CHAPTER 15 Pancreas 573

the underlying cause of inflammation is removed. By contrast, chronic

Bile duct A. NORMAL pancreatitis causes irreversible destruction of exocrine pancreas.
Duodenum
Acute Pancreatitis
Duct of
Acute pancreatitis is a reversible inflammatory disorder that varies
Santorini
in severity, from focal edema and fat necrosis to widespread hem-
Minor orrhagic necrosis. It is a relatively common and serious condition,
papilla with an annual incidence of 33 to 74 per 100,000 globally. In the
Western world the incidence is 5 to 35 per 100,000. Overall mortality
is about 5%. The incidence of acute pancreatitis is increasing due to
the obesity epidemic and related increase in gallstone disease.
Papilla
Duct of Wirsung Etiology and Pathogenesis. The most common cause of acute
of Vater
pancreatitis in the United States is the impaction of gallstones within
the common bile duct, impeding the flow of pancreatic enzymes
Bile duct through the ampulla of Vater (“gallstone pancreatitis”); this is closely
B. PANCREAS followed by pancreatitis secondary to excessive alcohol intake. Overall,
Duodenum DIVISUM
gallstones and chronic excessive alcohol use account for close to
80% of acute pancreatitis cases, with the remainder caused by a
Duct of
Santorini multitude of factors (Table 15.1). These include the following:
• Nongallstone-related obstruction of the pancreatic ducts (e.g., due to
Minor
pancreatic cancer or other periampullary neoplasms, pancreas
papilla
divisum, particulate solids that have precipitated from bile (“biliary
sludge”), or parasites, particularly Ascaris lumbricoides and
Clonorchis sinensis
• Metabolic disorders, in particular hypertriglyceridemia, hyperpara-
Papilla thyroidism, and other hypercalcemic states. Hypertriglyceridemia
of Vater Duct of Wirsung (above 1000 mg/dL) has been reported to cause 5% to 10% of cases
of acute pancreatitis.
• Medications, including anticonvulsants, cancer chemotherapeutic
FIG. 15.1 Pancreatic ductal anatomy in (A) normal pancreas and agents, thiazide diuretics, estrogens, and many others
(B) pancreatic divisum. • Infections with mumps virus or coxsackievirus, which can directly
5% develop acute or chronic pancreatitis, possibly related to inade- infect pancreatic exocrine cells
quate drainage of pancreatic secretions through the minor papilla.
• Annular pancreas is a relatively uncommon variant of pancreatic Of note, 10% to 20% of cases of acute pancreatitis have no identi-
fusion in which a ring of pancreatic tissue completely encircles fiable cause (idiopathic pancreatitis), although a growing body of
the duodenum. It can manifest with signs and symptoms of
duodenal obstruction such as gastric distention and vomiting. Table 15.1 Etiologic Factors in Acute Pancreatitis
• Ectopic pancreas is aberrantly situated pancreatic tissue, which oc- Metabolic
curs in about 2% of the population. Common sites are the stomach Alcohol use disordera
and duodenum, followed by the jejunum, Meckel diverticulum, and Hypertriglyceridemia
ileum. These embryologic rests are typically small (ranging from Hypercalcemia
millimeters to centimeters in diameter) and are located in the sub- Drugs (e.g., azathioprine)
mucosa; they are composed of normal pancreatic acini with occa- Genetic
sional islets. Though usually incidental and asymptomatic, ectopic Mutations in the cationic trypsinogen (PRSS1) and trypsin inhibitor
pancreas may become inflamed, leading to pain, ordrarelydcan (SPINK1) genes
cause mucosal bleeding. Approximately 2% of pancreatic neuroen- Mechanical
docrine tumors (Chapter 18) arise in ectopic pancreatic tissue. Gallstonesa
• Congenital cysts result from anomalous development of the pancre- Trauma
atic ducts. In polycystic disease, the kidneys, liver, and pancreas may Iatrogenic injury
all contain cysts (Chapter 12). Congenital cysts are generally uni- Perioperative injury
locular and range from microscopic to 5 cm in diameter. They Endoscopic procedures with dye injection
are lined by uniform cuboidal or flattened epithelium and are Vascular
enclosed in a thin, fibrous capsule. These benign cysts contain clear Shock
serous fluiddan important point of distinction from pancreatic Atheroembolism
cystic neoplasms, which are often mucinous (discussed later). Polyarteritis nodosa
Infectious
PANCREATITIS Mumps
Coxsackievirus
Inflammatory disorders of the pancreas are divided into acute and a
Most common causes in the United States.
chronic forms. In acute pancreatitis, function can return to normal if
574 CHAPTER 15 Pancreas

evidence suggests that many have an underlying genetic basis. For Three pathways can incite the initial enzyme activation that may
example, a subset of these patients with so-called idiopathic pancreatitis lead to acute pancreatitis (Fig. 15.2):
has underlying germline mutations affecting various genes: the auto- • Pancreatic duct obstruction. Impaction of a gallstone or biliary
somal dominant form is caused most often by mutations in the gene sludge or extrinsic compression of the ductal system by a mass
encoding trypsin, and most autosomal recessive disease is caused by blocks ductal flow, increases intraductal pressure, and allows accu-
mutations in CFTR. In those caused by mutations in the CFTR gene the mulation of an enzyme-rich interstitial fluid. Since lipase is
symptoms are restricted to the pancreas (Chapter 4). secreted in an active form, local fat necrosis may result. Injured
Acute pancreatitis is caused by autodigestion of the pancreas by tissues, periacinar myofibroblasts, and leukocytes then release
intraacinar activation of pancreatic enzymes. Study of hereditary proinflammatory cytokines that promote local inflammation and
forms of acute pancreatitis has revealed the key role of premature interstitial edema through a leaky microvasculature. Edema
activation of trypsin in this process. The feature shared by most forms further compromises local blood flow, causing vascular insuffi-
of hereditary pancreatitis is a defect that increases or sustains the ciency and ischemic injury to acinar cells.
activity of trypsin such as mutations in the PRSS1 gene, which encodes • Primary acinar cell injury. This pathogenic mechanism comes
trypsinogen, the proenzyme of pancreatic trypsin. The pathogenic into play in acute pancreatitis caused by hypertriglyceridemia,
mutations alter the site through which trypsin cleaves and inactivates alcohol use (discussed later), ischemia, viral infections
itself, abrogating an important negative feedback mechanism. This (e.g., mumps), drugs, and direct trauma to the pancreas. The
modification leads not only to the hyperactivation of trypsin but also toxicity of triglycerides is not fully understood. According to
to the activation of many other digestive enzymes that require trypsin one view large triglyceride-rich chylomicrons retard capillary cir-
cleavage for their activation. The released enzymes can inflict damage culation, leading to ischemic injury to pancreatic acinar cells.
on blood vessels, causing hemorrhage within the pancreatic substance. Injured cells release lipase into the interstitium, causing hydrolysis
Trypsin also converts prekallikrein to its activated form, thus initiating of triglycerides and local release of toxic free fatty acids release.
the kinin system, and, by activation of factor XII (Hageman factor), • Defective intracellular transport of proenzymes within acinar cells.
also sets in motion the clotting and complement systems (Chapter 3). In healthy acinar cells, digestive enzymes intended for zymogen

DUCT OBSTRUCTION ACINAR CELL INJURY DEFECTIVE INTRACELLULAR

TRANSPORT

CAUSES

Alcohol
Cholelithiasis Drugs
Ampullary obstruction Hypertriglyceridemia Metabolic injury
Alcohol use Ischemia Alcohol
Ductal concretions Viruses Duct obstruction

Interstitial edema Release of intracellular Delivery of proenzymes to

proenzymes and lysosomal lysosomal compartment
hydrolases
Impaired blood flow

MECHANISMS Ischemia Activation of enzymes Intracellular activation

(intracellular or extracellular) of enzymes

Acinar cell injury

ACTIVATED ENZYMES
Lipase
Phospholipase
Acute Fat necrosis
Proteases inflammation Elastase
LESIONS and edema

Proteolysis and parenchymal injury Damage to vessel walls, hemorrhage

ACUTE PANCREATITIS

FIG. 15.2 Proposed pathogenesis of acute pancreatitis.

 CHAPTER 15 Pancreas 575

granules (and eventually extracellular release), and hydrolytic en-

zymes destined for lysosomes are transported in discrete pathways
after synthesis in the endoplasmic reticulum. However, in at least
some animal models of metabolic injury, pancreatic proenzymes
and lysosomal hydrolases become packaged together. This results
in proenzyme activation, lysosomal rupture (action of phospholi-
pases), and local release of activated enzymes. A similar series of
events is very likely in human acute pancreatitis, although definitive
proof is lacking.

Alcohol consumption may cause pancreatitis by several mecha-

nisms (see Fig. 15.2). Alcohol transiently increases pancreatic exocrine
secretion and contraction of the sphincter of Oddi (the muscle regu-
lating the flow of pancreatic secretions through the papilla of Vater).
Alcohol also has direct toxic effects, including induction of oxidative A
stress in acinar cells, which leads to membrane damage; alcohol may
also lead to delivery of proenzymes to lysosomal compartment with
subsequent intracellular activation of trypsin and other digestive en-
zymes (discussed earlier). Finally, chronic alcohol ingestion results in
the secretion of protein-rich pancreatic fluid, which leads to the
deposition of inspissated protein plugs and obstruction of small
pancreatic ducts.

MORPHOLOGY
The basic alterations in acute pancreatitis are (1) microvascular
leakage causing edema; (2) necrosis of fat by lipases; (3) an
acute inflammatory reaction; (4) proteolytic destruction of B
pancreatic parenchyma and blood vessels leading to inter-
FIG. 15.3 Acute pancreatitis. (A) The microscopic field shows a region
stitial hemorrhage.
of fat necrosis (right) and focal pancreatic parenchymal necrosis (center).
In mild forms, there is interstitial edema and focal areas of fat necrosis in (B) The pancreas has been sectioned longitudinally to reveal dark areas
the pancreas and peripancreatic fat (Fig. 15.3A). Fat necrosis results from of hemorrhage in the pancreatic substance and a focal area of pale fat
enzymatic destruction of fat cells; the released fatty acids combine with necrosis in the peripancreatic fat (upper left).
calcium to form insoluble salts that precipitate in situ.
In more severe forms, such as acute necrotizing pancreatitis, the
damage also involves acinar and ductal cells, the islets of Langerhans, and cholecystitis with rupture, and occlusion of mesenteric vessels with
blood vessels (eFig. 15.1). Macroscopically, the pancreas exhibits red-black infarction of the bowel.
hemorrhagic areas interspersed with foci of yellow-white, chalky fat The manifestations of severe acute pancreatitis are attributable to
necrosis (Fig. 15.3B). Fat necrosis can also occur in extrapancreatic fat, systemic release of digestive enzymes and explosive activation of the
including the omentum and bowel mesentery, and even outside the inflammatory response. The initial clinical evaluation may reveal
abdominal cavity (e.g., in subcutaneous fat). In most cases, the peritoneum leukocytosis, disseminated intravascular coagulation (Chapter 10),
contains a serous, slightly turbid, brown-tinged fluid with globules of fat acute respiratory distress syndrome secondary to diffuse alveolar
(derived from enzymatically digested adipose tissue). In the most severe form, damage (Chapter 11), and diffuse fat necrosis. Peripheral vascular
hemorrhagic pancreatitis, extensive parenchymal necrosis is accompa- collapse (shock) can rapidly ensue as a result of increased microvas-
nied by diffuse hemorrhage within the substance of the gland (eFig. 15.2). cular permeability and consequent hypovolemia, compounded by
endotoxemia (from breakdown of the barriers between gastrointestinal
flora and the bloodstream) and renal failure due to acute tubular injury
(Chapter 12).
Clinical Features. Abdominal pain is the cardinal manifestation of Laboratory findings include elevation of serum lipase and amylase,
acute pancreatitis. Its severity varies from mild and uncomfortable to both of which increase 4 to 12 hours after onset of pain. Serum lipase
severe and incapacitating. Acute pancreatitis is diagnosed primarily by is the most specific and sensitive marker of acute pancreatitis, as
the presence of elevated plasma levels of lipase and amylase and the serum amylase has a short half-life and may return to normal in 3
exclusion of other causes of abdominal pain. In 80% of cases, acute to 5 days, whereas lipase levels remain elevated for 8 to 14 days.
pancreatitis is mild and self-limiting; the remaining 20% develop Hypocalcemia can result from precipitation of calcium in areas of fat
severe disease. necrosis; if persistent, it is a poor prognostic sign. The enlarged
Full-blown acute pancreatitis is a medical emergency of the first inflamed pancreas can be visualized by computed tomography (CT) or
order. Affected individuals usually experience the sudden calamitous magnetic resonance imaging (MRI).
onset of an “acute abdomen” with pain, guarding, and the ominous The crux of the management is supportive therapy (e.g., main-
absence of bowel sounds. Characteristically, the pain is constant, taining blood pressure and alleviating pain) and “resting” the pancreas
intense, and referred to the upper back; it must be differentiated from by total restriction of oral food and fluids. In 40% to 60% of cases of
similar pain due to perforated peptic ulcer, biliary colic, acute acute necrotizing pancreatitis, the necrotic debris becomes infected,
 CHAPTER 15 Pancreas 575.e1

eFIG. 15.1 Acute pancreatitis. Inflammation with necrosis and hemorrhage is seen here along with residual
pancreatic acini (diamond). The damage involves primarily the acinar cells, but the vasculature is also affected,
and if severe and extensive, even the islets of Langerhans may be destroyed. (From Klatt EC: Robbins and
Cotran Atlas of Pathology, ed 4, Fig. 9.6, Philadelphia, 2021, Elsevier.)
575.e2

eFIG. 15.2 Acute hemorrhagic pancreatitis. At autopsy, the stomach (square) is reflected superiorly, and the
spleen (diamond) can be seen at the far upper right. The pancreas is swollen and does not show the typical
tan, lobulated architecture. Instead, hemorrhagic necrosis appears as blotchy black to red areas. (From Klatt
EC: Robbins and Cotran Atlas of Pathology, ed 4, Fig. 9.4, Philadelphia, 2021, Elsevier.)