Developmental Anatomy and Physiology of the Stomach

Histology

Development of fetal human gastric mucosa occurs very early during fetal life. The first pit/gland structures are observed at 11 to 12 weeks of gestation. Between 11 and 17 weeks, the stratified surface epithelium is replaced by a simple mucous columnar epithelium, and gastric glands develop further. At this stage, the progenitor zone of the pit/gland structure is already localized in the isthmus, as in adult mucosa. ^,

The gastric mucosa is organized in vertical tubular units consisting of an apical pit region, an isthmus, and the actual gland region that forms the lower part of the vertical unit. The progenitor cell of the gastric unit gives rise to all epithelial cells. The mucus-producing pit cells migrate up toward the gastric lumen, and acid-secreting parietal cells (oxyntic; oxys is Greek for acid) migrate downward to the middle and lower regions of the gland. Chief (zymogenic) cells secrete pepsinogen and predominate at the base of glands. Neuroendocrine cells, including enterochromaffin cells (serotonin), enterochromaffin-like cells (ECLs; histamine), and D cells (somatostatin) are also present at the base of the gland.

The glands of the different anatomic parts of the stomach are lined with different types of cells ( Fig. 24.2 ). The cardiac glands are mostly populated by mucus-secreting or endocrine cells. The cardiac pits are irregular and shallow; the ratio of the length of pit-to-glands is approximately 1:1. In the body of the stomach, including the fundus, the glands are long and deep with straight pits. The ratio of the length of pits-to-glands is approximately 1:4. The gastric gland has parietal (oxyntic) cells that secrete hydrochloric acid and intrinsic factor, chief (zymogen, peptic) cells that secrete pepsinogen, and endocrine and mucous neck cells. The antrum and pylorus contain the pyloric glands, composed of mainly mucus, endocrine, and G cells. There are very few parietal or chief cells. The glands here are characterized by deep pits but short glands, with a pit-to-gland ratio close to 1:1. Mucus is also secreted along with bicarbonate (HCO ₃ ⁻ ) by the surface mucous cells between glands. Surface mucous cells secrete neutral mucus, rather than the sulfated mucus secreted by mucous neck cells, which reside in proximity to parietal cells. The surface mucous cells are cytoprotective, whereas the mucous neck cell functions as a stem cell precursor for surface mucus and parietal, chief, and endocrine cells.

Neuromuscular Functions

Gastric motility is controlled centrally as well as by local neurohormonal control of the muscle layers, which include outer longitudinal, middle circular, and inner oblique fibers. Neuronal control involves the intrinsic myenteric plexus, the extrinsic postganglionic sympathetic fibers of the celiac plexus, and the preganglionic parasympathetic fibers of the vagus nerve. The vagal afferents are both relaxatory and excitatory.

Functionally, the stomach can be divided into two parts: the proximal stomach and the antrum. The proximal stomach, consisting of the cardia, fundus, and a portion of the body, is responsible for the storage of food and is capable of accommodating a large volume of nutrients with receptive relaxation and no dramatic rise in intragastric pressure. Di Lorenzo et al. demonstrated that the receptive relaxation of the proximal stomach is negligible in infants; this might explain in part the increased incidence of reflux in newborns.

The rate at which the stomach empties into the duodenum also depends on the type and components of food ingested. Liquids and solids have different mechanisms of emptying. An increased tonic intraluminal pressure in the fundus is necessary for the emptying of liquids. Liquid emptying has an exponential pattern of emptying that is dependent on the volume ingested, as well as the osmolarity of the liquid. This is determined largely by the pressure differences between the stomach and duodenum and is modulated by receptors in the duodenum that slow gastric emptying when the caloric density or volume load reaching the duodenum is excessive.

Solid food emptying has an initial lag phase followed by a linear phase. The distal stomach, which consists of the antrum and pylorus, is responsible for grinding and emptying solid food. Gastric peristaltic waves originating in the body of the stomach propagate toward the pylorus. The antral contractions allow only the small particles and liquids to pass into the duodenum and drive the larger particles (>0.2 mm) back into the body of the stomach by retrograde propulsion. Food rich in carbohydrate leaves the stomach within a few hours. However, protein-rich food leaves more slowly, and emptying is slowest after a meal containing a significant amount of fat. Finally, the rate of emptying also depends on antral distension (gastrogastric reflex); concentration of lipid, protein, and acid in the duodenum (duodenogastric reflex); and colonic distension (cologastric reflex). ^,

Because of ingesting a meal, gastric distension stimulates “gastric mechanoreceptors”; hyperosmolality of the duodenal contents sensed by “duodenal osmoreceptors” initiates both enterogastric neural reflexes. Cholecystokinin (CCK) is released in response to this reflux and binds to CCK1 receptors (CCK1Rs) on gastric afferents, producing inhibition of the excitatory vagal efferents to the fundus. The primary inhibitory neurotransmitter is nitric oxide, which controls transpyloric flow, antral motility, and pyloric contraction. Serotonin is also involved in the inhibitory pathway. Appropriate propagation of gastric contractions or antroduodenal coordination is of great importance to the emptying of the stomach. Gastric motility is regulated by gastric myoelectric activity and consists of gastric slow waves and spike or second potentials. The gastric slow wave determines the propagation and maximum frequency of gastric contractions. It is generated in an area of the greater curvature that has the fastest rate of inherent rhythmicity and acts as a pacemaker controlling the rate and direction of propagation of gastric electrical activity. The normal frequency of gastric slow waves is 3 cycles per minute (cpm) in healthy humans. Abnormalities in the frequency of the gastric slow waves have been reported in a number of clinical settings, associated with gastric motor disorders and gastrointestinal symptoms. Gastric slow-wave activity can be measured noninvasively using the technique of electrogastrography (EGG). Gastric motor activity initially appears between the gestational ages of 14 and 24 weeks. EGG patterns at 35 weeks of gestation are similar to that of a full-term infant. EGG patterns continue to mature over the first 6 to 24 months, reaching a stable pattern.

A characteristic feature of fasting motor activity in the older child is the migrating motor complex (MMC), a highly organized propagated sequence of contractions that migrates from the stomach into the intestine and toward the ileum every 90 to 120 minutes. Three distinctive phases appear in sequence. Phase 1 is a pattern of quiescence that always follows phase 3. Phase 2 is a period of irregular contractions, varying in amplitude and periodicity. Because of this variation, some contractions are not propagated. Phase 3 is a distinctive pattern of regular high-amplitude contractions repeating at a maximal rate for 3 to 10 minutes and migrating from proximal to distal. The MMC begins anywhere from the esophagus to the ileum. About half of these contractions begin in the esophagus or the gastric body and migrate downward. Motilin is responsible for initiating phase 3 contractions that begin in the stomach. Gastric MMCs are present in newborns and preterm infants older than 32 weeks of gestation. In younger preterm infants, only uncoordinated, nonmigrating contractions are present. The clinical implications of nonmigrating phase 3 contractions in very preterm infants are unknown. Theoretically, nonmigrating phase 3 contractions should not cause feeding intolerance, because liquid gastric emptying is related to the function of fundus and not to antral peristalsis.

Gastric Secretions

The stomach secretes water, electrolytes, hydrochloric acid, and glycoproteins, including mucin, intrinsic factor, and enzymes ( Fig. 24.3 ).

Gastric motility and secretion are regulated by neural and humoral mechanisms. For convenience, the physiologic regulation of gastric secretion is usually discussed as being either cephalic or peripheral , which includes both gastric and intestinal influences, although these overlap. The cephalic influences are vagally mediated responses induced by activity in the central nervous system. The vagus nerve contains afferent fibers that transmit sensory information from the gut to the brainstem and efferent fibers that form the motor limb of the vagovagal reflexes. The cephalic phase of acid secretion is induced by sensory inputs of the thought, smell, sight, and taste of the food. The efferent fibers for this reflex are in the vagus nerves. Cephalic influences are responsible for one-third to one half of the acid secreted in response to a normal meal and are abolished by vagotomy. Vagal stimulation increases gastrin secretion by release of gastrin-releasing peptide (GRP), or bombesin. Other vagal fibers release acetylcholine, which acts directly on the cells in the glands in the body and the fundus of the stomach. Acetylcholine binds to M ₃ muscarinic receptors on the parietal cell and stimulates gastric acid secretion via calcium and phosphoinositol pathways.

The peripheral mechanisms include gastric influences, consisting of local reflex responses to gastrin, and intestinal influences, reflex, and hormonal feedback effects on gastric secretion initiated from the mucosa of the small intestine. Finally, the stomach also contains exocrine epithelial cells and endocrine-like neural regulatory cells.

Gastric Acid Secretion

Hydrochloric Acid Secretion

Golgi first proposed that the parietal cell was the source of gastric acid and that it was formed within the surface invaginations, which he termed secretory canaliculi . The ultrastructure of the parietal cell has numerous large mitochondria to provide adenosine triphosphate (ATP) for acid secretion. The H ⁺ ,K ⁺ -ATPase (gastric acid pump, or proton pump) is a membrane-embedded protein identified and isolated in the 1970s. Parietal cells express receptors for acetylcholine, gastrin, and histamine ( Fig. 24.4 ). The binding of these ligands to receptors on the surface of the parietal cell starts changes in second messengers that regulate the movement and location of the gastric proton pump. The H ⁺ ,K ⁺ -ATPase exchanges protons for potassium and is responsible for gastric luminal acidification. In the resting state, the enzyme is stored in the cytoplasmic tubulovesicles. When the parietal cells are stimulated, the tubulovesicular structures fuse with the apical membrane to form secretory canaliculus and the proton pumps start actively pumping H ⁺ ions in exchange for K ⁺ . The proteins involved in the translocation and fusion of H,K-ATPase include ezrin, actin, myosin, Rab GTPase, and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Ezrin, an actin-binding protein localized to the apical canalicular membrane of parietal cells, is crucial for tubulovesicle docking and fusion. Ezrin and MST4 work collaboratively to promote histamine-stimulated acid secretion.

Pumping H ⁺ out of the parietal cells in exchange for K ⁺ requires appreciable energy, and this is provided by hydrolysis of ATP. Cl ⁻ is also extruded down its electrochemical gradient through channels that are activated by cyclic adenosine monophosphate (cAMP) in the apical membrane. Ultimately, acid is generated from the dissociation of two molecules of water to form H ₃ O ⁺ and OH ⁻ . The H ₃ O ⁺ is secreted via the proton pump in exchange for K ⁺ , whereas the corresponding OH ⁻ combines in the cell with carbon dioxide to form HCO ₃ ⁻ . This reaction is catalyzed by carbonic anhydrase, and the parietal cells are particularly rich in this enzyme. The formed HCO ₃ ⁻ is extruded by a conductance pathway on the basolateral membrane in exchange for Cl ⁻ ions.

The H ⁺ ,K ⁺ -ATPase is a heterodimer composed of two noncovalently linked subunits, α and β. The α subunit contains the catalytic site of the enzyme, which is important for functioning of the H ⁺ ,K ⁺ -ATPase. It contains the cysteine residues where proton pump inhibitors bind. The β subunit appears to play a role in formation of tubulovesicle membranes and the transfer of enzyme to the apical membrane and may protect the enzyme from degradation.