CFTR). Secretin and VIP bind at the basolateral surface and cause an

increase in secondary messenger intracellular cyclic AMP and act on

the apical surface of the ductal cells opening the CFTR, which promotes

secretion. CCK, acting as a neuromodulator, markedly potentiates the

stimulatory effects of secretin. Acetylcholine also plays an important

role in ductal cell secretion. Intraluminal bicarbonate secreted from the

ductal cells helps neutralize gastric acid, increases the solubility of fatty

acids and bile acids, maintains an optimal pH for pancreatic and brush

border enzymes, and prevents intestinal mucosal damage.

■ ENZYME SECRETION

The acinar cell is highly compartmentalized for the production and

secretion of pancreatic enzymes. Proteins synthesized by the rough

endoplasmic reticulum are processed in the Golgi and then targeted

to the appropriate site: zymogen granules, lysosomes, or other cell

compartments. The zymogen granules migrate to the apical region of

the acinar cell awaiting the appropriate neural or hormonal stimulatory

response. The pancreas secretes amylolytic, lipolytic, and proteolytic

enzymes into the duct lumen. Amylolytic enzymes, such as amylase,

hydrolyze starch to oligosaccharides and to the disaccharide maltose.

The lipolytic enzymes include lipase, phospholipase A2

, and cholesterol

esterase. Bile salts inhibit lipase in isolation, but colipase, another

constituent of pancreatic secretion, binds to lipase and prevents this

inhibition. Bile salts activate phospholipase A and cholesterol esterase.

Proteolytic enzymes include endopeptidases (trypsin, chymotrypsin),

which act on internal peptide bonds of proteins and polypeptides;

exopeptidases (carboxypeptidases, aminopeptidases), which act on

the free carboxyl- and amino-terminal ends of peptides, respectively;

and elastase. The proteolytic enzymes are secreted as inactive zymogen

precursors. Ribonucleases (deoxyribonucleases, ribonuclease) are also

secreted. Enterokinase, an enzyme found in the duodenal mucosa

(“brush border”), cleaves the lysine-isoleucine bond of trypsinogen to

form trypsin. Trypsin then activates the other proteolytic zymogens

and phospholipase A2

 in a cascade. The nervous system initiates pancreatic enzyme secretion. The neurologic stimulation is cholinergic,

involving extrinsic innervation by the vagus nerve and subsequent

innervation by intrapancreatic cholinergic nerves. The stimulatory

neurotransmitters are acetylcholine and gastrin-releasing peptides.

These neurotransmitters activate calcium-dependent secondary messenger systems, resulting in the release of zymogens into the pancreas

duct. VIP is present in intrapancreatic nerves and potentiates the

effect of acetylcholine. In contrast to other species, there are no CCK

receptors on acinar cells in humans. CCK in physiologic concentrations stimulates pancreatic secretion by stimulating afferent vagal and

intrapancreatic nerves.

2658 PART 10 Disorders of the Gastrointestinal System

■ AUTOPROTECTION OF THE PANCREAS

Autodigestion of the pancreas is prevented by (1) the packaging of

pancreatic proteases in the precursor (proenzyme) form, (2) intracellular calcium homeostasis (low intracellular calcium in the cytosol of

the acinar cell promotes the destruction of spontaneously activated

trypsin), (3) acid-base balance, and (4) the synthesis of protective

protease inhibitors (pancreatic secretory trypsin inhibitor [PSTI] or

SPINK1), which can bind and inactivate ~20% of intracellular trypsin

activity. Chymotrypsin C can also lyse and inactivate trypsin. These

protease inhibitors are found in acinar cells, pancreatic secretions, and

the α1

- and α2

-globulin fractions of plasma. Loss of any of these four

protective mechanisms leads to premature enzyme activation, autodigestion, and ultimately acute pancreatitis.

■ ENTEROPANCREATIC AXIS AND

FEEDBACK INHIBITION

Pancreatic enzyme secretion is controlled, at least in part, by a negative

feedback mechanism induced by the presence of active serine proteases

in the duodenum and nutrients in the distal small intestine. For example, perfusion of the duodenal lumen with phenylalanine (stimulates

early digestion) causes a prompt increase in plasma CCK levels as well

as increased secretion of chymotrypsin and other pancreatic enzymes.

However, simultaneous perfusion with trypsin (stimulates late digestion) blunts both responses. Conversely, perfusion of the duodenal

lumen with protease inhibitors actually leads to enzyme hypersecretion. Available evidence supports the concept that the duodenum contains a peptide called CCK-releasing factor (CCK-RF) that is involved

in stimulating CCK release. It appears that serine proteases inhibit

pancreatic secretion by inactivating a CCK-releasing peptide in the

lumen of the small intestine. Thus, the integrative result of both bicarbonate and enzyme secretion depends on a feedback process for both

bicarbonate and pancreatic enzymes. Acidification of the duodenum

releases secretin, which stimulates vagal and other neural pathways to

activate pancreatic duct cells, which secrete bicarbonate. This bicarbonate then neutralizes the duodenal acid, and the feedback loop is

completed. Dietary proteins bind proteases, thereby leading to an

increase in free CCK-RF. CCK is then released into the blood in physiologic concentrations, acting primarily through the neural pathways

(vagal-vagal). This leads to acetylcholine-mediated pancreatic enzyme

secretion. Proteases continue to be secreted from the pancreas until

the protein within the duodenum is digested. At this point, pancreatic

protease secretion is reduced to basic levels, thus completing this step

in the feedback process. Additional hormonal feedback inhibition of

pancreatic enzyme secretion occurs via peptide YY and glucagon-like

peptide-1 following lipid or carbohydrate exposure to the ileum.

ACUTE PANCREATITIS

■ GENERAL CONSIDERATIONS

Recent U.S. estimates indicate that acute pancreatitis is the most

common inpatient principal gastrointestinal diagnosis, responsible for >250,000 hospitalizations per year. The annual incidence

ranges from 15–45/100,000 persons, depending on the distribution of etiologies (e.g., alcohol, gallstones, metabolic factors, drugs

[Table 348-1]) and country of study. The median length of hospital stay is

4 days, with a median hospital cost of ~$6000 and a mortality of ~1%.

The estimated cost annually approaches $3 billion. Hospitalization

rates increase with age and are higher among blacks and men. The

age-adjusted rate of hospital discharges with an acute pancreatitis diagnosis increased by 62% between 1988 and 2004. From 2000 to 2009,

the rate increased by 30%. Thus, the incidence of acute pancreatitis

continues to rise and is associated with substantial health care costs.

■ ETIOLOGY AND PATHOGENESIS

There are many causes of acute pancreatitis (Table 348-1), and the

mechanisms by which each of these conditions triggers pancreatic

inflammation have not been fully elucidated. Gallstones and alcohol

account for 80–90% of identified cases of acute pancreatitis in the

United States. Gallstones continue to be the leading cause of acute

TABLE 348-1 Causes of Acute Pancreatitis

Common Causes

Gallstones (including microlithiasis)

Alcohol (acute and chronic alcoholism)

Hypertriglyceridemia

Endoscopic retrograde cholangiopancreatography (ERCP), especially after

biliary manometry

Idiopathic

Uncommon Causes

Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline,

valproic acid, 5-aminosalicylic acid [5-ASA])

Connective tissue disorders and thrombotic thrombocytopenic purpura (TTP)

Pancreatic cancer

Hypercalcemia

Periampullary diverticulum

Pancreas divisuma

Hereditary pancreatitis

Cystic fibrosis

Renal failure

Infections (mumps, coxsackievirus, cytomegalovirus, echovirus, parasites)

Autoimmune (e.g., type 1 and type 2)

Trauma (especially blunt abdominal trauma)

Postoperative (abdominal and nonabdominal operations)

Causes to Consider in Patients with Recurrent Bouts of Acute

Pancreatitis without an Obvious Etiology

Occult disease of the biliary tree or pancreatic ducts, especially microlithiasis,

biliary sludge

Alcohol abuse

Metabolic: Hypertriglyceridemia, hypercalcemia

Anatomic: Pancreas divisuma

Pancreatic cancer

Intraductal papillary mucinous neoplasm (IPMN)

Hereditary pancreatitis

Cystic fibrosis

Idiopathic

a

Pancreas divisum is not believed to cause acute pancreatitis in isolation of another

disease precipitant.

pancreatitis in most series (30–60%). The risk of acute pancreatitis

in patients with at least one gallstone <5 mm in diameter is fourfold greater than that in patients with larger stones. Alcohol is the

second most common cause, responsible for 15–30% of cases in the

United States. The incidence of pancreatitis in alcoholics is surprisingly

low (5/100,000), indicating that in addition to the amount of alcohol

ingested, other factors affect a person’s susceptibility to pancreatic

injury, such as cigarette smoking and genetic predisposition. Acute

pancreatitis occurs in 5–10% of patients following endoscopic retrograde cholangiopancreatography (ERCP); however, this risk can be

decreased with proper patient selection and the use of a prophylactic

pancreatic duct stent and/or rectal nonsteroidal anti-inflammatory

drugs (NSAIDs; indomethacin). Risk factors for post-ERCP pancreatitis include minor papilla sphincterotomy, suspected sphincter of

Oddi dysfunction, prior history of post-ERCP pancreatitis, age <60

years, more than two contrast injections into the pancreatic duct, and

endoscopist experience.

Hypertriglyceridemia is the cause of acute pancreatitis in 1–4%

of cases; serum triglyceride levels are usually >1000 mg/dL. Most

patients with hypertriglyceridemic pancreatitis have undiagnosed or

uncontrolled diabetes mellitus. An additional subset has an underlying

derangement in lipid metabolism, probably unrelated to pancreatitis.

Such patients are prone to recurrent episodes of pancreatitis. Any factor

(e.g., alcohol or medications, such as oral contraceptives) that causes an

abrupt increase in serum triglycerides can potentially precipitate a bout

2659Acute and Chronic Pancreatitis CHAPTER 348

of acute pancreatitis. Patients with a deficiency of apolipoprotein CII

have an increased incidence of pancreatitis; apolipoprotein CII activates lipoprotein lipase, which is important in clearing chylomicrons

from the bloodstream. Although frequently entertained, <2% of cases

of acute pancreatitis are drug related. Drugs cause pancreatitis either by

a hypersensitivity reaction or by the generation of a toxic metabolite,

although in some cases, it is not clear which of these mechanisms is

operative (Table 348-1).

Pathologically, acute pancreatitis ranges from interstitial pancreatitis

(pancreas blood supply maintained), which is generally self-limited,

to necrotizing pancreatitis (pancreas blood supply interrupted). Autodigestion is a currently accepted pathogenic theory resulting when

proteolytic enzymes (e.g., trypsinogen, chymotrypsinogen, proelastase,

and lipolytic enzymes such as phospholipase A2

) are activated in the

pancreas acinar cell compartment rather than the intestinal lumen. A

number of factors (e.g., endotoxins, exotoxins, viral infections, ischemia, oxidative stress, lysosomal calcium, direct trauma) are believed

to facilitate premature activation of trypsin. Activated proteolytic

enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but can also activate other enzymes, such as elastase and

phospholipase A2

. Spontaneous activation of trypsin also can occur,

resulting in autodigestion.

■ ACTIVATION OF PANCREATIC ENZYMES IN THE

PATHOGENESIS OF ACUTE PANCREATITIS

Several studies have suggested that pancreatitis is a disease that evolves

in three phases. The initial phase is characterized by intrapancreatic

digestive enzyme activation and acinar cell injury. Trypsin activation

appears to be mediated by lysosomal hydrolases such as cathepsin

B that become colocalized with digestive enzymes in intracellular

organelles; it is currently believed that acinar cell injury is the consequence of trypsin activation. The second phase of pancreatitis involves

the activation, chemoattraction, and sequestration of leukocytes and

macrophages in the pancreas, resulting in an enhanced intrapancreatic inflammatory reaction. Neutrophil depletion induced by prior

administration of an antineutrophil serum has been shown to reduce

the severity of experimentally induced pancreatitis. There is also evidence to support the concept that neutrophils can activate trypsinogen.

Thus, intrapancreatic acinar cell activation of trypsinogen could be a

two-step process (i.e., an early neutrophil-independent and a later neutrophil-dependent phase). The third phase of pancreatitis is due to the

effects of activated proteolytic enzymes and cytokines, released by the

inflamed pancreas, on distant organs. Activated proteolytic enzymes,

especially trypsin, not only digest pancreatic and peripancreatic tissues

but also activate other enzymes such as elastase and phospholipase

A2

. The active enzymes and cytokines then digest cellular membranes and cause proteolysis, edema, interstitial hemorrhage, vascular

damage, coagulation necrosis, fat necrosis, and cellular necrosis in

the parenchyma. Cellular injury and death result in the liberation of

bradykinin peptides, vasoactive substances, and histamine that can

produce vasodilation, increased vascular permeability, and edema with

profound effects on other organs. The systemic inflammatory response

syndrome (SIRS) and acute respiratory distress syndrome (ARDS), as

well as multiorgan failure, may occur as a result of this cascade of local

and distant effects.

A number of genetic factors can increase the susceptibility and/or

modify the severity of pancreatic injury in acute pancreatitis, recurrent

acute pancreatitis, and chronic pancreatitis. All the major genetic susceptibility factors center on the control of trypsin activity within the

pancreatic acinar cell, in part because they were identified as candidate

genes linked to intrapancreatic trypsin control. Six genetic variants

have been identified as being associated with susceptibility to pancreatitis. The genes that have been identified include (1) cationic trypsinogen gene (PRSS1), (2) pancreatic secretory trypsin inhibitor (SPINK1),

(3) the cystic fibrosis transmembrane conductance regulator gene

(CFTR), (4) the chymotrypsin C gene (CTRC), (5) the calcium-sensing

receptor (CASR), and (6) claudin-2 (CLDN2). Among these variants,

only PRSS1 mutations are sufficient to precipitate acute pancreatitis in

the absence of other risk factors, whereas the other variants are disease

modifiers. Investigations of other genetic variants are currently underway, and new genes will be added to this list in the future.

APPROACH TO THE PATIENT

Abdominal Pain

Abdominal pain is the major symptom of acute pancreatitis. Pain

may vary from mild discomfort to severe, constant, and incapacitating distress. Characteristically, the pain, which is steady and boring

in character, is located in the epigastrium region and may radiate to

the back, chest, flanks, and lower abdomen. Nausea, vomiting, and

abdominal distention due to gastric and intestinal hypomotility are

also frequent complaints.

Physical examination frequently reveals a distressed and anxious

patient. Low-grade fever, tachycardia, and hypotension are common. Shock is not unusual and may result from (1) hypovolemia

secondary to exudation of blood and plasma proteins into the

retroperitoneal space; (2) increased formation and release of kinin

peptides, which cause vasodilation and increased vascular permeability; and (3) systemic effects of proteolytic and lipolytic enzymes

released into the circulation. Jaundice occurs infrequently; when

present, it may be a consequence of extrinsic compression due to

peripancreatic edema or a pancreatic head mass or of intraductal

obstruction from a common bile duct stone or sludge. Erythematous skin nodules due to subcutaneous fat necrosis rarely occur. In

10–20% of patients, there are pulmonary findings, including basilar

rales, atelectasis, and pleural effusion, the latter most frequently

left-sided. Abdominal tenderness and muscle rigidity are present

to a variable degree, but compared with the intense pain, these

signs may be less impressive. Bowel sounds are usually diminished

or absent. An enlarged pancreas from an acute fluid collection,

walled-off necrosis, or a pseudocyst may be palpable in the upper

abdomen later in the course of the disease (i.e., 4–6 weeks). A faint

blue discoloration around the umbilicus (Cullen’s sign) may occur

as the result of hemoperitoneum, and a blue-red-purple or greenbrown discoloration of the flanks (Turner’s sign) reflects tissue

breakdown of hemoglobin from severe necrotizing pancreatitis

with hemorrhage; both findings are rare but reflect an increased

clinical severity.

■ LABORATORY DATA

Serum amylase and lipase values threefold or more above normal are

strongly supportive of the diagnosis if alternate etiologies, including

gut perforation, ischemia, and infarction, are excluded. However, it

should be noted that there is no correlation between the severity of

pancreatitis and the degree of serum lipase and amylase elevations or

serial trends. After 3–7 days, even with continuing evidence of pancreatitis, total serum amylase values tend to return toward normal.

However, pancreatic lipase levels may remain elevated for 7–14 days.

It should be recognized that amylase elevations in serum and urine

occur in many conditions other than pancreatitis (see Chap. 347,

Table 347-2). Importantly, patients with acidemia (arterial pH ≤7.32)

may have spurious elevations in serum amylase. This finding explains

why patients with diabetic ketoacidosis may have marked elevations in

serum amylase without any other evidence of acute pancreatitis. On the

other hand, serum amylase levels can be spuriously low in the setting of

severe hypertriglyceridemia. Serum lipase activity increases in parallel

with amylase activity and is more specific than amylase, making it the

preferred test. A serum lipase measurement can be instrumental in differentiating a pancreatic or nonpancreatic cause for hyperamylasemia.

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

Patients with more severe disease may show hemoconcentration with

hematocrit values >44% and/or prerenal azotemia with a blood urea

nitrogen (BUN) level >22 mg/dL resulting from loss of plasma into the

retroperitoneal space and peritoneal cavity.

Hemoconcentration may be the harbinger of more severe disease, whereas azotemia is a significant risk factor for mortality.

Hyperglycemia is common and is due to multiple factors, including

2660 PART 10 Disorders of the Gastrointestinal System

decreased insulin release, increased glucagon release, and increased

output of adrenal glucocorticoids and catecholamines. Hypocalcemia

occurs in ~25% of patients, and its pathogenesis is incompletely understood. Although earlier studies suggested that the response of the parathyroid gland to a decrease in serum calcium is impaired, subsequent

observations have failed to confirm this phenomenon. Intraperitoneal

saponification of calcium by fatty acids in areas of fat necrosis occurs

occasionally, with large amounts (up to 6.0 g) dissolved or suspended

in ascitic fluid. Such “soap formation” may also be significant in

patients with pancreatitis, mild hypocalcemia, and little or no obvious

ascites. Hyperbilirubinemia (serum bilirubin >4.0 mg/dL) occurs in

~10% of patients. However, jaundice is transient, and serum bilirubin

levels return to normal in 4–7 days. Serum alkaline phosphatase and

transaminase levels may also be transiently elevated and parallel serum

bilirubin values. Elevations of alanine aminotransferase (ALT) >3× the

upper limit of normal are strongly associated with a gallstone etiology

in patients with acute pancreatitis. Approximately 5–10% of patients

have hypoxemia (arterial Po2

 ≤60 mmHg), which may herald the onset

of ARDS. Finally, the electrocardiogram is occasionally abnormal in

acute pancreatitis with ST-segment and T-wave abnormalities simulating myocardial ischemia.

An abdominal ultrasound is recommended in the emergency ward

as the initial diagnostic imaging modality and is most useful to evaluate

for gallstones and common bile duct dilation.

The Revised Atlanta Criteria have clearly outlined the morphologic features of acute pancreatitis on computed tomography (CT)

scan as follows: (1) interstitial pancreatitis, (2) necrotizing pancreatitis, (3) acute pancreatic fluid collection, (4) pancreatic pseudocyst,

(5) acute necrotic collection (ANC), and (6) walled-off necrosis

(WON) (Table 348-2 and Fig. 348-1). Radiologic studies useful in

the diagnosis of acute pancreatitis are discussed in Chap. 347 and

listed in Table 347-1.

■ DIAGNOSIS

Any severe acute pain in the abdomen or back should suggest the possibility of acute pancreatitis. The diagnosis is established by two of the

following three criteria: (1) typical abdominal pain in the epigastrium

that may radiate to the back, (2) threefold or greater elevation in serum

lipase and/or amylase, and (3) confirmatory findings of acute pancreatitis on cross-sectional abdominal imaging. Although not required for

diagnosis, markers of severity may include hemoconcentration (hematocrit >44%), admission azotemia (BUN >22 mg/dL), SIRS, and signs

of organ failure (Table 348-3).

The differential diagnosis should include the following disorders:

(1) perforated viscus, especially peptic ulcer; (2) acute cholecystitis

and biliary colic; (3) acute intestinal obstruction; (4) mesenteric

vascular occlusion; (5) renal colic; (6) inferior myocardial infarction;

(7) dissecting aortic aneurysm; (8) connective tissue disorders with

vasculitis; (9) pneumonia; and (10) diabetic ketoacidosis. It may be

difficult to differentiate acute cholecystitis from acute pancreatitis,

because an elevated serum amylase may be found in both disorders.

Pain of biliary tract origin is more right sided or epigastric than

periumbilical or left upper quadrant and can be more severe; ileus is

usually absent. Ultrasound is helpful in establishing the diagnosis of

cholelithiasis and cholecystitis. Intestinal obstruction due to mechanical factors can be differentiated from pancreatitis by the history of

crescendo-decrescendo pain, findings on abdominal examination,

and CT of the abdomen showing changes characteristic of mechanical

obstruction. Acute mesenteric vascular occlusion is usually suspected

in elderly debilitated patients with leukocytosis, abdominal distention, and bloody diarrhea, confirmed by CT or magnetic resonance

angiography. Vasculitides secondary to systemic lupus erythematosus

and polyarteritis nodosa may be confused with pancreatitis, especially

because pancreatitis may develop as a complication of these diseases.

Diabetic ketoacidosis is often accompanied by abdominal pain and

TABLE 348-2 Revised Atlanta Definitions of Morphologic Features of Acute Pancreatitis

DEFINITION COMPUTED TOMOGRAPHY FEATURES

Types of Acute Pancreatitis

Interstitial pancreatitis Acute inflammation of the pancreatic parenchyma and

peripancreatic tissues, but without recognizable tissue

necrosis

Pancreatic parenchyma enhancement by IV contrast agent and without

peripancreatic necrosis

Necrotizing

pancreatitis

Inflammation associated with pancreatic parenchymal

and/or peripancreatic necrosis

Lack of pancreatic parenchymal enhancement by IV contrast agent and/or presence

of findings of peripancreatic necrosis (see below—ANC and WON)

Morphologic Features

Acute pancreatic fluid

collection

Peripancreatic fluid associated with interstitial

edematous pancreatitis with no associated

peripancreatic necrosis. This term applies only to areas

of peripancreatic fluid seen within the first 4 weeks after

onset of interstitial edematous pancreatitis and without

the features of a pseudocyst.

Occurs in the setting of interstitial pancreatitis

Homogeneous collection with fluid density

Confined by normal peripancreatic fascial planes

No definable wall encapsulating the collection

Adjacent to pancreas (no intrapancreatic extension)

Pancreatic

pseudocyst

An encapsulated collection of fluid with a well-defined

inflammatory wall usually outside the pancreas

with minimal or no necrosis. This entity usually

occurs >4 weeks after onset of interstitial edematous

pancreatitis.

Well circumscribed, usually round or oval

Homogeneous fluid density

No solid component

Well-defined wall; that is, completely encapsulated

Maturation usually requires >4 weeks after onset of acute pancreatitis; occurs after

interstitial pancreatitis

Acute necrotic

collection (ANC)

A collection containing variable amounts of both fluid

and necrosis associated with necrotizing pancreatitis;

the necrosis can involve the pancreatic parenchyma

and/or the peripancreatic tissues.

Occurs in the setting of acute necrotizing pancreatitis

Heterogeneous and nonliquid density of varying degrees in different locations (some

appear homogeneous early in their course)

No definable wall encapsulating the collection

Location—intrapancreatic and/or extrapancreatic

Walled-off necrosis

(WON)

A mature, encapsulated collection of pancreatic and/

or peripancreatic necrosis that has developed a

well-defined inflammatory wall. WON usually occurs

>4 weeks after onset of acute necrotizing pancreatitis.

Heterogeneous with liquid and nonliquid density with varying degrees of loculations

(some may appear homogeneous)

Well-defined wall; that is, completely encapsulated

Location—intrapancreatic and/or extrapancreatic

Maturation usually requires >4 weeks after onset of acute necrotizing pancreatitis

Source: Data from P Banks et al: Gut 62:102, 2013.

2661Acute and Chronic Pancreatitis CHAPTER 348

elevated total serum amylase levels, thus closely mimicking acute

pancreatitis; however, the serum lipase level is often not elevated in

diabetic ketoacidosis, and pancreas imaging is normal.

■ CLINICAL COURSE, DEFINITIONS,

AND CLASSIFICATIONS

The Revised Atlanta Criteria define (1) phases of acute pancreatitis,

(2) severity of acute pancreatitis, and (3) radiographic definitions, as

outlined below.

Phases of Acute Pancreatitis Two phases of acute pancreatitis

have been defined, early (<2 weeks) and late (>2 weeks), which primarily describe the hospital course of the disease. In the early phase of

acute pancreatitis, which lasts 1–2 weeks, severity is defined by clinical

parameters rather than morphologic findings. Most patients exhibit

SIRS, and if this persists, patients are predisposed to organ failure.

Three organ systems should be assessed to define organ failure: respiratory, cardiovascular, and renal. Organ failure is defined as a score

of 2 or more for one of these three organ systems using the modified

Marshall scoring system. Persistent organ failure (>48 h) is the most

important clinical finding regarding severity of the acute pancreatitis

episode. Organ failure that affects more than one organ is considered

multisystem organ failure. CT imaging is usually not needed or recommended during the first 48 h of admission in acute pancreatitis.

The late phase is characterized by a protracted course of illness and

may require imaging to evaluate for local complications. The critical

clinical parameter of severity, as in the early phase, is persistent organ

failure. These patients may require supportive measures such as renal

dialysis, ventilator support, or need for supplemental nutrition via a

nasojejunal or parenteral route. The radiographic feature of greatest

importance to recognize in this phase is the development of necrotizing pancreatitis on CT imaging. Necrosis is associated with prolonged

hospitalization and, if infected, may require intervention (percutaneous, endoscopic, and/or surgical).

TABLE 348-3 Severe Acute Pancreatitis

Risk Factors for Severity

• Age >60 years

• Obesity, BMI >30 kg/m2

• Comorbid disease (based on Charlson comorbidity index)

Markers of Severity at Admission or within 24 h

• SIRS—defined by presence of 2 or more criteria:

• Core temperature <36° or >38°C

• Heart rate >90 beats/min

• Respirations >20/min or Pco2

 <32 mmHg

• White blood cell count >12,000/μL, <4000/μL, or 10% bands

• APACHE II (≥8 at 24 h)

• Hemoconcentration (hematocrit >44%)

• Admission BUN (>22 mg/dL)

• BISAP score (≥3 present)

• (B) BUN >25 mg/dL

• (I) Impaired mental status

• (S) SIRS: ≥2 of 4 present

• (A) Age >60 years

• (P) Pleural effusion

• Organ failure (Modified Marshall score) (≥1 present):

• Cardiovascular: systolic BP <90 mmHg, heart rate >130 beats/min

• Pulmonary: Pao2

 <60 mmHg

• Renal: serum creatinine >2.0 mg/dL

Markers of Severity during Hospitalization

• Persistent organ failure (≥48 h)

• Pancreatic or extrapancreatic necrosis

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; BISAP,

Bedside Index of Severity in Acute Pancreatitis; BMI, body mass index; BP, blood

pressure; BUN, blood urea nitrogen; SIRS, systemic inflammatory response syndrome.

Severity of Acute Pancreatitis Three classes of severity have

been defined: mild, moderately severe, and severe. Mild acute pancreatitis

is without local complications or organ failure. Most patients with

interstitial acute pancreatitis have mild pancreatitis. In mild acute pancreatitis, the disease is self-limited and subsides spontaneously, usually

within 3–7 days after onset. Oral intake can be resumed if the patient

is hungry, has normal bowel function, and is without nausea and

vomiting. Typically, a clear or full liquid diet has been recommended

for the initial meal; however, a low-fat solid diet is a reasonable choice

following recovery from mild acute pancreatitis.

Moderately severe acute pancreatitis is characterized by transient

organ failure (i.e., it resolves in <48 h) or local or systemic complications in the absence of persistent organ failure. These patients may or

may not have necrosis but may develop a local complication such as

a fluid collection that requires a prolonged hospitalization >1 week.

As with mild acute pancreatitis, the mortality rate for these patients

remains low.

Severe acute pancreatitis is characterized by persistent organ failure

(>48 h), involving one or more organs. A CT scan or magnetic resonance imaging (MRI) should be obtained to assess for necrosis and/

or complications. If a local complication is encountered, management

is dictated by clinical symptoms, evidence of infection, the maturity

of fluid collection, and clinical stability of the patient. Prophylactic

antibiotics are no longer recommended for severe acute pancreatitis.

Imaging in Acute Pancreatitis Two types of pancreatitis are

recognized on imaging as interstitial or necrotizing based on pancreatic

perfusion. CT imaging with IV contrast is best evaluated 3–5 days

into hospitalization if patients are not responding to supportive care

to assess for local complications such as necrosis. Recent studies

report the overutilization of CT imaging within 72 h for acute pancreatitis, including those with a mild severity of disease. The Revised

Atlanta Criteria also outline the terminology for local complications

and fluid collections along with a CT imaging template to guide

reporting of findings. Local morphologic features are summarized in

Table 348-2. Interstitial pancreatitis occurs in 90–95% of admissions

for acute pancreatitis and is characterized by diffuse gland enlargement, homogenous contrast enhancement, and mild inflammatory

changes or peripancreatic stranding. Symptoms generally resolve with

a week of hospitalization. Necrotizing pancreatitis occurs in 5–10% of

acute pancreatitis admissions and may not evolve until several days

of hospitalization. It is characterized by lack of pancreatic parenchymal enhancement by intravenous contrast agent and/or presence of

findings of peripancreatic necrosis. The natural history of pancreatic

and peripancreatic necrosis is variable because it may remain solid

or liquefy, remain sterile or become infected, and persist or disappear

over time. Importantly, those with only extrapancreatic necrosis have

a more favorable prognosis than patients with pancreatic necrosis

(with or without extrapancreatic necrosis). CT identification of local

complications, particularly necrosis, is critical in patients who are

not responding to therapy because patients with infected and sterile

necrosis are at greatest risk of mortality (Figs. 348-1 and 348-2). The

median prevalence of organ failure is >50% in necrotizing pancreatitis,

and is perhaps slightly higher in infected versus sterile necrosis. With

single-organ system failure, the mortality is 3–10%, but increases to

nearly 50% with multiorgan failure.

■ ACUTE PANCREATITIS MANAGEMENT

The management of patients with acute pancreatitis from the time

of diagnosis in the emergency ward to hospital discharge is briefly

reviewed, highlighting salient features based on severity and complications. It is important to recognize that 85–90% of cases of acute pancreatitis are self-limited and subside spontaneously, usually within 3–7 days

after onset, and do not exhibit organ failure or local complications.

The management of acute pancreatitis begins in the emergency

ward. After a diagnosis has been confirmed, early and aggressive fluid

resuscitation is critical. Additionally, intravenous analgesics are administered, severity is assessed, and a search for etiologies that may impact

acute care is begun. Patients who do not respond to aggressive fluid

2662 PART 10 Disorders of the Gastrointestinal System

resuscitation in the emergency ward should be considered for admission to a step-down or intensive care unit for aggressive fluid resuscitation, hemodynamic monitoring, and management of any organ failure.

Fluid Resuscitation and Monitoring Response to Therapy The

most important treatment intervention for acute pancreatitis is early,

aggressive intravenous fluid resuscitation to prevent systemic complications from the secondary systemic inflammatory response. The patient

is initially made NPO to minimize nutrient-induced stimulation of

the pancreas and is given intravenous narcotic analgesics to control

abdominal pain and supplemental oxygen (as needed).

Intravenous fluids of lactated Ringer’s or normal saline are initially

bolused at 15–20 mL/kg (1050–1400 mL), followed by 2–3 mL/kg

per hour (200–250 mL/h), to maintain urine output >0.5 mL/kg per

hour. Serial bedside evaluations are required every 6–8 h to assess vital

signs, oxygen saturation, and change in physical examination to optimize fluid resuscitation. Lactated Ringer’s solution has been shown to

A B C

FIGURE 348-2 Imaging features of a pancreaticopleural fistula secondary to acute pancreatitis. A. Pancreaticopleural fistula: pancreatic duct leak on endoscopic

retrograde cholangiopancreatography. Pancreatic duct leak (arrow) demonstrated at the time of retrograde pancreatogram in a patient with exacerbation of alcoholinduced acute pancreatitis. B. Pancreaticopleural fistula: computed tomography (CT) scan. Contrast-enhanced CT scan (coronal view) with arrows showing fistula tract

from pancreatic duct disruption in the pancreatic pleural fistula. C. Pancreaticopleural fistula: chest x-ray. Large pleural effusion in the left hemithorax from a disrupted

pancreatic duct. Analysis of pleural fluid revealed elevated amylase concentration. (Courtesy of Dr. K.J. Mortele, Brigham and Women’s Hospital; with permission.)

A B

C D

FIGURE 348-1 Evolution of changes of acute necrotizing pancreatitis on computed tomography (CT). A. CT scan of the abdomen without IV contrast performed on admission

for a patient with acute gallstone pancreatitis, showing mild peripancreatic stranding. B. Contrast-enhanced CT scan of the abdomen performed on the same patient 1

week after admission shows extensive intrapancreatic necrosis, evidenced by the lack of contrast enhancement in the pancreatic body with very minimal enhancement

noted at the distal most aspect of the pancreatic tail. C. Contrast-enhanced CT scan of the abdomen performed on the same patient 2 weeks after admission demonstrates

a semiorganized, heterogeneous fluid collection, referred to as an acute necrotic collection. On this image, a small area of viable pancreatic parenchyma is seen at the tail

of the pancreas. D. Contrast-enhanced CT scan of the abdomen performed on the same patient 5 weeks after admission demonstrates a well-encapsulated fluid collection,

essentially replacing the pancreas, referred to as walled-off necrosis.

2663Acute and Chronic Pancreatitis CHAPTER 348

decrease systemic inflammation (lower C-reactive protein levels from

admission) and may be a better crystalloid than normal saline. A

targeted resuscitation strategy with measurement of hematocrit and

BUN every 8–12 h is recommended to ensure adequacy of fluid resuscitation and monitor response to therapy, noting that a less aggressive

resuscitation strategy may be needed in milder forms of pancreatitis.

A rising BUN during hospitalization is not only associated with inadequate hydration but also higher in-hospital mortality.

A decrease in hematocrit and BUN during the first 12–24 h is strong

evidence that sufficient fluids are being administered. Serial measurements and bedside assessment for fluid overload are continued, and

fluid rates are maintained at the current rate. Adjustments in fluid

resuscitation may be required in patients with cardiac, pulmonary, or

renal disease. A rise in hematocrit or BUN during serial measurement

should be treated with a repeat volume challenge with a 2-L crystalloid

bolus followed by increasing the fluid rate by 1.5 mg/kg per hour. If the

BUN or hematocrit fails to respond (i.e., remains elevated or does not

decrease) to this bolus challenge and increase in fluid rate, consideration of transfer to an intensive care unit is strongly recommended for

hemodynamic monitoring.

Assessment of Severity and Hospital Triage Severity of acute

pancreatitis should be determined in the emergency ward to assist in

patient triage to a regular hospital ward or step-down unit or direct

admission to an intensive care unit. The Bedside Index of Severity

in Acute Pancreatitis (BISAP) incorporates five clinical and laboratory parameters obtained within the first 24 h of hospitalization

(Table 348-3)—BUN >25 mg/dL, impaired mental status (Glasgow

coma scale score <15), SIRS, age >60 years, and pleural effusion on

radiography—that can be useful in assessing severity. The presence

of three or more of these factors was associated with substantially

increased risk for in-hospital mortality among patients with acute pancreatitis. In addition, an elevated hematocrit >44% and admission BUN

>22 mg/dL are also associated with more severe acute pancreatitis.

Incorporating these indices with the overall patient response to initial

fluid resuscitation in the emergency ward can be useful at triaging

patients to the appropriate hospital acute care setting.

In general, patients with lower BISAP scores, hematocrits, and

admission BUNs tend to respond to initial management and can be

safely triaged to a regular hospital ward for ongoing care. If SIRS is

not present at 24 h, the patient is unlikely to develop organ failure or

necrosis. Therefore, patients with persistent SIRS at 24 h or underlying comorbid illnesses (e.g., chronic obstructive pulmonary disease,

congestive heart failure) should be considered for a step-down unit

setting if available. Patients with higher BISAP scores and elevations

in hematocrit and admission BUN who do not respond to initial fluid

resuscitation and exhibit evidence of respiratory failure, hypotension,

or organ failure should be considered for direct admission to an intensive care unit.

Special Considerations Based on Etiology A careful history,

review of medications, selected laboratory studies (liver profile, serum

triglycerides, serum calcium), and an abdominal ultrasound are recommended in the emergency ward to assess for etiologies that may

impact acute management. An abdominal ultrasound is the initial

imaging modality of choice and will evaluate the gallbladder, common

bile duct, and pancreatic head.

GALLSTONE PANCREATITIS Patients with evidence of ascending

cholangitis (rising white blood cell count, increasing liver enzymes)

should undergo ERCP within 24–48 h of admission. Patients with gallstone pancreatitis are at increased risk of recurrence, and consideration

should be given to performing a cholecystectomy during the same

admission in mild acute pancreatitis. An alternative for patients who

are not surgical candidates would be to perform an endoscopic biliary

sphincterotomy before discharge.

HYPERTRIGLYCERIDEMIA Serum triglycerides >1000 mg/dL are associated with acute pancreatitis. Initial therapy should focus on treatment

of hyperglycemia with intravenous insulin, which often corrects the

hypertriglyceridemia. Adjunct therapies may also include heparin or

plasmapheresis, but there is no compelling evidence these measures

improve clinical outcomes. Outpatient therapies include control of

diabetes if present, administration of lipid-lowering agents, weight loss,

and avoidance of drugs that elevate lipid levels.

Other potential etiologies that may impact acute hospital care

include hypercalcemia and post-ERCP pancreatitis. Treatment of hyperparathyroidism or malignancy is effective at reducing serum calcium.

Pancreatic duct stenting and rectal indomethacin administration are

effective at decreasing pancreatitis after ERCP. Drugs that cause pancreatitis should be discontinued. Multiple drugs have been implicated,

but only about 30 have been rechallenged (Class 1A) and found to be

causative.

Nutritional Therapy A low-fat solid diet can be administered to

subjects with mild acute pancreatitis once they are able to eat. Enteral

nutrition should be considered 2–3 days after admission in subjects

with more severe pancreatitis instead of total parenteral nutrition

(TPN). Enteral feeding maintains gut barrier integrity, limits bacterial

translocation, is less expensive, and has fewer complications than TPN.

Gastric feeding is safe; the benefits of nasojejunal enteral feeding over

gastric feeding remains under investigation.

Management of Local Complications (Table 348-4) Patients

exhibiting signs of clinical deterioration despite aggressive fluid resuscitation and hemodynamic monitoring should be assessed for local

complications, which may include necrosis, pseudocyst formation,

pancreas duct disruption, peripancreatic vascular complications,

and extrapancreatic infections. A multidisciplinary team approach

is recommended, including gastroenterology, surgery, interventional

radiology, and intensive care specialists, and consideration should also

be made for transfer to a tertiary pancreas center of excellence.

NECROSIS The management of necrosis requires a multidisciplinary

team approach. Percutaneous fine-needle aspiration of necrosis with

Gram stain and culture was previously performed to evaluate for

infected pancreatic necrosis in those with sustained leukocytosis, fever,

or organ failure. However, the current use of this technique varies

depending on institutional preference, with many abandoning this

diagnostic test to avoid potentially contaminating an otherwise sterile

collection, particularly when culture results will not lead to a clinical

decision to de-escalate antimicrobial therapy. Even though there is

currently no role for prophylactic antibiotics in necrotizing pancreatitis,

empiric antibiotics should be considered in those with clinical decompensation. Prophylactic antibiotics do not lead to improved survival

and may promote the development of opportunistic fungal infections.

Repeated CT or MRI imaging should also be considered with any

change in clinical course to monitor for complications (e.g., thromboses, hemorrhage, abdominal compartment syndrome).

In general, sterile necrosis is most often managed conservatively

unless complications arise. Once a diagnosis of infected necrosis is

established and an organism identified, targeted antibiotics should be

instituted. Pancreatic drainage and/or debridement (necrosectomy)

should be considered for definitive management of infected necrosis,

but clinical decisions are ultimately influenced by the clinical response

since almost two-thirds of patients respond to antibiotic treatment with

or without percutaneous drainage. Symptomatic local complications

as outlined in the Revised Atlanta Criteria typically require definitive

therapy.

A step-up approach (percutaneous or endoscopic transgastric/transduodenal drainage followed, if necessary, by surgical necrosectomy)

has been successfully reported by some pancreatic centers. One-third

of the patients successfully treated with the step-up approach did not

require major abdominal surgery. A randomized trial reported advantages to an initial endoscopic approach compared to an initial surgical

necrosectomy approach in select patients requiring intervention for

symptomatic WON. Taken together, a more conservative approach to

the management of infected pancreatic necrosis has evolved under the

close supervision of a multidisciplinary team. If conservative therapy

can be safely implemented, it is recommended to do so for 4–6 weeks

to allow the pancreatic collections to either resolve or evolve to develop

2664 PART 10 Disorders of the Gastrointestinal System

a more organized boundary (i.e., to “wall off ”) so that surgical or endoscopic intervention is generally safer and more effective.

PSEUDOCYST The incidence of pseudocyst is low, and most acute

collections resolve over time. Less than 10% of patients have persistent fluid collections after 4 weeks that would meet the definition of

a pseudocyst. Only symptomatic collections require intervention with

endoscopic or surgical drainage.

PANCREATIC DUCT DISRUPTION Pancreatic duct disruption may

present with symptoms of increasing abdominal pain or shortness of

breath in the setting of an enlarging fluid collection resulting in pancreatic ascites (ascitic fluid has high amylase level). Diagnosis can be

confirmed on magnetic resonance cholangiopancreatography (MRCP)

or ERCP. Placement of a bridging pancreatic stent for at least 6 weeks

is >90% effective at resolving the leak with or without parenteral nutrition and octreotide. Nonbridging stents are less effective (25–50%) but

should be considered with parenteral nutrition and octreotide prior to

surgical intervention.

PERIVASCULAR COMPLICATIONS Perivascular complications may

include splenic vein thrombosis with gastric varices and pseudoaneurysms, as well as portal and superior mesenteric vein thromboses. Gastric

varices rarely bleed but can be life-threatening. Similarly, life-threatening

bleeding from a ruptured pseudoaneurysm can be diagnosed and

treated with mesenteric angiography and embolization.

EXTRAPANCREATIC INFECTIONS Hospital-acquired infections occur

in up to 20% of patients with acute pancreatitis. Patients should be continually monitored for the development of pneumonia, urinary tract

infection, and line infection. Continued culturing of urine, monitoring

of chest x-rays, and routine changing of intravenous lines are important

during hospitalization.

Follow-Up Care Hospitalizations for moderately severe and severe

acute pancreatitis can be prolonged and last weeks to months and often

involve periods of intensive care unit admission and outpatient rehabilitation or subacute nursing care. Follow-up evaluation should assess for

development of diabetes, exocrine pancreatic insufficiency, recurrent

cholangitis, or infected fluid collections. As mentioned previously,

cholecystectomy should be performed during the initial hospitalization

for acute gallstone pancreatitis with mild clinical severity. For patients

with necrotizing gallstone pancreatitis, the timing of cholecystectomy

needs to be individualized.

■ RECURRENT ACUTE PANCREATITIS

Approximately 25% of patients who have had an attack of acute pancreatitis have a recurrence. The two most common etiologic factors

are alcohol and cholelithiasis. In patients with recurrent pancreatitis

without an obvious cause, the differential diagnosis should encompass

occult biliary tract disease, including microlithiasis, hypertriglyceridemia, pancreatic cancer, and hereditary pancreatitis (Table 348-1).

In one series of 31 patients diagnosed initially as having idiopathic or

recurrent acute pancreatitis, 23 were found to have occult gallstone disease. Thus, approximately two-thirds of patients with recurrent acute

pancreatitis without an obvious cause actually have occult gallstone

disease due to microlithiasis. Genetic defects as in hereditary pancreatitis and cystic fibrosis mutations can result in recurrent pancreatitis.

Other diseases of the biliary tree and pancreatic ducts that can cause

acute pancreatitis include choledochocele; ampullary tumors; pancreas

divisum; and pancreatic duct stones, stricture, and tumor. Approximately 2–4% of patients with pancreatic cancer present with acute

pancreatitis.

■ PANCREATITIS IN PATIENTS WITH AIDS

The incidence of acute pancreatitis is theoretically increased in patients

with AIDS for two reasons: (1) the high incidence of infections involving the pancreas such as infections with cytomegalovirus, Cryptosporidium, and the Mycobacterium avium complex; and (2) the frequent

use by patients with AIDS of medications such as pentamidine, trimethoprim-sulfamethoxazole, and protease inhibitors. The incidence

has been markedly reduced due to advances in therapy, including the

disuse of didanosine (Chap. 202).

CHRONIC PANCREATITIS AND EXOCRINE

PANCREATIC INSUFFICIENCY

■ PATHOPHYSIOLOGY

Chronic pancreatitis is a disease process characterized by irreversible

damage to the pancreas, in contrast to the reversible changes noted

TABLE 348-4 Complications of Acute Pancreatitis

Local

Pancreatic/peripancreatic fluid collections:

Acute necrotic collection (sterile or infected)

Walled-off necrosis (sterile or infected)

Pancreatic pseudocyst

Disruption of main pancreatic duct or secondary branches

Pancreatic ascites

Chylous ascites (secondary to disruption of lymphatic ducts)

Involvement of contiguous organs by necrotizing pancreatitis (e.g., colon

perforation)

Splanchnic thromboses (splenic vein, superior mesenteric vein,

and/or portal vein)

Bowel infarction/perforation

Gastric outlet obstruction

Biliary obstruction (jaundice)

Systemic

Pulmonary

Pleural effusion

Atelectasis

Mediastinal fluid

Pneumonitis

Acute respiratory distress syndrome

Hypoxemia (unrecognized)

Cardiovascular

Hypotension

Hypovolemia

 Nonspecific ST-T changes in electrocardiogram simulating myocardial

infarction

Pericardial effusion

Hematologic

Disseminated intravascular coagulation

Gastrointestinal hemorrhage

Peptic ulcer disease

Erosive gastritis

Hemorrhagic pancreatic necrosis with erosion into major blood vessels

Variceal hemorrhage secondary to splanchnic thrombosis

Renal

Oliguria (<300 mL/d)

Azotemia

Renal artery and/or renal vein thrombosis

Acute tubular necrosis

Metabolic

Hyperglycemia

Hypertriglyceridemia

Hypocalcemia

Encephalopathy

Sudden blindness (Purtscher’s retinopathy)

Central nervous system

Psychosis

Fat emboli

Fat necrosis

Subcutaneous tissues (erythematous nodules)

Bone

Miscellaneous (mediastinum, pleura, nervous system)