Department of Physiology: Digestive system Physiology-Review & illustrations-GIT secretion

Summary of main GIT secretion (see figure)

Structure and secretion of the salivary glands (see figure): At low flow rates, the duct cells reduce saliva osmolarity to about 100 mOsm/L; at high flow rates, there is less time for the ducts to absorb NaCl, and final saliva more closely resembles the primary isotonic solution produced by the acini. Salivation is stimulated by the thought, smell, or taste of food by conditioned reflexes and by nausea. Sleep, dehydration, fatigue, and fear all inhibit salivation. Stimuli are integrated by the salivary nuclei in the pons, and salivation is determined by the resulting parasympathetic tone. Efferent nerves reach the salivary glands via the glossopharyngeal and facial nerves. Acinar secretion is stimulated by the release of acetylcholine, which acts via the muscarinic receptors. The only hormonal effect on saliva secretion is from aldosterone, which increases ductal Na⁺ absorption and K⁺secretion (see figure). "THE BIG PICTURE: MEDICAL PHYSIOLOGY. Jonathan D. Kibble & Colby R. Halsey. 2009, The McGraw-Hill Companies".

Histology of gastric gland (see figure)

Gastric Cell Types and their Secretions (see figure)

Stimulation of gastric acid production (see figure & figure): There are several pathways that function together to stimulate gastric acid secretion. There is neural stimulation by the vagus nerve (see figure) (which releases the neurotransmitter acetylcholine), endocrine stimulation from gastrin, and paracrine stimulation from histamine. Oxyntic cells express receptors for acetylcholine, gastrin, and histamine, and each individual agonist is able to, stimulate acid secretion (figure).

Gastrin and acetylcholine stimulate secretion via an increase in intracellular Ca²⁺.

Histamine stimulates secretion via an increase in cyclic adenosine monophosphate (cAMP). Prostaglandin E2, which is produced locally in the stomach, is a physiologic antagonist of histamine at the oxyntic cell and acts by inhibiting the production of cAMP. NSAIDs (Non-Steriodal Anti-Inflammatory Drugs, like asprin, brufen, ponstan) inhibit prostaglandin formation and increase gastric acid secretion. There is strong cooperativity between acetylcholine, gastrin, and histamine. When histamine occupies its receptor at the oxyntic cell, there is potentiation of the stimulatory action of acetylcholine and gastrin upon the secretion of H⁺. Both gastrin and acetylcholine stimulate histamine release from the ECL cells; a large proportion of H+ secretion caused by gastrin is mediated via histamine secretion. This explains why H2- Histamine receptor antagonists, sold as over-the-counter antacid agents, are effective at reducing gastric acid production. However, because proton pump inhibitors block acid secretion at the final common pathway of all agonists (the H ⁺/K⁺-ATPase pump), these drugs are much more effective at blocking acid secretion than are the H2-receptor antagonists.

Drugs that inhibit gastric H⁺ secretion:
H2-receptor antagonists (e.g., cimetidine and ranitidine) competitively inhibit gastric acid secretion (both basal and stimulated secretion) from parietal cells by blocking histamine-mediated H⁺ secretion. This also reduces the potentiation effects of acetylcholine on gastric acid secretion.
Proton pump inhibitors (e.g., omeprazole) inhibit the proton (H⁺-K⁺ ATPase) pump of the parietal cells in the stomach, thus inhibiting gastric acid secretion into the lumen of the stomach.
Atropine is a cholinergic muscarinic receptor antagonist that inhibits gastric acid secretion by blocking acetylcholine-mediated H⁺ secretion.
Note: H2 receptor antagonists and proton pump inhibitors have a high therapeutic index because their effects are localized to parietal cells and therefore can be achieved with relatively low doses (this explains why these agents are available over the counter).
Conversely, the effects of atropine, an antimuscarinic agent, are nonselective and are seen throughout the body. Thus, H 2 receptor antagonists and proton pump inhibitors are the first-line agents for treating an acid-related disorder.

NOTES: Gastric mucosa is protected by the gastric mucus-bicarbonate barrier (see figure). Aspirin and other NSAIDs inhibit cyclooxygenase-1 (COX-1), an enzyme needed to produce prostaglandins, which stimulate protective mucus formation in mucous neck cells in the epithelium of the stomach. They also decrease the formation of HCO₃^-in these cells. Diminished mucus and HCO3- production leaves the mucosa unprotected from the effects of gastric acid and more prone to gastric ulcer formation.
"THE BIG PICTURE: MEDICAL PHYSIOLOGY. Jonathan D. Kibble & Colby R. Halsey. 2009, The McGraw-Hill Companies".

[In Zollinger-Ellison syndrome, there is hypersecretion of gastric acid and peptic ulceration. Zollinger-Ellison syndrome is caused by a gastrin-producing tumor (gastrinoma) that is usually located in the pancreas. The sine quo non of gastrinoma is ulceration located distal to the duodenal bulb. About half of all patients with a gastrinoma have multiple endocrine neoplasia syndrome].

[Gastric Ulcers: Gastric ulcers are commonly found on the lesser curvature between the corpus and antrum of the stomach.
– They are often caused by Helicobacter pylori, a gram-negative spiral bacillus, which secretes cytotoxins that disrupt the mucosal barrier, causing inflammation and destruction.
– H. pylori secretes high levels of membrane urease, which converts urea to ammonia (NH3). NH3 neutralizes gastric acid around the bacterium, allowing it to survive in the acidic lumen of the stomach.
The following features are also found in gastric ulcers:
– ↓gastric H⁺: The damaged mucosa allows H⁺ secreted from parietal cells into the lumen of the stomach to reenter the mucosa.
– ↑gastrin: The decrease in H⁺ stimulates gastrin secretion].

[Duodenal Ulcers: Duodenal ulcers are the most common ulcers and are often associated with increased gastric H+ secretion (but not necessarily).
– Duodenal ulcers frequently occur due to H. pylori. H. pylori inhibits somatostatin secretion, leading to increased gastric H⁺ secretion. There is also decreased HCO₃^-secretion in the duodenum, which impedes neutralization of the excess H⁺ delivered from the stomach].

Pepsins are proteolytic enzymes that attack proteins. The conversion of pepsinogen to pepsin occurs spontaneously when the pH is below 5; once active pepsin is present, it autocatalyses the conversion of pepsinogen to pepsin in a positive feedback manner.

Pepsinogen secretion is stimulated by acetylcholine from the vagal and by local acid-sensitive reflex mediated through ENS efferent neurons. local acid-sensitive reflex ensures that pepsinogen is released when H⁺ is available for its conversion to pepsin. "THE BIG PICTURE: MEDICAL PHYSIOLOGY. Jonathan D. Kibble & Colby R. Halsey. 2009, The McGraw-Hill Companies".

In summary: The three phases of gastric secretion are shown in figure.

Structure and secretion of the exocrine pancreas (see figure): Digestive enzymes aid in the digestion of fats, proteins, carbohydrates, and nucleic acids and are synthesized and secreted by grape-like acini. Pancreatic duct epithelial cells produce a copious amount of HCO₃⁻- rich fluid, which is added to the acinar secretion (see figure). Several hormones and neurotransmitters, called secretagogues, stimulate pancreatic enzyme secretion (see figure). The most important secretagogues are secretin, CCK & ACh. Secretin is released from the S cells in the duodenum in response to acidic chyme entering the
duodenum and stimulates pancreatic ductal cells (via cAMP) to increase the volume of secretion and the concentration of HCO₃^- in that secretion. As the HCO3- neutralizes the acidic environment of the small intestine, secretin release is inhibited. Secretin also decreases gastric acid secretion. acetylcholine, secreted from vagal efferents, and the hormone cholecystokinin; both of these agonists act by causing an increase in cytosolic Ca²⁺ concentration.

HCO₃^-secretion from the cell cytoplasm into the lumen occurs via the Cl-/ HCO3- exchange in the luminal cell membrane (see figure). To supply enough intracellular Cl⁻ to sustain the rate of Cl−/HCO₃⁻ exchange, Cl⁻ is recycled from the lumen into the cell via the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) Cl⁻ channel. Na⁺ is secreted into the duct lumen following HCO₃⁻ secretion; water follows by osmosis to produce fluid secretion. Pancreatic duct cells are stimulated to secrete HCO₃⁻in response to the hormone secretin, which acts via cAMP and opens the CFTR channels.

The relationship between pancreatic flow rate and the electrolyte compositions of pancreatic secretion is shown in figure.

[Cystic fibrosis is an autosomal recessive disease in where there is a defect in the epithelial transport protein CFTR (cystic fibrosis transmembrane conduction regulator) found in the lungs, pancreas, liver, genital tract, intestines, nasal mucosa, and sweat glands (see figure). This alters Cl- transport in and out of cells and inhibits some Na⁺ channels. In the lungs, Na+ and water are absorbed from secretions that then become thick and sticky. In the pancreas, secretions are thick and sticky because duct cells cannot secrete Cl- via the CFTR, and water normally follows this ion movement. Sweat is salty because Cl- is not being absorbed via the CFTR, so Na+ also remains in the duct lumen. Symptoms include cough, wheezing, repeated lung and sinus infections, salty taste to the skin, steatorrhea (foulsmelling, greasy stools), poor weight gain and growth, meconium ileus (in newborns), and infertility in men. Complications of this disease include bronchiectasis (abnormal dilation of the large airways), deficiency of fat-soluble vitamins (A, D, E, and K), diabetes, cirrhosis, gallstones, rectal prolapse, pancreatitis, osteoporosis, pneumothorax, cor pulmonale, and respiratory failure. Treatment involves daily physical therapy to help expectorate secretions from the lungs, antibiotics to treat lung infections, mucolytics, and bronchodilators].

Liver & Gallblader:

Functional Histology of liver (see figure).

Questions: Portal Hypertension (see figure)
1. Explain how suprahepatic pathology (such as hepatic vein thrombosis, tricuspid incompetence, and constrictive pericarditis) can increase portal vein pressure.
2. Explain how a cirrhotic liver can cause portal hypertension.
3. Explain how infrahepatic pathology (such as portal vein thrombosis) can cause portal hypertension.
4. Explain why the esophagus is sensitive to developing varices during portal hypertension associated with cirrhosis or infrahepatic causes.

Answers:

1. With suprahepatic causes, the pressure in the hepatic veins is elevated, causing pooling of blood in the liver and increasing pressure in the portal and splenic veins.
2. With cirrhotic livers (intrahepatic cause), blood fl ow through the liver is dramatically reduced because of the scarring. Thus, while the hepatic vein pressure is normal (low), the portal and splenic vein pressures are high.
3. With infrahepatic causes of portal hypertension, blockage in some of the portal veins will increase blood fl ow and pressure in the other veins.
4. Portal hypertension can result in a backup of pressure in the veins coming from the stomach and esophagus. The increased pressure causes enlargement and thinning of the vessel walls and can make them prone to rupture. Because of the superficial nature of the vessels serving the esophagus, the vessels are sensitive to forming varices and rupturing and bleeding into the esophagus. Esophageal varices occur more often from intrahepatic and infrahepatic causes, which directly affect pressure in the portal system
and the vessels serving the esophagus.
Comment: Normal hepatic vein pressure is less than 1 mm Hg, which allows the unimpeded fl ow of blood out of the liver. If hepatic vein pressure increases, blood pools in the liver, and the portal vein pressure can also become elevated.

Liver Metabolism (see figure).

Formation of Bile: Bile is produced continuously by hepatocytes in the liver and stored in the gallbladder. An average adult produces ~400 to 800 mL of bile each day (gallbladder stores ~ 50 mL of bile). Bile empties into the duodenum at the major duodenal papilla (of Vater). Bile is composed of water, bile salts, lecithin, cholesterol, bile pigments, and electrolytes (see figure & figure). Unlike other secretions, it does not contain digestive enzymes, but it does facilitate the digestion of lipids by acting as an emulsifying agent to increase the surface area of the lipids. Mechanism of isotonic NaCl and fluid reabsorption by the gallbladder epithelium is shown in the figure.

Bile Salts: Bile salts aid in digestion and absorption of lipids and lipid-soluble vitamins in the small intestine.
– Primary bile salts: The precursor of bile salts is cholesterol which is converted by liver to cholic acid or chenodeoxycholic acid. These acids then combined principally with amino acid glycine and to a lesser extent with taurine to form glyco- and tauro- conjugated bile acids. These bile acids form sodium and potassium salts in the alkaline hepatic bile.
– Secondary bile salts—conjugated deoxycholate (Cholic acid → deoxycholic acid) and lithocholate (Chenodeoxycholic acid → lithocholic acid) are produced by bacterial alteration of primary salts in the intestinal lumen.

Bile salts, along with phospholipids (e.g., lecithin), cholesterol, and ingested fats, form
stable droplets called micelles. The hydrophilic portions of bile salts and phospholipids are exposed at the outer surface of the micelle, while the hydrophobic portions, lipids, and cholesterol are sequestered in the hydrophobic interior. This emulsifies lipids and cholesterol, allowing them to mix with the aqueous contents of the intestinal lumen, exposing them to digestive enzymes (e.g., pancreatic lipase, phospholipase A2, and cholesterol esterase). These enzymes attach to the surface of the micelles, displacing bile salts so the lipids can be digested. Bile salts are almost entirely reabsorbed in the ileum and recirculated to the liver. This is referred to as enterohepatic circulation (see figure). Most primary and secondary bile salts are reabsorbed in the ileum by Na⁺-dependent secondary active transport and returned to the liver via the portal vein. The presence of bile salts throughout the length of the small intestine permits lipids to be absorbed.
– The rate of bile secretion by the liver is determined mainly by the rate of return of bile salts from the ileum. Small quantities of bile salts are excreted in feces

[The majority of gallstones (75%) are formed when the amount of cholesterol in bile exceeds the ability of bile salts and phospholipids to emulsify it, causing cholesterol to precipitate out of solution. Gallstones may also be caused by an increased amount of unconjugated bilirubin (often in the form of calcium bilirubinate) in the bile (“pigment stones”). Gallstones may be asymptomatic, or they can produce obstruction of a duct, causing severe pain, vomiting, and fever. Drugs (e.g., ursodiol) may be used to dissolve small cholesterol gallstones. Ursodiol decreases secretion of cholesterol into bile by reducing cholesterol absorption and suppressing liver cholesterol synthesis. This alters bile composition and allows reabsorption of cholesterol-containing gallstones. Because reabsorption is slow, therapy must continue for at least 9 months. Other treatment includes lithotripsy (shock wave obliteration of gallstones that allow the stone fragments to be excreted) and surgical removal of the gallbladder (cholecystectomy)].

Bile Pigment (see figure & figure): Bilirubin is a breakdown product of hemoglobin. It is hydrophobic and is present in plasma bound to albumin. Hepatocytes extract bilirubin from plasma and conjugate it with glucuronic acid to make it water soluble. Bilirubin diglucuronide is then secreted into bile. Unlike bile salts, most bile pigment is not reabsorbed but is excreted in the feces.

Electrolytes: Bile has elevated levels of HCO₃^-, Na⁺, and Cl^-. These electrolytes become concentrated in the gallbladder, where Na⁺ is actively reabsorbed, and HCO₃^- and Cl^- follow passively. HCO₃^-in bile helps neutralize acidic chyme in the intestine.

Regulation of Bile Secretion:
Cholecystokinin: Entry of lipid-rich chyme into the duodenum causes increased secretion of cholecystokinin, which causes the sphincter of Oddi to relax and the gallbladder to contract, gradually expelling bile into the small intestine.
– Cholecystokinin also stimulates pancreatic secretion of lipase (the major enzyme responsible for lipid breakdown), so both factors for lipid digestion are present in the duodenum.
- Acetylcholine: Release of acetylcholine by the vagus nerve also stimulates gallbladder contraction.

Stimulation of Digestive Enzymes :

1. Entry of acidic chyme into the duodenum stimulates the release of secretin into the blood. At the pancreas, secretin stimulates secretion of buffers, which enter the duodenum through the papilla of Vater. The buffers serve to neutralize the acidic chyme and bring the pH up to about 7.
2. In response to carbohydrates, fats, and proteins, cholecystokinin (CCK) is secreted into the blood. At the pancreas, CCK stimulates secretion of pancreatic proenzymes, including:
• Pancreatic proteases (e.g., trypsinogen, chymotrypsinogen, procarboxypeptidase, proelastase) (protein digestion)
• Pancreatic -amylase (starch digestion)
• Pancreatic lipase and colipase (lipid digestion)

The Functions of Major Digestive Tract Hormones (see figure).
Histology of small intestinal gland (see figure)

Small intestinal secretion (see figure)