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925CHAPTER 135 Pancreatitis
135
PANCREATITIS
CHRIS E. FORSMARK
ACUTE PANCREATITIS
DEFINITION
Acute pancreatitis is a discrete episode of cellular injury and inflammation in 
the pancreas, usually with symptoms of abdominal pain, nausea, and vomiting. 
It is accompanied by elevations in serum levels of amylase or lipase and/or 
radiographic evidence of pancreatic inflammation, edema, or necrosis. Although 
the pancreas can recover normal function and appearance after an episode, 
recovery may not be complete if the necrosis was substantial. In patients with 
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925.e2 CHAPTER 135 Pancreatitis
KEYWORDS
acute pancreatitis
chronic pancreatitis
pancreatic pseudocyst
exocrine insufficiency
endocrine insufficiency
ABSTRACT
Acute pancreatitis, which is most often caused by gallstones and alcohol, can 
cause systemic organ failure, pancreatic necrosis, and death. However, compli-
cations can be reduced and recurrence can be prevented by urgent diagnosis, 
an accurate identification of the cause, and effective management. Chronic 
pancreatitis, which has numerous genetic and environmental risk factors, can 
be difficult to diagnose early in its clinical course. Management includes iden-
tification of complications, assessment of residual pancreatic function, and 
treatment of pain, exocrine insufficiency, and endocrine insufficiency.
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926 CHAPTER 135 Pancreatitis
recurrent episodes, there can be a shift from acute inflammation, necrosis, 
and apoptosis to chronic inflammation and fibrosis that are characteristic of 
chronic pancreatitis. Acute and chronic pancreatitis are on a continuum, and 
it may be difficult to differentiate acute relapsing pancreatitis from evolving 
chronic pancreatitis. 
EPIDEMIOLOGY
The incidence of acute pancreatitis in the United States is estimated to be 
between 5 and 30 cases per 100,000 population,1 with about 275,000 hospital 
admissions annually, making acute pancreatitis the third most common gas-
trointestinal discharge diagnosis in U.S. hospitals. The cost of caring for these 
patients is about $4 to $6 billion annually. The incidence of acute pancreatitis 
is increasing in the United States and many other countries, owing to more 
frequent use of diagnostic tests and to an increasing prevalence of gallstones 
and other risk factors in the setting of the obesity epidemic. 
PATHOBIOLOGY
Acute pancreatitis is caused by premature activation of digestive enzymes 
within pancreatic acinar cells. Increased intracellular calcium and the activation 
of trypsinogen to trypsin appear to be the critical initial steps, with trypsin 
then activating other proteases within the gland.2 These activated enzymes 
produce cell injury and necrosis. Necrosis can involve the pancreas as well as 
surrounding fat and structures, thereby leading to fluid extravasation into the 
surrounding retroperitoneal spaces (“third space” losses). Although necrosis 
often may occur, necrosis sufficient to be visible on a contrast enhanced com-
puted tomographic (CT) scan is usually termed acute necrotizing pancreatitis 
and distinguished from the milder interstitial pancreatitis, in which necrosis 
is not visible on a CT scan. In addition to the local damage, the release of 
pro-inflammatory cytokines and activated digestive enzymes into the systemic 
circulation can produce a systemic inflammatory response syndrome and organ 
system failure, including hypotension, renal failure, and acute respiratory dis-
tress syndrome (Chapter 96). Gallstones (Chapter 146) and alcohol (Chapter 
30) together account for up to 75% of all cases of acute pancreatitis, but causes 
vary by age and sex, and the cause is unknown in a significant proportion of 
cases (Table 135-1).
Gallstones (Chapter 146)
Passage of a gallstone through the ampulla of Vater with transient obstruction 
of the pancreatic duct is the initiating event for gallstone pancreatitis. Only 
about 5% of all patients with gallstones develop pancreatitis, and patients with 
smaller gallstones (≤5 mm), which can pass the cystic duct and reach the 
ampulla, are at highest risk. Microlithiasis, defined as tiny gallstones and/or 
biliary sludge that are not easily visible on routine imaging, is often the cause 
in patients initially labeled as having acute idiopathic pancreatitis. 
Alcohol (Chapter 30)
More than 5 years of alcohol intake averaging more than 5 to 8 drinks daily is 
usually required before pancreatitis develops, but most people with this level of 
intake do not develop pancreatitis. A variety of cofactors have been proposed, 
including a high-fat diet, genetic variability in detoxifying enzymes, coexistent 
genetic mutations, and cigarette smoking. The evidence is strongest for smoking. 
By the time patients have a first clinical episode of acute alcoholic pancreatitis, 
most already have evidence of underlying chronic pancreatitis. The peak of 
alcoholic pancreatitis is in ages of 20 to 50, and it is much more common 
in men. The mechanism of alcoholic pancreatic injury involves a mixture of 
direct toxicity, oxidative stress, and alterations in pancreatic enzyme secretion. 
Drugs, Toxins, and Metabolic Factors
Drug-induced pancreatitis is a rare and generally idiosyncratic event. Although 
many drugs have been implicated, the evidence is most compelling for 
6-mercaptopurine and azathioprine (up to a 4% attack rate), as well as 
for valproic acid (the leading cause in an analysis of over 1000 cases of 
drug-induced acute pancreatitis).2b Other agents include L-asparaginase, 
didanosine, pentamidine, valproic acid, furosemide, mesalamine, ciprofloxa-
cin, prednisone, olanzapine, sulfonamides, and aminosalicylates. Toxins 
that may cause acute pancreatitis include methyl alcohol, organophosphate 
insecticides, and venom from certain scorpions.
Levels of serum triglycerides above 500 mg/dL, and usually greater than 
1000 mg/dL, can cause acute pancreatitis, but the mechanism is not known, 
and the risk appears to be higher in overweight persons.2c Hypercalcemia is 
an exceedingly rare cause of acute pancreatitis. 
Trauma
Iatrogenic trauma to the pancreas and pancreatic duct during performance of 
an endoscopic retrograde cholangiopancreatography (ERCP; Chapter 125) 
is a common cause of pancreatitis, with the risk averaging less than 5% for 
patients with simple common bile duct stones or malignancy.
Penetrating and blunt trauma, ranging from a contusion to severe crush injury 
and even transection of the gland, can cause pancreatitis. Acute presentation 
is the rule, but some patients with milder injury may present in a subacute 
or chronic fashion. Ischemic injury to the gland can occur after surgical pro-
cedures, especially cardiopulmonary bypass, and cause severe pancreatitis. 
Obstruction of the Pancreatic Duct
In addition to gallstones and microlithiasis, obstruction of the pancreatic duct 
by a pancreatic ductal adenocarcinoma (Chapter 185), an ampullary adenoma 
or carcinoma, or less likely, an intraductal papillary mucinous neoplasm can 
cause acute pancreatitis. The diagnosis of pancreatic duct obstruction is usually 
established with magnetic resonance imaging (MRI) with magnetic resonance 
cholangiopancreatography (MRCP), or with endoscopic ultrasound. Benign 
strictures of the pancreatic duct at the ampulla of Vater may be caused by celiac 
disease (Chapter 131), duodenal Crohn disease (Chapter 132), and periampul-lary diverticulum. Current evidence does not support the role of either sphincter 
of Oddi dysfunction or pancreatic divisum as primary causes of acute pancreatitis. 
Infections
Ascaris lumbricoides (Chapter 335) may cause pancreatitis by obstructing the 
pancreatic duct as the worms migrate through the ampulla of Vater. Viruses 
that may infect the pancreatic acinar cells directly and may cause pancreatitis 
include cytomegalovirus (Chapter 352), Coxsackie B virus (Chapter 355), 
adenovirus (Chapter 355), and mumps virus (Chapter 345). 
Autoimmune Pancreatitis
Two forms of autoimmune pancreatitis (AIP) have been identified.3 The 
most common presentation is obstructive jaundice that mimics pancreatic 
adenocarcinoma or chronic pancreatitis. These are discussed under “Chronic 
Pancreatitis.” 
ETIOLOGY EXAMPLES
Gallstones Gallstones (Chapter 146)
Microlithiasis
Drugs and toxins Ethyl and methyl alcohol (Chapters 30 and 102)
Tobacco (Chapter 29)
Azathioprine, 6-mercaptopurine, pentamidine, 
didanosine, sulfonamides, thiazides, 
aminosalicylates, valproic acid, and others
Scorpion venom (Chapter 104)
Organophosphate insecticides (Chapter 102)
Metabolic Hyperlipidemia (Chapter 195)
Hypercalcemia (Chapter 232)
Trauma Post-ERCP (Chapter 125)
Blunt or penetrating trauma
Postoperative
Obstruction of the 
pancreatic duct
Benign pancreatic duct stricture
Benign ampullary stricture (e.g., celiac disease, Crohn 
disease, diverticulum)
Ampullary adenoma or adenocarcinoma (Chapter 186)
Pancreatic ductal adenocarcinoma (Chapter 185)
Intraductal papillary mucinous neoplasm (Chapter 185)
Infections Cytomegalovirus (Chapter 346), mumps (Chapter 
345), rubella (Chapter 344), Coxsackie B (Chapter 
355), Candida (Chapter 318), histoplasmosis 
(Chapter 316), Ascaris (Chapter 335)
Genetics PRSS1 mutations
CFTR mutation
SPINK1 mutation
Other mutations
Autoimmune 
pancreatitis
Type 1
Type 2
Idiopathic pancreatitis
ERCP = endoscopic retrograde cholangiopancreatography.
CAUSES OF ACUTE PANCREATITISTABLE 135-1
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927CHAPTER 135 Pancreatitis
Genetics
Mutations in the cationic trypsinogen gene (PRSS1), which have been identified 
in families with hereditary pancreatitis, are more commonly seen in association 
with chronic pancreatitis but can present early in the course as acute pan-
creatitis. Many additional mutations and polymorphisms are associated with 
both acute and chronic pancreatitis. These affected genes include the cystic 
fibrosis conductance regulator (CFTR), serine protease inhibitor kazal type 
1 (SPINK1), chymotrypsin C, calcium sensing receptor, claudins, and others. 
CLINIC AL MANIFESTATIONS
Abdominal pain, nausea, and vomiting are the hallmark symptoms of acute 
pancreatitis. The abdominal pain is usually in the epigastric region and often 
radiates to the back. The pain is steady, reaches its maximum intensity over 
30 to 60 minutes, and persists for days. These characteristic symptoms may be 
masked in patients who present with delirium, multiple organ system failure, 
or coma.
The physical examination usually reveals tachycardia. Hypotension, tachyp-
nea, dyspnea, and low-grade fever are observed in more severe cases. Confusion, 
delirium, and, rarely, even coma may be present. The abdomen is often distended 
with diminished bowel sounds. Tenderness to palpation of the abdomen, which 
may be epigastric or more diffuse, is typical, whereas rebound and guarding 
are unusual. Dullness to percussion in the lower lung fields may be noted 
owing to pleural effusion. Rare physical findings include ecchymoses of the 
flank (Grey-Turner sign) or umbilicus (Cullen sign), which occur when fluid 
and blood tracks into these spaces from the retroperitoneum. Jaundice may 
be present if there is biliary obstruction by a stone. The presence of the sys-
temic inflammatory response syndrome (Chapter 100) is predictive of more 
severe pancreatitis. Tachycardia, dyspnea, tachypnea, orthostatic hypoten-
sion, pleural effusion, oxygen desaturation, or shock signals more substantial 
third-space losses, a higher likelihood of a variety of complications, and a 
worse prognosis. More severe pancreatitis is characterized by more substantial 
pancreatic and peripancreatic necrosis, more peripancreatic fluid collections, 
and more dysfunction of extra-pancreatic organs. 
DIAGNOSIS
The diagnosis of acute pancreatitis is suggested by clinical features and con-
firmed by laboratory and imaging studies that exclude other serious intra-
abdominal conditions and help define the severity and most likely cause of 
the pancreatitis.3b
The diagnosis of acute pancreatitis requires at least two of the following 
three criteria: abdominal pain consistent with pancreatitis, serum amylase or 
lipase of at least three times the upper limit of normal, or imaging findings 
consistent with acute pancreatitis on imaging (contrast CT, MRI, or ultra-
sound). Patients with mild pancreatitis have no local or systemic complications, 
with moderate pancreatitis have local or systemic complications that persist 
for less than 48 hours, and with severe pancreatitis have organ failure that 
persists for more than 48 hours.
Laboratory Tests
Amylase and Lipase
Most patients with acute pancreatitis have elevations in serum levels of amylase 
or lipase within a few hours of the onset of symptoms. Lipase is generally 
preferred over amylase as a diagnostic test because of its superior specificity. 
Although elevation to more than three times the upper limit of normal is the 
recommended cutoff for diagnosing acute pancreatitis, up to 25% of cases 
may not reach this threshold.4 Lipase levels tend to remain elevated longer 
than amylase levels, but both decline gradually over several days. Elevations 
more than three times the upper limit of normal are most specific for acute 
pancreatitis. Amylase and lipase levels may be normal in patients with acute 
pancreatitis, particularly if the measurement is delayed for several days after 
the onset of symptoms, and marked hypertriglyceridemia can interfere with 
their accurate measurement. Both enzymes are cleared by the kidney, and 
renal failure can falsely raise the level of these enzymes up to five times the 
upper limit of normal in the absence of pancreatitis.
Amylase and lipase levels also can be elevated in a variety of other condi-
tions that may mimic acute pancreatitis, including intestinal ischemia and 
infarction (Chapter 134), bowel obstruction (Chapter 133), cholecystitis 
(Chapter 146), and choledocholithiasis (Chapter 146). In addition, amylase 
levels may be elevated from ectopic pregnancy, acute salpingitis, and a variety 
of extra-abdominal conditions such as parotitis (Chapter 345), lung cancer 
(Chapter 182), and head trauma (Chapter 371).
In some patients, only the amylase level or the lipase level may be elevated. 
Serial measurements of amylase or lipase in patients with established acute 
pancreatitis are not useful in clinical decision making. In patients with recurrent 
attacks of pancreatitis, the peak level of amylase or lipase tends to diminish 
progressively. 
Other Laboratory Tests
In severe pancreatitis, leukocytosis, azotemia, and hemoconcentration may 
be seen. Failure of the blood urea nitrogen (BUN) level or hematocrit to 
normalize with fluid resuscitation is associated with more substantial third-
space losses and a worse prognosis. Hyperglycemia, hypocalcemia, and mild 
hypertriglyceridemia also can develop. Elevations in alanine aminotransferase 
levels more than three times the upper limit of normal are most suggestive of 
gallstones, although any significant elevation in liver chemistries should raise 
the possibility of gallstones (Chapter146). 
Determining Etiology
To identify the cause of acute pancreatitis, the history should focus on alcohol 
and tobacco use, previous biliary colic, drug history, family history, and recent 
trauma. Because gallstones are the leading cause of acute pancreatitis, account-
ing for about 40 to 50% of cases, all patients should have an abdominal ultra-
sound examination to look for gallstones. Gallstone pancreatitis should be 
suspected if stones or a dilated bile duct are seen on imaging studies, or if 
abnormal liver chemistries improve over a few days.
A careful history, often with corroboration from family members, will help 
diagnose alcoholic pancreatitis, which accounts for about 20% of cases, as well 
as medication- or toxin-induced pancreatitis and traumatic pancreatitis. Serum 
chemistries will help identify unusual cases caused by severe (>1000 mg/ 
dL) hypertriglyceridemia.
If these initial approaches are unrevealing, endoscopic ultrasound (or MRI 
with MRCP) can detect small gallstones, microlithiasis, or underlying pre-
malignant or malignant causes (particularly in patients over age 40 years). 
More specialized investigations, such as genetic testing, are usually reserved 
for patients who have had multiple attacks of unexplained pancreatitis.
Of the 25% of patients who do not have an identified cause after a basic 
initial evaluation, microlithiasis is the most common underlying explanation. 
With additional evaluation and testing, only about 10% of patients are ulti-
mately labeled as having idiopathic pancreatitis. Idiopathic pancreatitis is more 
common in women, and especially elderly women, than in men. 
Imaging Studies
Imaging studies are used not only in establishing the diagnosis but also in 
determining the cause and prognosis. In most patients, both ultrasound and 
CT are used in a complementary fashion.
Abdominal ultrasonography can confirm the presence of acute pancreatitis 
by documenting pancreatic enlargement, edema, or associated peripancre-
atic fluid collections. Visualization of the pancreas may be limited owing to 
body habitus or overlying intestinal gas. Importantly, ultrasonography is most 
accurate in identifying gallstones in the gallbladder or a dilated common bile 
duct in patients with gallstone pancreatitis.
CT is more accurate than ultrasonography in confirming the diagnosis of 
acute pancreatitis and in documenting the presence of pancreatic necrosis and 
peripancreatic fluid collections, but it is less accurate in identifying gallstones. 
CT is also particularly helpful in excluding intra-abdominal conditions that 
can mimic acute pancreatitis. Pancreatic parenchyma that opacifies on CT 
with intravenous contrast is still viable, whereas parenchyma that does not 
enhance is necrotic (Fig. 135-1). The extent of pancreatic necrosis has some 
prognostic importance but is generally not clear on CT until at least 3 days 
after presentation. CT scans are not routinely required in all patients with 
acute pancreatitis but should be performed when the diagnosis is not clear 
and in patients who have a first attack, severe disease, systemic complications, 
or disease that is slow to improve.
Magnetic resonance imaging (MRI) is equivalent to CT in its ability to doc-
ument acute pancreatitis, identify necrosis, and diagnose or exclude other 
diseases that could mimic acute pancreatitis. In addition, MRCP is much 
better than CT for identifying gallstones. In critically ill patients, MRI is more 
difficult than CT to perform.
ERCP and endoscopic ultrasonography are important in both diagnosis 
and therapy of acute pancreatitis. Endoscopic ultrasonography, which is pri-
marily used to establish the cause when the initial evaluation is unrevealing, 
is particularly accurate in identifying underlying malignancy, premalignant 
lesions such as ampullary adenoma, and small gallstones or microlithiasis. 
ERCP is not used for diagnosis, but it can be very useful for therapeutic 
purposes. 
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928 CHAPTER 135 Pancreatitis
Determining Severity
Severe pancreatitis is characterized by organ system failure and by local pan-
creatic complications such as necrosis, fluid collections, or pseudocysts. Organ 
failure can be: single or multiple; early- or late-onset; and progressive, persistent, 
or transient. In severe acute pancreatitis, renal failure, pulmonary failure, and 
circulatory failure most commonly occur as part of the systemic inflammatory 
response.
During the acute attack, poorly demarcated fluid collections around the 
pancreas track into various retroperitoneal and peritoneal spaces. Much of 
this inflammatory fluid will resolve, but some will form into a more rounded 
and circumscribed fluid collection, called a pseudocyst (Fig. 135-2). Similarly, 
areas of pancreatic and peripancreatic necrosis will eventually develop a sur-
rounding wall and begin to soften and liquefy, thereby becoming “walled-off 
pancreatic necrosis.” This process usually takes several weeks. It is important 
to distinguish pseudocysts from walled-off pancreatic necrosis; they appear 
similar on a CT scan but are easily distinguishable on MRI or endoscopic 
ultrasonography, because necrotic collections contain both solid and liquid 
material. Greater degrees or amounts of necrosis generally correlate with a 
higher risk of an adverse outcome, particularly if infection develops in the 
devitalized necrotic tissue. Although many patients with pancreatic necrosis 
may not develop organ system failure, organ system failure is quite rare in the 
absence of pancreatic necrosis.
Risk Stratification
A number of clinical features identify patients at higher risk, including patients 
who are older, obese or have more serious or more numerous comorbid 
conditions. Obesity in particular dramatically increases the risk of more 
severe pancreatitis. Additional clinical features that can be predictive include 
the presence of the systemic inflammatory response syndrome, particularly 
if it persists for more than 48 hours, and laboratory features consistent with 
intravascular volume depletion (elevated hematocrit or BUN). In addition 
to this qualitative estimate of prognosis, a number of multiple-factor scoring 
systems have been developed in an attempt to help guide clinicians in gauging 
prognosis, but there is no evidence that these complex multiple-factor scoring 
systems are superior to experienced clinical judgment. None are widely used 
except sometimes in large referral centers. 
 FIGURE 135-2. A large pseudocyst is seen (black arrows). in addition, ascites surround-
ing the liver (white arrows) is noted due to a leak from the pseudocyst (pancreatic ascites).
 FIGURE 135-1. a computed tomographic scan demonstrating a large area of pancreas 
which does not enhance with intravenous contrast (arrow), consistent with pancreatic 
necrosis.
General Supportive Care
The majority of patients will recover within several days, but it is usually not 
possible to identify these patients at the time of admission. A short protocolized 
stay in an emergency department may allow some patients with very mild acute 
pancreatitis to be discharged within 24 hours.5
All patients should initially be given nothing by mouth (NPO). Pain control 
often requires parenteral narcotics, and hydromorphone (in divided doses of 
1 to 2 mg IV every 4 to 6 hours initially, with titration as needed), is generally 
preferred. Patients with significant third-space loss, often augmented by prior 
poor oral intake or fluid losses through vomiting, will have evidence of intravas-
cular fluid depletion. Even in mild pancreatitis, fluid losses may be substantial. 
Appropriate fluid resuscitation (Chapter98) is recommended in all practice 
guidelines, but data are limited on the type, rate, and goals of fluid therapy.6 
In general, sufficient fluid resuscitation should be accomplished within the first 
24 hours of admission to correct blood pressure and pulse, reduce hemato-
crit and BUN to normal, and ensure a urine output of at least 0.5 mL/kg/hour. 
Although data for randomized trials are inconclusive, practice guidelines rec-
ommend lactated Ringer solution, in general 200 to 250 over the initial 12 to 
24 hours, then reduced if the patient displays early features of fluid overload. 
Of importance, too rapid an infusion of fluid worsens outcomes, primarily by 
increasing the risk of respiratory failure owing to fluid overload but also by 
increasing the risk of organ system failure, heart failure, and an abdominal com-
partment syndrome.
Treatment of nausea and vomiting may be needed, and 5-HT3 antagonists 
(Table 123-5) are generally preferred. Nasogastric suction is rarely needed.
Patients with mild or moderate pancreatitis can be fed when they feel able 
to tolerate it (e.g., enteral feeding if needed), even before enzyme levels are 
completely normalized or pain is absent. Beginning oral feeding within 48 
hours after hospitalization is as safe as starting later and also reduces hospital 
length of stay.A1 There is no need to begin with a clear liquid diet: feeding can 
be initiated with a low-fat solid diet as the first meal.
In patients with more severe pancreatitis (based upon early organ system 
failure, substantial third-space fluid losses, or comorbid conditions), admis-
sion to an intermediate care unit or intensive care unit (ICU) is appropriate.6b 
Careful monitoring for progressive organ system failure, metabolic compli-
cations, and fluid status is critical in these patients.6c In patients with severe 
pancreatitis, enteral nutrition (oral or tube feeding) is safer and less expensive 
than total parenteral nutrition, which should be utilized very rarely. Patients 
who appear to have sufficiently severe disease that they might not be able to 
eat for 5 to 7 days can be considered for tube feeding. Alternatively, waiting 
for up to 5 days to see if patients with severe acute pancreatitis can eat is 
reasonable, with tube feeding reserved for those who are unable to eat after 
5 days.A2 In patients given tube feeding, there is no difference if the tube is 
nasogastric, nasoduodenal, or nasojejunal. In addition, there is no evidence 
that elemental or semi-elemental formulas are better than standard polymeric 
formulas. 
Treatment of Complications
Most patients who develop acute gallstone pancreatitis have already passed 
the offending stone into the duodenum, but patients with a persistent or mul-
tiple stones are at higher risk of developing cholangitis and (possibly) more 
severe pancreatitis. Current practice guidelines recommend urgent ERCP in 
patients whose gallstone pancreatitis is complicated by evidence of cholangitis 
(e.g., fever, jaundice, right upper quadrant pain) and early ERCP for patients 
with evidence of a persistent bile duct stone (e.g., visible persistent stone on 
imaging study, jaundice, persistently dilated bile duct, or worsening liver chem-
istries at 48 hours after admission).7,8 In patients who have severe pancreatitis, 
as evidenced by early and progressive organ system failure but who do not 
have cholangitis, early ERCP is not better than conservative care.A3,A3b There 
is no other role for early endoscopic intervention in patients with acute 
pancreatitis.
The systemic complications (Table 135-2) that develop in patients with 
severe acute pancreatitis include some that are similar to those commonly 
TREATMENT 
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929CHAPTER 135 Pancreatitis
PROGNOSIS
More than 80% of all patients with acute pancreatitis recover promptly without 
developing severe pancreatitis. Mortality is usually from progressive multiple 
organ system failure, either from the acute pancreatitis itself or from hospi-
tal-acquired infections, including infection of pancreatic fluid collections or 
necrotic pancreatic tissue. Early organ failure (within 24 hours of admission), 
multiple organ system failure, and persistent or progressive (present beyond 
48 hours after admission) organ failure are associated with prolonged hospi-
talization, ICU admission, need for surgery, and death. Overall mortality is 
about 2%, but it can approach 30% in patients with more severe comorbid 
conditions (and particularly obesity) and in patients who develop pancreatic 
necrosis, infection, or organ system failure. Although high-quality ICU care 
reduces mortality, no specific therapy is currently proven to reduce these risks.
For patients with acute alcoholic pancreatitis, long-term mortality is about 
4-fold higher than in the general population, mostly owing to alcohol-related 
conditions. For other causes, long-term mortality is minimally elevated com-
pared with the general population. 
CHRONIC PANCREATITIS
DEFINITION
Chronic pancreatitis is a syndrome, associated with a wide spectrum of pre-
disposing risk factors and environmental triggers. Chronic pancreatitis usually 
evolves after episodes of recurrent acute pancreatitis, and the transition between 
acute and chronic pancreatitis may be difficult to identify.10 Common features 
include abdominal pain, exocrine and/or endocrine insufficiency, and imaging 
evidence of pancreatic atrophy, calcification, or dilated pancreatic duct.10b The 
progression of chronic pancreatitis is variable, but it often culminates in irre-
versible and widespread pancreatic fibrosis with chronic inflammation and 
damage to nerves, ducts, acini, and islets. 
EPIDEMIOLOGY
The prevalence of symptomatic chronic pancreatitis in western countries is 
about 25 to 30 per 100,000 persons, with an estimated incidence of 4 to 14 
cases/100,000. In the United States, chronic pancreatitis accounts for about 
125,000 outpatient visits and 25,000 hospitalizations annually. Interestingly, 
the prevalence of histologic evidence of chronic pancreatitis in autopsy studies 
approaches 5%, indicating that many people develop some pancreatic damage 
as a consequence of normal aging, other diseases (e.g., diabetes), or exposure 
to toxins (such as smoking or consumption of alcohol) but do not develop 
any symptoms or signs of chronic pancreatitis during life. 
PATHOBIOLOGY
Several genetic polymorphisms and mutations can predispose to chronic pan-
creatitis, and various environmental and immunologic triggers can initiate the 
disease.10c Episodes of acute inflammation, whether clinical or subclinical, 
eventually change the inflammatory milieu of the pancreas, with a shift to 
chronic inflammation, cell injury, cell death, the activation of pancreatic stel-
late cells, and the progression to fibrosis. This process becomes self-sustaining 
and produces the characteristic histologic damage.
encountered in other ICU patients (e.g., ventilator-associated pneumonia, line 
sepsis) as well as the specific metabolic complications of severe pancreatitis.9 
Hyperglycemia is common and may contribute to higher rates of infections. In 
severe acute pancreatitis, ionized calcium levels are usually normal, but hypo-
calcemia is common owing to a diminished serum albumin level; treatment 
is not needed in the absence of signs of hypocalcemia, such as tetany or a 
Chvostek sign (Chapter 232). Mild hypertriglyceridemia is common, but underly-
ing hypertriglyceridemia does not cause acute pancreatitis unless triglyceride 
levels surpass 1000 mg/dL. Triglyceride levels drop promptly when the patient is 
made NPO.
Infections in patients with acute pancreatitis include urinarytract infec-
tions, pneumonia, line infections, and C. difficile. High-quality nursing care, 
antibiotic stewardship, and careful attention to catheters and lines can mini-
mize these infections. In addition, patients with necrotizing pancreatitis may 
develop infected pancreatic necrosis, which typically occurs 2 to 3 weeks into 
the illness and is heralded by fever, leukocytosis, and worsening abdominal 
pain. The responsible organisms are usually gram-negative rods and other 
gut flora, but Staphylococcus aureus is an important agent as well. If infected 
necrosis is suspected, a contrast CT scan should be obtained. The finding of gas 
in the necrotic collection is a specific but not sensitive sign of infected necrosis. 
A CT-directed fine-needle aspiration of the necrotic area can be obtained for 
culture and Gram stain but is not required in patients in whom clinical features, 
such as fever, leukocytosis, and worsening abdominal pain, are strongly sug-
gestive of infected pancreatic necrosis. Antibiotics with appropriate penetra-
tion into necrosis (e.g., imepenem/cilastatin 500 mg IV/q 8 hours, meropenem 
500 mg IV/q 8 hours; or metronidazole 500 mg IV/q 8 hours plus ciprofloxacin 
400 mg IV/q 8 hours or ceftazidime 500 mg IV/q 8 hours; see Table 271-4 in 
Chapter 271) should be initiated if infection is suspected or documented, and 
the specific regimen can be tailored to the organism if known. Intravenous 
antibiotics should be continued for several weeks to allow the necrotic material 
to demarcate, begin to liquefy, and become encapsulated. If patients become 
septic, it is reasonable to place a percutaneous drain into the collection to 
stabilize the patient. When this walled-off necrosis is sufficiently liquefied to 
allow less invasive approaches, therapy can include percutaneous, endoscopic, 
or minimally invasive surgical therapy. Minimally invasive surgical approaches 
are preferable and of relatively low morbidity, and endoscopic minimally inva-
sive approaches may be even less morbid.A4-A5c Open surgical drainage should 
be avoided.
Fluid collections around the pancreas (acute peripancreatic fluid col-
lections) are common in acute pancreatitis and do not require any specific 
therapy. Most will resolve spontaneously, but some will mature into an encap-
sulated pseudocyst. It is important to distinguish a pseudocyst (usually outside 
the confines of the pancreas and filled with fluid) from an area of necrosis 
(usually inside the confines of the pancreas and a mixture of solid and liquid 
material). Although infected necrosis has a substantial impact on prognosis, 
prophylactic antibiotics are not beneficial.A6 Therapy also is not needed for 
asymptomatic pseudocysts, even if they are large, but therapy is indicated 
for pseudocysts that cause abdominal pain, obstruct a surrounding hollow 
viscus, or are associated with infection or bleeding. A pseudocyst can be treated 
successfully using endoscopic, percutaneous, or minimally invasive surgical 
techniques, and the choice among these approaches can be determined by 
local expertise.
Bleeding may be limited to within the pseudocyst itself or may reach the 
intestine through the pancreatic duct if the pseudocyst is in communication 
with the duct. In some patients, bleeding into the pseudocyst may be caused 
by a pseudoaneurysm of a nearby visceral artery; this type of bleeding may 
be massive. Unexplained gastrointestinal bleeding or a sudden, unexplained 
COMPLICATION EXAMPLES
Systemic complications Hypotension and shock
Adult respiratory distress syndrome
Acute renal failure
Disseminated intravascular coagulation
Hypocalcemia
Hypertriglyceridemia
Hyperglycemia
Encephalopathy and coma
Gastrointestinal bleeding Stress ulceration
Pseudoaneurysm
Local (pancreatic) complications Acute peripancreatic fluid collection
Pseudocyst (infected and sterile)
Acute necrotic collection
Walled-off pancreatic necrosis (infected 
and sterile)
Duodenal and biliary obstruction
COMPLICATIONS OF ACUTE PANCREATITISTABLE 135-2
drop in the hematocrit in a patient with pancreatitis or a pseudocyst should 
prompt an emergent CT scan, followed by embolization if a pseudoaneurysm 
is identified. 
Prevention of Relapsing Pancreatitis
Preventing relapse requires a clear knowledge of the precipitating cause. 
Abstinence from alcohol and tobacco should be strongly encouraged, includ-
ing referral to appropriate resources. Cholecystectomy prevents subsequent 
attacks of gallstone pancreatitis and should be accomplished within the index 
hospitalization.A7 In patients with presumed “idiopathic” acute pancreatitis, an 
empiric cholecystectomy can be considered provided that alternative causes 
have been excluded, because many of these patients have gallstones as the 
etiology.A8 In patients who have gallstone pancreatitis but who are not surgical 
candidates, endoscopic biliary sphincterotomy provides reasonable protection 
from subsequent attacks. Control of serum lipids prevents subsequent attacks 
of hyperlipidemic pancreatitis. Therapy of lesions that obstruct the pancreatic 
duct, such as strictures and ampullary adenomas, may also prevent relapse.
The risk of post-ERCP pancreatitis is reduced with careful patient selection, 
the use of peri-procedural nonsteroidal anti-inflammatory drug (NSAID) sup-
positories,A9 by aggressive intravenous hydration,A9b or by the placement 
of small caliber temporary pancreatic duct stents.
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930 CHAPTER 135 Pancreatitis
The mechanisms of pain of chronic pancreatitis are complex. Damage to 
pancreatic nociceptive nerves and neuroimmune interaction driven by the 
chronic inflammatory state is the primary cause of pain, but the chronic pain 
produces visceral, spinal cord, and central hyperalgesia.
Alcohol and Tobacco
Alcohol causes about 50% of all cases of chronic pancreatitis in the United 
States. The risk is dose dependent, but it usually requires sustained ingestion 
of alcohol of 4 to 5 drinks daily over more than 5 years. The majority of people 
(95%) who consume this much alcohol do not develop chronic pancreati-
tis, pointing to important cofactors such as genetic risk factors and cigarette 
smoking. Smoking increases the risk of chronic pancreatitis by 2- to 3-fold, 
with a dose-dependent effect. Smoking is estimated to account for 25% of the 
attributable risk of chronic pancreatitis, and continued smoking after diagnosis 
accelerates the course of the disease. These risks also appear to be synergistic, 
such that the combination of alcohol and tobacco is more than an additive 
effect. 
Genetic
Hereditary pancreatitis is an autosomal dominant disease characterized by 
early onset of acute and chronic pancreatitis, the development of exocrine and 
endocrine pancreatic insufficiency, and a high risk of pancreatic adenocarci-
noma (Chapter 185). Mutations in the trypsinogen (PRSS1) gene in these 
families appear to cause a gain in function in which the mutant trypsinogen, 
once activated to trypsin, is difficult to inactivate. This trypsin, if present in 
an amount that overwhelms normal protective mechanisms, can activate 
other pancreatic enzymes and lead to pancreatic damage and eventually to 
chronic pancreatitis. One of the protective mechanisms is a trypsin inhibitor 
called the SPINK1 protein. Loss of function mutations in SPINK1 predis-
poses to chronic pancreatitis. Major mutations in the cystic fibrosis con-
ductance regulator (CFTR) lead to cystic fibrosis (Chapter 83), which may 
be associated with chronic pancreatitis and pancreatic atrophy, depending 
upon the location of the mutation. Certain mutations in CFTR predispose 
to chronic pancreatitis, without causing the sinopulmonaryfeatures of classic 
cystic fibrosis. A number of additional genetic polymorphisms in the calcium 
sensing receptor, chymotrypsin C, claudins, and others are also associated 
with chronic pancreatitis. With the exception of PRSS1, these polymorphisms 
predispose to chronic pancreatitis and may function as modifying genes, but 
are not sufficient to cause chronic pancreatitis. 
Pancreatic Duct Obstruction
Chronic obstruction of the pancreatic duct by benign, premalignant, and 
malignant conditions can cause chronic pancreatitis to develop in the gland 
upstream from the obstruction. Examples include duodenal diseases causing 
obstruction at the ampulla (celiac disease, Crohn disease, ampullary adenoma 
or carcinoma), and benign (after severe pancreatitis, pancreatic surgery, or 
abdominal trauma), and malignant pancreatic duct strictures (pancreatic ductal 
adenocarcinoma, intraductal papillary mucinous neoplasms). 
Other Causes
Autoimmune pancreatitis is a disease that most often presents as a mass-like 
lesion in the pancreas with obstructive jaundice, mimicking cancer, but it also 
may present as chronic pancreatitis and rarely as acute pancreatitis.11 Because 
cancer is more common than autoimmune pancreatitis, it must be excluded 
(usually with endoscopic ultrasonography). Type 1 autoimmune pancreatitis 
(also called IgG4-disease) is characterized by diffuse swelling of the pancreas, 
elevation of the serum IgG4 level, and involvement of other organs, especially 
with biliary strictures, salivary gland inflammation, retroperitoneal fibrosis, and 
renal lesions. Histologically, these organs are infiltrated by chronic inflamma-
tory cells, especially plasma cells bearing IgG4 on their surface. Serum levels 
of IgG4 are also elevated. Type 2 autoimmune pancreatitis affects only the 
pancreas and is not associated with elevations in IgG4.
Although most chronic pancreatitis follows multiple episodes of acute pan-
creatitis, a single severe acute attack that causes substantial pancreatic necrosis 
can cause a ductal stricture or destroy enough gland to produce exocrine and 
endocrine insufficiency. Other diseases that cause repeated attacks of pancrea-
titis can lead to chronic pancreatitis. For example, hypertriglyceridemia causes 
recurrent acute pancreatitis that leads to chronic pancreatitis. 
CLINIC AL MANIFESTATIONS
Abdominal pain is the most common symptom and is responsible for the 
greatest negative impact on quality of life. The pain may be episodic or 
constant, and it is generally present in the epigastrium with radiation to the 
back. Some patients will present initially with an episode of acute pancreatitis 
and thereafter develop evidence of chronic pancreatitis, but others will have 
obvious chronic pancreatitis at their first presentation. If pain is episodic, 
the patient may be labeled as having acute pancreatitis or an acute flare of 
chronic pancreatitis. When pain is severe, nausea and vomiting may occur. 
Pain may worsen, improve, or remain stable over time. Up to 5% of patients 
do not have pain and instead present with exocrine (steatorrhea, weight loss) 
or endocrine (diabetes mellitus) pancreatic insufficiency. The disease tends to 
be progressive over time, even if the original cause (e.g., alcohol) is removed. 
The pain also may become self-perpetuating even if therapy is successful. 
DIAGNOSIS
The diagnosis may be suspected based on the clinical features but should be 
confirmed by tests that identify structural damage to the pancreas or derange-
ments in pancreatic function (Table 135-3).12 Serum levels of amylase or lipase 
are not useful for diagnosing chronic pancreatitis. Serum trypsinogen (also 
called trypsin) is abnormally low in patients with chronic pancreatitis that is 
advanced enough to cause steatorrhea but is often normal in patients with 
less advanced disease. Serum glucose levels will be elevated in patients with 
endocrine insufficiency.
Chronic pancreatitis is a slowly progressive disease in which visible damage 
to the gland (e.g., on a CT scan) and functional failure (e.g., steatorrhea or 
diabetes mellitus) may not be apparent for years. All diagnostic tests are most 
accurate when the disease is far advanced, and all are far less accurate in the 
early stages of disease.13
From a practical perspective, the diagnosis is established in most patients 
by CT or MRI.13b The diagnostic challenge lies with patients who present 
with a severe pain syndrome suggestive of chronic pancreatitis but who have 
a normal or minimally abnormal CT or MRI. In these patients, MRI with 
secretin-MRCP or endoscopic ultrasonography are the best choices, unless a 
secretin-based pancreatic function test is available. ERCP should not be used 
for diagnostic purposes alone.
In about 20% of patients, no clear cause of chronic pancreatitis is identified, 
and this may be more common in women. Some patients may have underlying 
genetic mutations, and others may be surreptitiously using alcohol and/or 
tobacco. Two general forms of idiopathic chronic pancreatitis are observed. 
In the first, pain is the predominant feature, and the onset of disease is in 
young adulthood. In the second, the onset is in middle age, and exocrine and 
endocrine insufficiency, rather than abdominal pain, are the major clinical 
manifestations. As more genetic polymorphisms are identified, the relative 
prevalence of idiopathic pancreatitis is shrinking.
Tests of Pancreatic Structure
Plain abdominal radiographs may demonstrate diffuse or focal pancreatic cal-
cification in patients with advanced chronic pancreatitis). Although specific 
for chronic pancreatitis, these findings are detected only after years of disease.
Abdominal ultrasound is of limited utility because overlying gas often limits 
the ability to visualize the pancreas. An abnormal pancreatic duct, pancreatic 
calcifications, gland atrophy, or changes in echotexture are seen in about 60% 
of patients.
CT is the most widely used diagnostic test for chronic pancreatitis, and 
high-quality images can be obtained of the pancreas and pancreatic duct. 
Characteristic findings include a dilated pancreatic duct, ductal or parenchymal 
calcifications, and atrophy (Fig. 135-3). These structural changes take years 
to develop, so CT is not as accurate in early or less advanced disease. Like 
CT, MRI allows detailed images of the pancreas, and the addition of MRCP 
STRUCTURAL FUNCTIONAL
Biopsy
Endoscopic ultrasonography
Magnetic resonance imaging with magnetic resonance 
cholangiopancreatography, with or without secretin 
infusion
Computed tomography
Endoscopic retrograde cholangiopancreatography
Ultrasonography
Plain abdominal radiography
Hormonal (secretin) test
Fecal elastase
Serum trypsin level
Fecal fat
Blood glucose level
∗Listed in approximate order of decreasing sensitivity
DIAGNOSTIC TESTS FOR 
CHRONIC PANCREATITIS∗
TABLE 135-3
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931CHAPTER 135 Pancreatitis
allows even better assessment of pancreatic duct morphology. Secretin can be 
administered at the time of MRCP to allow better visualization of the pancre-
atic duct. MRI with secretin-MRCP is more sensitive for detecting the early 
changes of chronic pancreatitis than is CT.14
Endoscopic ultrasonography allows very detailed images of the pancre-
atic parenchyma and duct (Fig. 135-4). Normal endoscopic ultrasonography 
essentially excludes chronic pancreatitis, whereas very abnormal endoscopic 
ultrasonography is highly consistent with chronic pancreatitis. ERCP provides 
the most detailed images of the pancreatic duct, as well as the opportunity 
to provide therapy (see below). Changes in the duct include dilation, irregu-
larity, ductal stones, andstrictures (Fig. 135-5). However, ERCP carries 
a risk of causing pancreatitis, so it should be utilized only when therapy 
is planned. 
Tests of Pancreatic Function
Quantification of fat in stool during a 72-hour collection while on a high-fat 
diet can be used to document steatorrhea but is rarely performed. Qualitative 
analysis of fat with Sudan staining of a stool specimen has poor sensitivity 
and specificity. Fecal levels of pancreatic elastase are diminished to less than 
100 μg/g in patients with advanced chronic pancreatitis and steatorrhea. The 
test can be performed while patients are taking pancreatic enzyme therapy.
For a pancreatic function test, a tube is passed into the duodenum, where 
pancreatic secretions are collected over the course of 1 hour in 15 minute 
aliquots and analyzed for bicarbonate concentration after a supraphysiologic 
dose of secretin is administered. A normal study is defined by at least one of 
the samples having a bicarbonate concentration of 80 mEq/L or more. The 
test becomes abnormal earlier in the disease process than any other test, so 
it is best suited to diagnose chronic pancreatitis earlier in its clinical course.15 
However, the test is not widely available or used.
 
 FIGURE 135-3. a computed tomographic scan demonstrating diffuse pancreatic 
calcification in a patient with long-standing chronic pancreatitis (arrows).
 FIGURE 135-4. an endoscopic ultrasound in a patient with chronic pancreatitis, dem-
onstrating a dilated pancreatic duct (marks on margin of main duct).
 FIGURE 135-5. an endoscopic retrograde cholangiopancreatography demonstrating 
a very irregular pancreatic duct with areas of dilation and stricturing in a patient with 
chronic pancreatitis (arrows).
Medical therapy starts with vigorous attempts to assist patients in stopping 
alcohol and tobacco.15b
Treatment of Pain
Many patients will require analgesics. It is appropriate to start with the less 
potent agents first (such as tramadol 50-100 mg every 6 hours). In most patients, 
it is helpful to add an adjunctive agent such as a tricyclic antidepressant (e.g., 
amitriptyline starting at 50 mg at night, or nortriptyline starting at 10 mg at 
night), a selective serotonin reuptake inhibitor, or a combined serotonin and 
norepinephrine uptake inhibitor at the usual starting dose (Table 369-5). Limited 
evidence supports the role of pregabalin (starting at 75 mg two times daily), 
which can be combined with some the antidepressant agents. Antioxidants 
(mixtures of selenium, vitamins E and C, β-carotene, and methionine) may 
also have some beneficial effect on pain in selected patients with preexisting 
deficiencies.16
Sudden worsening of pain should lead to a search for specifically treatable 
complications, including pseudocyst, obstruction of a surrounding hollow organ 
(e.g., duodenum or bile duct), or superimposed carcinoma. A good quality CT or 
MRI is usually sufficient to exclude these possibilities. These imaging tests also 
help in choosing appropriate therapy. Patients with a dilated duct (generally 
>5 mm) are the best candidates for endoscopic and surgical therapy. Patients 
without duct dilation are not suitable for most endoscopic and surgical therapy 
and must rely instead on medical therapy (Table 135-4). Unfortunately, pain 
often persists despite therapy. A celiac plexus block using bupivacaine can be 
performed relatively easily and safely, but substantial relief of pain is unpredict-
able and is achieved for only weeks or months. 
Other Medical Therapy
Pancreatic enzyme therapy is commonly used to treat exocrine insufficiency 
and occasionally to treat pain, although evidence is lacking on its effective-
ness for pain. Autoimmune pancreatitis responds promptly to steroid therapy17 
(usually 40 mg of prednisone daily for 4 weeks, with a taper of 5 mg/week over 
the next 7 weeks), but relapse commonly occurs, particularly in patients with 
biliary obstruction. Continuing prednisolone therapy at 5 to 7.5 mg daily for 
three years can significantly reduce the relapse rate.A10 
Endoscopic Therapy and Lithotripsy
ERCP can be used to dilate strictures and place stents across the stricture. 
Ductal stones, if they are not too large and are not impacted, may also be 
removed. Larger stones usually require lithotripsy to reduce the stone to frag-
ments that are manageable. MRCP is useful in patients who have a dominant 
TREATMENT 
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932 CHAPTER 135 Pancreatitis
obstruction in the pancreatic head with upstream ductal dilation. Such MRCP 
therapy is technically successful in more than 80% of carefully selected patients, 
and pain relief may be seen in 70 to 80% of patients, although treatment usually 
requires several endoscopic procedures. 
Surgical Therapy
Surgery also generally requires a dilated pancreatic duct and is somewhat 
more effective and more durable than is endoscopic therapy.A11,A11b Surgery can 
involve decompression of the pancreatic duct, resection of the pancreas, or a 
combination of the two. The most commonly performed procedure, the modi-
fied Puestow procedure, involves a longitudinal incision of the pancreatic duct 
from the body of the pancreas to as close to the duodenum as possible, and 
this duct is overlaid with a defunctionalized small intestinal limb to drain it. 
At the time of surgery, ductal strictures can be incised and ductal stones can 
be removed. The procedure is relatively simple in patients with a dilated pan-
creatic duct (>5 mm). Pain relief in the short term is good (>80%), with about 
50% obtaining long-term relief of pain. Alternative surgical procedures for pain 
include partial resection of the pancreas, typically the head of the gland. These 
operations, which include the classic pancreatico-duodenectomy (Whipple 
operation) as well as several variations of a duodenum-preserving pancreatic 
head resection, provide equal short-term pain reliefA12 and better long-term 
pain relief than a modified Puestow, but perhaps with higher morbidity. Total 
pancreatectomy, usually coupled with auto-transplantation of harvested 
islet cells, has been performed at a small number of centers but is generally 
considered a therapy of last resort because diabetes mellitus is common after 
the procedure and pain relief is inconsistent. 
Exocrine Insufficiency
Steatorrhea and maldigestion do not occur until approximately 90% of pan-
creatic enzyme secretion is lost, usually after at least 5 to 10 years of disease. 
Patients may note weight loss and oily stools, but often do not complain of 
diarrhea. Patients with chronic pancreatitis and exocrine insufficiency maldigest 
fat, protein, and carbohydrates, but fat maldigestion is usually most severe 
(including fat soluble vitamins, particularly vitamin D). The diagnosis of exocrine 
insufficiency is usually suggested by symptoms of oily or floating stools and 
weight loss. A formal 72-hour stool fat analysis is the most accurate method 
to document steatorrhea and to gauge effectiveness of therapy but is rarely 
done. Instead, the clinical features and a fecal elastase lower than 100 μg/g 
stool, coupled with an appropriate response to enzyme replacement therapy, 
is the best substitute for 72-hour fecal fat testing.
Pancreatic enzyme replacement therapy (Table 135-5) can normalize fat 
and fat-soluble vitamin absorption, maintain normal nutrition and weight, and 
prevent complications such as osteoporosis.A13 Both enteric-coated capsules 
and non–enteric-coated tablets are available. Enzymes are identified by the 
lipase content of the pill or capsule, although they all contain proteases and 
amylase as well. The goal of enzyme therapy is to provide atleast 10% of normal 
pancreatic output with each meal (90,000 USP units of lipase/meal). Since most 
patients are still producing some enzymes (including gastric lipase), it may not 
be necessary to prescribe the full dosage of 90,000 USP units with each meal; 
40,000 to 50,000 is a reasonable starting point.
If non–enteric-coated preparations are selected, cotreatment with an 
H2-blocker (e.g., ranitidine 150 mg twice daily or equivalent) or proton 
pump inhibitor (e.g., omeprazole 20 mg daily or equivalent) is required to 
prevent acid denaturation of enzymes; such cotreatment is not needed with 
Medical therapy Analgesics and adjunctive agents
	•	 	Tramadol	50	mg,	1-2	three	times	daily
	•	 	Amitryptiline,	starting	at	50	mg	at	night
	•	 	Nortriptyline,	starting	at	10	mg	at	night
	•	 	SSRIs	(e.g.,	citalopram,	fluoxetine,	sertraline,	 
paroxetine) at recommended starting dose (see 
Table 369-5)
	•	 	Gabapentin,	starting	at	100	mg	at	night
	•	 	Pregabalin,	starting	at	75	mg	two	times	daily
Antioxidants
	•	 	Typical	mixture	containing	vitamin	C	(1000	mg),	
vitamin E (300 IU), selenium (500 μg), methionine 
(2 g), and β-carotene (10,000 IU) total daily dose
Neurolysis Endoscopic ultrasonography–guided neurolysis
Endoscopic therapy Stent
Stone removal, lithotripsy
Surgical therapy Pancreaticojejunostomy (modified Puestow operation)
Partial pancreatic resection (Whipple operation, duodenum 
preserving pancreatic head resection, others)
Total pancreatectomy with islet-cell auto-transplantation
CT = computed tomography; SSRI = selective serotonin reuptake inhibitor.
TREATMENT FOR PAINTABLE 135-4
PRODUCT FORMULATION LIPASE CONTENT/CAPSULE OR PILL
Zenpep Enteric-coated porcine 3000; 5000; 10,000; 15,000; 20,000; 
25,000; 40,000
Creon Enteric-coated porcine 3000; 6000; 12,000; 24,000; 36,000
Pancreaze Enteric-coated porcine 4200; 10,500; 16,800; 21,000
Pertzye Enteric-coated porcine 
with bicarbonate
4000; 8000; 16,000
Viokace Non-enteric-coated 
porcine tablet*
10,440; 20,880
∗Needs to be coadministered with an H2 blocker (e.g., ranitidine 150 mg twice daily) or a proton 
pump inhibitor (e.g., omeprazole 20 mg/day)
ENZYME THERAPY FOR EXOCRINE 
PANCREATIC INSUFFICIENCY
TABLE 135-5
enteric-coated preparations. Enzymes should be split during the meal (usually 
during and immediately after the meal). Supplementation with vitamin D (400 
to 1000 IU daily) and calcium (1.0 to 1.5 g daily) is appropriate because of the 
risks of osteoporosis (Chapter 230) and osteopenia. Measurement of fat soluble 
vitamin levels and periodic bone mineral density testing are recommended. 
The success of enzyme therapy is generally defined as weight gain, reduction 
or absence of visible oil in the stool, and correction of fat-soluble vitamin levels. 
Failure of enzyme therapy is most often due to an inadequate dose. Increasing 
the dose up to the full 90,000 USP units with meals and encouraging compliance 
is appropriate as a first step. No generic products are available in the United 
States, so cost may be a major cause of noncompliance. Some patients may not 
respond owing to the presence of a second disease that also causes malabsorp-
tion, such as small intestinal bacterial overgrowth. 
Endocrine Insufficiency
Like exocrine insufficiency, diabetes mellitus (Chapter 216) is a very late com-
plication of chronic pancreatitis, occurring years or decades after the onset 
of disease. In contrast to type 1 diabetes mellitus, destruction of the entire 
islet, which has been termed type 3C diabetes mellitus, reduces secretion of 
both insulin and glucagon.18 The absence of glucagon increases the risk that 
overly aggressive insulin therapy may lead to hypoglycemia. In most patients, 
therefore, insulin treatment is not aimed at exceedingly tight glucose control. 
Unfortunately, these patients are at similar risk for microvascular complications 
as are all other patients with diabetes. 
Complications
Pancreatic pseudocyst: Pseudocysts, when they are discovered in patients 
with chronic pancreatitis, are generally mature and have a visible capsule sur-
rounding them. As in acute pancreatitis, benign pseudocysts in chronic pancre-
atitis do not require therapy if they are not producing symptoms and are not 
infected. However, some cystic structures in and around the pancreas are cystic 
neoplasms (Chapter 185), not pseudocysts. Symptomatic pseudocysts require 
drainage, whereas neoplasms require resection. Features that suggest a cystic 
neoplasm include a cyst with a thick or nodular wall, a cyst with multiple internal 
septations, or a cyst occurring in a patient who does not have a history of pan-
creatitis. Any combination of these features should lead to further investigation, 
generally with endoscopic ultrasonography and aspiration.
Symptomatic pseudocysts can be treated with endoscopic, percutaneous or 
surgical therapy with equal efficacy. In most centers, endoscopic ultrasonog-
raphy-guided drainage is becoming first-line therapy with excellent short- and 
long-term results. Complications of pseudocysts include infection, bleeding 
(discussed above), and rupture. Pseudocysts may leak into the peritoneal com-
partment (pancreatic ascites) or track into the chest (pancreatic pleural effu-
sion). Patients usually present with abdominal distension or dyspnea, rather 
than abdominal pain. Amylase level in the fluid is usually greater than 4,000 
U/L. Endoscopic therapy with stent placement across the connection between 
pseudocyst and pancreatic duct is highly effective in this situation.
Malignancy: Chronic pancreatitis is a strong risk factor for pancreatic ductal 
adenocarcinoma (Chapter 185), with a lifetime risk of about 4%, which is 8- to 
16-fold above the general population.19 The risk of cancer is much higher in 
patients with hereditary pancreatitis, in whom the risk may range as high as 
40 to 70%. Other genetic causes and smoking also increase the risk of second-
ary pancreatic malignancy, as may type 3C diabetes mellitus. It may be difficult 
to visualize cancer in an already diseased pancreas.
PREVENTION
Currently, there are no reliable methods to prevent chronic pancreatitis. Patients 
at risk for chronic pancreatitis, such as members of families with hereditary 
pancreatitis or patients with strong genetic predispositions, should avoid 
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alcohol and tobacco. Similarly, patients with established chronic pancreatitis 
should avoid these agents, which hasten the progression of the disease. 
PROGNOSIS
With prolonged follow-up of 10 to 20 years, the majority of patients will develop 
exocrine or endocrine insufficiency. Overall mortality is increased 3- to 6-fold 
compared with age-matched controls. Patients who are older, smoke, or have 
alcohol as the cause are at highest risk of mortality. Overall, 10-year survival 
approximates 70%, and 20-year survival is about 45%. Death is usually not 
due to pancreatitis itself but rather to malignancy, postoperative complica-
tions, and complications of alcohol (Chapter 30) or tobacco (Chapter 29).
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GENERAL REFERENCES
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933.e1CHAPTER 135 Pancreatitis
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