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E-Fig. 39.2 Endoscopic retrograde cholangiopancreatography shows
the pancreatic ductal system in pancreas divisum. The upper duct (i.e.,
dorsal pancreas) was visualized by injecting contrast into the duct of
Santorini. The lower duct (i.e., ventral pancreas) was highlighted by
injecting the duct of Wirsung.
CHAPTER 39 Diseases of the Pancreas
404.e1
CHAPTER 39 Diseases of the Pancreas
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405
Smoking
Smoking was once thought to be a risk factor due to its synergism with
alcohol. However, studies have suggested that cigarette smoking is an
independent risk factor for acute and chronic pancreatitis by mechanisms that are unclear.
Autoimmune Pancreatitis
Autoimmune pancreatitis (AIP) is a benign disease representing two
distinct but overlapping immune-mediated inflammatory conditions
of the pancreas referred to as type 1 and type 2 AIP. Type 1 is the classic
and more common form of AIP. It is characterized histologically by a
periductal lymphoplasmacytic infiltrate, storiform fibrosis, obliterative
phlebitis, and abundant immunoglobulin G4 (IgG4) immunostaining
(>10 IgG4-positive cells per high-power field).
The most common manifestation of AIP is obstructive jaundice,
which closely mimics pancreatic cancer with focal enlargement of the
pancreatic head. AIP can also manifest as acute pancreatitis in up to
15% to 30% of individuals, and about 5% of patients evaluated for
acute or chronic pancreatitis have AIP. AIP has a peak incidence in
the sixth or seventh decades of life and tends to affect men twice as
often as women. Serum IgG4 levels are elevated to more than two times
the upper limit of normal in most patients. Computed tomography
(CT) typically demonstrates diffuse enlargement of the pancreas with
delayed (rim) enhancement and a diffusely irregular, attenuated main
pancreatic duct. More than 60% of individuals have clinical and histologic involvement of other organs, including the biliary tree, retroperitoneum, lacrimal and salivary glands, lymph nodes, periorbital tissues,
kidneys, thyroid, lungs, meninges, aorta, breast, prostate, pericardium,
and skin. Although a majority of patients initially respond to glucocorticoids, a significant portion of patients relapse once glucocorticoids
are discontinued. Immunomodulator drugs have been used in those
that fail steroids, relapse or cannot be weaned off steroids.
A less common form of AIP (type 2 AIP) has a similar clinical and
radiographic presentation in the pancreas, but in contrast to type 1 disease, it requires histologic confirmation of an idiopathic duct centric
pancreatitis lesion. Other hallmarks of type 1 disease are absent such
that IgG4 levels are normal and other organs are not involved. Type 2
AIP is similarly steroid responsive but unlike type 1 disease, relapse is
uncommon.
Pancreas Divisum
At approximately 4 weeks’ gestation, the dorsal pancreas forms as
an evagination from the duodenum, and shortly thereafter, the ventral pancreas forms from the hepatic diverticulum (E-Fig. 39.2). At
approximately the eighth intrauterine week of life, the ventral pancreas rotates posterior to the duodenum and comes to rest posterior
and inferior to the head portion of the dorsal pancreas with associated
fusion of the main ducts. If fusion is incomplete, the duct of Wirsung
drains only the ventral pancreas through the major ampulla, and the
duct of Santorini drains the bulk of the pancreas (i.e., dorsal pancreas)
through the relatively small accessory (minor) ampulla. This anomaly,
called pancreas divisum, occurs in 5% to 10% of the general population
and is associated with acute and chronic pancreatitis.
Theories suggest that pancreatitis results from relative outflow
obstruction of the main dorsal duct through the small accessory
ampulla. Endoscopic papillotomy, stent placement across the minor
papilla, and surgical sphincteroplasty are therapeutic maneuvers that
may reduce the incidence of recurrent pancreatitis by increasing drainage through the accessory papilla. While there are studies that appear
to show an association between pancreas divisum and pancreatitis,
there is controversy as to whether pancreas divisum is truly a cause of
acute recurrent pancreatitis.
Clinical Presentation
The hallmark of acute pancreatitis is persistent abdominal pain. In
atypical cases, patients may have unexplained organ failure or postoperative ileus. The onset of pain is typically sudden, severe, and worse
when supine. Pain is usually located in the upper abdomen and may
radiate to the back, chest, and flanks. Nausea and vomiting are common. Physical examination usually reveals severe upper abdominal
tenderness that is sometimes associated with guarding.
Pancreatic enzymes, vasoactive substances (e.g., kinins), and other
toxic substances (e.g., elastase, phospholipase A2) are liberated by the
inflamed pancreas and extravasate along fascial planes in the retroperitoneal space, lesser sac, and peritoneal cavity. These materials cause
chemical irritation and contribute to the development of ileus, chemical peritonitis, third-space losses of protein-rich fluid, hypovolemia,
and hypotension. The toxic molecules may reach the systemic circulation by lymphatic and venous pathways and contribute to subcutaneous fat necrosis and end-organ damage, including shock, renal failure,
and respiratory insufficiency (i.e., atelectasis, effusions, and acute
respiratory distress syndrome [ARDS]). Grey Turner sign (i.e., ecchymosis of the flank) or Cullen sign (i.e., ecchymosis in the periumbilical
region) may be associated with hemorrhagic pancreatitis.
Metabolic problems, which are common in severe disease, include
hypocalcemia, hyperglycemia, and acidosis. Hypocalcemia is most
commonly caused by concomitant hypoalbuminemia. Other mechanisms include complexing of calcium to released free fatty acids, protease-induced degradation of circulating parathyroid hormone (PTH),
and failure of PTH to release calcium from bone.
Acute pancreatitis is associated with a variety of local and vascular
complications, including local spread of inflammation to contiguous
organs. The most common include peripancreatic fluid collections,
pseudocyst formation, obstruction of the duodenum or bile duct,
and exocrine or endocrine insufficiency. Less common complications
include pancreatic fistula formation, vascular thrombosis (i.e., splenic,
portal and superior mesenteric veins), colonic necrosis, and development of an arterial pseudoaneurysm. Trypsin can activate plasminogen
to plasmin and induce clot lysis. However, trypsin also can activate
prothrombin and thrombin and produce thrombosis leading to disseminated intravascular coagulation.
Acute peripancreatic fluid collections are pools of peripancreatic
fluid confined by normal peripancreatic fascial planes without a definable wall encapsulating the collection. These fluid collections occur
during the first 4 weeks after interstitial pancreatitis. When a localized
acute peripancreatic fluid collection persists beyond 4 weeks, it is likely
to develop into a pancreatic pseudocyst.
Pancreatic pseudocysts (E-Fig. 39.3) are encapsulated fluid collections with well-defined inflammatory walls and are usually located
outside the pancreas with minimal or no necrosis. They occur a minimum of 4 weeks after the onset of acute pancreatitis. Although most
pseudocysts remain asymptomatic, presenting symptoms may include
abdominal pain, early satiety, nausea, and vomiting due to compression of the stomach or gastric outlet. Rapidly enlarging pseudocysts
may rupture, hemorrhage, obstruct the extrahepatic biliary tree, erode
into surrounding structures, and become infected.
The term acute necrotic collection describes a nonorganized accumulation of heterogeneous fluid and necrotic material in the setting
of necrotizing pancreatitis. The necrosis may involve the pancreatic
parenchyma or peripancreatic tissue, or both. Walled-off pancreatic
necrosis is a mature, encapsulated collection of pancreatic or peripancreatic necrosis that usually occurs more than 4 weeks after the onset
of necrotizing pancreatitis.
Abdominal compartment syndrome is diagnosed when the
intra-abdominal pressure exceeds 20 mm Hg and there are signs of new
406 SECTION VI Gastrointestinal Disease
respiratory, renal, or vascular organ failure. Intra-abdominal hypertension typically occurs early and is the result of pancreatic inflammation and fluid third spacing. Abdominal compartment syndrome
is associated with mortality rates ranging up to 50% to 75% in various
reports. Suggested treatment includes analgesics, sedation, nasogastric
tube decompression, and fluid restriction. If these measures do not
result in improvement, percutaneous catheter decompression followed
if unsuccessful by a surgical laparotomy is recommended. The ability
of this approach to improve outcomes is the focus of ongoing research.
Diagnosis and Differential Diagnosis
The diagnosis of acute pancreatitis is based on a combination of clinical, biochemical, and radiologic factors. A diagnosis of acute pancreatitis requires two of the following three features: abdominal pain
characteristic of acute pancreatitis; serum amylase or lipase levels, or
both, at least three times the upper limit of normal; and characteristic
findings of acute pancreatitis on imaging.
Elevated serum amylase levels may occur in a wide variety of other
conditions, including bowel perforation, intestinal obstruction or ischemia, acute appendicitis, cholecystitis, tubo-ovarian disease, and renal
failure. Serum amylase levels may be normal in patients with hypertriglyceridemia or alcohol-induced acute pancreatitis. Serum lipase is
preferred because it is more sensitive and specific than serum amylase
for the diagnosis of acute pancreatitis. The serum lipase level remains
normal in some nonpancreatic conditions associated with an elevated
serum amylase level, including macroamylasemia (i.e., formation of
large molecular complexes between amylase and abnormal immunoglobulins), salivary gland disorders, and tubo-ovarian disease, but
it may similarly rise in appendicitis, renal disease, and cholecystitis.
The serum lipase concentration is more sensitive than that of amylase because it remains elevated longer and may be diagnostic even for
patients seeking medical attention several days after symptom onset.
Repeated measurements of serum pancreatic enzymes have little value
in assessing clinical progress, and the magnitude of serum amylase or
lipase elevation does not correlate with the severity of pancreatitis.
Contrast-enhanced computed tomography (CECT) or magnetic
resonance imaging (MRI) of the pancreas should be used for patients
whose diagnosis is unclear or who fail to improve within the first 48 to
72 hours after hospital admission. Imaging findings supporting acute
pancreatitis include pancreatic enlargement, peripancreatic inflammatory changes, and extrapancreatic fluid collections. Imaging does
not exclude the diagnosis of acute pancreatitis because the pancreas
appears normal in 15% to 30% of those with mild disease. CECT is
also useful for assessing disease severity based on the presence and
extent of complications such as pancreatic necrosis and acute peripancreatic fluid collections. Pancreatic imaging should be performed after
adequate fluid resuscitation to minimize the risk of contrast-induced
nephrotoxicity.
MRI is preferred for patients with a contrast allergy and renal insufficiency because T2-weighted images without gadolinium contrast can
similarly diagnose pancreatic necrosis. Early imaging (within 72 hours
of symptom onset) can underestimate the existence and extent of pancreatic necrosis. Gallstone pancreatitis should be suspected in patients
with transient elevation in liver function test results, particularly a
serum ALT level elevated more than 3-fold. Transabdominal ultrasonography should be performed in all patients with acute pancreatitis
when considering a diagnosis of gallstone pancreatitis.
Prognosis
The distinction between interstitial and necrotizing acute pancreatitis has important prognostic implications (Fig. 39.3). Interstitial pan-
creatitis is characterized by an intact microcirculation and uniform
enhancement of the gland on CECT. Necrotizing pancreatitis is characterized by disruption of the pancreatic microcirculation so that large
areas (>3 cm or >30%) of pancreatic parenchyma do not enhance on
CECT. Approximately 20% to 30% of patients with acute pancreatitis
have necrotizing pancreatitis.
The finding of pancreatic necrosis predicts a more severe course,
particularly infection in the necrotic pancreatic tissue, also called
infected necrosis. Infection is a strong determinant of the severity of
illness and accounts for a large percentage of the deaths from acute
pancreatitis. Infected necrosis develops in 30% to 50% of patients with
acute necrotizing pancreatitis but not in those with interstitial disease.
Infected necrosis should be suspected in patients with persistent systemic inflammatory response syndrome (SIRS) or organ dysfunction.
The diagnosis can be made if extraluminal gas is seen on CECT. More
commonly, CT-guided needle aspiration is obtained for Gram stain
and culture of necrotic material, or antibiotics are given empirically
based on clinical suspicion after appropriate cultures are obtained.
Antibiotics that penetrate pancreatic tissue, including cephalosporins,
carbapenems, quinolones, and metronidazole, are used for treatment
of infected necrosis.
Risk assessment should be performed for all patients to stratify the
severity of illness. The current classification includes mild, moderate,
and severe forms. Mild acute pancreatitis, the most common form, is
characterized by the absence of organ failure and pancreatic necrosis.
Mild pancreatitis usually does not require pancreatic imaging, and
patients recover within several days with restoration of normal pancreatic function and gland architecture. Patients with mild acute pancreatitis account for 80% of all attacks and less than 5% of the overall
mortality rate.
Moderately severe pancreatitis is characterized by local complications and/or transient organ failure over a time period of less than 48
hours. Local complications include pancreatic necrosis (with or without infection) and acute peripancreatic fluid collections or pancreatic
pseudocysts. Death from moderately severe pancreatitis is much less
common than in cases of severe pancreatitis.
Severe acute pancreatitis is defined by persistent organ failure
extending for more than 48 hours. Severe acute pancreatitis occurs in
15% to 20% of patients. Most individuals with persistent organ failure
have underlying necrotizing disease. The respiratory, cardiovascular,
and renal systems are most commonly affected. Early deaths (within
the first week) are most often the result of multiple organ failure
caused by the release of inflammatory mediators and cytokines. Late
deaths are more likely to result from local or systemic infection. The
risks of infection and death correlate with disease severity and pancreatic necrosis. The overall mortality approaches 30% among patients
with persistent organ failure.
Despite the importance of recognizing severe disease, most patients
are initially admitted to the hospital without necrosis or organ failure,
and methods to predict individuals more likely to progress to severe
disease during the initial several days of hospitalization have been
defined. A combination of clinical assessment, scoring systems, serum
markers, and CECT scanning provides the most useful prognostic
information (Table 39.2). Regardless of the prognostic factor chosen,
there are significant limitations in predicting disease severity.
Clinical predictors of a poor outcome include severe comorbid
illnesses, older age (≥60 years), obesity, and long-term, heavy alcohol use. Laboratory findings associated with increased mortality
include blood urea nitrogen elevation (>20 mg/dL) on admission or a
rise during the first 24 hours of admission, hemoconcentration from
third spacing of fluids reflected by an elevated hematocrit of 44 or
greater on admission, and serum markers reflecting a robust systemic
inflammatory response, such as a C-reactive protein level greater than
E-Fig. 39.3 Computed tomography scan shows a large pancreatic
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pseudocyst.
CHAPTER 39 Diseases of the Pancreas
406.e1
CHAPTER 39 Diseases of the Pancreas
407
A
Fig. 39.3 Contrast-enhanced computed tomography demonstrates interstitial pancreatitis (A) and necrotizing
pancreatitis (B).
B
TABLE 39.2 Predictors of Severe Pancreatitis
Criteria Prognostic Indicators
a
Signs
Patient characteristics Comorbid illnesses
Laboratory values BUN level of 20 mg/dL or higher and any rise in BUN during the first 24 hr of admission associated with increased
Imaging findings Pleural effusion
Scoring systems
Ranson’s criteria Eleven prognostic indicators, including five available on admission (age >55 yr, WBC >16,000/mm3, glucose >200 mg/
Acute Physiologic and Chronic Health
Evaluation (APACHE II) system
Bedside Index for Severity of Acute
Pancreatitis (BISAP)
AST, Aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; CRP, C-reactive protein; GCS, Glasgow Coma Scale; Hct, hematocrit; LDH, lactate dehydrogenase; SIRS, systemic inflammatory response syndrome; WBC, white blood cells.
a
SIRS predisposes to multiple organ dysfunction and pancreatic necrosis. SIRS is defined by two or more of these criteria persisting for more than
48 hours.
Heart rate: >90 beats/min
Temperature: >38° C or <36° C
White blood cell count: >12,000 or <4,000 cells/μL or >10% bands
Respiratory rate >20 beats/min or Paco2 <32 mm Hg
Age >55 yr
Obesity (BMI >30 kg/m2)
mortality
Serum creatinine >1.8 mg/dL within first 24 hr
Hemoconcentration with Hct ≥44 on admission or failure of Hct to decrease in first 24 to 48 hr with volume resuscita-
tion predicts severe pancreatitis
Serum marker reflecting a systemic inflammatory response, CRP >150 mg/dL
Pancreatic necrosis
Acute extrapancreatic fluid collections
dL, LDH >350 IU/L, AST >250 U/L) and six measured at the end of the first 48 hr (Hct decreased >10, BUN >5 mg/dL,
Po2 <60 mm Hg, base deficit >4 mEq/L, serum calcium <8 mg/dL, estimated fluid sequestration >6 L); mortality rate
of 10–20% for three to five signs and >50% for six or more signs
Calculated by assigning points based on age, heart rate, temperature, respiratory rate, mean arterial pressure, Pao2,
pH, potassium, sodium, creatinine, Hct, WBC, GCS, and previous health status
Five variables available in initial 24 hr: BUN >25 mg/dL, impaired mental status (GCS score <15), finding of SIRS,
age >60 yr, and pleural effusion on imaging. Each variable adds 1 point to the total score, and scores of 3, 4, and 5
correspond to mortality rates of 5.3%, 12.7%, and 22.5%, respectively.
150 mg/dL (sensitivity of 80%, specificity of 76%, positive predictive
value of 67%, and negative predictive value of 86%). Imaging studies
predicting a severe outcome include a pleural effusion seen on chest
radiography within the first 24 hours or pancreatic imaging identifying
necrosis. Unfortunately, CT evidence of severe acute pancreatitis lags
behind clinical findings, and an early CT study can underestimate the
severity of the disorder.
Severe pancreatitis is predicted by organ dysfunction, including shock (systolic blood pressure <90 mm Hg), respiratory failure
(Pao2 ≤60 mm Hg), and acute renal injury (creatinine >2.0 mg/L after
408 SECTION VI Gastrointestinal Disease
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rehydration). SIRS predisposes to multiple organ dysfunction and
pancreatic necrosis.
Well-established scoring systems include Ranson’s criteria, Acute
Physiologic and Chronic Health Evaluation II (APACHE II), APACHE
combined with scoring for obesity (APACHE-O), the Glasgow Scoring
System, and Bedside Index for Severity of Acute Pancreatitis (BISAP).
With increasing scores, the likelihood of a complicated, prolonged,
and fatal outcome increases. Unfortunately, because these scoring systems have a high false-positive rate (i.e., in many patients with high
score, severe pancreatitis does not develop), they are not universally
used. During the first 48 to 72 hours, a rising hematocrit or BUN, persistent SIRS after fluid resuscitation or the presence of pancreatic or
peripancreatic necrosis on cross-sectional imaging constitute evidence
of evolving severe pancreatitis.
Treatment
Early steps in the management of patients with acute pancreatitis can
decrease severity, morbidity, and mortality (Fig. 39.4). Prevention of
complications depends largely on monitoring, vigorous hydration,
and early recognition of pancreatic necrosis and choledocholithiasis.
Patients with multiorgan dysfunction and those with predicted development of severe disease are at greatest risk for adverse outcomes and
should be treated when possible in a care unit with intensive monitoring capability and multidisciplinary input.
Supportive Care
Patients with acute pancreatitis are treated supportively with aggressive intravenous hydration, parenteral analgesics, and bowel rest.
Supplemental oxygen is recommended initially for all patients.
Nasogastric tube suction is indicated for symptomatic relief in patients
with nausea, vomiting, and ileus. No specific treatments are effective
in limiting systemic complications. Agents that put the pancreas to rest
(e.g., somatostatin, calcitonin, glucagon, H2-receptor antagonists) and
enzyme inhibitors (e.g., aprotinin, gabexate mesylate) have not been
shown to lower disease-related morbidity and mortality.
Antibiotics
Antibiotic therapy is no longer recommended for patients with sterile
necrosis due to the lack of proven benefit. For patients with suspected
infected necrosis, appropriate antibiotics are initiated before the confirmatory diagnosis, with the initial choice taking into consideration
the likely pathogenic organisms and the ability of the antimicrobials
to penetrate into necrotic pancreatic tissues. After culture results are
available, the antibiotics can be tailored appropriately.
Fluid Management
Vigorous fluid resuscitation is important for maintaining the microcirculation and perfusion of the pancreas during the early phase of
acute pancreatitis. Early aggressive intravenous hydration during the
first 12 to 24 hours after the onset of symptoms translates into a potential benefit of reduced pancreatic necrosis and organ failure. Vigorous
fluid therapy is of little value after 24 hours. Crystalloid, the preferred
intravenous fluid, is administered at an initial rate of 250 to 500 mL/
hour or 5 to 10 mL/kg/hr with a preceding bolus infusion for individuals with severe volume depletion. Lactated Ringer’s solution may
be the preferred crystalloid replacement because in one comparative
study, it reduced the incidence of inflammatory markers by more than
80% compared with normal saline infusion. Goal-directed fluid therapy is recommended for patients with acute pancreatitis. Goal-directed
therapy is defined as titration of intravenous fluids every few hours to
specific clinical and biochemical targets of perfusion (e.g., heart rate,
blood pressure, urine output, BUN, and hematocrit). Caution must be
used for the elderly and those with underlying cardiovascular or renal
impairment.
Analgesia
Despite the theoretical concern that narcotic analgesia may result in
sphincter of Oddi spasm and worsening pancreatitis, there is no evidence to support withholding narcotics from patients with acute
pancreatitis. The physician should consider liberal use of patient-controlled analgesia, although this approach has not been compared prospectively with on-demand analgesia. There is no evidence to indicate
superiority of a specific opiate. Patients administered repeated doses of
narcotic analgesics should have oxygen saturation monitored due to
risks of unrecognized hypoxia.
Nutritional Care
Patients with mild acute pancreatitis can begin oral feeding within
24 hours of admission without waiting for resolution of pain or normalization of serum pancreatic enzyme levels. Early introduction of a
low-fat solid diet is as safe as the traditional approach of progressive
advancement from a clear liquid diet and is associated with a shorter
length of hospital stay.
For patients with predicted severe pancreatitis or small bowel ileus,
early introduction of oral intake may not be tolerated due to postprandial abdominal pain, nausea, and vomiting. These individuals can have
nutrition introduced as nasoenteric or nasogastric feeding. Enteral
feeding is preferable to total parenteral nutrition (TPN) because it is
less expensive than TPN and is associated with a reduction in systemic
infection, need for surgical intervention, organ failure, and mortality.
Enteral feeding is usually well tolerated, even by patients with an ileus.
Nasogastric feeding offers a safe alternative to nasojejunal feeding
because it appears to be equally safe and effective. Parenteral nutrition
should be reserved for patients who cannot achieve sufficient caloric
intake through the enteral route or those in whom enteral access cannot be maintained.
Management of Recurrence and Necrosis
Gallstone pancreatitis. The risk of gallstone pancreatitis (see also
Chapter 45) recurrence is as high as 50% to 75% within 6 months of the
initial episode, and cholecystectomy before discharge is recommended
for patients with mild attacks of pancreatitis. Cholecystectomy
performed during the initial admission for patients with suspected
biliary pancreatitis is associated with substantial reductions in mortality
and gallstone-related complications, readmission for recurrent
pancreatitis, and pancreaticobiliary complications. Cholecystectomy
is often delayed in patients with severe pancreatitis to allow for better
exposure of the ductal anatomy at the time of surgery. Urgent ERCP
(Video 39.1) with identification and clearance of bile duct stones is
recommended for patients with documented choledocholithiasis on
imaging, cholangitis or strong evidence of ongoing biliary obstruction,
as suggested by imaging and laboratory data. Biliary sphincterotomy
leaving the gallbladder in situ is considered an effective alternative for
those who are not candidates for cholecystectomy.
Acute fluid collections and pseudocysts. Acute peripancreatic
fluid collections do not require any specific therapy, other than
supportive therapy that is standard for acute pancreatitis. Most
remain sterile and are reabsorbed spontaneously during the first
several weeks after the onset of acute pancreatitis. When a localized
acute peripancreatic fluid collection persists beyond 4 weeks, it is
likely to develop into a pancreatic pseudocyst. While patients with
asymptomatic pseudocysts should be followed, for those who are
symptomatic, pseudocyst drainage should be considered. Indications
for pseudocyst drainage include suspicion of infection or progressive
Establish the diagnosis of acute
pancreatitis with 2 of the following:
1. Characteristic abdominal pain
2. Amylase/lipase 3x upper limit of normal
3. Characteristic findings on abdominal imaging
CHAPTER 39 Diseases of the Pancreas
409
Initial resuscitation
• Vigorous fluids to maintain
urine output 0.5 mL/kg/hr:
• Severe volume depletion:
500–1000 mL/hr
• Not severe: 300–500 mL/hr
• No volume depletion:
250–350 mL/hr
• Supplemental oxygen
• Analgesia with parenteral
narcotics
Mild disease
• Prognostic signs favorable
• Systemic complications absent
• Usually interstitial pancreatitis
• CT scan not indicated
Interstitial pancreatitis Necrotizing pancreatitis
Medical treatment
• ICU required
• Fluid resuscitation
• Treat systemic complications
• Consider enteral feeding TPN
• Consider ERCP
Assess initial
disease severity
• Bedside assessment
• APACHE II score
• Ranson’s criteria
• BISAP score
• Organ failure, SIRS
• Pancreatic necrosis
• CRP at 48 hr
• Prognostic signs unfavorable
• APACHE II 8, Ranson’s 3,
CRP 150 mg/dL, BISAP score 3
• Systemic complications present
(MSOF, SIRS)
• Usually necrotizing pancreatitis
• CT scan indicated
Work-up the etiology
• History (personal and FH)
• Medications
• LFTs
• Serum TGs
• Serum calcium
• Abdominal US
Severe disease
• ICU required
• Fluid resuscitation
• Treat systemic complications
• Consider enteral feeding TPN
For GSP
• Consider ERCP
Medical treatment
Clinical
improvement
Continue medical
treatment
Infected necrosis Sterile necrosis
Step-up approach
Percutaneous drainage followed by
minimally invasive retroperitoneal
necrosectomy (endoscopic or surgical)
Fig. 39.4 Management algorithm for acute pancreatitis. Some of the guidelines, such as the diagnostic utility
of the C-reactive protein (CRP) level, require further validation. Antibiotic use, including the type and duration
of treatment, continues to be examined, and these suggested approaches will likely be modified by the findings of future studies. APACHE II, Acute Physiologic and Chronic Health Evaluation II; BISAP, Bedside Index
for Severity of Acute Pancreatitis; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; FH, family history; GPA, CT-guided percutaneous aspiration; GSP, gallstone pancreatitis; ICU,
intensive care unit; LFTs, liver function tests; MSOF, multiple system organ failure; R/O, rule out; SIRS, systemic inflammatory response syndrome; TGs, triglycerides; TPN, total parenteral nutrition; US, ultrasound.
No improvement
or deterioration
R/O infected
necrosis by GPA
Continue medical treatment
If no improvement—late necrosectomy
410 SECTION VI Gastrointestinal Disease
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enlargement with associated symptoms including biliary obstruction,
abdominal pain, early satiety, and nausea and vomiting due to stomach
compression or gastric outlet obstruction. In symptomatic patients,
if the pseudocyst is mature and encapsulated, treatment can involve
endoscopic, surgical, or percutaneous drainage. Based on available
expertise, endoscopic ultrasound (EUS) guided drainage is preferred
with cystogastrostomy or cystoduodenostomy.
Sterile pancreatic and extrapancreatic necrosis. Sterile pancre-
atic necrosis usually is treated with supportive medical care during the
first several weeks, even in patients with multiple organ failure. After
the acute pancreatic inflammatory process has subsided and coalesced
into an encapsulated structure (e.g., walled-off pancreatic necrosis),
débridement may be required for intractable abdominal pain, vomiting caused by extrinsic compression of stomach or duodenum, biliary
obstruction, failure to thrive or persistent systemic toxicity. Débridement is delayed for at least 4 to 6 weeks after the onset of pancreatitis
and can be performed by a combination of endoscopic, radiologic, and
surgical techniques. Asymptomatic pancreatic necrosis does not warrant intervention, regardless of the extent and location.
Infected pancreatic and extrapancreatic necrosis. The develop-
ment of infection in the necrotic collection is the main indication for
therapy. The development of fever leukocytosis and increasing abdominal pain suggests infection of the necrotic tissue. A CT scan may reveal
evidence of air bubbles in the necrotic cavity.
Infected pancreatic necrosis is best treated with drainage or débridement, or both. Routine CT-guided fine-needle aspiration to diagnose
infected necrosis is not recommended given that clinical and imaging
signs are accurate in the majority of patients. In addition, there is a high
false-negative rate of the samples. Thus, débridement warrants consideration when infected necrosis is suspected, even if infection is not documented. The consensus is that the best outcomes are achieved when
invasive interventions are delayed for a minimum of 4 weeks after the
onset of disease to allow liquefaction of necrotic tissues and a fibrous
rim to form around the necrosis (i.e., walled-off pancreatic necrosis).
This delay makes drainage end débridement easier and reduces the risk
of complications or death. Patients with infected necrosis are initially
treated with broad-spectrum antibiotics and medical support to allow
encapsulation of the necrotic collections, which may facilitate intervention and reduce complications of bleeding and perforation. When there
is dramatic clinical deterioration, patients are not stable and delay is not
feasible, and early intervention with a percutaneous drain is required.
Traditional management of infected pancreatic necrosis has been
open surgical necrosectomy with closed irrigation by indwelling
catheters, necrosectomy with closed drainage without irrigation, or
necrosectomy and open packing. The open surgical approaches are
associated with a high morbidity (34% to 95%) and mortality (11% to
39%) rates. A more conservative step-up approach using percutaneous
catheter drainage as the initial treatment has gained favor, and a delay
in invasive treatment is now standard. The step-up approach consists of antibiotic administration, percutaneous drainage as needed,
and after a delay of several weeks, minimally invasive débridement, if
required. This approach is superior to traditional open necrosectomy
with respect to the risk of major complications or death. If the percutaneous approach fails, it is followed by a less invasive, video-assisted
retroperitoneal débridement (VARD) or endoscopic transluminal
drainage with or without necrosectomy, provided expertise is available.
CHRONIC PANCREATITIS
Definition and Epidemiology
Chronic pancreatitis is characterized by inflammation, fibrosis, and
irreversible loss of acinar (exocrine) and islet (endocrine) cell function.
TABLE 39.3 Causes of Chronic Pancreatitis
(TIGAR-O)
Toxic-Metabolic
Alcohol
Tobacco
Hypercalcemia
Hypertriglyceridemia
Chronic renal failure
Idiopathic
Early onset
Late onset
Tropical
Genetic
Autosomal dominant-cationic trypsinogen (PRSS1)
Autosomal recessive-CFTR, SPINK1, chymotrypsin C
Autoimmune
Isolated (types 1 and 2)
Syndromic (Sjögren’s, inflammatory bowel disease, primary biliary
cholangitis)
Recurrent Acute Pancreatitis
Postnecrotic severe acute pancreatitis
Post-irradiation
Ischemic vascular
Obstructive
Benign-pancreas divisum, sphincter of Oddi dysfunction, post-traumatic
pancreatic duct stricture
Neoplastic-pancreatic ductal adenocarcinoma, IPMN, ampullary tumor
CFTR, Cystic fibrosis transmembrane conductance regulator; IPMN,
intraductal papillary mucinous neoplasia; PRSS1, serine protease 1;
SPINK1, serine peptidase inhibitor Kazal type 1.
This disorder contrasts with acute pancreatitis, which is usually nonprogressive. The two conditions may overlap because recurrent attacks
of acute pancreatitis may lead to chronic pancreatitis, and individuals
with chronic pancreatitis may experience exacerbations of acute pancreatitis. The annual incidence of chronic pancreatitis ranges from 5 to
100,000 people.
Pathology
Chronic pancreatitis can be classified using a system termed
“TIGAR-O,” which refers to toxic-metabolic, idiopathic, genetic,
autoimmune, recurrent and severe acute pancreatitis, and obstructive (Table 39.3). The most common cause of chronic pancreatitis
is chronic alcoholism, accounting for 45% to 65% of cases. Alcohol
can cause episodes of acute pancreatitis, but at the time of the initial
attack, structural and functional abnormalities often indicate underlying chronic pancreatitis. Because most alcohol users do not develop
pancreatitis, the presumption is that unidentified genetic, dietary, or
environmental influences must coexist with alcohol use. Smoking is a
causal, dose-dependent risk factor for chronic pancreatitis. The effect
of smoking is synergistic with alcohol consumption and contributes
profoundly to the development and progression of the disease.
Twenty percent of US patients with chronic pancreatitis have no
immediately demonstrable cause. Gallstone pancreatitis, the major
cause of acute pancreatitis, rarely leads to chronic pancreatitis. Calcific
CHAPTER 39 Diseases of the Pancreas
411
pancreatitis is a major cause of chronic pancreatitis in South India and
other parts of the tropics. Autoimmune pancreatitis, genetic mutations
(CFTR, SPINK1, PRSS1, CTRC, CASR), obstruction (e.g., tumors,
sphincter of Oddi dysfunction, pancreas divisum), hypertriglyceridemia, and hypercalcemia are potential causes of cases initially labeled
idiopathic.
Clinical Presentation
Most patients with chronic pancreatitis experience episodic or continuous pain. Occasionally, patients exhibit exocrine or endocrine insufficiency in the absence of pain. Other patients are asymptomatic and are
found to have chronic pancreatitis incidentally on imaging.
The pain of chronic pancreatitis is typically epigastric, often radiates to the back, is occasionally associated with nausea and vomiting,
and may be partially relieved by sitting upright or leaning forward. The
pain is often worse 15 to 30 minutes after eating. Early in the course
of chronic pancreatitis, the pain may occur in discrete attacks; as the
condition progresses, the pain tends to become continuous.
The pain of chronic pancreatitis is poorly understood. Possible
causes include inflammation of the pancreas, increased intrapancreatic pressure, neural inflammation, and extrapancreatic causes, such as
stenosis of the common bile duct and duodenum.
Glucose intolerance occurs with some frequency in chronic pancreatitis, but overt diabetes mellitus usually manifests late in the course of
disease. Diabetes in patients with chronic pancreatitis is different from
typical type 1 diabetes in that the pancreatic alpha cells, which produce
glucagon, are also affected, increasing the risk of hypoglycemia.
Clinically significant endocrine or exocrine insufficiency (i.e.,
protein and fat deficiencies) does not occur until more than 90% of
pancreatic function is lost. Steatorrhea usually occurs before protein
deficiencies because lipolytic activity decreases faster than proteolysis. Mild pancreatic exocrine insufficiency (PEI) may take the form of
abdominal bloating or malabsorption of fat-soluble vitamins (A, D,
E, K) and vitamin B12, although clinically symptomatic vitamin deficiency is uncommon. Because reduced vitamin D absorption can result
in osteoporosis, osteopenia, and fractures, periodic assessment of vitamin D levels and bone densitometry are recommended. More severe
PEI may lead to overt malabsorption and weight loss.
Diagnosis and Differential Diagnosis
Because direct biopsy of the pancreas has considerable risk, the diagnosis of chronic pancreatitis is typically based on indirect tests of
pancreatic structure and function. Marked structural changes usually
correlate with severe functional impairment. In early chronic pancreatitis, however, mild abnormalities of pancreatic function can precede
the morphologic changes seen on imaging. Studies of pancreatic structure may remain normal even with advanced deterioration of pancreatic function.
Laboratory evaluations of serum pancreatic enzymes, such as amylase and lipase, are frequently normal in the setting of well-established
chronic pancreatitis, even during painful exacerbations. Serum pancreatic enzymes neither confirm nor exclude the diagnosis.
Tests of Function
Function tests assess pancreatic secretory reserve of ductal function or
acinar function by measuring secretion of bicarbonate ions (HCO
digestive enzymes, respectively. Direct tests (e.g., secretin stimulation)
involve stimulation of the pancreas through the administration of hormonal secretagogues. Indirect tests measure the consequences of pancreatic insufficiency, and although more widely available, the results
usually are not abnormal until enzyme output has declined by more
than 90%. Thus they are insensitive to early pancreatic insufficiency.
−
) or
3
Clinicians have preferentially relied on noninvasive methods to circumvent the challenges associated with direct pancreatic function
tests. Clinically available indirect tests of pancreatic function include
analyses of fecal fat, fecal elastase, and serum trypsin.
The secretin stimulation test takes advantage of the normal response
of pancreatic ductular cells to secrete HCO
and exogenously administered secretin. The observation that HCO
−
in response to physiologic
3
−
3
production is impaired early in the course of chronic pancreatitis led to
the use of this test to diagnose early-stage disease (sensitivity of 95%).
The test involves oral placement of a double-lumen gastroduodenal
catheter for aspiration and quantitative measurement of pancreatic
enzyme and HCO
−
production before and after stimulation with
3
intravenous secretin. This test is primarily performed for patients with
suspected chronic pancreatitis who have chronic abdominal pain but
negative or equivocal results of imaging studies. Peak pancreatic fluid
−
HCO
concentrations of less than 80 mEq/L represent pancreatic
3
insufficiency. The secretin stimulation test has been infrequently used
in clinical practice because the study is labor intensive and is associated
with discomfort. Endoscopic collection methods have simplified pancreatic fluid collection and made the test more suitable for clinical use.
The 72-hour fecal fat determination is sometimes used for detection
of steatorrhea (fecal fat >7 g/24 hours), but the test is not specific for
pancreatic exocrine insufficiency. The test also lacks sensitivity because
steatorrhea occurs only in advanced chronic pancreatitis. Because the
quantitative fecal fat test is inconvenient, unpleasant for patients, and
prone to laboratory error, a qualitative assay is used preferentially in
clinical practice to assess for malabsorption.
Determination of fecal elastase is the most commonly used noninvasive indirect test for the diagnosis of pancreatic exocrine insufficiency. Elastase, a protease synthesized by pancreatic acinar cells, is
useful for evaluating insufficiency because it is stable in stool, unaffected by pancreatic enzyme replacement, and correlates well with
stimulated pancreatic function test results. Moderate to severe exocrine insufficiency is based on fecal elastase values of less than 200 μg/g
of stool. False-positive results can be seen with diarrheal illnesses, due
to a dilutional effect.
Tests of Structure
Imaging findings with CT scan, ultrasound, and MRI may show
changes of chronic pancreatitis include ductal abnormalities (e.g.,
dilation, stones, irregular beaded walls, and side branch ectasia),
parenchymal abnormalities (e.g., calcification, inhomogeneity, atrophy), gland contour changes, and pseudocysts (E-Fig 39.4). Imaging
studies are often normal or inconclusive in the early stages of disease
(see E-Fig. 39.4). CT imaging and MRI are also helpful in identifying
complications of chronic pancreatitis including pseudocysts, portosplenic venous thrombosis, arterial pseudoaneurysms, and pancreatic
duct fistulas.
CT scanning is often considered the preferred initial test for diagnosis of chronic pancreatitis. Magnetic resonance cholangiopancreatography is a noninvasive diagnostic imaging modality that provides
visualization of the pancreatic parenchyma similar to CT scanning
but with improved duct imaging resulting in a greater sensitivity for
diagnosis of chronic pancreatitis. MRI pancreatic duct images are
similar to those obtained by ERCP but without the risk of precipitating acute pancreatitis. Stimulation of the pancreas using IV secretin
enhances main and side branch pancreatic duct visualization, which
may improve the diagnostic accuracy for chronic pancreatitis. ERCP
provides reliable structural information about the pancreatic ductular
system including ductal dilation, strictures, abnormal side branches,
communicating pseudocysts, and ductal stones and fistulas. ERCP is
highly effective for visualizing these ductal and duct-related findings,
E-Fig. 39.4 Computed tomography scan shows calcifications and small
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pseudocysts in the pancreas that are consistent with a diagnosis of
chronic pancreatitis.
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