Chapter 9 THE EXOCRINE PANCREAS

Introduction

The pancreas is a mixed exocrine-endocrine gland attached to the duodenum. The exocrine pancreas produces digestive enzymes that are excreted into the lumen of the intestine. The hormones produced by the endocrine cells enter into the bloodstream and are distributed throughout the body. Hence, the diseases of the exocrine pancreas are in the domain of the gastroenterologist, whereas diabetes and other endocrine diseases are traditionally treated by endocrinologists.

The relative clinical significance of various pancreatic diseases is presented in Figure 9-1. Diseases of the exocrine pancreas are not as common as other gastrointestinal diseases, but are nevertheless a significant clinical problem. Carcinoma of the pancreas is the sixth most common human cancer, and its incidence is increasing.

Figure 9-1 Relative importance of the most common pancreatic diseases.

Normal and Structure and Function

ANATOMY AND HISTOLOGY

To understand the clinical manifestations of pancreatic diseases a brief review of the development and macroscopic and microscopic anatomy of the pancreas is in order.

The pancreas is a solid retroperitoneal organ that has three main parts: head, body, and tail.

The normal pancreas measures approximately 15 cm and extends from the duodenum to the spleen. It is located in the retroperitoneum anterior to the aorta of the epigastrium and is fixed by fibrous tissue to the posterior abdominal wall. It is best visualized by computed tomography (CT, Fig. 9-2).

Figure 9-2 Pancreas as seen radiologically by computed tomography. It is located retroperitoneally between the spleen and the liver.

The connective tissue of the retroperitoneum contains numerous nerve endings and Pacinian corpuscles, which accounts for the pain that often accompanies pancreatic disease.

Histologically the exocrine pancreas consists of acini and ducts.

The secretory unit of the exocrine pancreas consists of acinar cells and excretory ducts (Fig. 9-4). The acinar cells are specialized protein-secreting cells arranged coronally around a centrally located intercalated duct. They are cuboidal and have abundant cytoplasm filled with zymogen granules. Zymogen granules contain proenzymes (zymogens) that are excreted into the ducts. The ductal cells are polarized and specialized for fluid and electron transport. These cells contribute bicarbonates, minerals, and water to the pancreatic juices. The ducts also contain scattered mucus-producing cells.

Figure 9-4 Diagram of the exocrine pancreatic acini and ducts.

PHYSIOLOGY

The pancreas produces approximately 1500 mL of digestive juices per day. This pancreatic juice consists of (1) water, (2) minerals, (3) enzymes, (4) nonenzymatic proteins, and (5) mucus.

The pancreatic secretion has three main functions: (1) to provide digestive enzymes, (2) to protect the tissues from autodigestion by its own enzyme, and (3) to neutralize the acidity of the chyme arriving in the duodenum from the stomach.

Digestive enzymes are produced by the acinar cells.

Pancreatic acinar cells produce some 20 enzymes, which represent the primary digestive components of the pancreatic juice. These enzymes are proteins synthesized on the rough endoplasmic reticulum and packaged into membrane-bounded cytoplasmic granules. The contents of these granules are extruded into the intercalated ducts. Functionally these enzymes can be classified into several groups, most important of which are proteolytic, lipolytic, and amylolytic enzymes, and nucleases (Table 9-1).

Table 9-1 Pancreatic Enzymes

ENZYME CLASS	FUNCTION	TYPICAL ENZYMES
Proteolytic enzymes	Split peptide bonds of proteins forming oligopeptides and free amino acids	Trypsinogen Chymotrypsinogen Proelastase Procarboxypeptidase A and B
Lipolytic enzymes	Hydrolyze the bonds between fatty acids and glycerol or cholesterol esters	Lipase Phospholipase A₂ Carboxylesterlipase Colipase
Amylolytic enzymes	Breakdown of starch	Amylase
Nucleases	Breakdown of DNA and RNA	RNase DNase

All proteolytic enzymes are secreted in an inactive form, meaning as proenzymes that require additional activation to become functionally active. Other enzymes are secreted in an active form.

Nonenzymatic proteins secreted by acinar cells have regulatory functions but may also play a role in pancreatic diseases.

In addition to the enzyme, acinar cells secrete several proteins, the function of which is not fully understood. Nevertheless, it appears that these proteins play some regulatory roles. Some of these nonenzymatic secretory products are listed as follows:

Trypsin inhibitor. It inactivates the prematurely activated trypsinogen. It is copackaged into granules together with trypsinogen, thus serving as an internal blocker of this proteolytic enzyme. Note that the activation of trypsinogen into trypsin occurs only in the small intestine under the influence of intestinal enterokinase.

Protein GP2. It is linked to the inner surface of zymogen granules and is thought to prevent reflux of the extruded enzymes from the intercalated duct into the acinar cells.

Lithostathine. The function of this protein is unknown, but it is thought that it may prevent the formation of pancreatic stones. However, both protein GP2 and lithostathine may form intraductal plugs in dehydrated persons and those with cystic fibrosis and chronic pancreatitis.

Pancreatitis-associated protein. This protein is found in low concentration under normal conditions, but it is present in high concentration in pancreatitis. It has been suggested that it has a bacteriostatic role, preventing infection and the formation of pancreatic abscesses.

Pancreatic juice contains salts and bicarbonates.

Pancreatic juice contains several ions in large concentration. These ions include Na⁺, K⁺, Ca²⁺, Cl⁻, and bicarbonate (HCO₃⁻). Calcium is secreted by the acinar cells, whereas HCO₃⁻ and other ions are secreted by the ductal cells. The concentration of Na⁺ and K⁺ does not change, but the concentration of HCO₃⁻ and Cl⁻ does. The entry of Cl⁻ into the lumen of ducts depends on the proper function of the cystic fibrosis transmembrane conductance regulator (CFTR). Ductal cells have receptors for secretin, and on stimulation with secretin they secrete HCO₃⁻. In that process Cl⁻ is exchanged for HCO₃⁻, and accordingly the juices flowing from a stimulated pancreas are rich in HCO₃⁻. Bicarbonate renders the pancreatic juice alkaline, and its pH rises over 8.0. The alkalinity of pancreatic juices discharged into the intestine neutralizes the acidity of the gastric juices as they enter the duodenum, and thus allows normal functioning of the pancreatic enzymes in the intestinal chyme.

Pancreatic secretion is low during the fasting phase but increases 10-fold during the digestive phase.

The secretory activity of the pancreas is under complex neurohumoral control. Two secretory phases are recognized: the fasting state and the digestive phase.

In the fasting state (interdigestive period) the basal secretory rate of the pancreas is relatively low. It is predominantly under parasympathetic control. Acetylcholine released from the terminal branches of the vagus nerve maintains a low level of constitutional secretory activity, which is inhibited by adrenergic stimuli.

Basal pancreatic secretion oscillates depending on intestinal motility. However, even with heightened stimulation during intestinal contraction, pancreatic secretion reaches only 10% to 20% of the maximum achieved during the digestive phase.

In the digestive phase, when the food enters the gastrointestinal tract, pancreatic secretion increases approximately 10 times over the basal rate. This increase is a consequence of stimulation by the intestinal hormones cholecystokinin and secretin.

Cholecystokinin (CCK) is released from the duodenal neuroendocrine cells 10 to 30 minutes after ingestion of the food. The most potent stimulants for the release of CCK are lipids, but small peptones and amino acids in the food also stimulate these cells. The neuroendocrine cells of the duodenum that produce CCK-releasing factors may have a paracrine effect and also stimulate CCK release. Cholecystokinin stimulates the acinar cells to secrete pancreatic enzymes.

Secretin is released from the neuroendocrine cells in the small intestine mostly in response to intestinal acidification by the gastric contents admixed with the food. Bile acids and lipids also stimulate secretin release. Secretin stimulates release of bicarbonates in the pancreas. It appears that CCK and secretin act in concert because injection of pure secretin never has the same effect as a combined CCK-secretin stimulation or, for that matter, as food itself.

The digestive phase pancreatic secretion has three interval phases: cephalic, gastric, and intestinal.

Like other parts of the gastrointestinal tract the pancreatic digestive phase stimulated by food has three interval phases called cephalic, gastric, and intestinal (Fig. 9-5).

Cephalic phase. Mere exposure to food triggers the so-called cephalic phase, which is a reflex and most likely mediated by acetylcholine (ACh) released from the vagus nerve. It account for about 25% of the pancreatic secretion.

Gastric phase. Entry of food into the stomach starts the second phase. The pancreas is stimulated by polypeptide hormones released from the gastric neuroendocrine cells, vagal stimulation, and the changes in the pH in the contents that reach the duodenum. This phase accounts for 10% to 20% of the pancreatic secretion.

Intestinal phase. The third phase of stimulated pancreatic secretion begins with the entry of food into the duodenum. It provides 50% to 80% of the pancreatic secretion and is mediated mostly by CCK and secretin.

Figure 9-5 Neurohumoral control of pancreatic function. The stimulatory and inhibitory factors stem from the vagus and sympathetic nerves and the gastrointestinal hormones. Cholecystokinin (CCK) and secretin play the pivotal role in stimulating pancreatic secretion. ACh, acetylcholine.

Pearl

> The pancreas has a huge reserve capacity and is capable of producing much larger amounts of enzyme than needed. Hence, pancreatic insufficiency becomes clinically apparent only after a loss of 80% to 90% of all acini.

Stimuli from the distal small intestine inhibit digestive phase pancreatic secretion.

The exact mechanisms that reduce digestive phase pancreatic secretion are not fully understood. It is, however, well known that lipid in the distal small intestine has a negative feedback effect and is a potent stimulus for the reduction of pancreatic secretion. Polypeptide YY is the most significant inhibitor substance. Somatostatin and glucagon also contribute to the inhibition of pancreatic secretion.

Clinical and Laboratory Evaluation of Pancreatic Diseases

The evaluation of suspected acute or chronic pancreatic disease includes taking a complete history and performing a physical examination, as well as conducting standard laboratory tests and specialized tests aimed at detecting pancreatic disease. Additional testing includes sampling of the ascites fluid, if present, CT and ultrasound examination, or ERCP.

FAMILY AND PERSONAL HISTORY

Family and person history may provide some clues about the nature of pancreatic diseases. Here we concentrate on acute pancreatitis as the prototype of pancreatic diseases. Later we will see that acute pancreatitis can progress to chronic pancreatitis. The risk factors for acute pancreatitis that may be discovered by careful history taken from the patient are listed in Table 9-2.

Table 9-2 Risk Factors for Acute Pancreatitis

TYPE OF RISK FACTOR	SPECIFIC DISEASE/ASSOCIATION
Hereditary and metabolic diseases	Cystic fibrosis Hyperlipidemia Hyperparathyroidism Hemochromatosis End-stage renal disease Diabetic ketoacidosis
Social/nutritional factors	Alcoholism Severe malnutrition
Hepatobiliary diseases	Biliary stones Biliary/ampullary tumors
Infections	Viral infections: mumps, coxsackie B, HIV Worm infestation
Medical and surgical procedures	Post-ERCP Surgery of the biliary/duodenal/pancreatic lesions Postrenal transplant
Drugs	Thiazides, furosemide, valproic acid, azathioprine, corticosteroids, oral contraceptives, sulfonamides
External factors	Trauma to the abdomen Hypothermia Scorpion bites Organophosphate poisoning