the islet in an area of discontinuity in the non-B cells surrounding the periphery. The afferent arteriole

then breaks into a capillary bed within the islet. Blood exits the islet through an efferent collecting

venule. The hormones from the islet cells are secreted directly into this rich capillary network within

the islet.

7 The most critical role of the pancreatic islet cells is the secretion of insulin and glucagon to

maintain glucose homeostasis. Pancreatic endocrine secretion also regulates pancreatic exocrine

secretion. Insulin stimulates pancreatic exocrine secretion, amino acid transport, and synthesis of

protein and enzymes, whereas glucagon acts in a counter-regulatory fashion, inhibiting the same

processes. The role of somatostatin is controversial. Somatostatin may have a direct inhibitory effect on

pancreatic acinar cells, which possess somatostatin receptors. It may also act through an inhibitory

effect on islet B cells.

PANCREATIC PHYSIOLOGY

Exocrine Function

The pancreas secretes 1.5 to 3 L of a pancreatic fluid daily. The enzymes and zymogens play a major

role in the digestive activity of the gastrointestinal tract. Pancreatic fluid is alkaline (pH 7.6 to 9.0) and

carries over 20 proteolytic enzymes and zymogens to the duodenum. The enzymes are released into the

duodenum in their inactive state; the fluid serves to neutralize gastric acid and provides an optimal

milieu for the function of these enzymes.

Pancreatic secretion is regulated via an intimate interaction of both hormonal and neural pathways

that integrate the function of the pancreas, biliary tract, and small intestine. Vagal (parasympathetic)

afferent and efferent pathways strongly affect pancreatic secretion. The secretion of enzyme-rich fluid is

largely dependent on the vagal stimulation, whereas fluid and electrolyte secretion are more dependent

on the direct hormonal effects of the secretin and cholecystokinin (CCK). Parasympathetic stimulation

also causes the release of VIP, which also serves to stimulate secretin secretion.18

Table 52-1 Pancreatic Endocrine Cell Types

Many neuropeptides also influence pancreatic secretion in an inhibitory fashion. These include

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

pancreastatin, enkephalin, glucagon, and galanin. While these neuropeptides are known to play a role in

regulation of pancreatic secretion, the mechanisms of action and the intricate interplay between the

neuropeptides is not fully understood.18

Bicarbonate Secretion

Bicarbonate is the most physiologically important ion secreted by the pancreas. Bicarbonate is formed

from carbonic acid by the enzyme carbonic anhydrase. The secretion of water and electrolytes

originates in the centroacinar and intercalated duct cells (Fig. 52-4). These cells secrete 20 mmol of

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bicarbonate per liter in the basal state and up to 150 mmol/L in the maximally stimulated state.18 The

bicarbonate secreted from the ductal cells is primarily derived from the plasma. Chloride efflux through

the cystic fibrosis transmembrane conductance regulator (CFTR) leads to depolarization and bicarbonate

entry through the sodium bicarbonate cotransporter.18 As a result, chloride secretion varies inversely

with bicarbonate secretion; the sum of these two anions balances the sodium and potassium cations and

remaining constant and equal to that of the plasma.

Both secretin and VIP stimulate bicarbonate secretion by increasing intracellular cyclic AMP, which

acts on the CFTR.18 Gastric acid is the primary stimulus for release of secretin. Secretin is released from

the duodenal mucosa in response to a duodenal lumen pH of less than 3.0 due to gastric acid.

The duodenum and jejunum release CCK in response to the presence of long-chain fatty acids, some

essential amino acids (methionine, valine, phenylalanine, and tryptophan), and gastric acid. CCK is

weak direct stimulator of bicarbonate secretion, but it acts as a neuromodulator and potentiates the

stimulatory effects of secretin. Gastrin and acetylcholine are also weak stimulators of bicarbonate

secretion.19 Bicarbonate secretion is inhibited by atropine (vagal stimulation) and can be reduced by

50% after truncal vagotomy.20 Islet cell peptides including somatostatin, pancreatic polypeptide,

glucagon, galanin, and pancreastatin are thought to inhibit exocrine secretion.

Enzyme Secretion

Pancreatic enzymes originate in the acinar cells, which are highly compartmentalized. Proteins are

synthesized in the rough endoplasmic reticulum, processed in the Golgi apparatus, and then targeted to

the appropriate cell compartment (zymogen granules, lysosomes, etc.). The acinar cells secrete enzymes

that fall into three major enzyme groups: amylolytic enzymes, lipolytic enzymes, and proteolytic

enzymes. Amylolytic enzymes such as amylase hydrolyze starch to oligosaccharides and the disaccharide

maltose. Lipolytic enzymes such as lipase, phospholipase A, and cholesterol esterase function work in

conjunction with bile salts to digest fats and cholesterol. Proteolytic enzymes include endopeptidases

(trypsin and chymotrypsin) and exopeptidases (carboxypeptidase). Endopeptidases act on the internal

peptide bonds of proteins and polypeptides and exopeptidases act on the free carboxy- and aminoterminal ends of proteins. Proteolytic enzymes are secreted as inactive precursors. Enterokinase cleaves

the lysine–isoleucine bond in trypsinogen to create the active enzyme trypsin. Trypsin then activates the

other proteolytic enzyme precursors.18

The different pancreatic enzymes are not secreted in fixed ratios. They change in response to dietary

alterations and stimuli such as gastric acid, hormones, and neuropeptides. When enzyme secretion is

absent or impaired, malabsorption or incomplete digestion occurs, leading to fat and protein loss

through the gastrointestinal tract. This is seen in patients with acute and chronic pancreatitis (who have

destruction of the exocrine pancreas) and in patients who have undergone surgical resection of all or

part of the pancreas. These patients often present with weight loss and steatorrhea secondary to

malabsorption of nutrients. These signs and symptoms can be corrected by oral replacement of

pancreatic enzymes with meals.

The nervous system initiates pancreatic enzyme secretion. This involves extrinsic innervation by the

vagus nerve and subsequent innervation by the intrapancreatic cholinergic fibers. The

neurotransmitters, acetylcholine and gastrin-releasing peptide activate calcium-dependent release of

zymogen granules.18 In addition, CCK is a predominant regulator of enzyme secretion, doing so through

activation of specific membrane-bound receptors and calcium-dependent second messenger pathways.

Secretin and VIP weakly stimulate acinar cell secretion directly, but also potentiate the effect of CCK on

acinar cells (Fig. 52-5). Insulin is required locally and serves in a permissive role for secretin and CCK

to promote exocrine secretion.18

Through the secretion of the three classes of enzymes, the pancreas regulates complete digestion of

carbohydrates, fats, and proteins. Autodigestion of the pancreas by these proteolytic enzymes is

prevented by packaging of proteases in an inactive precursor form and by the synthesis of protease

inhibitors including pancreatic secretory trypsin inhibitor (PSTI), serine protease inhibitor, kazal type 1

(SPINK1), and protease serine 1 (PRSS1). These enzymes are found in the acinar cell and loss of these

protective mechanisms can lead to activation, autodigestion, and acute pancreatitis. Mutations in the

SPINK1 and PRSS1 genes are known to cause one of the aggressive familial forms of chronic

pancreatitis, leading to recurrent episodes of pancreatitis, with associated exocrine and endocrine

insufficiency.21,22

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Figure 52-5. Schematic diagram of the acinar cell, demonstrating receptors for exocrine secretagogues and their intracellular bases

of action. Six distinct classes of receptors are known, with principal ligands shown. CCK, cholecystokinin; VIP, vasoactive intestinal

peptide; CRGP, calcitonin gene–related peptide; DAG, diacylglycerol.

Table 52-2 Characteristic Results of Secretin Testing: Volume, Bicarbonate

Concentration, and Enzyme Secretion Changes in Pancreatic Disease

Processes

Tests of Pancreatic Exocrine Function

8 Several tests are useful in the assessment of pancreatic exocrine function. Such tests are useful in both

diagnosing and determining the etiology of exocrine insufficiency (chronic pancreatitis, malnutrition,

cancer, and Zollinger–Ellison syndrome) (Table 52-2). Steatorrhea from pancreatic exocrine dysfunction

is the result of lipase deficiency and is usually not present until lipase secretion is reduced by 90%. The

secretin test, the dimethadione test (DMO) and the Lundh test require duodenal intubation. The classic

test of pancreatic exocrine function is the secretin test.23 A patient fasts overnight. A double-lumen tube

is then placed in the duodenum. Basal collections are performed for 20 minutes and analyzed for total

volume, bicarbonate output, and enzyme secretion. An intravenous bolus of 2 units of secretin per

kilogram is given and four collections every 20 minutes are analyzed for volume, bicarbonate levels,

and enzyme levels.

Normal values for the standard secretin stimulation test are 2.0 mL of pancreatic fluid per kilogram

per hour, bicarbonate concentration of 80 mmol/L, bicarbonate output of >10 mmol/L in 1 hour, and

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amylase secretion of 6 to 18 International Units/kg. The maximal bicarbonate concentration provides

the greatest discrimination between normal subjects and patients with chronic pancreatitis.24 The results

of the secretin stimulation test for different pancreatic disease processes is shown in Table 52-2.

The pancreas metabolizes the anticonvulsant drug trimethadione to its metabolite, DMO. After

placing a double-lumen tube in the duodenum, patients are given 0.45 g of trimethadione three times

daily for 3 days. Secretin is given through the double-lumen tube to maximally stimulate pancreatic

secretion. To measure pancreatic exocrine function, the duodenal output of DMO is analyzed.25

The Lundh test directly measures pancreatic enzyme secretion in response to a meal of carbohydrate,

fat, and protein. A patient fasts overnight, then has a double-lumen duodenal tube placed. After basal

duodenal fluid collection, patients are given a meal consisting of 18 g of corn oil, 15 g of casein, and 40

g of glucose in 300 mL of water. Duodenal fluid is collected every 30 minutes for 2 hours and analyzed

for trypsin, amylase, and lipase. This test relies on endogenous secretin and CCK secretion and may be

abnormal in diseases involving the intestinal mucosa.

N-benzoyl-1-tyrosyl paraaminobenzoic acid (BT-PABA) is cleaved by chymotrypsin to form

paraaminobenzoic acid (PABA), which is then excreted in the urine. The PABA test is performed by

administering 1 g of BT-PABA in 300 mL of water orally. Urine is then collected for 6 hours. Patients

with chronic pancreatitis excrete less than 60% of the ingested dose of PT-PABA.

Suspected pancreatic exocrine dysfunction can also be confirmed giving patients a test meal and

measuring serum levels of the islet cell hormone pancreatic polypeptide (PP). Basal and meal-stimulated

levels of serum PP are reduced in severe chronic pancreatitis and after extensive pancreatic resection.

After an overnight fast, a test meal of 20% protein, 40% fat, and 40% carbohydrate is ingested. The

normal basal range of PP is 100 to 250 pg/mL. In severe chronic pancreatitis, the basal levels are often

less than 50 pg/mL. The normal response to a meal is a rise in PP levels to 700 to 1,000 pg/mL for 2 to

3 hours after the meal. In severe disease, this response is decreased to less than 250 pg/mL. PP release

depends on intact pancreatic innervation and can also be decreased after truncal vagotomy, antrectomy,

or in the setting of diabetic autonomic neuropathy.

The triolein breath test is a noninvasive test of pancreatic exocrine insufficiency or malabsorption, but

does not differentiate between the two.26 25 g of 14C-labeled corn oil (triglycerides) are given to the

patient orally. The metabolite, 14C-carbon dioxide, can be measured in the breath 4 hours after

administration. Patients with disorders of fat digestion or malabsorption exhale less than 3% of the dose

per hour. The test can be repeated after pancreatic enzyme replacement. Patients with pancreatic

insufficiency will achieve a normal rate of excretion of 14C-carbon dioxide, whereas patients with

enteric disorders (malabsorption) show no improvement.

Many tests can help differentiate between steatorrhea caused by pancreatic exocrine insufficiency

versus malabsorption (Table 52-3). The secretin test, the PABA test, and PP will be normal in intestinal

malabsorption and abnormal in pancreatic insufficiency. The fecal fat test measures intraluminal

digestion products. Fecal fat content is measured over a 24-hour time period. If the fecal fat is elevated

to more than 20 g this indicates pancreatic insufficiency, whereas steatorrhea in the presence of low

levels of fecal fat (<20 g) indicates intestinal dysfunction. A reduction of fecal fat can be used to

demonstrate adequate replacement of pancreatic enzymes in patients with exocrine insufficiency.

However, this test is time consuming and disliked by patients and pancreatic enzyme replacement is

often titrated based on symptom relief if the clinical situation leads to a high index of suspicion for

pancreatic exocrine insufficiency (i.e., long-standing chronic pancreatitis) or once the diagnosis of

pancreatic insufficiency is made.

Table 52-3 Differential Diagnosis of Intestinal and Pancreatic Steatorrhea

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