Secretion is the process of releasing a substance from a cell or gland. In the gastrointestinal (GI) tract, it mainly occurs in the mouth, stomach, and small intestine and is important for the digestion and absorption of food.
21.1 Salivary Secretion
Formation of Saliva
Saliva is formed by three pairs of salivary glands: the parotid, the submandibular, and the sublingual glands.
– The average adult secretes ~1 L of saliva per day: 250 mL is secreted by the parotid gland, 700 mL by the submandibular gland, and 50 mL by the sublingual gland.
Structure of the Salivary Glands
Acinar (berry-like) cells secrete primary saliva, which has a similar composition to plasma.
While passing through the ducts before being excreted into the mouth, primary saliva is modified into secondary saliva (Fig. 21.1):
– Na+ and Cl− content is progressively lowered by reabsorption in the ducts.
– K+ and HCO3− content is increased by secretion in the ducts.
When saliva secretion rates are elevated, primary saliva is not modified as much before being secreted because there is less time available for secretion and absorption of ions. As a consequence, saliva secreted in high volumes has an electrolyte composition closer to primary saliva but is always hypotonic with respect to plasma.
Composition and Functions
Saliva is alkaline during stimulated secretion because of its elevated HCO3− content. This neutralizes acid produced by bacteria in the oral cavity and prevents dental caries.
Saliva has a higher concentration of K+ and lower concentrations of Na+ and Cl− relative to plasma at normal secretion rates. It also contains the following substances:
– Ptyalin, an α-amylase, starts the process of digestion of complex carbohydrates.
– Lingual lipase starts the process of digestion of triglycerides.
– Lysozyme, immunoglobulin A (IgA), and lactoferrin help prevent bacterial overgrowth in the oral cavity.
Sjögren syndrome is an autoimmune disease causing keratoconjunctivitis sicca (diminished tear production) and xerostomia (dry mouth). It is also associated with rheumatoid arthritis (in 50% of cases) and lupus. Lymphocytes and plasma cells infiltrate secretory glands and cause injury. Diminished tear production causes dry, itchy, gritty eyes; diminished saliva production makes swallowing difficult and increases the likelihood of development of dental caries. Rheumatoid arthritis causes joint pain, swelling, and stiffness. Treatment for dry eyes involves the use of artificial tears. Dry mouth may be relieved by artificial saliva, taking frequent sips of water, and chewing gum to stimulate saliva flow. If this is insufficient, pilocarpine, an anticholinergic drug, may be used to stimulate saliva production. Nonsteroidal antiinflammatory drugs (NSAIDs), hydroxychloroquine (an antimalarial drug), and immunosuppressants (e.g., methotrexate and cyclosporine) are used for rheumatoid arthritis.
Fig. 21.1 Saliva secretion.
Primary saliva is produced in acinar cells and has a composition similar to plasma. Primary saliva is modified in the excretory ducts, forming secondary saliva. As saliva passes through the excretory ducts, Na+ and Cl− are reabsorbed, and K+ and HCO3− are secreted into the lumen. The saliva becomes hypotonic as Na+ and Cl− reabsorption is greater than K+ and HCO3− secretion, and the ducts are relatively impermeable to water. At high flow rates, this modification process lags, and the composition of secondary saliva becomes similar to that of primary saliva.
Fig. 21.2 Stimulation of salivary secretion.
Many factors stimulate saliva secretion, including the taste and smell of food, tactile stimulation of the buccal mucosa, mastication, and nausea. Conditioned reflexes also play a role; for example, the clattering of dishes when preparing a meal can induce saliva secretion. Saliva secretion is stimulated via the sympathetic and parasympathetic nervous system.
Regulation of Saliva Secretion
Saliva secretion is regulated by both the parasympathetic and sympathetic nervous systems. Both systems increase saliva production, although the parasympathetic system causes a much greater volume response.
Taste, smell, mastication, nausea, and conditioned reflexes stimulate the facial nerve (cranial nerve [CN] VII) and the glossopharyngeal nerve (CN IX), causing the release of acetylcholine (Fig. 21.2).
– Acetylcholine interacts with muscarinic (M3) receptors on acinar cells to stimulate second messengers inositol 1,4,5-triphosphate (IP3) and Ca2+, resulting in an increased volume of saliva, increased [HCO3], and increased O2consumption (Fig. 21.3).
– Acetylcholine also releases kallikrein, which activates bradykinin, a potent vasodilator. Vasodilation improves blood flow to the salivary glands.
Parasympathetic stimulation also causes myoepithelial cells to contract, facilitating movement of saliva from the ducts into the oral cavity.
Sympathetic activity causes the release of norepinephrine.
– Norepinephrine binds to β2-adrenergic receptors on acinar cells to stimulate the second messenger cyclic adenosine monophosphate (cAMP). This briefly produces small increases in the volume of saliva. It also stimulates an increased concentration of mucus and facilitates the movement of saliva from the salivary ducts into the oral cavity.
Fig. 21.3 Regulation of saliva secretion in acinar cells.
Parasympathetic stimulation of the facial and glossopharnygeal nerves cause the release of acetylcholine (ACh). ACh binds to M3 muscarinic receptors and activates inositol 1,4,5-triphosphate (IP3). This increases cytostolic [Ca2+] and increases the conductivity of the luminal anion channels, resulting in the production of watery saliva and increased exocytosis of salivary enzymes. Binding of ACh to M3 receptors also causes the contraction of myoepithelial cells and emptying of the acini. Sympathetic stimulation causes the release of norepinephrine, which acts upon β2 receptors. This causes an increase in cyclic adenosine monophosphate (cAMP) and the secretion of highly viscous saliva, which has a high concentration of mucin.
21.2 Secretion in the Stomach
Functional Anatomy of the Gastric Mucosa
The gastric mucosa contains several gastric glands, many of which open into a common outlet (gastric pits) on the surface of the mucosa (Fig. 21.4A,B). Within each gland there are different cell types (Fig. 21.4B), each secreting a unique substance or substances. Parietal cells secrete hydrochloric acid (HCl) and intrinsic factor (IF), chief cells secrete pepsinogens, neuroendocrine cells secrete gastrin (G cells) and somatostatin (D cells), and enterochromaffin cells secrete histamine. These secretions mix with the mucus produced by neck cells.
Fig. 21.4 (A) Gastric mucosa. (B) Structure of the gastric glands.
From Thieme Atlas of Anatomy, Neck and Internal Organs, © Thieme 2006, Illustration by Markus Voll.
HCl is secreted by parietal cells in the stomach.
– Basal acid output (BAO) is the baseline amount of HCl produced in a given period in the absence of any stimulatory factors. It is usually < 10 mmol/h.
– Maximal acid output (MAO) is the amount of HCl produced in a given period when stimulants (e.g., histamine) are administered. It is usually < 50 mmol/h.
HCl functions to break up cells, to denature proteins for easier digestion, to kill many ingested bacteria, and to convert pepsinogen to pepsin.
IF is a glycoprotein secreted by parietal cells when stimulated by acetylcholine.
IF binds vitamin B12, following its liberation from R protein by trypsin in the small intestine (see page 233). The IF–B12 complex is essential for absorption of vitamin B12 in the terminal ileum.
Lack of IF leads to pernicious anemia, which is a frequent complication of achlorhydria (absence of gastric acid secretion due to parietal cell failure).
Pernicious anemia (a type of megaloblastic anemia) is a disease resulting from malabsorption of vitamin B12. It is caused by an autoimmune reaction to gastric parietal cells that results in a lack of intrinsic factor (IF). Vitamin B12 deficiency causes inhibition of DNA synthesis in red blood cell production. Anemia may be asymptomatic, or there may be any of the following signs and symptoms: fatigue; pallor (seen most readily by inspection of the conjunctiva or mucous membranes); dizziness, particularly upon standing (postural hypotension); headache; shortness of breath; coldness of the hands and feet; palpitations; and glossitis (swelling and soreness of the tongue). In severe cases, anemia can cause chest pain (angina due to hypoxia of cardiac muscle) and heart failure (as the heart has to work harder to oxygenate tissues). Treatment is with vitamin B12 intramuscular injections given on a monthly basis for life. This allows vitamin B12 to enter the body but bypass intestinal absorption, which fails in the absence of IF. Note, pernicious anemia takes time to develop because the liver stores vitamin B12.
– Pepsinogen is secreted by gastric chief cells into the lumen and is converted to its active form, pepsin, in the presence of HCl.
– Pepsin is an enzyme that breaks down proteins. It has an optimum pH value of ~ 2.
– Gastrin is secreted by G cells in the antrum of the stomach.
– Gastrin increases H+ and histamine secretion in response to the presence of food in the stomach.
– Gastrin inhibits gastric emptying via enterogastric reflex (see page 209 and 210).
Mucus is secreted by mucous neck cells in the epithelium of the stomach. It is useful for lubrication and protection of gastric epithelial cells from the effects of the strongly acidic environment in the lumen. Mucous neck cells also secrete HCO3−, which becomes trapped in the mucous layer and further contributes to epithelial protection. Mucus and HCO3− combine to form the gastric mucosal barrier.
Gastric blood supply and mucosal protection
The stomach has a rich mucosal blood supply, supplied by the right and left gastric arteries, the right and left gastro-omental arteries, and the short gastric arteries. It is drained by corresponding veins that empty into the portal vein (some indirectly). This rich blood supply contributes to gastric mucosal protection by ensuring that if gastric H+ ions manage to penetrate the epithelium, then they are rapidly removed.
Acid Secretion in the Stomach
Mechanism of Acid Secretion in Parietal Cells
The following sequence of events results in HCl secretion into the lumen of the stomach and secretion of HCO3− into the bloodstream (Fig. 21.5):
– CO2 derived from cellular metabolism combines with water within cells to form H2CO3. This is catalyzed by carbonic anhydrase. H2CO3 then dissociates to form HCO3− and H+.
– The luminal membranes of parietal cells contain an H+−K+ ATPase, which actively secretes H+ into the lumen of the stomach in exchange for K+.
– Simultaneously, HCO3− is secreted into the bloodstream in exchange for Cl−. This results in accumulation of Cl− within the cell and then to passive secretion of Cl− into the lumen of the stomach.
Extraction of CO2 from the bloodstream and the secretion of HCO3− into it causes venous blood leaving the actively secreting stomach to be more alkaline than arterial blood (“alkaline tide”).
Fig. 21.5 HCl secretion by parietal cells.
The H+−K+ ATPase pump in the luminal membrane of parietal cells drives H+ into the lumen in exchange for K+ (1). The K+ circulates back into the lumen via luminal K+ channels. For every H+ secreted, one HCO3− leaves the blood side of the cell in exchange for Cl− (2). The HCO3− ions are obtained from the CO2 and OH− produced by cellular metabolism. This reaction is catalyzed by carbonic anhydrase (CA). Cl− accumulates within the cell and then diffuses into the lumen via Cl− channels (3). Thus, one Cl− ion reaches the lumen for each H+ ion secreted. H+ and Cl− combine to form HCl. (ATP, adenosine triphosphate)
Stimulation of Acid Secretion
Vagal stimulation. The vagus nerve directly stimulates parietal cells to secrete H+. Acetylcholine is released from the nerve, which activates muscarinic (M3) receptors on parietal cells. The M3 receptor is G-protein coupled (Gs), and activation causes the release of the second messenger, IP3, and increased intracellular [Ca2+]. These stimulate the H+−K+ATPase, which actively secretes H+ into the lumen of the stomach in exchange for K+.
– The vagus nerve indirectly stimulates the secretion of H+ by acting on G cells, causing the secretion of gastrin. Gastrin-releasing peptide (GRP, or bombesin) is the neurotransmitter.
Gastrin. Gastrin is released in response to amino acids, distention of the stomach, and vagal stimulation.
– Gastrin stimulates parietal cells to secrete H+ via interaction with the cholecystokinin B (CCKB) receptor. The CCKB receptor is Gs coupled, and activation causes the release of IP3 and increased intracellular [Ca2+]. These stimulate the H+−K+ ATPase, which actively secretes H+ into the lumen of the stomach in exchange for K+.
Histamine. Histamine is released by enterochromaffin (H) cells in the fundus of the stomach.
– It acts on H2 receptors on parietal cells, causing the release of H+. The H2 receptor is Gs-protein coupled, and activation causes an increase in the second messenger, cAMP. cAMP stimulates the H+−K+ ATPase, which actively secretes H+ into the lumen of the stomach in exchange for K+.
Note: There is potentiation of the effects of acetylcholine, histamine, and gastrin on gastric acid secretion, as each stimulates gastric acid production via a different mechanism. The implications of this are that low concentrations of two or more stimulants can produce a large increase in gastric acid production. One of the stimulants must be histamine for potentiation to occur (i.e., acetylcholine and gastrin do not potentiate each other’s effects on gastric acid production).
Zollinger–Ellison syndrome is a condition caused by gastrin-secreting pancreatic adenomas that lead to multiple ulcers in the stomach and duodenum. These ulcers are frequently drug resistant and are accompanied by diarrhea and steatorrhea (increased fat content of stools), as well as all of the usual peptic ulcers symptoms (e.g., burning abdominal discomfort, heartburn, nausea and vomiting, and weight loss). Tests for the condition will show raised serum gastrin and gastric acid levels. Treatment involves the use of proton pump inhibitors (e.g., omeprazole) that inhibit gastric acid production and surgical resection of the offending tumor, if this is possible. If surgery is not an option, or if full resection is not possible, then chemotherapy may be employed to slow tumor growth. The 5-year survival rate is low (19%) if there are metastases (usually to the liver).
Inhibition of Acid Secretion
Low pH. Following gastric emptying, H+ secretion causes the pH of the lumen of the stomach to decrease. When pH is < 2, gastrin secretion by G cells is inhibited by somatostatin released from D cells. This, in turn, causes negative feedback inhibition of further H+ secretion.
Somatostatin. Somatostatin inhibits the release of gastrin and histamine (from G cells and enterochromaffin cells, respectively), which indirectly decreases H+ secretion.
– It also activates Gi, which, in turn, inhibits adenylate cyclase and reduces cAMP levels. This antagonizes increases in cAMP produced by histamine.
Note: The effect of somatostatin on G cells is much more important than its effects on enterochromaffin cells.
Prostaglandins. Prostaglandins also inhibit gastric acid secretion by activating Gi, which, in turn, inhibits adenylate cyclase and reduces cAMP levels. This antagonizes increases in cAMP produced by histamine.
The regulation of gastric acid secretion is illustrated in Fig. 21.6.
Fig. 21.6 Regulation of gastric acid secretion.
Gastric acid secretion is stimulated in phases by neural, local gastric, and intestinal factors. Food intake leads to reflex secretion of gastric juices (1). The vagus nerve releases acetylcholine (ACh), which directly activates parietal cells in the fundus at M3 cholinoceptors (2). Gastrin-releasing peptide (GRP) also released by the vagus nerve stimulates gastrin secretion from G cells in the antrum (3). Gastrin released into the systemic circulation activates parietal cells via cholecystokinin B (CCKB) receptors. The glands in the fundus contain H cells (enterochromaffin cells), which are activated by gastrin, ACh, and β2-adrenergic substances. H cells release histamine, which has a paracrine effect on neighboring parietal cells (via H2 receptors). Gastric acid secretion is inhibited by a pH < 3.0. This inhibits G cells via a negative feedback mechanism and activates antral D cells, which secrete somatostatin (SIH). SIH inhibits H cells in the fundus (minor effect) and G cells in the antrum (major effect). GRP released by neurons acts on D cells in the fundus and antrum to inhibit SIH secretion. Secretin and gastrointestinal polypeptide (GIP) released from the small intestine have an inhibitory effect on gastric acid secretion (1). This adjusts the composition of chyme from the stomach to the needs of the small intestine. (cGRP, calcitonin gene-related peptide)
Peptic Ulcer Disease
An ulcer is a lesion extending through the mucosa and submucosa into deeper structures of the wall of the GI tract. Ulcers are the result of the breakdown of the mucosal barrier (mucus and HCO3−) that normally protects the lining of the GI tract and/or increased secretion of H+ or pepsin.
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.
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+
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, H2 receptor antagonists and proton pump inhibitors are the first-line agents for treating an acid-related disorder.
Gastric ulcer formation with nonsteroidal antiinflammatory drugs
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.
Diagnosis and treatment of H. pylori infection
H. pylori can be diagnosed by the carbon 13−urea breath test. This involves fasting for ~6 hours and then drinking a solution of 13C–urea in water. Breath samples are then taken at intervals. If H. pylori is present, 13C–urea is broken down to 13CO2 by urease and will be measurable in the expired breath.
Multiple drug regimens are recommended for patients who test positive for H. pylori. Therapy includes use of a proton pump inhibitor plus bismuth for 6 to 8 weeks to reduce the secretion of HCl, along with antimicrobials (metronidazole, tetracycline, clarithromycin, or amoxicillin) for 2 weeks to eradicate the causative H. pylori infection.
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.
21.3 Secretion by the Liver
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) (Fig. 21.7).
Implications of the shared emptying of the common bile duct and pancreatic duct
The fact that the common bile duct and the pancreatic duct both empty into the major duodenal papilla has important clinical implications. A tumor at the head of the pancreas, for example, may obstruct the common bile duct, causing biliary reflux into the liver with jaundice. Similarly, a gallstone that lodges in the common bile duct may obstruct the terminal part of the pancreatic duct, causing acute pancreatitis.
Composition of Bile
Bile is composed of water, bile salts, lecithin, cholesterol, bile pigments, and electrolytes (Fig. 21.8). 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.
Drug dosage in hepatic disease
Hepatic disease (e.g., hepatitis and cirrhosis) has the potential to affect the pharmacokinetics of many drugs; however, because hepatic reserves are large, disease has to be severe for changes in drug metabolism to occur. The mechanisms by which the pharmacokinetics may be altered include reduced hepatic blood flow, which reduces the first-pass metabolism of drugs taken orally (and rectally to a lesser extent); reduced plasma protein binding, affecting both the distribution and elimination of drugs; and reduced plasma clearance of a drug if it is eliminated by metabolism and/or into bile. A dose reduction may be necessary in hepatic disease, depending on the extent of the disease and the particular drug or drugs being administered.
Bile salts aid in digestion and absorption of lipids and lipid-soluble vitamins in the small intestine.
– Primary bile salts are glycine or taurine conjugates of cholate and chenodeoxycholate that are synthesized from cholesterol by hepatocytes.
– Secondary bile salts—conjugated deoxycholate and lithocholate—are produced by bacterial alteration of primary salts in the intestinal lumen.
Fig. 21.7 Extrahepatic bile ducts and pancreatic ducts.
Anterior view with the gallbladder opened and the duodenum opened and windowed. The common bile duct (formed from the joining of the left and right hepatic ducts with the cystic duct) and the pancreatic duct both empty their secretions into the duodenum at the major duodenal papilla (of Vater). Superior to the major papilla is the minor duodenal papilla, which receives secretions from the accessory pancreatic duct.
From Thieme Atlas of Anatomy, Neck and Internal Organs, © Thieme 2006, Illustration by Markus Voll.
Micelles. 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.
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).
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 (Fig. 21.9). Unlike bile salts, most bile pigment is not reabsorbed but is excreted in the feces.
Jaundice refers to the yellow pigmentation of the skin, sclerae, and mucous membranes due to raised plasma bilirubin.
Prehepatic (or hemolytic) jaundice: Excess bilirubin (e.g., from hemolysis), or an in-born failure of bilirubin metabolism results in unconjugated bilirubin remaining in the bloodstream. Unconjugated bilirubin is water insoluble and so does not appear in urine.
Hepatocellular (or hepatic) jaundice: In hepatocellular jaundice, there is diminished hepatocyte function, leading to an increased amount of both conjugated and unconjugated bilirubin. Diminished hepatocyte function may follow cirrhosis, autoimmune diseases, drug damage (e.g., acetaminophen and barbiturates), or viral infections (e.g., hepatitis A, B, and C; Epstein–Barr virus).
Posthepatic (obstructive) jaundice: This form of jaundice usually occurs following blockage of the common bile duct by gallstones. In this case, plasma-conjugated bilirubin rises. Conjugated bilirubin is water soluble and appears in urine (making it dark). At the same time, less conjugated bilirubin passes into the gut and is converted to stercobilin, making feces appear paler.
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.
Fig. 21.8 Bile components and hepatic secretion of bile.
Bile contains electrolytes, bile salts (bile acids), cholesterol, lecithin, bilirubin, steroid hormones, and drug metabolites, among other things. Bile salts are essential for fat digestion. Hepatocytes secrete bile into biliary canaliculi. The liver synthesizes cholate and chenodeoxycholate (primary bile salts) from cholesterol. The intestinal bacteria convert some of them into secondary bile salts, such as deoxycholate and lithicholate. Bile salts are conjugated with taurine and glycine in the liver and are secreted into bile in this form.
Fig. 21.9 Bilirubin metabolism and excretion.
Bilirubin is (mostly) formed from the breakdown of hemoglobin (Hb). It is conjugated by hepatocytes to form bilirubin diglucuronide and is secreted in bile into the small intestine. In the gut, anaerobic bacteria break bilirubin down into the colorless compound stercobilinogen. It is partially oxidized to stercobilin, the brown compound that colors the stools, and excreted in feces (~85%). About 15% of bilirubin is deconjugated by bacteria and returned to the liver via the enterohepatic circulation. A small portion (~1%) reaches the systemic circulation and is excreted by the kidneys as urobilinogen.
Fig. 21.10 Mechanism for the release of bile from the gallbladder.
When fats enter the duodenum, cholecystokinin (CCK) is released from I cells of the duodenum. CCK binds to CCKA receptors and induces gallbladder contraction, and thus the secretion of bile. Gallbladder contraction is also stimulated by the neuronal plexus of the gallbladder wall, which is innervated by preganglionic fibers of the vagus nerve. (ACh, acetylcholine)
Regulation of Bile Secretion
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 (Fig. 21.10).
– 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.
Release of acetylcholine by the vagus nerve also stimulates gallbladder contraction.
Bile Salt Recirculation to the Liver
Bile salts are almost entirely reabsorbed in the ileum and recirculated to the liver (Fig. 21.11). This is referred to as enterohepatic circulation. 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.
Fig. 21.11 Enterohepatic circulation of bile salts.
Bile salts are synthesized in the liver from cholesterol and released into the small intestine via the common bile duct. Conjugated bile salts are reabsorbed in the terminal ileum by the Na+ symport carrier ISBT (ileum sodium bile acid cotransporter) and returned to the liver via the portal vein. This allows the bile salts to be available for fat digestion and absorption throughout the small intestine.
21.4 Secretion by the Exocrine Pancreas
Formation and Composition of Pancreatic Secretion
The volume of pancreatic juice secreted daily is ~500 to 1500 mL. It empties into the duodenum at the major duodenal papilla (of Vater) (see Fig. 21.7).
Acinar cells secrete a solution that is rich in digestive enzymes: proteases, amylase, and lipase, which break down proteins, starch, and lipids, respectively.
Ductal cells secrete an isotonic solution that contains a high concentration of HCO3− and lowered levels of Cl− (compared with plasma) (Fig. 21.12). This alkaline secretion neutralizes acid in the small intestine and provides an alkaline environment for pancreatic enzymes to operate optimally.
Stimulation of Exocrine Pancreas Secretion
Secretion of pancreatic juice is controlled by secretin and cholecystokinin. Vagal activity potentiates the effects of these hormones.
Secretin is released from the S cells in the duodenum in response to acidic chyme entering the duodenum.
– Secretin stimulates pancreatic ductal cells (via cAMP) to increase the volume of secretion and the concentration of HCO3− in that secretion (see Fig. 21.12). As the HCO3− neutralizes the acidic environment of the small intestine, secretin release is inhibited.
– Secretin also decreases gastric acid secretion.
Fig. 21.12 Secretion in pancreatic duct cells.
HCO3− is secreted from the luminal membrane of the ducts via an anion exchanger (AE) that simultaneously absorbs Cl− from the lumen (1). This apical Cl−−HCO3− exchanger relies on keeping the intracellular Cl− concentration below a critical threshold so that the pump can continue to operate. The mechanism for achieving this is secretin-mediated Cl− secretion via the cystic fibrosis transmembrane conduction regulator (CFTR) channel in response to elevated intracellular cyclic adenosine monophosphate (cAMP) (2). Movement of Cl− by this mechanism draws water into the duct lumen. This is why in cystic fibrosis the duct contents are bicarbonate-poor and viscous because failure to secrete Cl− inhibits the apical exchanger, and water is not moved into the duct lumen. The secreted HCO3− is absorbed in part from the blood via a Na+−HCO3− symporter (NBC; ) and in part is the product of the CO2 + OH− reaction in the cytosol (4) catalyzed by carbonic anhydrase (CA). For each HCO3− secreted, one H+ ion leaves the cell on the blood side via the Na+−H+ exchanger (NHE1; ). (ATP, adenosine triphosphate; PKA, protein kinase A)
Cholecystokinin is released from the I cells in response to amino acids, small peptides, and lipids entering the duodenum.
– Cholecystokinin stimulates pancreatic acinar cells (via IP3 and increased intracellular [Ca2+]) to release proteases, amylase, and lipase.
– Cholecystokinin also stimulates gallbladder contraction and ejection of bile into the duodenum. Pancreatic lipase and bile is needed to deal with the lipid load being presented to the duodenum.
– Vagovagal reflexes cause the release of acetylcholine in response to H+, small peptides, amino acids, and fatty acids entering the duodenum.
– Acetylcholine stimulates the release of pancreatic enzymes.
Note: Cholecystokinin and acetylcholine augment the effects of secretin on pancreatic ductal cells to increase HCO3− secretion. This is because they stimulate their respective pancreatic secretions via different second messenger pathways.
The overall effect of secretin, cholecystokinin, and acetylcholine in pancreatic juice secretion is shown in Fig. 21.13.
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. 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 (foul-smelling, 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.
Fig. 21.13 Stimulation of pancreatic juice secretion.
Pancreatic juice secretion is stimulated by vagal mechanisms (acetylcholine, ACh) and the hormone cholecystokinin (CCK, minor effect). Both cause an increase in cytostolic [Ca2+], which stimulates Cl− and proenzyme secretion. Secretin increases HCO3− and H2O secretion by the ducts. The effects of secretin are potentiated by ACh and CCK by increasing [Ca2+].
Table 21.1 summarizes GI secretion.