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Secretions of the salivary glands and stomach
BASIC SCIENCE
Secretions of the salivary glands and stomach
digestion of starches to oligosaccharides. Ptyalin activity is maintained over a wide pH range and its activity is terminated only when it reaches the low pH in the stomach. In addition the Ca content prevents Ca salts from dissolving from teeth. Prolonged poor salivary secretion (dry mouth or xerostomia) is associated with tooth decay and buccal ulceration that may become infected due to uncontrolled bacterial growth. There are three main pairs of glands: Parotid glands are the largest, anterior and below the ear and discharge into the cheek near the upper second molars. They produce about 25% of total output. Parotid gland secretion is a serous fluid, consisting of electrolytes and enzymes. Submandibular glands produce about 70% of the daily secretion, containing electrolytes, enzymes and mucins, which drains into the mouth from ducts below the tongue. Sublingual glands produce a mucus-rich fluid, also containing antigens and antibodies, draining either directly into the buccal cavity or into the submandibular gland duct. The glands have a large unit blood flow and metabolism reflecting their high metabolic rate. Stimulation of parasympathetic nerves to the glands generates local vasodilatation through vasoactive intestinal peptide (VIP) co-released at the nerve endings.
Christopher Fry
Abstract The secretions of the gastro-intestinal tract and associated organs enable the food that we eat to be broken down into small molecules available for absorption. For each secretion it is necessary to understand: its function and composition; how it is formed; and how secretion is controlled. In this article secretions from the salivary glands and stomach are considered. Most secretions flow into the lumen of the tract (mouth, stomach lumen), with the exception of hormones such as gastrin and histamine, which are secreted into the interstitium and blood. Saliva is concerned with: protecting the mouth against microorganisms and ulceration; facilitating swallowing; and initiating digestion of starches. It is produced from three pairs of glands that secrete mucus and an alkaline ionic solution containing an amylase, ptyalin. The primary ionic secretion is modified along the salivary duct, the extent of which depends on flow rate: at low rates ion reabsorption produces a hypotonic solution, as flow rate increases the solution approaches isotonicity. Flow rate is controlled by the autonomic nervous system, predominantly the parasympathetic branch. Gastric secretions contain: mucus to protect the stomach wall; acid as hydrochloric acid (HCl) to kill remaining microorganisms and initiate hydrolysis of food; an inactive proteolytic enzyme pepsinogen and hormones (gastrin and histamine); as well as the only essential molecule intrinsic factor, which binds vitamin B12 for later absorption in the ileum. Gastric pits in the mucosa have specialized cells to produce mucus, acid and intrinsic factor (parietal cells) and pepsinogen (chief cells). Specialized G-cells produce gastrin through interacting neural (acetylcholine), paracrine (histamine) and endocrine (gastrin-dependent) controls; enterochromaffin cells produce histamine. Acid secretion is also regulated by interacting acetylcholine, histamine and gastrin-dependent pathways, with the vagus nerve having a prominent regulatory role. Gastric secretions occur in three phases: cephalic, gastric and intestinal e the regulatory processes behind these phases are considered in this article.
Formation of saliva The salivary gland consists of blind-ended acini that drain into salivary ducts. Typically the acinus consists of serous or mucus cells. These cells produce the primary secretion along with amylase and glycoprotein mucins respectively. The electrolyte content of this secretion is similar to plasma. However, the fluid is not produced by ultrafiltration, as in the nephron, but probably by secretion chloride ions of (Cl) and bicarbonate ions (HCO 3) into the acinus, which then attracts sodium ions (Naþ) and potassium ions (Kþ) and water through the tight junctions between adjacent cells. Modification of the primary secretion occurs in the secretory ducts, which produce a hypotonic fluid due to the reabsorption of Naþ and Cl, along with the secretion of some Kþ and HCO 3. Water cannot follow by osmosis upon the reabsorption of Naþ and Cl, resulting in the dilute secretion (Figure 1). Modification of the primary secretion is attenuated as the flow rate increases, although the fluid is always hypotonic and enriched in Kþ and HCO 3 compared to extracellular fluid.
Keywords acid production; autonomic nervous system; control of secretion flow; gastric secretions; salivary glands
Control of salivary secretion The major control is exerted by the autonomic nervous system, with a predominant role of parasympathetic nerves. However, stimulation of either branch will increase flow. Sympathetic fibres travel from the superior cervical ganglion, whilst parasympathetic fibres come from branches of the facial nerve (mainly to the parotid glands) or the glossopharyngeal nerve. Parasympathetic stimulation not only increases blood flow, and thus the rate of primary secretion, but also augments secretion of amylase and mucins and modifies the transport properties of the ductal epithelium, by increasing HCO 3 , but decreasing transport of Naþ and Kþ. The functional muscarinic receptors on salivary glands are mainly the M3 subtype, similar to that on bladder smooth muscle cells. This is of significance when considering the
Salivary secretions Saliva and salivary glands Saliva is produced from salivary glands at a rate of 1.0e1.5 litres per day. It is an ionic solution, modified from extracellular fluid and contains also mucins and an a-amylase (ptyalin), as well as a minor component of certain immunoglobulins. It has a number of functions that include: facilitating swallowing; protection of the buccal cavity against infection and ulceration; and some
Christopher Fry DSc PhD is Professor of Physiology at the Postgraduate Medical School, University of Surrey, UK.
SURGERY 27:12
503
Ó 2009 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
produces mainly mucus; the oxyntic region that produces mucus, acid, pepsinogen and intrinsic factor; and the pyloric region that secretes mucus and gastrin from G-cells. The oxyntic, gastric pit (Figure 2a) typically contains three cell types: the neck cells which are contiguous with the surface epithelium and produce mucus; parietal (or oxyntic) cells that secrete acid and intrinsic factor; and chief (or peptic) cells that produce pepsinogen.
Saliva flow 150
[Na+]
Concentration (mM)
[Na+] [CI–]
[HCO3–] [K+] [CI–]
100
The mucus layer The mucoproteins and mucopolysaccharides that constitute mucus form a viscous fluid that adheres to the mucosa itself, protecting it from mechanical abrasion from solid food as well as the acid environment of the stomach lumen. Acid protection is also conferred by HCO 3 secretion from the same region, and maintains the mucus at a slightly alkaline pH. Effective acid protection requires both mucus and HCO 3 secretion as the former reduces the diffusion of the HCO 3 -rich aqueous secretion away from the mucosal surface (Figure 2b). The alkaline environment also protects the mucosa from pepsin, as the enzyme requires a pH <5 for activity. The mucus layer needs continuous renewal otherwise acid may degrade the mucosal surface, eventually producing ulceration. Local irritation of the mucosa increases mucus and HCO 3 secretion through the mediation of locally generated prostaglandins. Several factors can degrade the mucosal barrier. Catecholamines suppress HCO 3 secretion and thus may contribute to stress ulcers. Many anti-inflammatory agents reduce prostaglandin production and so will limit renewal of the mucosal barrier. Finally, alcohol will increase acid production and if sufficient may overwhelm the mucosal barrier.
50 [HCO3–] 0
[K+] 0
1
2
3
4
Salivary flow (ml/minute) Figure 1 The dependence of salivary composition on saliva flow rate. The concentrations of the principal ions, Naþ, Kþ, Cl and HCO 3 , are shown as a function of flow rate. The dotted lines show the plasma concentrations of the respective ions.
side-effect of dry mouth for patients prescribed antimuscarinic agents for conditions such as overactive bladder. Sympathetic stimulation causes a transient increase of salivary secretion: it increases secretion of saliva rich in amylase and mucins, as well as release of vasodilator peptides, but this is offset by direct local vasoconstriction. The dry mouth associated with ‘fright and flight’ is due to direct sympathetic stimulation.
Acid secretion The rate of gastric acid secretion varies between fasting and feeding, but when stimulated the [Hþ] can increase to between 10 mM (pH 2.0) and 100 mM (pH 1.0), and on occasions to as much as 140 mM (pH 0.85); the major anion is Cl. The [Kþ] is always greater than plasma, so that prolonged vomiting generates not only a metabolic alkalosis, but also may be accompanied by hypokalaemia. The parietal cell is highly specialized, with a system of canaliculi that greatly increase the apical surface area and which collect the secreted hydrochloric acid (HCl) to a common duct at the surface of the cell. This surface area increases even more when acid production is stimulated. HCl is secreted by the parietal cell through a process of active transport as Hþ have to be pumped into the canaliculus (Figure 2c) against an astonishing one million-fold gradient concentration gradient e from pH 7.0 ([Hþ]; 0.1 mM) inside the cell to a canaliculus pH of about pH 1 ([Hþ]; 100 mM). In molecular terms Hþ and HCO 3 are formed within the cell from the hydration of carbon dioxide (CO2), whereupon the Hþ are removed across the apical surface via an HþeKþ adenosine triphosphatase (ATPase) (proton pump) and HCO 3 removed across the baso-lateral surface in exchange for Cl. The resultant secretion of Hþ is therefore accompanied by an alkaline tide in the blood. Cl follow Hþ into the canaliculus through an ion channel. Acid secretion may be attenuated by proton pump inhibitors, such as omeprazole, which irreversibly inactivate the HþeKþ ATPase, themselves being activated only in an acid environment.
Gastric secretions Nature of the secretions The stomach is a storage organ that delivers food to the duodenum at a rate at which it can be subsequently digested and absorbed. The secretions of the stomach facilitate the digestion process in a number of ways. The major secretion is acid that assists in converting food to a semi-liquid chyme, destroys most bacteria ingested with food and carries out some hydrolysis of fats and starches. Pepsins also secreted by the stomach assist in the initial hydrolysis of proteins, although it is not essential for this process. Pepsins are secreted in an inactive form, pepsinogens, and converted to an active form in the acid environment of the stomach lumen. A thin layer of mucus is also secreted to protect the gastric wall against the acid luminal contents. The only essential gastric secretion is intrinsic factor, a glycoprotein required for the absorption of vitamin B12 in the terminal ileum, by forming a complex resistant to digestion. Finally the stomach produces gastrin and histamine, important in the regulation of acid secretion. The gastric mucosa Surface columnar epithelial cells secrete mucus and a HCO 3 -rich fluid, but this surface is also covered with numerous ducts leading to gastric pits from which the remaining secretions are formed. The stomach may be divided into three regions based upon these secretions: a small region below the oesophageal sphincter that
SURGERY 27:12
504
Ó 2009 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
a
b
Cells of the gastric pit
Mucous layer pH 2.0
Gastric pit
Mucus lumen
Surface mucous cells
Mucus layer
Oxyntic gland
Isthmus
HCO3–
HCO3–
Mucous neck cells Neck Parietal cells
7.0 Mucus droplets
ECF cells
Gastric epithelial cell
Base Chief cells
c
Lumen of gastric pit
Parietal cell
Canaliculus
HCI CI– K+
H+ ATP CO2 + H2O
H+ + HCO3–
M3 CI– H2 Gast
Figure 2 a Structure of the gastric pit, showing the main cells. b Diagram of the mucous layer to illustrate the pH gradient between the surface of the gastric epithelium and the bulk solution within the gastric lumen. c Diagram of a parietal cell showing the intracellular pathways responsible for the generation of hydrochloric acid (HCl) in the canaliculus of the cell. The major secretagogue membrane receptors are also shown: M3, muscarinic receptors; H2, histamine receptors; gast, gastrin receptors. The inset shows a representative drawing of a parietal cell with the major canalicular infoldings, and numerous mitochondria characteristic of these cells.
Histamine is released from enterochromaffin-like (ECL) cells in the gastric mucosa. It should be noted that histamine is also a potent vasodilator increasing blood flow to the region to support the raised metabolism required to support Hþ secretion. Gastrin is produced from G-cells in the pyloric antrum, and also from a population in the duodenum. There is considerable interplay between the different pathways, which renders the whole process of acid secretion efficient and
Control of acid and pepsinogen secretion Several secretagogues, each acting via specific receptors on the baso-lateral surface of the parietal cell stimulate HCl secretion. Most importantly these are acetylcholine (M3 receptor); histamine (H2 receptor) and gastrin. Acetylcholine is released from postganglionic parasympathetic fibres that innervate the stomach mucosa and to some extent from enteric nervous system fibres.
SURGERY 27:12
505
Ó 2009 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
easily regulated, as described below. Acetylcholine and gastrin not only exert a direct effect on the parietal cell itself, but also stimulate ECF cells to release histamine. In addition, a gastrinreleasing peptide may be released from cholinergic fibres to exert a direct effect on G-cells. The release of pepsinogen from chief cells mirrors that of Hþ and involves the same secretagogues, such as acetylcholine and gastrin, except that secretin and CCK also stimulate release (see below).
presence of amino acids and peptides. Duodenal G-cells release gastrin to stimulate gastric parietal cells. A further hormone, or group of similar peptides, entero-oxyntin may complement this stimulation. After a while the duodenum exerts an inhibitory effect on gastric secretion elicited by increasing acidity of the chyme, as further gastric emptying occurs, products of fat digestion and increasing hypertonicity of the chyme as duodenal digestion proceeds. Acid causes the release of secretin from the duodenum, this exerts inhibitory effects on G-cells and gastric parietal cells themselves, and activates a local inhibitory reflex. Two further hormones, cholecystokinin and gastric inhibitory peptide, are released by duodenal fatty acids and monoglycerides and decrease acid secretion in a manner similar to that of secretin. A
The integration of gastric secretion production during a meal When the stomach is empty a basal secretion occurs, about 10% of the maximum rate, which has some diurnal rhythm, greatest in the evening. However, after a meal secretion increases rapidly and is associated with three phases: A cephalic phase, elicited by the sight, smell and taste of food A gastric phase, elicited by the presence of food in the stomach An intestinal phase, elicited by chyme in the duodenum. This phase is however transitory and eventually acid secretion is reduced.
Helicobacter pylori. A Gram-negative, urease-positive bacterium, requiring low levels of oxygen to survive, that inhabits the stomach and duodenum. It causes a chronic inflammation of the mucosa and is linked to the development of gastric, duodenal and gastric ulcers as well as cancers, such as mucosa-associated lymphoid tissue lymphomas (MALTomas). Treatment is with proton pump inhibitors and antibiotics.
The cephalic phase: this is mediated by the vagus, as vagotomy abolishes this phase. Cholinergic fibres and cholinergic neurones from intramural plexuses release acetylcholine that activates the parietal cells and also elicits gastrin and histamine release. Other factors such as hypoglycaemia in cerebral arterial blood also evoke gastric secretions. The central control of gastric secretion is complex but in part is controlled by the hypothalamus. The gastric phase: most of the secretions occur during this phase. The main stimuli are distension of the stomach by the presence of food and the products of protein digestion. Stretch receptors in the stomach wall initiate local, enteric and central, vasovagal cholinergic reflexes. The process is self-regulating as when luminal pH falls below 2.0 gastric secretions are blocked. Of interest is that in patients with duodenal ulcers this negative feedback control is attenuated. Amino acids, especially tryptophan and phenylalanine, and small peptides also elicit acid secretion, possibly by an effect on G-cells to release gastrin. Other agents in food, such as caffeine and alcohol also stimulate acid secretion.
ZollingereEllison syndrome. This is a rare disorder characterized by gastrinomas in the pancreas or duodenum that release abnormal amounts of gastrin and hence cause excessive acid secretion. The maintained acid secretion can eventually cause gastric or duodenal ulcers. Symptoms therefore include: nausea and vomiting; burning abdominal pain; gastro-esophageal reflux and diarrhoea. Treatment is with proton pump inhibitors, and surgical removal in the proportion considered malignant. ZollingereEllison syndrome may be associated with multiple endocrine neoplasia, type 1 (MEN 1) in which there are multiple tumours in the endocrine system.
The intestinal phase: when chyme initially enters the duodenum acid secretion is stimulated due to mechanical distension and the
SURGERY 27:12
506
Ó 2009 Elsevier Ltd. All rights reserved.
Secretions of the salivary glands and stomach
digestion of starches to oligosaccharides. Ptyalin activity is maintained over a wide pH range and its activity is terminated only when it reaches the low pH in the stomach. In addition the Ca content prevents Ca salts from dissolving from teeth. Prolonged poor salivary secretion (dry mouth or xerostomia) is associated with tooth decay and buccal ulceration that may become infected due to uncontrolled bacterial growth. There are three main pairs of glands: Parotid glands are the largest, anterior and below the ear and discharge into the cheek near the upper second molars. They produce about 25% of total output. Parotid gland secretion is a serous fluid, consisting of electrolytes and enzymes. Submandibular glands produce about 70% of the daily secretion, containing electrolytes, enzymes and mucins, which drains into the mouth from ducts below the tongue. Sublingual glands produce a mucus-rich fluid, also containing antigens and antibodies, draining either directly into the buccal cavity or into the submandibular gland duct. The glands have a large unit blood flow and metabolism reflecting their high metabolic rate. Stimulation of parasympathetic nerves to the glands generates local vasodilatation through vasoactive intestinal peptide (VIP) co-released at the nerve endings.
Christopher Fry
Abstract The secretions of the gastro-intestinal tract and associated organs enable the food that we eat to be broken down into small molecules available for absorption. For each secretion it is necessary to understand: its function and composition; how it is formed; and how secretion is controlled. In this article secretions from the salivary glands and stomach are considered. Most secretions flow into the lumen of the tract (mouth, stomach lumen), with the exception of hormones such as gastrin and histamine, which are secreted into the interstitium and blood. Saliva is concerned with: protecting the mouth against microorganisms and ulceration; facilitating swallowing; and initiating digestion of starches. It is produced from three pairs of glands that secrete mucus and an alkaline ionic solution containing an amylase, ptyalin. The primary ionic secretion is modified along the salivary duct, the extent of which depends on flow rate: at low rates ion reabsorption produces a hypotonic solution, as flow rate increases the solution approaches isotonicity. Flow rate is controlled by the autonomic nervous system, predominantly the parasympathetic branch. Gastric secretions contain: mucus to protect the stomach wall; acid as hydrochloric acid (HCl) to kill remaining microorganisms and initiate hydrolysis of food; an inactive proteolytic enzyme pepsinogen and hormones (gastrin and histamine); as well as the only essential molecule intrinsic factor, which binds vitamin B12 for later absorption in the ileum. Gastric pits in the mucosa have specialized cells to produce mucus, acid and intrinsic factor (parietal cells) and pepsinogen (chief cells). Specialized G-cells produce gastrin through interacting neural (acetylcholine), paracrine (histamine) and endocrine (gastrin-dependent) controls; enterochromaffin cells produce histamine. Acid secretion is also regulated by interacting acetylcholine, histamine and gastrin-dependent pathways, with the vagus nerve having a prominent regulatory role. Gastric secretions occur in three phases: cephalic, gastric and intestinal e the regulatory processes behind these phases are considered in this article.
Formation of saliva The salivary gland consists of blind-ended acini that drain into salivary ducts. Typically the acinus consists of serous or mucus cells. These cells produce the primary secretion along with amylase and glycoprotein mucins respectively. The electrolyte content of this secretion is similar to plasma. However, the fluid is not produced by ultrafiltration, as in the nephron, but probably by secretion chloride ions of (Cl) and bicarbonate ions (HCO 3) into the acinus, which then attracts sodium ions (Naþ) and potassium ions (Kþ) and water through the tight junctions between adjacent cells. Modification of the primary secretion occurs in the secretory ducts, which produce a hypotonic fluid due to the reabsorption of Naþ and Cl, along with the secretion of some Kþ and HCO 3. Water cannot follow by osmosis upon the reabsorption of Naþ and Cl, resulting in the dilute secretion (Figure 1). Modification of the primary secretion is attenuated as the flow rate increases, although the fluid is always hypotonic and enriched in Kþ and HCO 3 compared to extracellular fluid.
Keywords acid production; autonomic nervous system; control of secretion flow; gastric secretions; salivary glands
Control of salivary secretion The major control is exerted by the autonomic nervous system, with a predominant role of parasympathetic nerves. However, stimulation of either branch will increase flow. Sympathetic fibres travel from the superior cervical ganglion, whilst parasympathetic fibres come from branches of the facial nerve (mainly to the parotid glands) or the glossopharyngeal nerve. Parasympathetic stimulation not only increases blood flow, and thus the rate of primary secretion, but also augments secretion of amylase and mucins and modifies the transport properties of the ductal epithelium, by increasing HCO 3 , but decreasing transport of Naþ and Kþ. The functional muscarinic receptors on salivary glands are mainly the M3 subtype, similar to that on bladder smooth muscle cells. This is of significance when considering the
Salivary secretions Saliva and salivary glands Saliva is produced from salivary glands at a rate of 1.0e1.5 litres per day. It is an ionic solution, modified from extracellular fluid and contains also mucins and an a-amylase (ptyalin), as well as a minor component of certain immunoglobulins. It has a number of functions that include: facilitating swallowing; protection of the buccal cavity against infection and ulceration; and some
Christopher Fry DSc PhD is Professor of Physiology at the Postgraduate Medical School, University of Surrey, UK.
SURGERY 27:12
503
Ó 2009 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
produces mainly mucus; the oxyntic region that produces mucus, acid, pepsinogen and intrinsic factor; and the pyloric region that secretes mucus and gastrin from G-cells. The oxyntic, gastric pit (Figure 2a) typically contains three cell types: the neck cells which are contiguous with the surface epithelium and produce mucus; parietal (or oxyntic) cells that secrete acid and intrinsic factor; and chief (or peptic) cells that produce pepsinogen.
Saliva flow 150
[Na+]
Concentration (mM)
[Na+] [CI–]
[HCO3–] [K+] [CI–]
100
The mucus layer The mucoproteins and mucopolysaccharides that constitute mucus form a viscous fluid that adheres to the mucosa itself, protecting it from mechanical abrasion from solid food as well as the acid environment of the stomach lumen. Acid protection is also conferred by HCO 3 secretion from the same region, and maintains the mucus at a slightly alkaline pH. Effective acid protection requires both mucus and HCO 3 secretion as the former reduces the diffusion of the HCO 3 -rich aqueous secretion away from the mucosal surface (Figure 2b). The alkaline environment also protects the mucosa from pepsin, as the enzyme requires a pH <5 for activity. The mucus layer needs continuous renewal otherwise acid may degrade the mucosal surface, eventually producing ulceration. Local irritation of the mucosa increases mucus and HCO 3 secretion through the mediation of locally generated prostaglandins. Several factors can degrade the mucosal barrier. Catecholamines suppress HCO 3 secretion and thus may contribute to stress ulcers. Many anti-inflammatory agents reduce prostaglandin production and so will limit renewal of the mucosal barrier. Finally, alcohol will increase acid production and if sufficient may overwhelm the mucosal barrier.
50 [HCO3–] 0
[K+] 0
1
2
3
4
Salivary flow (ml/minute) Figure 1 The dependence of salivary composition on saliva flow rate. The concentrations of the principal ions, Naþ, Kþ, Cl and HCO 3 , are shown as a function of flow rate. The dotted lines show the plasma concentrations of the respective ions.
side-effect of dry mouth for patients prescribed antimuscarinic agents for conditions such as overactive bladder. Sympathetic stimulation causes a transient increase of salivary secretion: it increases secretion of saliva rich in amylase and mucins, as well as release of vasodilator peptides, but this is offset by direct local vasoconstriction. The dry mouth associated with ‘fright and flight’ is due to direct sympathetic stimulation.
Acid secretion The rate of gastric acid secretion varies between fasting and feeding, but when stimulated the [Hþ] can increase to between 10 mM (pH 2.0) and 100 mM (pH 1.0), and on occasions to as much as 140 mM (pH 0.85); the major anion is Cl. The [Kþ] is always greater than plasma, so that prolonged vomiting generates not only a metabolic alkalosis, but also may be accompanied by hypokalaemia. The parietal cell is highly specialized, with a system of canaliculi that greatly increase the apical surface area and which collect the secreted hydrochloric acid (HCl) to a common duct at the surface of the cell. This surface area increases even more when acid production is stimulated. HCl is secreted by the parietal cell through a process of active transport as Hþ have to be pumped into the canaliculus (Figure 2c) against an astonishing one million-fold gradient concentration gradient e from pH 7.0 ([Hþ]; 0.1 mM) inside the cell to a canaliculus pH of about pH 1 ([Hþ]; 100 mM). In molecular terms Hþ and HCO 3 are formed within the cell from the hydration of carbon dioxide (CO2), whereupon the Hþ are removed across the apical surface via an HþeKþ adenosine triphosphatase (ATPase) (proton pump) and HCO 3 removed across the baso-lateral surface in exchange for Cl. The resultant secretion of Hþ is therefore accompanied by an alkaline tide in the blood. Cl follow Hþ into the canaliculus through an ion channel. Acid secretion may be attenuated by proton pump inhibitors, such as omeprazole, which irreversibly inactivate the HþeKþ ATPase, themselves being activated only in an acid environment.
Gastric secretions Nature of the secretions The stomach is a storage organ that delivers food to the duodenum at a rate at which it can be subsequently digested and absorbed. The secretions of the stomach facilitate the digestion process in a number of ways. The major secretion is acid that assists in converting food to a semi-liquid chyme, destroys most bacteria ingested with food and carries out some hydrolysis of fats and starches. Pepsins also secreted by the stomach assist in the initial hydrolysis of proteins, although it is not essential for this process. Pepsins are secreted in an inactive form, pepsinogens, and converted to an active form in the acid environment of the stomach lumen. A thin layer of mucus is also secreted to protect the gastric wall against the acid luminal contents. The only essential gastric secretion is intrinsic factor, a glycoprotein required for the absorption of vitamin B12 in the terminal ileum, by forming a complex resistant to digestion. Finally the stomach produces gastrin and histamine, important in the regulation of acid secretion. The gastric mucosa Surface columnar epithelial cells secrete mucus and a HCO 3 -rich fluid, but this surface is also covered with numerous ducts leading to gastric pits from which the remaining secretions are formed. The stomach may be divided into three regions based upon these secretions: a small region below the oesophageal sphincter that
SURGERY 27:12
504
Ó 2009 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
a
b
Cells of the gastric pit
Mucous layer pH 2.0
Gastric pit
Mucus lumen
Surface mucous cells
Mucus layer
Oxyntic gland
Isthmus
HCO3–
HCO3–
Mucous neck cells Neck Parietal cells
7.0 Mucus droplets
ECF cells
Gastric epithelial cell
Base Chief cells
c
Lumen of gastric pit
Parietal cell
Canaliculus
HCI CI– K+
H+ ATP CO2 + H2O
H+ + HCO3–
M3 CI– H2 Gast
Figure 2 a Structure of the gastric pit, showing the main cells. b Diagram of the mucous layer to illustrate the pH gradient between the surface of the gastric epithelium and the bulk solution within the gastric lumen. c Diagram of a parietal cell showing the intracellular pathways responsible for the generation of hydrochloric acid (HCl) in the canaliculus of the cell. The major secretagogue membrane receptors are also shown: M3, muscarinic receptors; H2, histamine receptors; gast, gastrin receptors. The inset shows a representative drawing of a parietal cell with the major canalicular infoldings, and numerous mitochondria characteristic of these cells.
Histamine is released from enterochromaffin-like (ECL) cells in the gastric mucosa. It should be noted that histamine is also a potent vasodilator increasing blood flow to the region to support the raised metabolism required to support Hþ secretion. Gastrin is produced from G-cells in the pyloric antrum, and also from a population in the duodenum. There is considerable interplay between the different pathways, which renders the whole process of acid secretion efficient and
Control of acid and pepsinogen secretion Several secretagogues, each acting via specific receptors on the baso-lateral surface of the parietal cell stimulate HCl secretion. Most importantly these are acetylcholine (M3 receptor); histamine (H2 receptor) and gastrin. Acetylcholine is released from postganglionic parasympathetic fibres that innervate the stomach mucosa and to some extent from enteric nervous system fibres.
SURGERY 27:12
505
Ó 2009 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
easily regulated, as described below. Acetylcholine and gastrin not only exert a direct effect on the parietal cell itself, but also stimulate ECF cells to release histamine. In addition, a gastrinreleasing peptide may be released from cholinergic fibres to exert a direct effect on G-cells. The release of pepsinogen from chief cells mirrors that of Hþ and involves the same secretagogues, such as acetylcholine and gastrin, except that secretin and CCK also stimulate release (see below).
presence of amino acids and peptides. Duodenal G-cells release gastrin to stimulate gastric parietal cells. A further hormone, or group of similar peptides, entero-oxyntin may complement this stimulation. After a while the duodenum exerts an inhibitory effect on gastric secretion elicited by increasing acidity of the chyme, as further gastric emptying occurs, products of fat digestion and increasing hypertonicity of the chyme as duodenal digestion proceeds. Acid causes the release of secretin from the duodenum, this exerts inhibitory effects on G-cells and gastric parietal cells themselves, and activates a local inhibitory reflex. Two further hormones, cholecystokinin and gastric inhibitory peptide, are released by duodenal fatty acids and monoglycerides and decrease acid secretion in a manner similar to that of secretin. A
The integration of gastric secretion production during a meal When the stomach is empty a basal secretion occurs, about 10% of the maximum rate, which has some diurnal rhythm, greatest in the evening. However, after a meal secretion increases rapidly and is associated with three phases: A cephalic phase, elicited by the sight, smell and taste of food A gastric phase, elicited by the presence of food in the stomach An intestinal phase, elicited by chyme in the duodenum. This phase is however transitory and eventually acid secretion is reduced.
Helicobacter pylori. A Gram-negative, urease-positive bacterium, requiring low levels of oxygen to survive, that inhabits the stomach and duodenum. It causes a chronic inflammation of the mucosa and is linked to the development of gastric, duodenal and gastric ulcers as well as cancers, such as mucosa-associated lymphoid tissue lymphomas (MALTomas). Treatment is with proton pump inhibitors and antibiotics.
The cephalic phase: this is mediated by the vagus, as vagotomy abolishes this phase. Cholinergic fibres and cholinergic neurones from intramural plexuses release acetylcholine that activates the parietal cells and also elicits gastrin and histamine release. Other factors such as hypoglycaemia in cerebral arterial blood also evoke gastric secretions. The central control of gastric secretion is complex but in part is controlled by the hypothalamus. The gastric phase: most of the secretions occur during this phase. The main stimuli are distension of the stomach by the presence of food and the products of protein digestion. Stretch receptors in the stomach wall initiate local, enteric and central, vasovagal cholinergic reflexes. The process is self-regulating as when luminal pH falls below 2.0 gastric secretions are blocked. Of interest is that in patients with duodenal ulcers this negative feedback control is attenuated. Amino acids, especially tryptophan and phenylalanine, and small peptides also elicit acid secretion, possibly by an effect on G-cells to release gastrin. Other agents in food, such as caffeine and alcohol also stimulate acid secretion.
ZollingereEllison syndrome. This is a rare disorder characterized by gastrinomas in the pancreas or duodenum that release abnormal amounts of gastrin and hence cause excessive acid secretion. The maintained acid secretion can eventually cause gastric or duodenal ulcers. Symptoms therefore include: nausea and vomiting; burning abdominal pain; gastro-esophageal reflux and diarrhoea. Treatment is with proton pump inhibitors, and surgical removal in the proportion considered malignant. ZollingereEllison syndrome may be associated with multiple endocrine neoplasia, type 1 (MEN 1) in which there are multiple tumours in the endocrine system.
The intestinal phase: when chyme initially enters the duodenum acid secretion is stimulated due to mechanical distension and the
SURGERY 27:12
506
Ó 2009 Elsevier Ltd. All rights reserved.