division, which passes to the right in the lesser omentum before innervating the liver and biliary tract.

The remainder of the anterior vagal fibers parallels the lesser curvature of the stomach, branching to

the anterior gastric wall. The posterior vagus nerve branches into the celiac division, which passes to

the celiac plexus, and a posterior gastric division, which innervates the posterior gastric wall.

Figure 44-2. Arterial blood supply of the stomach.

Figure 44-3. Lymphatic drainage of the stomach.

Approximately 90% of the fibers in the vagal trunks are afferent, transmitting information from the

gastrointestinal tract to the central nervous system (CNS). Parasympathetic afferent fibers are not

responsible for the sensation of gastric pain. Only 10% of vagal nerve fibers are motor or secretory

efferents. Parasympathetic efferent fibers contained in the vagus originate in the dorsal nucleus of the

medulla. Vagal efferent fibers pass without synapse to contact postsynaptic neurons in the gastric wall

in the myenteric and submucous plexuses. Secondary neurons directly innervate gastric smooth muscle

or epithelial cells. Acetylcholine is the neurotransmitter of primary vagal efferent neurons.

The gastric sympathetic innervation is derived from spinal segments T5 through T10. Sympathetic

fibers leave the corresponding spinal nerve roots by way of gray rami communicantes and enter a series

of bilateral prevertebral ganglia (Fig. 44-5). From these ganglia, presynaptic fibers pass through the

greater splanchnic nerves to the celiac plexus, where they synapse with secondary sympathetic neurons.

Postsynaptic sympathetic nerve fibers enter the stomach in association with blood vessels. Afferent

sympathetic fibers pass without synapse from the stomach to dorsal spinal roots. Pain of gastroduodenal

origin is sensed through afferent fibers of sympathetic origin.

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Figure 44-4. Vagal innervation of the stomach.

Figure 44-5. Derivation of gastric sympathetic innervation.

MICROSCOPIC ANATOMY

The glandular portions of the stomach are lined by a simple columnar epithelium composed of surface

mucous cells. The luminal surface, visualized by scanning electron microscopy, appears cobblestoned,

interrupted at intervals by gastric pits. Opening into the gastric pits are one or more gastric glands that

impart functional significance to the gastric mucosa. The mucosa of the human stomach is composed of

three distinct types of gastric glands – cardiac, oxyntic, and antral.

In humans, cardiac glands occupy a narrow zone adjacent to the esophagus and mark a transition

from the stratified squamous epithelium of the esophagus to the simple columnar epithelium of the

stomach. The surface and gastric pit mucous cells of the cardia are not distinguishable from those in

other areas of the stomach. Cardiac glands contain mucous and undifferentiated and endocrine cells but

not the parietal or chief cells that are prominent in the adjacent oxyntic mucosa. Cardiac glands are

usually branched and connect with relatively short gastric pits. The functional properties of cardiac

glands include the secretion of mucus.

2 Oxyntic glands are the most distinctive feature of the human stomach. They occupy the fundus and

body of the stomach and contain the oxyntic or parietal cells, which are the sites of acid production.

Oxyntic glands also contain chief cells, the site of gastric pepsinogen synthesis. The tubular oxyntic

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glands are usually relatively straight but sometimes branch; several glands may empty into a single

gastric pit. The glands are divided into three regions: (a) the isthmus, containing surface mucous cells

and a few scattered parietal cells; (b) the neck, with a heavy concentration of parietal cells and a few

neck mucous cells; and (c) the base of the gland, containing chief cells, undifferentiated cells, a few

parietal cells, and some mucous neck cells. Endocrine cells are scattered throughout all three regions of

oxyntic glands.

The most distinctive cell of the gastric mucosa is the acid-secreting parietal cell. Parietal cells have an

unusual ultrastructural specialization in the form of intracellular canaliculi, a network of clefts

extending to the basal cytoplasm and often encircling the nucleus, which is continuous with the gland

lumen (Fig. 44-6). The surface area provided by the intracellular secretory canaliculi is large and is

further magnified by microvilli lining the canaliculi. In parietal cells that are not stimulated to secrete

acid, the secretory canaliculi are collapsed and inconspicuous. On stimulation, a severalfold increase in

canalicular surface area occurs, the intracellular clefts become prominent, and the communication with

the luminal surface is readily identified. These changes create an intracellular space in communication

with the gastric lumen into which hydrogen ions are secreted at high concentration.

The cytoplasm of the parietal cell also contains an abundance of large mitochondria. Mitochondria are

estimated to occupy 30% to 40% of the cytoplasmic volume of unstimulated parietal cells, reflecting the

extremely high oxidative activity of these cells. The oxygen consumption rate of isolated parietal cells is

approximately five times higher than that of gastric mucous cells. The cytoplasm also contains a limited

amount of rough endoplasmic reticulum, presumed to be the production site of intrinsic factor, which is

also secreted by parietal cells.

Figure 44-6. Resting and stimulated parietal cell, emphasizing morphologic transformation with increase in secretory canalicular

membrane surface area that occurs with acid secretion.

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Figure 44-7. Contrasting morphology of antral gastrin cell (left) with basally oriented secretory granules, and gastric mucous cell

(right) with apical mucous granules.

In addition to parietal cells, the oxyntic glands contain the gastric chief cells, which synthesize and

secrete pepsinogen. Chief cells are most abundant in the basal region of the oxyntic glands. The cells

have a morphology typical of protein-secreting exocrine cells and are similar in ultrastructural

appearance to pancreatic acinar cells. Rough endoplasmic reticulum is abundant in the cytoplasm and

extends between secretory granules. Zymogen granules containing pepsinogen are most concentrated in

the apical cytoplasm. Pepsinogen is released by exocytosis from secretory granules at the apical surface

of chief cells.

Antral glands occupy the mucosa of the distal stomach and pyloric channel. Antral glands are

relatively straight and often empty through deep gastric pits. Although most cells in the antral glands

are mucus secreting, gastrin cells are the distinctive feature of this mucosa. Gastrin cells are pyramid

shaped, with a narrow area of luminal contact apically and a broad surface overlying the lamina propria

basally (Fig. 44-7). Gastrin cells are identified immunocytochemically by the presence of the peptide.

Granules ranging from 150 to 400 nm in diameter are the sites of gastrin storage and are most

numerous in the basal cytoplasm. Gastrin is released by exocytotic fusion of the secretory granule with

the plasma membrane. In contrast to secretion from chief cells, emptying of gastrin-containing granules

occurs at the basal membrane rather than at the apical region of the cell. Gastrin thus released diffuses

to and enters submucosal capillaries in close apposition to the lamina propria.

GASTRIC PEPTIDES

The stomach contains a number of biologically active peptides in nerves and mucosal endocrine cells,

including gastrin, somatostatin, ghrelin, gastrin-releasing peptide, vasoactive intestinal polypeptide

(VIP), substance P, glucagon, and calcitonin gene–related peptide. The peptides with the greatest

importance to human disease and clinical surgery are gastrin, somatostatin, and ghrelin.

Gastrin

The synthesis, secretion, and action of gastrin have been extensively studied, and many aspects of the

biology of gastrin appear to be shared by other gastrointestinal peptide hormones.1 The gene that

encodes for gastrin was isolated using a human DNA library. The human gastrin gene contains three

exons; two exons consist of coding sequences. The major active product is encoded by a single exon. In

adults, the gastrin gene is expressed primarily in mucosa cells of the gastric antrum, with lower levels

of expression in the duodenum, pituitary, and testis. During embryonic development, the gastrin gene is

transiently active in pancreatic islets and colonic mucosa.

The human gene encompasses approximately 4,100 base pairs and directs the synthesis of a peptide of

101 amino acids (Fig. 44-8). The resulting peptide, preprogastrin, contains the sequence of gastrin

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within its amino acid sequence. Preprogastrin consists of a signal peptide of 21 amino acids, an

intervening peptide of 37 amino acids, the 34-residue region of the gastrin molecule, and a carboxylterminal extension of nine amino acids. Gastrin is derived from its preprohormone by the sequential

enzymatic cleavage of the signal peptide, the intervening peptide, and the carboxyl-terminal extension.

The signal peptide region of preprogastrin consists of a series of hydrophobic amino acids that direct

the nascent peptide into the endoplasmic reticulum as it is translated from messenger RNA. After

directing the preprogastrin molecule into the rough endoplasmic reticulum, the signal peptide is

removed. The remaining peptide is termed progastrin. Progastrin is further processed as it traverses the

endoplasmic reticulum to mature secretory vesicles. Enzymatic cleavage at a pair of basic amino acid

residues proximal to the gastrin 34 (G34

) sequence removes the intervening peptide. A similar cleavage

removes a six-amino-acid fragment at the carboxyl-terminal end. The peptide that remains has a GlyArg-Arg sequence at the carboxyl terminus. Carboxypeptidase cleaves the Arg residues, and the peptide

that results is termed glycine-extended gastrin. G34

is formed by cleavage of the Gly-Arg-Arg sequence

and amidation of the carboxyl-terminal phenylalanine. Gastrin, like most gastrointestinal peptide

hormones, requires terminal amidation for biologic activity. Gastrin 17 (G17

), the most abundant form

of gastrin in the human antrum, is formed by further processing that removes the first 17 amino acids at

the amino terminus of G34

. G34

is the predominate molecular form of gastrin in the duodenum.

Figure 44-8. Sequential processing of preprogastrin molecule.

3 The most important stimulant of gastrin release is a meal. Small peptide fragments and amino acids

that result from intragastric proteolysis are the most important food components that stimulate gastrin

release. The most potent gastrin-releasing activities are demonstrated by the amino acids tryptophan

and phenylalanine. Ingested fat and glucose do not cause gastrin release. Gastric distention by a meal

activates cholinergic neurons and stimulates gastrin release. As the meal empties and distention

diminishes, VIP-containing neurons are activated, which stimulate somatostatin secretion and thus

attenuate gastrin secretion.

Postprandial luminal pH also strongly affects gastrin secretion. Gastrin release is inhibited when

acidification of an ingested meal causes the intraluminal pH to fall below 3.0. Conversely, maintaining

intragastric pH above 3.0 potentiates gastrin secretion after ingestion of protein or amino acids.2

Pernicious anemia and atrophic gastritis, which produce chronic achlorhydria, are associated with

fasting hypergastrinemia and an exaggerated gastrin meal response. Release of mucosal somatostatin

occurs with gastric acidification and this peptide has been implicated in the inhibition of gastrin release

that occurs when luminal pH falls.

The vagus nerve appears to both stimulate and inhibit gastrin release.3 In humans, vagally mediated

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